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  • CLASSES

    Acetaminophen, Antihistamine, Non-Opioid Antitussive, and Decongestant Combinations
    Acetaminophen, Non-Opioid Antitussive, Decongestant, and Expectorant Combinations
    Daytime/Nighttime Cough and Cold Combinations

    DEA CLASS

    OTC

    DESCRIPTION

    Oral prescription analgesic, non-opioid antitussive, expectorant and decongestant combination
    Used to provide temporary relief from common cold, allergies, or flu symptoms such as mild pain, cough, nasal congestion, headache, sore throat, and fever

    COMMON BRAND NAMES

    Alka-Seltzer Plus Day Severe Cold & Flu, Alka-Seltzer Plus Severe Cough Mucus & Congestion, Alka-Seltzer Plus Severe Sinus, Cold & Cough, Delsym Cough + Cold, MooreBrand Severe Cold Relief, Mucinex Children's Cold, Cough & Sore Throat, Mucinex Children's FreeFrom Daytime/Nighttime, Mucinex Cold, Flu & Sore Throat, Mucinex Fast-Max, Mucinex Fast-Max Cold & Flu, Mucinex Fast-Max Cold, Flu & Sore Throat, Mucinex Fast-Max Severe Congestion & Cold, Mucinex Freefrom Cold & Flu Daytime, Mucinex Junior Cold & Flu, Mucinex Multi-Symptom Cold and Fever Children's, Mucinex Sinus-Max, Mucinex Sinus-Max Pressure, Pain & Cough, Robitussin CF MAX Severe Multi-Symptom Cough Cold + Flu, Robitussin Severe Multi-Symptom Daytime/Nighttime Could Cold + Flu, Sine-Off Cold and Cough, Sudafed Cold and Cough, Sudafed PE Cold and Cough, Sudafed PE Head Congestion + Flu, Sudafed PE Pressure + Pain + Cold, Theraflu ExpressMax Severe Cold & Cough, Tylenol Cold, Tylenol Cold & Flu Severe, Tylenol Cold Multi-Symptom Severe Daytime, Tylenol Cold Severe Head Congestion, Tylenol Cold+Mucus, Tylenol Warming Cough and Severe Congestion, Vicks DayQuil Cold & Flu, Vicks Nyquil Cold & Flu

    HOW SUPPLIED

    Acetaminophen, Dextromethorphan Hydrobromide, Guaifenesin, Phenylephrine Hydrochloride/Acetaminophen, Dextromethorphan, Guaifenesin, Phenylephrine/MooreBrand Severe Cold Relief/Mucinex Sinus-Max/Sine-Off Cold and Cough/Sudafed PE Head Congestion + Flu/Theraflu ExpressMax Severe Cold & Cough/Tylenol Cold & Flu Severe/Vicks DayQuil Cold & Flu Oral Tab
    Alka-Seltzer Plus Day Severe Cold & Flu Oral Pwd F/Recon
    Alka-Seltzer Plus Severe Cough Mucus & Congestion/Alka-Seltzer Plus Severe Sinus, Cold & Cough/Mucinex Fast-Max Cold & Flu/Mucinex Fast-Max Cold, Flu & Sore Throat/Mucinex Sinus-Max Pressure, Pain & Cough Oral Cap
    Mucinex Cold, Flu & Sore Throat/Mucinex Fast-Max Cold & Flu/Mucinex Fast-Max Cold, Flu & Sore Throat/Robitussin CF MAX Severe Multi-Symptom Cough Cold + Flu/Robitussin Severe Multi-Symptom Daytime/Nighttime Could Cold + Flu/Tylenol Cold & Flu Severe/Vicks DayQuil Cold & Flu/Vicks Nyquil Cold & Flu Oral Sol
    Theraflu ExpressMax Severe Cold & Cough Oral Liq

    DOSAGE & INDICATIONS

    For the temporary relief ofcough, fever, headache, mild pain, nasal congestion, and sore throat (pharyngitis) associated with the common cold, allergic rhinitis, hay fever or other allergies; for nasal congestion associated with sinusitis or minor upper respiratory tract infections.
    NOTE: In January 2007, the CDC warned caregivers and healthcare providers of the risk for serious injury or fatal overdose from the administration of cough and cold products to children and infants less than 2 years of age. This warning followed an investigation of the deaths of three (3) infants less than 6 months of age that were attributed to the inadvertent inappropriate use of these products. The symptoms preceding these deaths have not been clearly defined, and there is a lack of conclusive data describing the exact cause of death. The report estimated that 1519 children less than 2 years of age were treated in emergency departments during 2004—2005 for adverse events related to cough and cold medications. In October 2007, the FDA Nonprescription Drug Advisory Committee and the Pediatric Advisory Committee recommended that nonprescription cough and cold products containing pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, brompheniramine, phenylephrine, clemastine, or guaifenesin not be used in children less than 6 years of age. In January 2008, the FDA issued a Public Health Advisory recommending that OTC cough and cold products not be used in infants and children less than 2 years. An official ruling regarding the use of these products in children greater than 2 years has not yet been announced. The FDA recommends that if parents and caregivers use cough and cold products in children greater than 2 years, labels should be read carefully, caution should be used when administering multiple products, and only measuring devices specifically designed for use with medications should be used. While some combination cough/cold products containing these ingredients are available by prescription only and are not necessarily under scrutiny by the FDA, clinicians should thoroughly assess each patient's use of similar products, both prescription and nonprescription, to avoid duplication of therapy and the potential for inadvertent overdose.
    Oral dosage (tablets containing acetaminophen 500 mg, dextromethorphan 30 mg, guaifenesin 600 mg, phenylephrine 15 mg; e.g., Phenflu G)

    NOTE: Rx-only product.

    Adults, Adolescents, and Children >= 12 years

    1 tablet PO four times daily; do not exceed 4 tablets within 24 hours.

    Geriatric

    See adult dosage; elderly may be more sensitive to the effects of this medicine, adjust adult dose accordingly.

    Children 6—11 years

    One-half tablet PO four times daily; do not exceed 2 tablets within 24 hours.

    MAXIMUM DOSAGE

    NOTE: Do not exceed recommended dosage limits for the specific product prescribed; the following are general guidelines:

    Adults

    Acetaminophen 2000 mg/day PO; dextromethorphan 120 mg/day PO; guaifenesin 2400 mg/day PO; phenylephrine 60 mg/day PO.

    Geriatric

    Acetaminophen 2000 mg/day PO; dextromethorphan 120 mg/day PO; guaifenesin 2400 mg/day PO; phenylephrine 60 mg/day PO.

    Adolescents

    Acetaminophen 2000 mg/day PO; dextromethorphan 120 mg/day PO; guaifenesin 2400 mg/day PO; phenylephrine 60 mg/day PO.

    Children

    >= 12 years: Acetaminophen 2000 mg/day PO; dextromethorphan 120 mg/day PO; guaifenesin 2400 mg/day PO; phenylephrine 60 mg/day PO.
    6—11 years: Acetaminophen 1000 mg/day PO; dextromethorphan 60 mg/day PO; guaifenesin 1200 mg/day PO; phenylephrine 30 mg/day PO.
    < 6 years: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; however, lower doses may be warranted due to the potential for decreased metabolism of one or more ingredients.

    Renal Impairment

    Dosage may require modification based on clinical response and degree of renal impairment, but no quantitative guidelines are available.
     
    Intermittent hemodialysis
    In theory, phenylephrine is dialyzable but no objective data are available.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.
    It may be advisable to avoid grapefruit juice during use due to the potential for increased bioavailability of dextromethorphan.

    Oral Solid Formulations

    Tablets may be broken in half for ease of administration.

    STORAGE

    Generic:
    - Do not refrigerate
    - Store between 68 to 77 degrees F
    Alka-Seltzer Plus Day Severe Cold & Flu:
    - Store at room temperature (between 59 to 86 degrees F)
    Alka-Seltzer Plus Severe Cough Mucus & Congestion:
    - Store between 59 to 77 degrees F
    Alka-Seltzer Plus Severe Sinus, Cold & Cough:
    - Store between 59 to 77 degrees F
    Delsym Cough + Cold:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    MooreBrand Severe Cold Relief:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at room temperature (between 59 to 86 degrees F)
    Mucinex Children's Cold, Cough & Sore Throat:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Mucinex Children's FreeFrom Daytime/Nighttime:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Mucinex Cold, Flu & Sore Throat:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Mucinex Fast-Max:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Mucinex Fast-Max Cold & Flu:
    - Avoid excessive heat (above 104 degrees F)
    - Store between 68 to 77 degrees F
    Mucinex Fast-Max Cold, Flu & Sore Throat:
    - Do not refrigerate
    - Store between 68 to 77 degrees F
    Mucinex Fast-Max Severe Congestion & Cold:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Mucinex Freefrom Cold & Flu Daytime:
    - Do not refrigerate
    - Store between 68 to 77 degrees F
    Mucinex Junior Cold & Flu:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Mucinex Multi-Symptom Cold and Fever Children's:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Mucinex Sinus-Max:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Mucinex Sinus-Max Pressure, Pain & Cough:
    - Avoid excessive heat (above 104 degrees F)
    - Store between 68 to 77 degrees F
    Phenflu DM:
    - Protect from light
    - Protect from moisture
    - Store at room temperature (between 59 to 86 degrees F)
    Phenflu G:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Robitussin CF MAX Severe Multi-Symptom Cough Cold + Flu:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Robitussin Severe Multi-Symptom Daytime/Nighttime Could Cold + Flu:
    - Store between 68 to 77 degrees F
    Sine-Off Cold and Cough:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at room temperature (between 59 to 86 degrees F)
    Sudafed Cold and Cough:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Sudafed PE Cold and Cough:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Sudafed PE Head Congestion + Flu:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Sudafed PE Pressure + Pain + Cold:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Theraflu ExpressMax Severe Cold & Cough :
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Tylenol Cold:
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tylenol Cold & Flu Severe:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Tylenol Cold Multi-Symptom Severe Daytime:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Tylenol Cold Severe Head Congestion:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Tylenol Cold+Mucus:
    - Do not refrigerate
    - Store between 68 to 77 degrees F
    Tylenol Warming Cough and Severe Congestion :
    - Do not refrigerate
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vicks DayQuil Cold & Flu:
    - Store between 68 to 77 degrees F
    - Store in a dry place
    Vicks Nyquil Cold & Flu:
    - Store between 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: This monograph discusses the precautions and contraindications of acetaminophen; dextromethorphan; guaifenesin; phenylephrine combination product. Clinicians may wish to consult the individual monographs for more information about the specific precautions of each agent.
     
    The guaifenesin component of acetaminophen; dextromethorphan; guaifenesin; phenylephrine may alter some laboratory tests. It may increase renal clearance for urate and lower serum uric acid levels. Guaifenesin may produce an increase in urinary 5-hydroxyindoleacetic acid and may therefore interfere with the interpretation of this diagnostic test for carcinoid syndrome. Guaifenesin may also falsely elevate the VMA test for catechols. Products containing guaifenesin should be discontinued at least 48 hours prior to the collection of urine specimens for such laboratory tests.

    Acetaminophen hypersensitivity

    Acetaminophen; dextromethorphan; guaifenesin; phenylephrine products are contraindicated in individuals with known acetaminophen hypersensitivity, dextromethorphan hypersensitivity, guaifenesin hypersensitivity, or hypersensitivity to phenylephrine or other sympathomimetic amines. This product is contraindicated in patients with idiosyncrasy to sympathomimetic amines which may be manifested by drug-induced insomnia, dizziness, weakness, tremor, or arrhythmias. Patients known to be hypersensitive to other sympathomimetic amines may exhibit cross sensitivity with phenylephrine.

    MAOI therapy

    Acetaminophen; dextromethorphan; guaifenesin; phenylephrine should not be used concurrently with Monoamine Oxidase Inhibitors (MAOIs) or within 2 weeks of discontinuing MAOI therapy.

    Driving or operating machinery

    Because acetaminophen; dextromethorphan; guaifenesin; phenylephrine may cause sedation, patients should be advised to avoid driving or operating machinery until they know how this product will affect them. Patients should not self-medicate with this product if they consume 3 or more alcoholic beverages per day because of the acetaminophen component and subsequent potential for liver damage. In addition, the patient should be informed that alcohol consumption may intensify the sedative effects of the drug.

    Alcoholism, hepatic disease, hepatitis

    Acetaminophen, dextromethorphan, and phenylephrine are metabolized in the liver. Therefore, it is possible that metabolism of one or all of these product ingredients may be reduced in those with significant hepatic disease. It is suggested that liver function tests be monitored in this patient population. Dosage adjustments of acetaminophen; dextromethorphan; guaifenesin; phenylephrine combination products may be required, as drug accumulation or prolonged duration of action can occur in patients with hepatic dysfunction. Patients with alcoholic hepatic disease, alcoholism, or viral hepatitis are at risk for acetaminophen-induced hepatotoxicity since glucuronide conjugation of the drug may be decreased. Depletion of hepatic glutathione reserves limits the ability of the liver to conjugate acetaminophen which predisposes the patient to further hepatic injury. Although short courses (< 5 days) of normal adult doses of acetaminophen have been administered safely to patients with stable chronic liver disease.

    Renal disease, renal failure, renal impairment

    There are no data on the use of acetaminophen; dextromethorphan; guaifenesin; phenylephrine combinations in patients with renal disease, renal impairment, or renal failure. However, the metabolites of acetaminophen can accumulate in renal impairment. Chronic acetaminophen administration should be avoided in patients with underlying renal disease (see Adverse Reactions), although it may be used for episodic pain.

    Acute myocardial infarction, angina, atrial fibrillation, atrial flutter, AV block, bradycardia, bundle-branch block, cardiac arrhythmias, cardiac disease, cardiomyopathy, coronary artery disease, heart failure, hypertension, myocardial infarction, tachycardia, ventricular fibrillation, ventricular tachycardia

    Various adverse cardiovascular effects are possible following administration of acetaminophen; dextromethorphan; guaifenesin; phenylephrine. Phenylephrine is contraindicated in patients with coronary artery disease (e.g., angina, history of myocardial infarction, acute myocardial infarction), severe or uncontrolled hypertension, and cardiac arrhythmias (tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular tachycardia) because of its detrimental cardiovascular effects in these conditions (i.e., increased myocardial oxygen demand, chronotropy, proarrhythmic potential, and vasoactivity). Products with phenylephrine should be used with considerable caution in patients with bradycardia, partial heart block (AV block, bundle-branch block), controlled or mild hypertension, heart failure, cardiomyopathy, ischemic heart disease, or other cardiac disease due to the sympathomimetic effects of phenylephrine.

    Asthma, bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, tobacco smoking

    In general, antitussives such as dextromethorphan should not be used in patients with a productive cough, or cough specifically associated with ACE inhibitor therapy. Additionally, acetaminophen; dextromethorphan; guaifenesin; phenylephrine should not be used in patients with persistent or chronic cough such as occurs with asthma, chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis), tobacco smoking, or any other condition where cough is associated with excessive secretions, unless under the supervision of a health care professional. Dextromethorphan should not be used for a cough that is associated with heart failure. Additionally, tobacco smoking induces CYP1A2 and may potentially increase the risk for acetaminophen-induced hepatotoxicity during overdose via enhanced generation of acetaminophen's hepatotoxic metabolite, NAPQI. In one study, current tobacco smoking was found to be very frequent in patients admitted with acetaminophen poisoning. Tobacco smoking appears to be an independent risk factor of severe hepatotoxicity, acute liver failure, and death following acetaminophen overdose.

    Aneurysm, arteriosclerosis, cerebrovascular disease, intracranial bleeding, organic brain syndrome, stroke

    Products containing phenylephrine should be avoided if possible in patients with cerebrovascular disease such as cerebral arteriosclerosis, aneurysm, intracranial bleeding, history of stroke, or organic brain syndrome because of the potential sympathomimetic (presumably alpha) effects in the CNS and the potential for cerebrovascular hemorrhage.

    Bladder obstruction, prostatic hypertrophy, urinary retention

    Products containing phenylephrine, including acetaminophen; dextromethorphan; guaifenesin; phenylephrine combination products, may exacerbate urinary retention and should be used with extreme caution in patients with this symptomatology. A worsening of symptoms may occur in patients with bladder obstruction or benign prostatic hypertrophy.

    Closed-angle glaucoma, increased intraocular pressure

    Acetaminophen; dextromethorphan; guaifenesin; phenylephrine should not be used in patients with closed-angle glaucoma. Increased intraocular pressure may occur from the sympathomimetic actions of phenylephrine, precipitating an acute attack of glaucoma. Elderly patients are more susceptible to these effects, including possible precipitation of undiagnosed glaucoma.

    Diabetes mellitus, hyperthyroidism, peripheral vascular disease, thyrotoxicosis

    The sympathomimetic actions of phenylephrine can exacerbate diabetes mellitus, peripheral vascular disease, and hyperthyroidism. Acetaminophen; dextromethorphan; guaifenesin; phenylephrine is relatively contraindicated in patients with these conditions. Phenylephrine is contraindicated for use in thyrotoxicosis.

    Bone marrow suppression, immunosuppression, infection, neutropenia

    Patients should be instructed to discontinue acetaminophen; dextromethorphan; guaifenesin; phenylephrine and check with their prescriber if cough or pain persists or worsens after 7 days of use, or if fever persists or worsens after 3 days of use. In addition, patients should be instructed to contact their health care provider if their cough is accompanied or followed by rash or headache. A physician should be contacted immediately if sore throat is severe, lasts more than 2 days, or is accompanied or followed by fever, headache, nausea/vomiting, or rash. Recommended dosages of these products should not be exceeded. Extreme caution is advised in patients with bone marrow suppression (e.g., neutropenia) or immunosuppression, since the acetaminophen component of the drug can mask some symptoms of acute infection (e.g., fever, pain).

    G6PD deficiency

    Patients with G6PD deficiency who use excessive doses of acetaminophen may be at increased risk for drug-induced hemolysis. During acetaminophen overdose, cyanosis may not be apparent in patients with pre-existing anemia, in spite of dangerously high blood concentrations of methemoglobin. Many prescription and non-prescription products contain acetaminophen. Advise patients to read labels carefully while taking acetaminophen; dextromethorphan; guaifenesin; phenylephrine to avoid acetaminophen overexposure.

    Labor, obstetric delivery, pregnancy

    Acetaminophen; dextromethorphan; guaifenesin; phenylephrine is classified as FDA pregnancy risk category C. It is generally recommended to avoid systemic phenylephrine during pregnancy due to the potential vasoconstrictive effects. Do not administer phenylephrine during late pregnancy, labor, or obstetric delivery. When administered at this time, phenylephrine may cause fetal anoxia or bradycardia by increasing the contractility of the uterus and decreasing uterine blood flow. Because dextromethorphan acts as a low affinity antagonist to the glutamate receptor subtype N-methyl-D-aspartate (NMDA) in the CNS, there has been some concern about its safe use during pregnancy. The majority of animal studies have not found teratogenic effects. Human surveillance data and retrospective studies have shown dextromethorphan to be relatively safe during the first trimester. The results of a controlled study suggested that the use of dextromethorphan during pregnancy does not pose a risk to the fetus; however, due to the small sample size, an increased risk of rare malformations could not be ruled out. Therefore, acetaminophen; dextromethorphan; guaifenesin; phenylephrine should only be used in pregnancy if the potential benefits are greater than the risks, and use should be limited to short-term, "as needed" administration under the supervision of a qualified health care professional. Non-pharmacologic methods (e.g., fluids and rest) are recommended to be tried first for symptomatic relief of colds during pregnancy.

    Breast-feeding

    Use acetaminophen; dextromethorphan; guaifenesin; phenylephrine combination products with caution during breast-feeding. The potential adverse effects, if any, of acetaminophen; dextromethorphan; guaifenesin; phenylephrine combination products to a nursing infant are unknown. Acetaminophen has not been associated with any observable changes in nursing infants of mothers that took acetaminophen while breast-feeding; acetaminophen is a maternal medicine that is usually compatible with breast feeding. Dextromethorphan is likely excreted into breast milk due to the relatively low molecular weight of the drug; however, available data suggest compatibility with breast-feeding. It is not known whether phenylephrine is distributed into breast milk; however, the low molecular weight of the drug would suggest possible passage. In the treatment of cold and cough symptoms, individual products to target specific symptoms are generally preferred to combination products for the lactating mother. For nasal congestion, non-systemic decongestant preparations such as intranasal sodium chloride or temporary use of intranasal decongestants should be considered prior to consideration of an oral decongestant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safe and effective use of acetaminophen; dextromethorphan; guaifenesin; phenylephrine combination products in young children (below the age of 6 years), infants, and neonates has not been established. Some products are not for use in children less than 12 years of age. The adverse effects of sympathomimetic agents can be severe, especially in infants and young children; CNS stimulation, increased blood pressure, and tachycardia may occur. In January 2007, the CDC warned caregivers and healthcare providers of the risk for serious injury or fatal overdose from the administration of cough and cold products to children and infants less than 2 years of age. In October 2007, the FDA Nonprescription Drug Advisory Committee and the Pediatric Advisory Committee recommended that nonprescription cough and cold products containing pseudoephedrine, dextromethorphan, chlorpheniramine, diphenhydramine, brompheniramine, phenylephrine, clemastine, or guaifenesin not be used in children less than 6 years of age. In January 2008, the FDA issued a Public Health Advisory recommending that OTC cough and cold products not be used in infants and children less than 2 years. An official ruling regarding the use of these products in children greater than 2 years has not yet been announced. The FDA recommends that if parents and caregivers use cough and cold products in children greater than 2 years, labels should be read carefully, caution should be used when administering multiple products, and only measuring devices specifically designed for use with medications should be used. While some combination cough/cold products containing these ingredients are available by prescription only and are not necessarily under scrutiny by the FDA, clinicians should thoroughly assess each patient's use of similar products, both prescription and nonprescription, to avoid duplication of therapy and the potential for inadvertent overdose. Other factors that can lead to inadvertent overdoses in children include substituting adult acetaminophen formulations for pediatric formulations for convenience, misreading or interpreting instructions, or administering more acetaminophen due to persistent fever. Repeated overdoses of acetaminophen in children in combination with decreased nutrition may lead to changes in the metabolism of acetaminophen leading to hepatotoxicity. This combination leads to decreases in sulfation, glucuronidation, and glutathione production.

    Geriatric

    Geriatric patients are more likely to experience adverse effects from sympathomimetic amines. Initial doses of acetaminophen; dextromethorphan; guaifenesin; phenylephrine may need to be reduced and doses should be carefully titrated taking into account the beneficial effects and potential adverse reactions of the drug. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, cough, cold, and allergy medications should be used only for a limited duration (less than 14 days) unless there is documented evidence of enduring symptoms that cannot otherwise be alleviated and for which a cause cannot be identified and corrected.

    ADVERSE REACTIONS

    Severe

    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    myocarditis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    renal papillary necrosis / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    methemoglobinemia / Early / Incidence not known

    Moderate

    nephrolithiasis / Delayed / Incidence not known
    excitability / Early / Incidence not known
    psychosis / Early / Incidence not known
    hallucinations / Early / Incidence not known
    psychological dependence / Delayed / Incidence not known
    confusion / Early / Incidence not known
    dysarthria / Delayed / Incidence not known
    hypertension / Early / Incidence not known
    angina / Early / Incidence not known
    erythema / Early / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    dysuria / Early / Incidence not known
    urinary retention / Early / Incidence not known
    colitis / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    thrombocytosis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    encephalopathy / Delayed / Incidence not known
    hypoprothrombinemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    hemolysis / Early / Incidence not known
    withdrawal / Early / Incidence not known
    medication overuse headache / Delayed / Incidence not known

    Mild

    dizziness / Early / Incidence not known
    headache / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    drowsiness / Early / Incidence not known
    insomnia / Early / Incidence not known
    restlessness / Early / Incidence not known
    irritability / Delayed / Incidence not known
    vomiting / Early / Incidence not known
    nausea / Early / Incidence not known
    fever / Early / Incidence not known
    purpura / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    abdominal pain / Early / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Abiraterone: (Moderate) Abiraterone inhbits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. If dextromethorphan- related side effects occur, a dose reduction or discontinuation of dextromethorphan may be necessary. In an in vivo drug-drug interaction trial, the Cmax and AUC of the CYP2D6 substrate dextromethorphan were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily along with prednisone 5 mg twice daily. The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold.
    Acarbose: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Acebutolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Acetaminophen; Caffeine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Acetaminophen; Caffeine; Pyrilamine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Acetaminophen; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Additive CNS depression may occur if dichloralphenazone is used concomitantly with any of the sedating H1 blockers. Use caution with this combination. Dosage reduction of one or both agents may be necessary.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Acetaminophen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Aclidinium; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Acrivastine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Albiglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Albuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Aldesleukin, IL-2: (Moderate) Aldesleukin, IL-2 may affect CNS function significantly. Therefore, psychotropic pharmacodynamic interactions could occur following concomitant administration of drugs with significant CNS activity. Use with caution.
    Alfentanil: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering alfentanil with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Aliskiren; Amlodipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Alogliptin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Alogliptin; Pioglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like sedating H1 blockers, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alpha-blockers: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Alpha-glucosidase Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Alprazolam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Amantadine: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Additive drowsiness may also occur.
    Ambenonium Chloride: (Moderate) The therapeutic benefits of ambenonium may be diminished when coadministered with drugs known to exhibit anticholinergic properties including sedating H1-blockers. When concurrent use cannot be avoided, monitor the patient for reduced ambenonium efficacy.
    Ambrisentan: (Major) Sympathomimetics can antagonize the effects of vasodilators when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
    Amikacin: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Amiloride: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Aminoglycosides: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Amiodarone: (Moderate) Use of dextromethorphan with amiodarone may result in increased and prolonged dextromethorphan exposure. Amiodarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. (Moderate) Use phenylephrine with caution in patients receiving amiodarone. Amiodarone possesses alpha-adrenergic blocking properties and can directly counteract the effects of phenylephrine. Phenylephrine also can block the effects of amiodarone. Monitor patients for decreased pressor effect and decreased amiodarone activity if these agents are administered concomitantly.
    Amlodipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Amlodipine; Atorvastatin: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Amlodipine; Benazepril: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Amlodipine; Celecoxib: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Amlodipine; Olmesartan: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Amlodipine; Valsartan: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Amobarbital: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Amoxapine: (Major) Concomitant use of amoxapine with sympathomimetics should be avoided whenever possible; use with caution when concurrent use cannot be avoided. One drug information reference suggests that cyclic antidepressants potentiate the pharmacologic effects of direct-acting sympathomimetics, but decrease the pressor response to indirect-acting sympathomimetics, however, the data are not consistent. (Moderate) Additive anticholinergic effects may be seen when amoxapine is used concomitantly with drugs are known to possess relatively significant antimuscarinic properties, including sedating H1-blockers. Antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature Additive sedation may also occur.
    Amphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Amphetamine; Dextroamphetamine Salts: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Amphetamine; Dextroamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Angiotensin II receptor antagonists: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin II receptor antagonists. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Angiotensin-converting enzyme inhibitors: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by angiotensin-converting enzyme inhibitors. Well-controlled hypertensive patients receiving phenylephrine at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Antacids: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Anticholinergics: (Moderate) The anticholinergic effects of sedating H1-blockers may be enhanced when combined with other antimuscarinics. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur when antimuscarinics are combined with sedating antihistamines.
    Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and diphenhydramine could result in additive depressant effects. Careful monitoring is recommended during combined use. A dose reduction of one or both drugs may be warranted. (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and doxylamine could result in additive depressant effects. Careful monitoring is recommended during combined use. A dose reduction of one or both drugs may be warranted.
    Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
    Aprepitant, Fosaprepitant: (Minor) Use caution if acetaminophen and aprepitant are used concurrently and monitor for an increase in acetaminophen-related adverse effects for several days after administration of a multi-day aprepitant regimen. Acetaminophen is a minor (10 to 15%) substrate of CYP3A4. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of acetaminophen. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. (Minor) Use caution if diphenhydramine and aprepitant are used concurrently and monitor for a possible decrease in the efficacy of diphenhydramine. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Diphenhydramine is a CYP2C9 substrate and aprepitant is a CYP2C9 inducer. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant. When a 3-day regimen of aprepitant (125 mg/80 mg/80 mg) given to healthy patients on stabilized chronic warfarin therapy (another CYP2C9 substrate), a 34% decrease in S-warfarin trough concentrations was noted, accompanied by a 14% decrease in the INR at five days after completion of aprepitant.
    Arformoterol: (Moderate) Caution and close observation should be used when arformoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Aripiprazole: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of doxylamine and aripiprazole due to the risk for additive CNS depression.
    Artemether; Lumefantrine: (Moderate) Lumefantrine is an inhibitor and diphenhydramine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased diphenhydramine concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Use of dextromethorphan with lumefantrine may result in increased dextromethorphan exposure. Lumefantrine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Articaine; Epinephrine: (Moderate) Coadministration of articaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue articaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Asenapine: (Moderate) Using drugs that can cause CNS depression, such as sedating H1-blockers, concomitantly with asenapine may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.
    Aspirin, ASA; Butalbital; Caffeine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Aspirin, ASA; Caffeine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like sedating H1-blockers and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Aspirin, ASA; Carisoprodol: (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Atenolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Atenolol; Chlorthalidone: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Atomoxetine: (Moderate) Due to the potential for additive increases in blood pressure and heart rate, atomoxetine should be used cautiously with vasopressors such as phenylephrine. Consider monitoring the patient's blood pressure and heart rate at baseline and regularly if vasopressors are coadministered with atomoxetine.
    Atropine: (Major) Atropine blocks the vagal reflex bradycardia caused by sympathomimetic agents, such as phenylephrine, and increases its pressor effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Atropine blocks the vagal reflex bradycardia caused by sympathomimetic agents, such as phenylephrine, and increases its pressor effect. (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Atropine; Difenoxin: (Major) Atropine blocks the vagal reflex bradycardia caused by sympathomimetic agents, such as phenylephrine, and increases its pressor effect. (Moderate) An enhanced CNS depressant effect may occur when diphenoxylate/difenoxin is combined with other CNS depressants. Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as sedating H1 blockers, may produce additive effects with diphenoxylate/difenoxin if used concomitantly.
    Atropine; Edrophonium: (Major) Atropine blocks the vagal reflex bradycardia caused by sympathomimetic agents, such as phenylephrine, and increases its pressor effect.
    Avanafil: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Azelastine: (Major) Avoid concomitant use of azelastine and sedating H1-blockers due to risk for additive CNS depression.
    Azelastine; Fluticasone: (Major) Avoid concomitant use of azelastine and sedating H1-blockers due to risk for additive CNS depression. (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Azilsartan; Chlorthalidone: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Baclofen: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including skeletal muscle relaxants, such as baclofen.
    Barbiturates: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Beclomethasone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension. (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Bendroflumethiazide; Nadolol: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Benzodiazepines: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Benzphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers. This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Beta-blockers: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Betamethasone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Betaxolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bethanechol: (Moderate) Bethanechol offsets the effects of sympathomimetics at sites where sympathomimetic and cholinergic receptors have opposite effects. (Moderate) Drugs that possess antimuscarinic properties, such as diphenhydramine, are pharmacologic opposites of bethanechol. These agents should not be used with bethanechol except when the specific intent is to counteract excessive actions of one or the other.
    Bisoprolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering acetaminophen with boceprevir due to an increased potential for acetaminophen-related adverse events. If acetaminophen dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of acetaminophen. Acetaminophen is partially metabolized by the hepatic isoenzyme CYP3A4; boceprevir inhibits this isoenzyme. Coadministration may result in elevated acetaminophen plasma concentrations.
    Bretylium: (Moderate) Monitor blood pressure and heart rate closely when sympathomimetics are administered with bretylium. The pressor and arrhythmogenic effects of catecholamines are enhanced by bretylium.
    Brimonidine; Timolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Bromocriptine: (Moderate) The combination of bromocriptine with phenylephrine may cause headache, tachycardia, other cardiovascular abnormalities, seizures, and other serious effects. Concurrent use of bromocriptine and phenylephrine should be approached with caution. One case report documented worsening headache, hypertension, premature ventricular complexes, and ventricular tachycardia in a post-partum patient receiving bromocriptine for lactation suppression who was subsequently prescribed acetaminophen; dichloralphenazone; isometheptene for a headache. A second case involved a post-partum patient receiving bromocriptine who was later prescribed phenylpropanolamine; guaifenesin and subsequently developed hypertension, tachycardia, seizures, and cerebral vasospasm.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Brompheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Budesonide: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Budesonide; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Bumetanide: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Bupivacaine Liposomal: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Epinephrine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Bupivacaine; Lidocaine: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Bupivacaine; Meloxicam: (Moderate) Coadministration of bupivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue bupivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Buprenorphine: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Major) Reserve concomitant prescribing of buprenorphine and doxylamine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Buprenorphine; Naloxone: (Major) Reserve concomitant prescribing of buprenorphine and diphenhydramine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Major) Reserve concomitant prescribing of buprenorphine and doxylamine for use in patients in whom alternate treatment options are inadequate. Limit dosages and durations to the minimum required and monitor patients closely for respiratory depression and sedation. Gradually tapering a patient off other CNS depressants or decreasing to the lowest effective dose is preferred in most cases of patients being treated for opioid use disorder. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Also monitor for signs of urinary retention or reduced gastric motility during concomitant use. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death as well as urinary retention and/or severe constipation, which may lead to paralytic ileus. (Moderate) If concomitant use of buprenorphine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Bupropion: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of bupropion is necessary. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
    Bupropion; Naltrexone: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of bupropion is necessary. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and bupropion is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
    Busulfan: (Moderate) Use busulfan and acetaminophen together with caution; concomitant use may result in increased busulfan levels and increased busulfan toxicity. Separating the administration of these drugs may mitigate this interaction; avoid giving acetaminophen within 72 hours prior to or concurrently with busulfan. Busulfan is metabolized in the liver through conjugation with glutathione; acetaminophen decreases glutathione levels in the blood and tissues and may reduce the clearance of busulfan.
    Butabarbital: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Butalbital; Acetaminophen: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Butalbital; Acetaminophen; Caffeine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Butorphanol: (Moderate) Concomitant use of butorphanol with sedating H1-blockers can potentiate the effects of butorphanol on CNS and/or respiratory depression. Use together with caution. If a CNS depressant needs to be used with butorphanol, use the smallest effective dose and the longest dosing frequency of butorphanol. (Moderate) The rate of butorphanol absorption through the nasal mucosa is decreased when administered with sympathomimetic nasal decongestants such as phenylephrine. However, the extent of absorption is not decreased. A slower onset of action should be expected if butorphanol is administered concurrently with or immediately following a sympathomimetic nasal decongestant.
    Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Caffeine; Sodium Benzoate: (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs.
    Calcium-channel blockers: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Canagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Canagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and sedating H1-blockers. CNS depressants can potentiate the effects of cannabidiol.
    Capecitabine: (Minor) Use caution if coadministration of capecitabine with diphenhydramine is necessary, and monitor for an increase in diphenhydramine-related adverse reactions. Diphenhydramine is a CYP2C9 substrate; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Capsaicin; Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants can potentiate the sedative effects of either agent.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Carbamazepine: (Minor) Carbamazepine may potentially accelerate the hepatic metabolism of acetaminophen. In addition, due to enzyme induction, carbamazepine may increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Clinicians should be alert to decreased effect of acetaminophen. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted.
    Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including sedating h1-blockers.
    Carbidopa; Levodopa; Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Carbinoxamine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Cardiac glycosides: (Moderate) Carefully monitor patients receiving cardiac glycosides and vasopressors concurrently due to the increased risk of arrhythmia.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics like diphenhydramine. (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics like doxylamine.
    Carisoprodol: (Moderate) Carisoprodol is metabolized to meprobamate, a significant CNS depressant. Carisoprodol can cause additive CNS depression if used concomitantly with other CNS depressants. Additive effects of sedation and dizziness, which can impair the ability to undertake tasks requiring mental alertness, may occur if carisoprodol is taken with sedating H1-blockers. Utilize appropriate caution if carisoprodol is coadministered with another CNS depressant.
    Carteolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Carvedilol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Celecoxib; Tramadol: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and sedating H1-blockers. Concurrent use may result in additive CNS depression.
    Cetirizine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and sedating H1-blockers. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Cetirizine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and sedating H1-blockers. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Charcoal: (Minor) Activated charcoal binds many drugs within the gut. Administering charcoal dietary supplements at the same time as a routine acetaminophen dosage would be expected to interfere with the analgesic and antipyretic efficacy of acetaminophen. Charcoal is mostly used in the setting of acetaminophen overdose; however, patients should never try to treat an acetaminophen overdose with charcoal dietary supplements. Advise patients to get immediate medical attention for an acetaminophen overdose.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Chlordiazepoxide: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlordiazepoxide; Amitriptyline: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chlordiazepoxide; Clidinium: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Chloroprocaine: (Moderate) Coadministration of chloroprocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue chloroprocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Chlorothiazide: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorpheniramine; Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Chlorpheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Chlorpromazine: (Moderate) Additive anticholinergic and sedative effects may be seen when chlorpromazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Additive anticholinergic and sedative effects may be seen when chlorpromazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription motion sickness, allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines.
    Chlorthalidone: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorthalidone; Clonidine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Chlorzoxazone: (Moderate) Additive CNS depression is possible if chlorzoxazone is used concomitantly with other CNS depressants including sedating H1-blockers. Additive effects of sedation and dizziness can occur, which can impair the ability to undertake tasks requiring mental alertness. Dosage adjustments of one or both medications may be necessary.
    Cholestyramine: (Moderate) Cholestyramine has been shown to decrease the absorption of acetaminophen by roughly 60%. Experts have recommended that cholestyramine not be given within 1 hour of acetaminophen if analgesic or antipyretic effect is to be achieved.
    Choline Salicylate; Magnesium Salicylate: (Moderate) Prolonged concurrent use of acetaminophen and salicylates is not recommended. Although salicylates are rarely associated with nephrotoxicity, high-dose, chronic administration of salicylates combined other analgesics, including acetaminophen, significantly increases the risk of analgesic nephropathy, renal papillary necrosis, and end-stage renal disease. Additive hepatic toxicity may occur, especially in combined overdose situations. Do not exceed the recommended individual maximum doses when these agents are given concurrently for short-term therapy.
    Ciclesonide: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Cinacalcet: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of cinacalcet is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and cinacalcet is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
    Citalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with citalopram. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Clevidipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Clobazam: (Moderate) Clobazam, a benzodiazepine, may cause drowsiness or other CNS effects. Additive drowsiness may occur when clobazam is combined with CNS depressants such as sedating H1-blockers. In addition, caution is recommended when administering clobazam with medications extensively metabolized by CYP2D6 such as diphenhydramine because clobazam has been shown to inhibit CYP2D6 in vivo and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Use of dextromethorphan with clobazam may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Clobazam inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. A dosage reduction of dextromethorphan may be necessary for some patients. During one in vivo study, co-administration of dextromethorphan and clobazam resulted in increased AUC and Cmax of dextromethorphan by 90% and 59%, respectively.
    Clonazepam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Clonidine: (Major) The cardiovascular effects of sympathomimetics, such as phenylephrine, may reduce the antihypertensive effects produced by clonidine. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Clorazepate: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Clozapine: (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination. (Moderate) Clozapine exhibits clinically significant anticholinergic effects and sedation that may be additive with other medications that may cause anticholinergic effects and sedation, including antihistamines such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines and to avoid tasks requiring mental alertness until they are aware of the effects of the combination.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Cocaine: (Major) Avoid concomitant use of additional vasoconstrictor agents with cocaine. If unavoidable, prolonged vital sign and ECG monitoring may be required. Myocardial ischemia, myocardial infarction, and ventricular arrhythmias have been reported after concomitant administration of topical intranasal cocaine and vasoconstrictor agents during nasal and sinus surgery. The risk for nervousness, irritability, convulsions, and other cardiac arrhythmias may increase during coadministration.
    Codeine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Codeine; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Codeine; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Codeine; Phenylephrine; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Codeine; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering codeine with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    COMT inhibitors: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Corticosteroids: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Cortisone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Cyclobenzaprine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cyclobenzaprine and diphenhydramine. Concomitant use may result in additive CNS depression or anticholinergic effects. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cyclobenzaprine and doxylamine. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Dacomitinib: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of dacomitinib is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and dacomitinib is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
    Dantrolene: (Moderate) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect (e.g., drowsiness) may occur when dantrolene is combined with other CNS depressants.
    Dapagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapagliflozin; Saxagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Dapsone: (Moderate) Coadministration of dapsone with acetaminophen may increase the risk of developing methemoglobinemia. Advise patients to discontinue treatment and seek immediate medical attention with any signs or symptoms of methemoglobinemia.
    Daratumumab; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Darifenacin: (Minor) Use of dextromethorphan with darifenacin may result in increased dextromethorphan exposure. Darifenacin is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
    Deflazacort: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Delavirdine: (Moderate) Use of dextromethorphan with delavirdine may result in increased dextromethorphan exposure. Delavirdine inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Desloratadine: (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of desloratadine with CNS depressants such as other H1-blockers.
    Desloratadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Minor) Although desloratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of desloratadine with CNS depressants such as other H1-blockers.
    Desmopressin: (Moderate) Although the pressor activity of desmopressin is very low compared to its antidiuretic activity, large doses of desmopressin should be used with other pressor agents like phenylephrine only with careful patient monitoring.
    Desogestrel; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Desvenlafaxine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with desvenlafaxine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, the manufacturer of desvenlafaxine recommends that the dose of CYP2D6 substrates, such as dextromethorphan, be reduced by up to 50% if used with desvenlafaxine 400 mg/day, a CYP2D6 inhibitor.
    Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as diphenhydramine, may have additive effects and worsen drowsiness or sedation. (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as doxylamine, may have additive effects and worsen drowsiness or sedation.
    Dexamethasone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Dexbrompheniramine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Dexmedetomidine: (Moderate) Co-administration of dexmedetomidine with sedating antihistamines is likely to lead to an enhancement of CNS depression.
    Dextroamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of some antihistamines, such as the sedating H1-blockers (i.e., diphenhydramine). This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Dextromethorphan; Quinidine: (Moderate) Caution is recommended when administering quinidine with medications extensively metabolized by CYP2D6 such as diphenhydramine because quinidine inhibits CYP2D6 and may increase concentrations of drugs metabolized by this enzyme. (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of quinidine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Concomitant use may increase dextromethorphan exposure and side effects. Dextromethorphan is a CYP2D6 substrate and quinidine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
    Diazepam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Diethylpropion: (Major) Diethylpropion has vasopressor effects. Coadministration with other vasopressors may have the potential for serious cardiac adverse effects such as hypertensive crisis and cardiac arrhythmias.
    Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
    Diflunisal: (Moderate) Acetaminophen plasma concentrations can increase by approximately 50% following administration of diflunisal. Acetaminophen has no effect on diflunisal concentrations. Acetaminophen in high doses has been associated with severe hepatotoxic reactions; therefore, caution should be exercised when using these agents concomitantly.
    Digitoxin: (Moderate) Carefully monitor patients receiving cardiac glycosides and vasopressors concurrently due to the increased risk of arrhythmia.
    Digoxin: (Moderate) Carefully monitor patients receiving cardiac glycosides and vasopressors concurrently due to the increased risk of arrhythmia.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Dihydroergotamine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Diltiazem: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Diphenoxylate; Atropine: (Major) Atropine blocks the vagal reflex bradycardia caused by sympathomimetic agents, such as phenylephrine, and increases its pressor effect. (Moderate) An enhanced CNS depressant effect may occur when diphenoxylate/difenoxin is combined with other CNS depressants. Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as sedating H1 blockers, may produce additive effects with diphenoxylate/difenoxin if used concomitantly.
    Disopyramide: (Moderate) The anticholinergic effects of sedating H1-blockers may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including disopyramide. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) The anticholinergic effects of sedating H1-blockers, such as diphenhydramine, may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including disopyramide. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Donepezil: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Donepezil; Memantine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dopamine: (Moderate) Monitor blood pressure during concomitant use of dopamine and other vasopressors, such as phenylephrine, due to the risk for severe hypertension.
    Dorzolamide; Timolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Doxazosin: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to its active metabolites. Although not specifically studied, cytochrome P450 enzyme inhibitors including diphenhydramine may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if products containing diphenhydramine are coadministered with doxercalciferol.
    Doxorubicin Liposomal: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Doxorubicin: (Minor) Diphenhydramine is a CYP2D6 inhibitor and doxorubicin is a major substrate of CYP2D6. However, these drugs are often used together in treatment.
    Dronabinol: (Moderate) Concurrent use of dronabinol, THC with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity. Dronabinol, THC has been associated with occasional hypotension, hypertension, syncope, and tachycardia. In a study of 7 adult males, combinations of IV cocaine and smoked marijuana, 1 g marijuana cigarette, 0 to 2.7% delta-9-THC, increased the heart rate above levels seen with either agent alone, with increases plateauing at 50 bpm. (Moderate) Use caution if coadministration of dronabinol with antihistamines is necessary. Concurrent use of dronabinol, THC with antihistamines may result in additive drowsiness, hypertension, tachycardia, and possibly cardiotoxicity.
    Dronedarone: (Moderate) Dronedarone is an inhibitor of CYP2D6. Diphenhydramine is a substrate for CYP2D6. The concomitant administration of dronedarone and CYP2D6 substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution. (Moderate) Use of dextromethorphan with dronedarone may result in increased dextromethorphan exposure. Dronedarone inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Droperidol: (Moderate) Sedating H1-blockers have additive or potentiating sedative and other CNS effects with droperidol. Following administration of droperidol, lower doses of the other CNS depressant may need to be used.
    Drospirenone; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Dulaglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Duloxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with duloxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Dutasteride; Tamsulosin: (Moderate) Use caution if coadministration of diphenhydramine with tamsulosin is necessary, especially at a tamsulosin dose higher than 0.4 mg, as the systemic exposure of tamsulosin may be increased resulting in increased treatment-related adverse reactions including hypotension, dizziness, and vertigo. Tamsulosin is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor.
    Dyphylline: (Moderate) Use of sympathomimetics with dyphylline should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias.
    Dyphylline; Guaifenesin: (Moderate) Use of sympathomimetics with dyphylline should be approached with caution. Coadministration may lead to adverse effects, such as tremors, insomnia, seizures, or cardiac arrhythmias.
    Efavirenz: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Minor) Drugs that induce the hepatic isoenzymes CYP2E1 and CYP1A2, such as efavirenz, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Elexacaftor; tezacaftor; ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Eliglustat: (Major) In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), coadministration of scheduled diphenhydramine and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily during the course of antihistamine treatment; however coadministration of eliglustat with both diphenhydramine and a strong or moderate CYP3A inhibitor is contraindicated. It is unclear whether a single dose of diphenhydramine warrants modification of eliglustat therapy. Diphenhydramine is a substrate and moderate inhibitor of CYP2D6; eliglustat is a substrate and inhibitor of CYP2D6 and a CYP3A substrate. Coadministration of eliglustat with CYP2D6 inhibitors, such as diphenhydramine, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); the effects of a single diphenhydramine dose are unknown. In addition, coadministration of eliglustat with CYP2D6 substrates (e.g., diphenhydramine) may result in increased concentrations of the concomitant drug; monitor patients closely for anticholinergic adverse events. (Moderate) Use of dextromethorphan with eliglustat may result in increased dextromethorphan exposure. Eliglustat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Eltrombopag: (Moderate) Eltrombopag is a UDP-glucuronyltransferase inhibitor. Acetaminophen is a substrate of UDP-glucuronyltransferases. The significance or effect of this interaction is not known; however, elevated concentrations of acetaminophen are possible. Monitor patients for adverse reactions if these drugs are coadministered.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with diphenhydramine as there is a potential for decreased diphenhydramine concentrations. Diphenhydramine is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Caution is warranted when elvitegravir is administered with diphenhydramine as there is a potential for decreased diphenhydramine concentrations. Diphenhydramine is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Caution is warranted when elvitegravir is administered with diphenhydramine as there is a potential for decreased diphenhydramine concentrations. Diphenhydramine is a substrate of CYP2C9, while elvitegravir is a CYP2C9 inducer. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Empagliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Linagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Empagliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Enalapril; Felodipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Enflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Entacapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Epinephrine: (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Epoprostenol: (Major) Avoid use of sympathomimetic agents with epoprostenol. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including epoprostenol. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Ergoloid Mesylates: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergonovine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergot alkaloids: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergotamine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Ergotamine; Caffeine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension. (Moderate) CNS-stimulating actions of caffeine can be additive with other CNS stimulants or psychostimulants like phenylephrine; caffeine should be avoided or used cautiously. Excessive caffeine ingestion (via medicines, supplements or beverages including coffee, green tea, other teas, guarana, colas) may contribute to side effects like nervousness, irritability, insomnia, or tremor.
    Ertugliflozin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Ertugliflozin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Ertugliflozin; Sitagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Escitalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with escitalopram. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Esketamine: (Moderate) Closely monitor patients receiving esketamine and diphenhydramine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep. (Moderate) Closely monitor patients receiving esketamine and doxylamine for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Esmolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Estazolam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Eszopiclone: (Moderate) A reduction in the dose of eszopiclone and concomitantly administered CNS depressants, such as sedating H1-blockers, should be considered to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethacrynic Acid: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression. (Major) The risk of developing hepatotoxicity from acetaminophen appears to be increased in patients who regularly consume alcohol. Patients who drink more than 3 alcohol-containing drinks a day and take acetaminophen are at increased risk of developing hepatotoxicity. Acute or chronic alcohol use increases acetaminophen-induced hepatotoxicity by inducing CYP2E1 leading to increased formation of the hepatotoxic metabolite of acetaminophen. Also, chronic alcohol use can deplete liver glutathione stores. Administration of acetaminophen should be limited or avoided altogether in patients with alcoholism or patients who consume alcohol regularly.
    Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethinyl Estradiol; Norgestrel: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Etomidate: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Exenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Minor) Although an interaction is possible, these drugs may be used together. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least 1 hour prior to an exenatide injection. When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (at 0 hours) and at 1, 2 and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively. Additionally, acetaminophen Tmax was delayed from 0.6 hours in the control period to 0.9, 4.2, 3.3, and 1.6 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before exenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying from exenatide use) and the clinical impact has not been assessed.
    Ezogabine: (Moderate) Caution is advisable during concurrent use of ezogabine and medications that may affect voiding such as diphenhydramine, a sedating antihistamine (H1-blocker). Ezogabine has caused urinary retention requiring catheterization in some cases. The anticholinergic effects of diphenhydramine on the urinary tract may be additive. Additive sedation or other CNS effects may also occur. (Moderate) Caution is advisable during concurrent use of ezogabine and medications that may affect voiding such as doxylamine, a sedating antihistamine (H1-blocker). Ezogabine has caused urinary retention requiring catheterization in some cases. The anticholinergic effects of doxylamine on the urinary tract may be additive. Additive sedation or other CNS effects may also occur.
    Fedratinib: (Moderate) Use of dextromethorphan with fedratinib may result in increased dextromethorphan exposure. Fedratinib is a moderate inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Felodipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and diphenhydramine. Concurrent use may result in additive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and doxylamine. Concurrent use may result in additive CNS depression. (Moderate) Use fenfluramine and dextromethorphan with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19 and a mild-to-moderate inhibitor of CYP2C9. Concomitant use of fenofibric acid with CYP2C19 and CYP2C9 substrates, such as diphenhydramine, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 and CYP2C9 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diphenhydramine during coadministration with fenofibric acid.
    Fentanyl: (Major) Pain control may be impaired if fentanyl nasal spray is administered in patients receiving vasoconstrictive nasal decongestants (e.g., phenylephrine); do not titrate fentanyl nasal spray dose in such patients. This interaction is not expected with other fentanyl administration routes. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fentanyl with dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Fexofenadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Finasteride; Tadalafil: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Flibanserin: (Moderate) The concomitant use of flibanserin with CNS depressants, such as sedating H1-blockers, may increase the risk of CNS depression (e.g., dizziness, somnolence) compared to the use of flibanserin alone. Patients should avoid activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after each dose and until they know how flibanserin affects them.
    Fludrocortisone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Flunisolide: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Fluoxetine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold.
    Fluphenazine: (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Additive sedative effects may be seen when fluphenazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Flurazepam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Fluticasone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Fluticasone; Salmeterol: (Moderate) Caution and close observation should also be used when salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects. (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Fluticasone; Vilanterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as vilanterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects. (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Fluvoxamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluvoxamine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
    Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Formoterol; Mometasone: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects. (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Fospropofol: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics like fospropofol.
    Furosemide: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of diphenhydramine and gabapentin. Concurrent use may result in additive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of doxylamine and gabapentin. Concurrent use may result in additive CNS depression.
    Galantamine: (Moderate) Concurrent use of sedating H1-blockers and galantamine should be avoided if possible. Galantamine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of galantamine.
    Gentamicin: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Ginger, Zingiber officinale: (Minor) In vitro studies have demonstrated the positive inotropic effects of certain gingerol constituents of ginger; but it is unclear if whole ginger root exhibits these effects clinically in humans. It is theoretically possible that excessive doses of ginger could affect the action of vasopressors like phenylephrine; however, no clinical data are available.
    Givosiran: (Moderate) If possible, avoid concomitant use of dextromethorphan with givosiran due to the risk of increased dextromethorphan-related adverse reactions. If use is necessary, consider decreasing the dextromethorphan dose. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Dextromethorphan is a sensitive CYP2D6 substrate. Givosiran may moderately reduce hepatic CYP2D6 enzyme activity because of its pharmacological effects on the hepatic heme biosynthesis pathway.
    Glimepiride; Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Glipizide; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Glyburide; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Glycopyrrolate; Formoterol: (Moderate) Caution and close observation should be used when formoterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Grapefruit juice: (Minor) Intake of grapefruit juice or seville orange juice increased dextromethorphan bioavailability in one study. Patients with increased concentrations of dextromethorphan may experience drowsiness or serotonergic side effects (dizziness, nervousness or restlessness, nausea, vomiting, stomach upset) not usually noted with prescribed or nonprescription product doses. Grapefruit juice and seville orange juice contain compounds that can inhibit P-glycoprotein in the intestinal wall, and dextromethorphan absorption may be affected by P-glycoprotein activity. Dextromethorphan is largely metabolized by CYP2D6, so this particular interaction with grapefruit juice may be more relevant in patients who are poor CYP2D6 metabolizers.
    Green Tea: (Moderate) Some, but not all, green tea products contain caffeine. Caffeine should be avoided or used cautiously with phenylephrine. CNS stimulants and sympathomimetics are associated with adverse effects such as nervousness, irritability, insomnia, and cardiac arrhythmias.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Guaifenesin; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Guanabenz: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of guanabenz when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Halogenated Anesthetics: (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as diphenhydramine, a sedating H1-blocker. Additive anticholinergic effects may occur. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or CNS effects may also occur. (Moderate) Haloperidol can potentiate the actions of other CNS depressants such as the sedating H1-blockers. Additive anticholinergic effects may occur. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or CNS effects may also occur. (Moderate) Non-cardiovascular drugs with alpha-blocking activity such as haloperidol, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Heparin: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hyaluronidase, Recombinant; Immune Globulin: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Hydantoins: (Minor) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, leading to reduced efficacy of medications like acetaminophen. In addition, the risk of hepatotoxicity from acetaminophen may be increased with the chronic dosing of acetaminophen along with phenytoin. Adhere to recommended acetaminophen dosage limits. Acetaminophen-related hepatotoxicity has occurred clinically with the concurrent use of acetaminophen 1300 mg to 6200 mg daily and phenytoin. Acetaminophen cessation led to serum transaminase normalization within 2 weeks.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Sympathomimetics, such as phenylephrine, can antagonize the antihypertensive effects of methyldopa when administered concomitantly. Blood pressure should be monitored closely to confirm that the desired antihypertensive effect is achieved. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Hydrocodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hydrocodone; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hydrocortisone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Hydromorphone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Ibuprofen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Iloperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when iloperidone is given in combination with other centrally-acting medications, such as sedating H1-blockers.
    Iloprost: (Major) Avoid use of sympathomimetic agents with iloprost. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including iloprost. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Imatinib: (Major) Imatinib, STI-571 may affect the metabolism of acetaminophen. In vitro, imatinib was found to inhibit acetaminophen O-glucuronidation at therapeutic levels. Therefore, systemic exposure to acetaminophen is expected to be increased with coadministration of imatinib. Chronic acetaminophen therapy should be avoided in patients receiving imatinib. (Moderate) Use of dextromethorphan with imatinib may result in increased dextromethorphan exposure. Imatinib inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Incretin Mimetics: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Indacaterol: (Moderate) Administer sympathomimetics with caution with beta-agonists such as indacaterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Indacaterol; Glycopyrrolate: (Moderate) Administer sympathomimetics with caution with beta-agonists such as indacaterol. The cardiovascular effects of beta-2 agonists may be potentiated by concomitant use. Monitor the patient for tremors, nervousness, increased heart rate, or other additive side effects.
    Indapamide: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of vasodilators when administered concomitantly. Patients should be monitored to confirm that the desired antihypertensive effect is achieved.
    Insulin Degludec; Liraglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Insulin Glargine; Lixisenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
    Insulins: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Iobenguane I 131: (Major) Discontinue sympathomimetics for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart sympathomimetics until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as sympathomimetics, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
    Ionic Contrast Media: (Major) The intravascular injection of a contrast medium should never be made after the administration of vasopressors since they strongly potentiate neurologic effects. Serious neurologic sequelae, including permanent paralysis, have been reported after cerebral arteriography, selective spinal arteriography, and arteriography of vessels supplying the spinal cord.
    Ipratropium; Albuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with acetaminophen may result in increased serum concentrations of acetaminophen. Acetaminophen is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Contraindicated) Concomitant use of monoamine oxidase inhibitors and sedating H1-blockers is contraindicated due to increased anticholinergic effects. (Contraindicated) Dextromethorphan products are contraindicated in patients taking a monoamine oxidase inhibitor (MAOI) or in patients who have taken an MAOI within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of an MAOI. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotonergic agents, a sufficient amount of time must be allowed for clearance of the serotonergic agent and its active metabolites. (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Isoflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of sympathomimetics, including phenylephrine, which can increase the risk of developing cardiac arrhythmias and hypotension.
    Isoniazid, INH: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
    Isoniazid, INH; Rifampin: (Major) Agents which induce the hepatic isoenzyme CYP2E1, such as isoniazid, may potentially increase the risk for acetaminophen-induced hepatotoxicity via generation of a greater percentage of acetaminophen's hepatotoxic metabolites. The combination of isoniazid and acetaminophen has caused severe hepatotoxicity in at least one patient; studies in rats have demonstrated that pre-treatment with isoniazid potentiates acetaminophen hepatotoxicity. (Moderate) Concomitant use of acetaminophen with rifampin may increase the known risk of hepatotoxicity in relation to each drug. Severe hepatic dysfunction including fatalities were reported in patients taking rifampin with other hepatotoxic agents.
    Isradipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Kanamycin: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Ketamine: (Moderate) Closely monitor vital signs when ketamine and phenylephrine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phenylephrine may enhance the sympathomimetic effects of ketamine. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Labetalol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Lamivudine, 3TC; Zidovudine, ZDV: (Minor) Both acetaminophen and zidovudine, ZDV undergo glucuronidation. Competition for the metabolic pathway is thought to have caused a case of acetaminophen-related hepatotoxicity. This interaction may be more clinically significant in patients with depleted glutathione stores, such as patients with acquired immunodeficiency syndrome, poor nutrition, or alcoholism.
    Lamotrigine: (Moderate) Monitor patients for possible loss of lamotrigine efficacy and seizure activity during coadministration with acetaminophen. Acetaminophen may induce glucuronidation pathways involved in lamotrigine metabolism. During a study among 12 healthy volunteers, concomitant administration of acetaminophen 4 g/day with lamotrigine at steady-state increased the formation clearance of lamotrigine glucuronide conjugates by 45%, decreased lamotrigine AUC by 20%, and reduced lamotrigine trough concentrations by 25%.
    Lanthanum Carbonate: (Minor) The manufacturer recommends that oral compounds known to interact with antacids, such as acetaminophen, should not be taken within 2 hours of dosing with lanthanum carbonate.
    Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and sedating H1-blockers. Concurrent use may result in additive CNS depression. (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and dextromethorphan. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and sedating antihistamines (H1-blockers). Dosage adjustments of lemborexant and sedating H1-blockers may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants. Patients should generally avoid nonprescription antihistamine products that are marketed as sleep-aids concurrently with lemborexant.
    Levalbuterol: (Moderate) Caution and close observation should be used when albuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Levamlodipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Levobetaxolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Levobunolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Levocetirizine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of cetirizine and sedating H1-blockers. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Levomilnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with levomilnacipran. Dextromethorphan has serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Levorphanol: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Levothyroxine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Levothyroxine; Liothyronine (Porcine): (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Levothyroxine; Liothyronine (Synthetic): (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Lidocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Lidocaine; Epinephrine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Lidocaine; Prilocaine: (Moderate) Coadministration of lidocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue lidocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Linagliptin; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Linezolid: (Major) Linezolid may enhance the hypertensive effect of phenylephrine. Initial doses of phenylephrine, if given by intravenous infusion, should be reduced and subsequent dosing titrated to desired response. Closely monitor blood pressure during coadministration. Linezolid is an antibiotic that is also a weak, reversible nonselective inhibitor of monoamine oxidase (MAO). Therefore, linezolid has the potential for interaction with adrenergic agents, such as phenylephrine. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering linezolid with dextromethorphan. Linezolid is an antibiotic that is also a reversible, non-selective MAO inhibitor and has potential to interact with serotonergic agents. Dextromethorphan has serotonergic activity. However, the potential for interaction has been studied. Subjects were administered dextromethorphan (two 20-mg doses given 4 hours apart) with or without linezolid. No serotonin syndrome effects (confusion, delirium, restlessness, tremors, blushing, diaphoresis, hyperpyrexia) have been observed in normal subjects receiving linezolid and dextromethorphan.
    Liothyronine: (Moderate) Sympathomimetic amines should be used with caution in patients with thyrotoxicosis since these patients are unusually responsive to sympathomimetic amines. Based on the cardiovascular stimulatory effects of sympathomimetic drugs, the concomitant use of sympathomimetics and thyroid hormones can enhance the effects on the cardiovascular system. Patients with coronary artery disease have an increased risk of coronary insufficiency from either agent. Concomitant use of these agents may increase this risk further. In addition, dopamine at a dose of >= 1 mcg/kg/min and dopamine agonists (e.g., apomorphine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole, rotigotine) may result in a transient reduction in TSH secretion. The reduction in TSH secretion is not sustained; hypothyroidism does not occur.
    Liraglutide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Lixisenatide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Minor) When 1,000 mg acetaminophen was given 1 or 4 hours after 10 mcg lixisenatide, the AUC was not significantly changed, but the acetaminophen Cmax was decreased by 29% and 31%, respectively and median Tmax was delayed by 2 and 1.75 hours, respectively. Acetaminophen AUC, Cmax, and Tmax were not significantly changed when acetaminophen was given 1 h before lixisenatide injection. The mechanism of this interaction is not available (although it may be due to delayed gastric emptying) and the clinical impact has not been assessed. To avoid potential pharmacokinetic interactions that might alter effectiveness of acetaminophen, it may be advisable for patients to take acetaminophen at least one hour prior to lixisenatide subcutaneous injection.
    Lofexidine: (Major) Monitor for excessive sedation during coadministration of diphenhydramine and lofexidine due to the potential for additive CNS depressant effects. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known. (Moderate) Monitor for additive sedation during coadministration of lofexidine and doxylamine. Lofexidine can potentiate the effects of CNS depressants. Patients should be advised to avoid driving or performing any other tasks requiring mental alertness until the effects of the combination are known.
    Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day PO for >= 3 days/week). The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Loop diuretics: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
    Loratadine: (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as other H1-blockers.
    Loratadine; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics. (Minor) Although loratadine is considered a 'non-sedating' antihistamine, dose-related sedation has been noted. For this reason, it would be prudent to monitor for drowsiness during concurrent use of loratadine with CNS depressants such as other H1-blockers.
    Lorazepam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Lorcaserin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with lorcaserin. Both medications have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, lorcaserin inhibits CYP2D6-mediated metabolism of dextromethorphan, increasing dextromethorphan Cmax by approximately 76% and AUC by approximately 2-fold. Increased dextromethorphan exposure may result in adverse effects consistent with the serotonin syndrome.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Loxapine: (Moderate) Patients taking loxapine can have reduced pressor response to phenylephrine. (Moderate) Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with other drugs having anticholinergic activity and CNS depressant properties such as traditional antipsychotic agents, including loxapine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of diphenhydramine, which is a CYP2C19 substrate. Monitor patients for adverse effects of diphenhydramine, such as CNS depression. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
    Lumacaftor; Ivacaftor: (Minor) Concomitant use of diphenhydramine and lumacaftor; ivacaftor may alter diphenhydramine exposure; monitor for diphenhydramine efficacy and adverse events. Diphenhydramine is partially metabolized by CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of diphenhydramine through the CYP2C19 pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear.
    Lumacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as diphenhydramine. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may lead to increased exposure to CYP2C9 substrates; however, the clinical impact of this has not yet been determined.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and diphenhydramine. Concurrent use may result in additive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and doxylamine. Concurrent use may result in additive CNS depression.
    Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications. Sedating H1-blockers are associated with sedation; therefore, additive effects may be seen during concurrent use with other drugs having CNS depressant properties such as antipsychotics. Additive drowsiness or other CNS effects may occur.
    Macitentan: (Major) Avoid use of sympathomimetic agents with macitentan. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including macitentan. Sympathomimetics can increase blood pressure, increase heart rate, and may cause vasoconstriction resulting in chest pain and shortness of breath in these patients. Patients should be advised to avoid amphetamine drugs, decongestants (including nasal decongestants) and sympathomimetic anorexiants for weight loss, including dietary supplements. Intravenous vasopressors may be used in the emergency management of pulmonary hypertension patients when needed, but hemodynamic monitoring and careful monitoring of cardiac status are needed to avoid ischemia and other complications.
    Maprotiline: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker. (Moderate) Use maprotiline and sympathomimetics together with caution and close clinical monitoring. Regularly assess blood pressure, heart rate, the efficacy of treatment, and the emergence of sympathomimetic/adrenergic adverse events. Carefully adjust dosages as clinically indicated. Maprotiline has pharmacologic activity similar to tricyclic antidepressant agents and may cause additive sympathomimetic effects when combined with agents with adrenergic/sympathomimetic activity.
    Mecamylamine: (Major) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by mecamylamine. Close monitoring of blood pressure or the selection of alternative therapeutic agents may be needed.
    Meclizine: (Major) Meclizine is an H1-blocker which exhibits significant anticholinergic effects. The anticholinergic effects of meclizine may be enhanced when combined with other drugs with antimuscarinic activity, including other sedating H1-blockers. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive sedation may also occur. (Major) The anticholinergic and sedative effects of meclizine may be enhanced when combined with other drugs with antimuscarinic activity, including other sedating antihistamines (H1-blockers). Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Meglitinides: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Melatonin: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of melatonin and sedating H1-blockers due to the risk for additive CNS depression.
    Memantine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Meperidine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Meperidine; Promethazine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Mephobarbital: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Mepivacaine: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Mepivacaine; Levonordefrin: (Moderate) Coadministration of mepivacaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue mepivacaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including sedating H1-blockers.
    Metaproterenol: (Major) Caution and close observation should also be used when metaproterenol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Metaxalone: (Moderate) Concomitant administration of metaxalone with other CNS depressants can potentiate the sedative effects of either agent.
    Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Repaglinide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Rosiglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Saxagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Metformin; Sitagliptin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Methadone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Methamphetamine: (Moderate) Amphetamines may pharmacodynamically counteract the sedative properties of sedating H1-blockers. This effect may be clinically important if a patient is receiving an antihistamine agent for treatment of insomnia. Alternatively, if a patient is receiving an amphetamine for treatment of narcolepsy, the combination with a sedating antihistamine may reverse the action of the amphetamine. Coadminister with caution and monitor for altered response to drug therapy.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Methocarbamol: (Moderate) Methocarbamol may cause additive CNS depression if used concomitantly with other CNS depressants such as sedating H1-blockers. Combination therapy can cause additive effects of sedation and dizziness, which can impair the patient's ability to undertake tasks requiring mental alertness. Dosage adjustments of either or both medications may be necessary.
    Methohexital: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Methyclothiazide: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Methyldopa: (Major) Sympathomimetics, such as phenylephrine, can antagonize the antihypertensive effects of methyldopa when administered concomitantly. Blood pressure should be monitored closely to confirm that the desired antihypertensive effect is achieved.
    Methylene Blue: (Major) Because of the potential risk and severity of serotonin syndrome, coadministration of dextromethorphan and IV methylene blue should be avoided if possible. Methylene blue has been demonstrated to be a potent monoamine oxidase inhibitor (MAOI) and may cause potentially fatal serotonin toxicity (serotonin syndrome) when combined with serotonin reuptake inhibitors (SRIs). Dextromethorphan increases central serotonin effects. If methylene blue is judged to be indicated, all SRIs, including dextromethorphan, must be ceased prior to treatment/procedure/surgery. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Methylergonovine: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Methylphenidate Derivatives: (Moderate) Methylphenidate derivatives can potentiate the actions of both exogenous (such as dopamine and epinephrine) and endogenous (such as norepinephrine) vasopressors. It is advisable to monitor cardiac function if these medications are coadministered. Vasopressors include medications such as epinephrine, dopamine, midodrine, and non-prescription medications such as pseudoephedrine and phenylephrine.
    Methylprednisolone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Methysergide: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
    Metolazone: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Metoprolol: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with diphenhydramine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and diphenhydramine is a CYP2D6 inhibitor. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for metoprolol-related adverse reactions, including bradycardia and hypotension, during coadministration with diphenhydramine. Concomitant use may increase metoprolol serum concentrations which would decrease the cardioselectivity of metoprolol. Metoprolol is a CYP2D6 substrate and diphenhydramine is a CYP2D6 inhibitor. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Metyrapone: (Major) Coadministration of metyrapone and acetaminophen may result in acetaminophen toxicity. Acetaminophen glucuronidation is inhibited by metyrapone. It may be advisable for patients to avoid acetaminophen while taking metyrapone. (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as sedating H1-blockers, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Metyrosine: (Moderate) The concomitant administration of metyrosine with sedating H1-blockers can result in additive sedative effects.
    Midazolam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Midodrine: (Major) Midodrine stimulates alpha-adrenergic receptors. Coadministration of midodrine with other vasoconstrictive agents, such as phenylephrine, may enhance or potentiate the effects of midodrine.
    Miglitol: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Milnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with milnacipran. Dextromethorphan has serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants, such as sedating H1-blockers. Caution should be exercised when using these agents concurrently.
    Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as acetaminophen (> 4 g/day for >= 3 days/week). The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as diphenhydramine may be increased when co-administered with mirabegron. Diphenhydramine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary. (Minor) Use of dextromethorphan with mirabegron may result in increased dextromethorphan exposure. Mirabegron moderately inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
    Mirtazapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with mirtazapine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Consistent with the CNS depressant effects of mirtazapine, additive effects may occur with other CNS depressants such as diphenhydramine. Mirtazapine should be administered cautiously with such agents because the CNS effects on cognitive performance and motor skills can be additive. (Moderate) Monitor for unusual drowsiness and sedation during coadministration of doxylamine and mirtazapine due to the risk for additive CNS depression.
    Mitotane: (Moderate) Mitotane can cause sedation, lethargy, vertigo, and other CNS side effects. Concomitant administration of mitotane and CNS depressants, including sedating h1-blockers, may cause additive CNS effects. (Minor) Use caution if mitotane and acetaminophen are used concomitantly, and monitor for decreased efficacy of acetaminophen. Mitotane is a strong CYP3A4 inducer and acetaminophen is a minor (10% to 15%) CYP3A4 substrate; coadministration may result in decreased plasma concentrations of acetaminophen.
    Molindone: (Moderate) An enhanced CNS depressant effect may occur when sedating h1-blockers are combined with other CNS depressants including molindone.
    Mometasone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Monoamine oxidase inhibitors: (Contraindicated) Concomitant use of monoamine oxidase inhibitors and sedating H1-blockers is contraindicated due to increased anticholinergic effects. (Contraindicated) Dextromethorphan products are contraindicated in patients taking a monoamine oxidase inhibitor (MAOI) or in patients who have taken an MAOI within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of an MAOI. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotonergic agents, a sufficient amount of time must be allowed for clearance of the serotonergic agent and its active metabolites. (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Morphine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Nabilone: (Moderate) Concomitant use of nabilone with other CNS depressants, such as sedating H1-blockers, can potentiate the effects of nabilone on respiratory depression. (Moderate) Concurrent use of nabilone with sympathomimetics (e.g., amphetamine or cocaine) may result in additive hypertension, tachycardia, and possibly cardiotoxicity. In a study of 7 adult males, combinations of cocaine (IV) and smoked marijuana (1 g marijuana cigarette, 0 to 2.7% delta-9-THC) increased the heart rate above levels seen with either agent alone, with increases reaching a plateau at 50 bpm.
    Nadolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nafarelin: (Moderate) If use of a topical nasal decongestants (e.g., oxymetazoline, tetrahydrozoline, phenylephrine nasal) is necessary during therapy with intranasal nafarelin, the decongestant should not be used for at least 2 hours after nafarelin is administered.
    Nalbuphine: (Moderate) Concomitant use of nalbuphine with other CNS depressants, such as sedating H1-blockers, can potentiate the effects of nalbuphine on respiratory depression, CNS depression, and sedation.
    Naproxen; Pseudoephedrine: (Major) Pseudoephedrine can potentiate the effects and increase the toxicity of other sympathomimetics by adding to their sympathomimetic activity. Although no data are available, pseudoephedrine should be used cautiously in patients using significant quantities of other sympathomimetics.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with diphenhydramine; adjust the nebivolol dose according to blood pressure response. Concomitant use may increase the exposure of nebivolol. Nebivolol is a CYP2D6 substrate and diphenhydramine is a moderate CYP2D6 inhibitor. (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Nefazodone: (Moderate) An enhanced CNS depressant effect may occur when sedating H1-blockers are combined with other CNS depressants including nefazodone. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with nefazodone. Both drugs have serotonergic activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    Nicardipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Nicotine: (Minor) Vasoconstricting nasal decongestants such as oxymetazoline, phenylephrine, pseudoephedrine, and tetrahydrozoline prolong the time to peak effect of nasally administered nicotine (i.e. nicotine nasal spray); however, no dosage adjustments are recommended.
    Nifedipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Nimodipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
    Nisoldipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Nitrates: (Moderate) Sympathomimetics can antagonize the antianginal effects of nitrates, and can increase blood pressure and/or heart rate. Anginal pain may be induced when coronary insufficiency is present.
    Non-Ionic Contrast Media: (Major) Do not administer non-ionic contrast media intra-arterially after the administration of vasopressors since they strongly potentiate neurologic effects.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Norethindrone; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Norgestimate; Ethinyl Estradiol: (Moderate) Acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. Patients taking acetaminophen concomitantly may experience an increase in estrogen related side effects.
    Olanzapine: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Olanzapine; Fluoxetine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of fluoxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and fluoxetine is a strong CYP2D6 inhibitor. Concomitant use with another strong CYP2D6 inhibitor increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Olanzapine; Samidorphan: (Moderate) Olanzapine exhibits anticholinergic effects that may be clinically significant. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with olanzapine. Some medications exhibit additive anticholinergic effects include sedating H1-blockers. Olanzapine may also cause additive sedation with many of these drugs.
    Oliceridine: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) If concomitant use of oliceridine and dextromethorphan is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients. (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Olopatadine; Mometasone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) As a cytochrome P450 isoenzyme inducers, rifabutin could induce the metabolism of acetaminophen. An increase in acetaminophen-induced hepatotoxicity may be seen by increasing the metabolism of acetaminophen to its toxic metabolite, NAPQI. Also, the analgesic activity of acetaminophen may be reduced.
    Omeprazole; Sodium Bicarbonate: (Minor) Antacids can delay the oral absorption of acetaminophen, but the interactions are not likely to be clinically significant as the extent of acetaminophen absorption is not appreciably affected.
    Opiate Agonists: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Opicapone: (Moderate) COMT inhibitors should be given cautiously with other agents that cause CNS depression, including sedating H1-blockers, due to the possibility of additive sedation. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Oritavancin: (Moderate) Administration of oritavancin, a weak inducer of CYP2D6 and CYP3A4, with dextromethorphan resulted in a 31% reduction in the ratio of dextromethorphan to dextrorphan concentrations in the urine. The efficacy of dextromethorphan may be reduced if these drugs are administered concurrently. (Moderate) Diphenhydramine is metabolized by CYP2C9, CYP2C19 and CYP2D6; oritavancin is a weak inducer of CYP2D6 and a weak CYP2C9 and CYP2C19 inhibitor. Coadministration may result in altered diphenhydramine plasma concentrations. If these drugs are administered concurrently, monitor for diphenydramine toxicity, such as drowsiness, or decreased effectiveness.
    Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties, like sedating H1-blockers and orphenadrine, are used concomitantly. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
    Oxazepam: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
    Oxycodone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Oxymorphone: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Oxytocin: (Major) The administration of prophylactic vasopressors with oxytocin can cause severe, persistent hypertension, as the 2 drugs may have a synergistic and additive vasoconstrictive effect. This interaction was noted when oxytocin was given 3 to 4 hours after prophylactic vasoconstrictor in conjunction with caudal anesthesia. The incidence of such an interaction may be decreased if vasopressors are not administered prior to oxytocin.
    Ozanimod: (Contraindicated) Coadministration of ozanimod with dextromethorphan is contraindicated. Allow at least 14 days between discontinuation of ozanimod and initiation of dextromethorphan. Consider if an alternative to dextromethorphan would be appropriate. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for serious and possibly fatal drug interactions with dextromethorphan, including serotonin syndrome. (Major) Coadministration of ozanimod with sympathomimetics such as phenylephrine is not routinely recommended due to the potential for hypertensive crisis. If coadministration is medically necessary, closely monitor the patient for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Sympathomimetics may increase blood pressure by increasing norepinephrine concentrations and monoamine oxidase inhibitors (MAOIs) are known to potentiate these effects. Concomitant use of ozanimod with pseudoephedrine did not potentiate the effects on blood pressure. However, hypertensive crisis has occurred with administration of ozanimod alone and also during coadministration of sympathomimetic medications and other selective or nonselective MAO inhibitors.
    Paliperidone: (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and diphenhydramine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them. (Moderate) Coadministration of drugs with CNS depressant effects, including paliperidone and doxylamine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
    Panobinostat: (Major) Avoid coadministrating panobinostatwith sensitive CYP2D6 substrates such as dextromethorphan due to increased dextromethorphan exposure. Consider alternatives to dextromethorphan if possible. If concomitant use cannot be avoided, closely monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Panobinostat inhibits CYP2D6. When a single 60-mg dose of dextromethorphan (DM) was administered after 3 doses of panobinostat (20 mg on days 3, 5, and 8), the DM Cmax increased by 20% to 200% and DM exposure (AUC) increased by 20% to 130% (interquartile ranges) vs. when DM was given alone; however, the change in exposure was highly variable among the patients studied.
    Papaverine: (Moderate) Concurrent use of papaverine with potent CNS depressants such as diphenhydramine could lead to enhanced sedation. (Moderate) Concurrent use of papaverine with potent CNS depressants such as doxylamine could lead to enhanced sedation.
    Paromomycin: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Paroxetine: (Moderate) Monitor for dextromethorphan-related side effects, such as dizziness or drowsiness, if concomitant use of paroxetine is necessary. For patients receiving combination dextromethorphan; bupropion, do not exceed a maximum dose of 45 mg dextromethorphan; 105 mg bupropion once daily. Additionally, monitor patients for signs and symptoms of serotonin syndrome. Concomitant use may increase dextromethorphan exposure and the risk for serotonin syndrome. Dextromethorphan is a CYP2D6 substrate and paroxetine is a strong CYP2D6 inhibitor. Concomitant use with paroxetine increased dextromethorphan overall exposure by 2.69-fold. (Moderate) Of the selective serotonin reuptake inhibiting antidepressants (SSRIs), paroxetine is considered the most anticholinergic. Additive anticholinergic effects may be seen when paroxetine is used with antihistamines having anticholinergic properties such as diphenhydramine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Pazopanib: (Moderate) Use of dextromethorphan with pazopanib may result in increased dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. Results from drug-drug interaction trials conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP2D6 and dextromethorphan is a CYP2D6 substrate. Coadministration of dextromethorphan and pazopanib resulted in an increase of 33% to 64% in the ratio of dextromethorphan to dextrorphan concentrations in the urine, indicating reduced CYP2D6 metabolism to the dextrorphan metabolite.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to diphenhydramine if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP1A2 and CYP2D6 inhibitor, while diphenhydramine is a CYP1A2 and CYP2D6 substrate. (Minor) Monitor for adverse effects associated with increased exposure to dextromethorphan if peginterferon alfa-2b is coadministered. Peginterferon alfa -2b is a CYP2D6 inhibitor, while dextromethorphan is a CYP2D6 substrate.
    Penbutolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Penicillin G Benzathine; Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Penicillin G Procaine: (Moderate) Coadministration of penicillin G procaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue penicillin G procaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentazocine; Naloxone: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with sedating H1-blockers may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentobarbital: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Pergolide: (Major) Avoid concomitant use of ergot alkaloids and vasopressors due to synergistic vasoconstriction and severe hypertension.
    Perindopril; Amlodipine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
    Perphenazine: (Moderate) Additive anticholinergic and sedative effects may be seen when perphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Additive anticholinergic and sedative effects may be seen when perphenazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription allergy, sleep, cough, and cold product labels carefully for additional interacting antihistamines.
    Perphenazine; Amitriptyline: (Moderate) Additive anticholinergic and sedative effects may be seen when perphenazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Additive anticholinergic and sedative effects may be seen when perphenazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription allergy, sleep, cough, and cold product labels carefully for additional interacting antihistamines.
    Pertuzumab; Trastuzumab; Hyaluronidase: (Minor) H1-blockers (antihistamines), when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients receiving these medications may require larger amounts of hyaluronidase for equivalent dispersing effect.
    Phendimetrazine: (Major) Phendimetrazine is a phenylalkaline sympathomimetic agent. All sympathomimetics and psychostimulants, including other anorexiants, should be used cautiously or avoided in patients receiving phendimetrazine. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmia.
    Phenelzine: (Contraindicated) Concomitant use of monoamine oxidase inhibitors and sedating H1-blockers is contraindicated due to increased anticholinergic effects. (Contraindicated) Dextromethorphan products are contraindicated in patients taking a monoamine oxidase inhibitor (MAOI) or in patients who have taken an MAOI within the last 14 days, due to the risk of serious and possibly fatal drug interactions, including serotonin syndrome. A washout period of at least 14 days should elapse between the start of dextromethorphan after discontinuation of an MAOI. Patients should read nonprescription product labels carefully. Before initiating an MAOI after using other serotonergic agents, a sufficient amount of time must be allowed for clearance of the serotonergic agent and its active metabolites. (Contraindicated) In general, sympathomimetics should be avoided in patients receiving MAOIs due to an increased risk of hypertensive crisis. This applies to sympathomimetics including stimulants for ADHD, narcolepsy or weight loss, nasal, oral, and ophthalmic decongestants and cold products, and respiratory sympathomimetics (e.g., beta agonist drugs). Some local anesthetics also contain a sympathomimetic (e.g., epinephrine). In general, medicines containing sympathomimetic agents should not be used concurrently with MAOIs or within 14 days before or after their use.
    Phenobarbital: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Atropine blocks the vagal reflex bradycardia caused by sympathomimetic agents, such as phenylephrine, and increases its pressor effect. (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Phenothiazines: (Moderate) Other non-cardiovascular drugs with alpha-blocking activity such as phenothiazines, directly counteract the effects of phenylephrine and can counter the desired pharmacologic effect. They also can be used to treat excessive phenylephrine-induced hypertension.
    Phenoxybenzamine: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Phentermine: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias.
    Phentermine; Topiramate: (Major) Because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias. (Moderate) Monitor for increased CNS effects if topiramate is coadministered with diphenhydramine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. (Moderate) Monitor for increased CNS effects if topiramate is coadministered with doxylamine. Although not specifically studied, coadministration of CNS depressant drugs with topiramate may potentiate CNS depression, such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents.
    Phentolamine: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Phosphodiesterase inhibitors: (Minor) The therapeutic effect of phenylephrine injection may be decreased in patients receiving phosphodiesterase inhibitors. A decreased pressor effect of phenylephrine might occur. Monitor for proper blood pressure when these drugs are used together,
    Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including sedating antihistamines. Sedating H1-blockers are associated with anticholinergic effects and sedation; therefore, additive effects may be seen during concurrent use with pimozide. Additive drowsiness or other CNS effects may occur.
    Pindolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Pioglitazone: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pioglitazone; Glimepiride: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pioglitazone; Metformin: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes.
    Pirbuterol: (Moderate) Caution and close observation should also be used when pirbuterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects.
    Pitolisant: (Major) Avoid coadministration of pitolisant with diphenhydramine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like diphenhydramine, may reduce pitolisant efficacy. (Major) Avoid coadministration of pitolisant with doxylamine as the effect of pitolisant may be decreased. Pitolisant increases histamine concentrations in the brain; therefore, H1-receptor antagonists like doxylamine, may reduce pitolisant efficacy.
    Plazomicin: (Minor) Diphenhydramine may mask vestibular symptoms (e.g. dizziness, tinnitus, or vertigo) that are associated with ototoxicity induced by aminoglycosides. Antiemetics block the histamine or acetylcholine response that causes nausea due to vestibular emetic stimuli such as motion.
    Pneumococcal Vaccine, Polyvalent: (Moderate) Concomitant administration of antipyretics, such as acetaminophen, may decrease an individual's immunological response to the pneumococcal vaccine. A post-marketing study conducted in Poland using a non-US vaccination schedule (2, 3, 4, and 12 months of age) evaluated the impact of prophylactic oral acetaminophen on antibody responses to Prevnar 13. Data show that acetaminophen, given at the time of vaccination and then dosed at 6 to 8 hour intervals for 3 doses on a scheduled basis, reduced the antibody response to some serotypes after the third dose of Prevnar 13 when compared to the antibody responses of infants who only received antipyretics 'as needed' for treatment. However, reduced antibody responses were not observed after the fourth dose of Prevnar 13 with prophylactic acetaminophen.
    Posaconazole: (Moderate) Posaconazole and acetaminophen should be coadministered with caution due to an increased potential for acetaminophen-related adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of acetaminophen. These drugs used in combination may result in elevated acetaminophen plasma concentrations, causing an increased risk for acetaminophen-related adverse events.
    Potassium-sparing diuretics: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear at high risk for significant elevations in blood pressure, however, increased blood pressure has been reported in some patients.
    Pramipexole: (Moderate) Concomitant use of pramipexole with other CNS depressants, such as sedating H1-blockers, can potentiate the sedation effects of pramipexole.
    Pramlintide: (Moderate) Sympathomimetic agents and adrenergic agonists tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when pseudoephedrine, phenylephrine, and other sympathomimetics are administered to patients taking antidiabetic agents. Epinephrine and other sympathomimetics, through stimulation of alpha- and beta- receptors, increase hepatic glucose production and glycogenolysis and inhibit insulin secretion. Also, adrenergic medications may decrease glucose uptake by muscle cells. For treatment of cold symptoms, nasal decongestants may be preferable for short term, limited use (1 to 3 days) as an alternative to systemic decongestants in patients taking medications for diabetes. (Minor) Because pramlintide has the potential to delay the absorption of concomitantly administered medications, medications should be administered at least 1 hour before or 2 hours after pramlintide injection when the rapid onset of a concomitantly administered oral medication is a critical determinant of effectiveness (i.e., analgesics).
    Prazosin: (Major) Sympathomimetics can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Prednisolone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Prednisone: (Moderate) The therapeutic effect of phenylephrine may be increased in patient receiving corticosteroids, such as hydrocortisone. Monitor patients for increased pressor effect if these agents are administered concomitantly.
    Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of diphenhydramine and pregabalin. Concurrent use may result in additive CNS depression. (Moderate) Monitor for excessive sedation and somnolence during coadministration of doxylamine and pregabalin. Concurrent use may result in additive CNS depression.
    Prilocaine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
    Prilocaine; Epinephrine: (Moderate) Coadministration of prilocaine with oxidizing agents, such as acetaminophen, may increase the risk of developing methemoglobinemia. Monitor patients closely for signs and symptoms of methemoglobinemia if coadministration is necessary. If methemoglobinemia occurs or is suspected, discontinue prilocaine and any other oxidizing agents. Depending on the severity of symptoms, patients may respond to supportive care; more severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen. (Moderate) Diphenhydramine may potentiate the arrhythmogenic effects of epinephrine.
    Primidone: (Major) Because diphenhydramine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Moderate) Because doxylamine can cause pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including anxiolytics, sedatives, and hypnotics, such as barbiturates. (Minor) Chronic therapy with barbiturates can increase the metabolism and decrease the effectiveness of acetaminophen. During acute overdoses, barbiturates can enhance the formation of toxic acetaminophen metabolites.
    Probenecid; Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    Procarbazine: (Major) Because procarbazine exhibits some monoamine oxidase inhibitory (MAOI) activity, sympathomimetic drugs should be avoided. As with MAOIs, the use of a sympathomimetic drug with procarbazine may precipitate hypertensive crisis or other serious side effects. In the presence of MAOIs, drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. In general, do not use a sympathomimetic drug unless clinically necessary (e.g., medical emergencies, agents like dopamine) within the 14 days prior, during or 14 days after procarbazine therapy. If use is necessary within 2 weeks of the MAOI drug, in general the initial dose of the sympathomimetic agent must be greatly reduced. Patients should be counseled to avoid non-prescription (OTC) decongestants and other drug products, weight loss products, and energy supplements that contain sympathomimetic agents. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with procarbazine, an antineoplastic agent with monoamine oxidase inhibitor (MAOI) activity. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Use procarbazine and sedating H1-blockers together with caution; additive central nervous system depression may occur.
    Prochlorperazine: (Moderate) Additive anticholinergic and sedative effects may be seen when Prochlorperazine is used with first generation antihistamines, such as diphenhydramine. Patients should be informed to read non-prescription allergy, sleep, and cough and cold product labels carefully for additional interacting antihistamines. (Moderate) Additive anticholinergic and sedative effects may be seen when prochlorperazine is used with first generation antihistamines, such as doxylamine. Patients should be informed to read non-prescription cough and cold product labels carefully for additional interacting antihistamines.
    Promethazine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Promethazine; Dextromethorphan: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Promethazine; Phenylephrine: (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of diphenhydramine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects. (Moderate) Monitor for unusual drowsiness and sedation, urinary retention, and reduced gastric motility during coadministration of doxylamine and promethazine. Concomitant use may result in additive CNS depression or anticholinergic effects.
    Propafenone: (Minor) Use of dextromethorphan with propafenone might increase dextromethorphan exposure. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor. In vitro studies suggest that propafenone inhibits CYP2D6, but clinically relevant interactions have not been reported due to this potential action. Dextromethorphan is a CYP2D6 substrate.
    Propofol: (Moderate) Initially, vasopressors may reduce propofol serum concentrations due to increased metabolic clearance secondary to increased hepatic blood flow. An increase in the propofol dose may be required. Additionally, the vasopressor dose may need to be increased over time due to tachyphylaxis. Thus, these drugs may drive each other in a progressively myocardial depressive loop, which could lead to cardiac arrhythmias or cardiac failure. (Minor) Because sedating H1-blockers cause sedation, an enhanced CNS depressant effect may occur when they are combined with general anesthetics.
    Propoxyphene: (Moderate) Concomitant use of opioid agonists with diphenhydramine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with diphenhydramine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. (Moderate) Concomitant use of opioid agonists with doxylamine may cause excessive sedation and somnolence. Limit the use of opioid pain medication with doxylamine to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Propranolol: (Minor) Close monitoring of blood pressure or the selection of alternative therapeutic agents to the sympathomimetic agent may be needed in patients receiving a beta-blocker. Sympathomimetics, such as amphetamines, phentermine, and decongestants (e.g., pseudoephedrine, phenylephrine), and many other drugs, may increase both systolic and diastolic blood pressure and may counteract the activity of the beta-blockers. Concurrent use increases the risk of unopposed alpha-adrenergic activity. Increased blood pressure, bradycardia, or heart block may occur due to excessive alpha-adrenergic receptor stimulation.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) The cardiovascular effects of sympathomimetics may reduce the antihypertensive effects produced by diuretics. Well-controlled hypertensive patients receiving decongestant sympatho