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  • CLASSES

    Combination Agents for Obesity

    BOXED WARNING

    Alcoholism, substance abuse

    Phentermine; topiramate products are federally controlled substances because they contain phentermine and can be abused or lead to drug dependence. Patients should be advised to keep this product in a safe place, to protect it from theft and to never give the drug product to anyone else, because it may cause death or harm them. Selling or giving away this medicine is against the law. It is advisable to use phentermine-containing agents with caution in patients with a known history of substance abuse. Phentermine is related chemically and pharmacologically to amphetamines. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. However, the abuse and dependence potential of phentermine; topiramate has not been systematically evaluated. As with most controlled substances, the least amount reasonable should be prescribed or dispensed at one time to limit the potential for overuse or drug diversion.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, other weight loss medications should be considered first in patients with a substance abuse disorder. There are insufficient data on the use of phentermine; topiramate in patients with obesity and alcoholism; however, topiramate might exert therapeutic benefits in patients with alcohol use disorder.[62881]

    DEA CLASS

    Rx, schedule IV

    DESCRIPTION

    Combination of an anorectic sympathomimetic amine (phentermine) and carbonic anhydrase inhibitor antiepileptic (topiramate)
    Used for weight reduction and management in obese adults, overweight adults with at least 1 weight-related comorbidity, and pediatric patients 12 years and older with an initial BMI in the 95th percentile or greater standardized for age and sex
    Available through Qsymia REMS program due to teratogenic concerns; consult www.QsymiaREMS.com or 1-888-998-4887 in the U.S.

    COMMON BRAND NAMES

    Qsymia

    HOW SUPPLIED

    Qsymia Oral Cap ER: 11.25-69mg, 15-92mg, 3.75-23mg, 7.5-46mg

    DOSAGE & INDICATIONS

    For the treatment of obesity and for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity.
    Oral dosage
    Adults

    Initially, 3.75 mg/23 mg (phentermine/topiramate extended-release) PO once daily in the morning (avoid evening dosing) for 14 days. Increase to the recommended dose of 7.5 mg/46 mg PO once daily after 14 days. Evaluate weight loss at recommended dose after 12 weeks; if the patient has not lost at least 3% of baseline weight, increase the dose to 11.25 mg/69 mg PO once daily for 14 days, followed by a final increase to 15 mg/92 mg PO once daily. Evaluate weight loss at 12 weeks at the higher dose; if the patient has not lost at least 5% of baseline weight, discontinue as the patient is not likely to achieve and sustain meaningful weight loss with continued treatment.[51256] Guidelines recommend an initial dose of 3.75 mg/23 mg per day and a low maintenance dose of 7.5 mg/46 mg per day in obese patients with depression or an anxiety disorder.[62881] INTENDED USE: For those with an initial body mass index (BMI) of 30 kg/m2 or more, or those with a BMI of 27 kg/m2 or more in the presence of at least 1 weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes). The effect of this product on cardiovascular morbidity/mortality has not been determined. Safety and efficacy are not established for use with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and dietary supplements/herbal preparations. DISCONTINUATION: Discontinue the 15 mg/92 mg dose gradually by dosing every other day for at least 1 week before stopping treatment altogether, to avoid precipitating a seizure.[51256]

    Children and Adolescents 12 to 17 years

    Initially, 3.75 mg/23 mg (phentermine/topiramate extended-release) PO once daily in the morning (avoid evening dosing) for 14 days. Increase to the recommended dose of 7.5 mg/46 mg PO once daily after 14 days. Evaluate BMI reduction at recommended dose after 12 weeks; if the patient has not lost at least 3% of baseline BMI, increase the dose to 11.25 mg/69 mg PO once daily for 14 days, followed by a final increase to 15 mg/92 mg PO once daily. If weight loss exceeds 2 lbs (0.9 kg)/week, consider dosage reduction. Evaluate weight loss at 12 weeks at the higher dose; if the patient has not lost at least 5% of baseline BMI, discontinue as the patient is not likely to achieve and sustain meaningful weight loss with continued treatment. INTENDED USE: For those with an initial BMI in the 95th percentile or greater standardized for age and sex. The effect of this product on cardiovascular morbidity/mortality has not been determined. Safety and efficacy are not established for use with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and dietary supplements/herbal preparations. DISCONTINUATION: Discontinue the 15 mg/92 mg dose gradually by dosing every other day for at least 1 week before stopping treatment altogether, to avoid precipitating a seizure.[51256]

    MAXIMUM DOSAGE

    Adults

    15 mg phentermine/92 mg topiramate extended-release PO daily.

    Geriatric

    15 mg phentermine/92 mg topiramate extended-release PO daily.

    Adolescents

    15 mg phentermine/92 mg topiramate extended-release PO daily.

    Children

    12 years: 15 mg phentermine/92 mg topiramate extended-release PO daily.
    1 to 11 years: Safety and efficacy have not been established.

    Infants

    Do not use.

    Neonates

    Do not use.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment (Child Pugh Class A): No dose adjustment required.
    Moderate hepatic impairment (Child Pugh Class B): Do not exceed 7.5 mg/46 mg PO once daily.
    Severe hepatic impairment (Child Pugh Class C): Avoid use.

    Renal Impairment

    CrCl 50 mL/minute or greater: No dose adjustment required.
    CrCl less than 50 mL/minute: Do not exceed 7.5 mg/46 mg PO once daily.
     
    Intermittent hemodialysis
    Avoid use in patients with end-stage renal disease on dialysis.

    ADMINISTRATION

    Hazardous Drugs Classification
    Topiramate is classified a hazardous drug.
    NIOSH 2016 List: Group 3
    NIOSH (Draft) 2020 List: Table 2
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure and require additional protective equipment. Eye/face and respiratory protection may be needed during preparation and administration.

    Oral Administration
    Oral Solid Formulations

    Extended-release capsules (e.g., Qsymia)
    Consistent with good practices, do not open, crush, cut, or chew the extended-release capsules or the capsule contents.
    Administer the capsules once daily in the morning with or without food.
    Avoid late evening administration because of the possibility of insomnia.

    STORAGE

    Qsymia:
    - Protect from moisture
    - Store between 59 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Phentermine; Topiramate is contraindicated in any person with a known hypersensitivity or idiosyncrasy to sympathomimetic amines.

    MAOI therapy

    Because of the risk of hypertensive crisis due to the interaction between monoamine oxidase inhibitors (MAOIs) and sympathomimetic amines such as phentermine, the use of phentermine; topiramate is contraindicated during or within 14 days of MAOI therapy.

    Alcoholism, substance abuse

    Phentermine; topiramate products are federally controlled substances because they contain phentermine and can be abused or lead to drug dependence. Patients should be advised to keep this product in a safe place, to protect it from theft and to never give the drug product to anyone else, because it may cause death or harm them. Selling or giving away this medicine is against the law. It is advisable to use phentermine-containing agents with caution in patients with a known history of substance abuse. Phentermine is related chemically and pharmacologically to amphetamines. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. However, the abuse and dependence potential of phentermine; topiramate has not been systematically evaluated. As with most controlled substances, the least amount reasonable should be prescribed or dispensed at one time to limit the potential for overuse or drug diversion.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, other weight loss medications should be considered first in patients with a substance abuse disorder. There are insufficient data on the use of phentermine; topiramate in patients with obesity and alcoholism; however, topiramate might exert therapeutic benefits in patients with alcohol use disorder.[62881]

    Cardiac arrhythmias, cardiac disease, coronary artery disease, heart failure, myocardial infarction, stroke

    Phentermine; topiramate can cause an increase in resting heart rate. In clinical evaluation, a higher number of patients receiving phentermine; topiramate experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute compared to placebo. The clinical significance of a heart rate elevation with treatment is unclear, but may be of concern primarily for those with cardiac disease or cerebrovascular disease (e.g., patients with a history of sinus tachycardia, acute myocardial infarction or stroke in the previous 6 months, life-threatening cardiac arrhythmias, or congestive heart failure). Periodic measurement of resting heart rate is advised for all patients, especially those at high risk for a cardiovascular event; in addition, monitoring during treatment initiation and dose escalation is recommended for all patients. Clinicians should instruct their patients to inform health care providers of palpitations or feelings of a racing heartbeat while at rest. For patients who experience a sustained increase in resting heart rate during therapy, dose reduction or discontinuation should be considered. Of note, the effect of phentermine; topiramate on cardiovascular morbidity and mortality has not been established.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate is a preferred weight loss medication in obese patients with existing hypertension, with careful monitoring of heart rate. Phentermine; topiramate is not a preferred weight loss medication in patients with an established atherosclerotic coronary artery disease or a history or risk of cardiac arrhythmias, but is reasonable to use with caution if weight loss goals are met, with careful monitoring of blood pressure and heart rate. Heart rhythm should also be monitored in those with a history or risk of arrhythmias. The AACE/ACE Obesity Guidelines state that data are insufficient regarding the benefits of the use of phentermine; topiramate in obese patients with heart failure and the use of this product in this population should be avoided.[62881]

    Glaucoma, increased intraocular pressure

    Phentermine; topiramate is contraindicated in patients with glaucoma. A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in pediatric patients and adults treated with topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic findings can include myopia, mydriasis, anterior chamber shallowing, ocular hyperemia (redness), choroidal detachments, retinal pigment epithelial detachments, macular striae, and increased intraocular pressure. This syndrome may be associated with supraciliary effusion resulting in anterior displacement of the lens and iris, with secondary angle closure glaucoma. Symptoms typically occur within 1 month of initiating treatment with topiramate but may occur at any time during therapy. The primary treatment to reverse symptoms is immediate discontinuation of phentermine; topiramate. Elevated intraocular pressure of any etiology, if left untreated, can lead to serious adverse events including permanent loss of vision.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, other weight loss medications (i.e., orlistat, lorcaserin, and liraglutide) are preferred treatment options for patients with glaucoma; the use of phentermine; topiramate is contraindicated.[62881]

    Hyperthyroidism, thyroid disease

    Phentermine; topiramate is contraindicated in patients with hyperthyroidism since sympathomimetics like phentermine can exacerbate these conditions. This product should also be used with caution in patients with thyroid disease.[51256]

    Anxiety, behavioral changes, depression, insomnia, schizophrenia, suicidal ideation

    Phentermine; topiramate can cause mood disorders, including depression, and anxiety, as well as insomnia. Patients with a history of depression may be at increased risk of recurrent depression or other mood disorders while taking phentermine; topiramate. For clinically significant or persistent symptoms consider dose reduction or withdrawal of this obesity treatment. Avoid phentermine; topiramate use in patients with a history of suicidal attempts or active suicidal ideation. Antiepileptic drugs (AEDs), including topiramate, a component of phentermine; topiramate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behavior, and any unusual changes in mood or behavior during treatment. Discontinue phentermine; topiramate in patients who experience suicidal thoughts or behavioral changes.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate may be considered in obese patients with depression, using low initial and maintenance doses; avoid maximum dosing. The maximum daily dose should also be avoided if possible in patients with a comorbid anxiety disorder. All patients undergoing weight loss therapy should be monitored for mood disorders, depression, and suicidal ideation. Evidence assessing safety and efficacy of weight loss medications in patients with a psychotic disorder (e.g., schizophrenia) is insufficient, and the AACE/ACE Obesity Guidelines recommend avoidance of phentermine; topiramate in these patients. The AACE/ACE Obesity Guidelines recommend that patients receiving an antipsychotic be treated with structured lifestyle modifications to promote weight loss and weight gain prevention; metformin may be beneficial for modest weight loss and metabolic improvements in patients receiving an antipsychotic.[62881]

    Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

    Phentermine; topiramate can cause cognitive dysfunction (e.g., impairment of concentration/attention, difficulty with memory, and speech or language problems, particularly word-finding difficulties). Rapid titration or high initial doses may be associated with higher rates of cognitive events such as attention, memory, and language/word-finding difficulties. Since this treatment has the potential to impair cognitive function, patients should be cautioned about driving or operating machinery or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and motor performance. If cognitive impairment persists, consider dose reduction; consider a withdrawal of therapy for symptoms that are moderate to severe, bothersome, or those which fail to resolve with dose reduction.[51256] Alcohol may aggravate these effects, so advise patients to avoid ethanol ingestion while taking phentermine; topiramate. Coadministration with other CNS depressants may potentiate CNS depression or other centrally mediated effects of these agents, such as dizziness, cognitive adverse reactions, drowsiness, light-headedness, impaired coordination, and somnolence.[51256]

    Dialysis, renal disease, renal failure, renal impairment

    Use phentermine; topiramate with caution in any patients with renal disease. Phentermine; topiramate can cause an increase in serum creatinine that reflects a decrease in renal function as noted by a decrease in glomerular filtration rate (GFR). On average, the serum creatinine gradually declines but remains elevated over baseline values. After discontinuation of short-term treatment with phentermine; topiramate, the changes in serum creatinine and GFR appear reversible although the effect of chronic treatment on renal function or renal disease is not known. Therefore, measurement of serum creatinine prior to starting therapy and during treatment is recommended. If persistent elevations in creatinine occur, reduce the dose or discontinue. Both phentermine and topiramate are cleared by renal excretion and exposure to phentermine; topiramate is increased in patients with moderate (CrCl 30 to less than 50 mL/minute) and severe (CrCl less than 30 mL/minute) renal impairment; therefore, a lower maximum daily dose is recommended in these populations. The use of this product has not been studied in patients with renal failure on dialysis; avoid use in this patient population.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate can be used with appropriate caution in obese patients with mild renal impairment (i.e., CrCl 50 to 79 mL/minute). A dose of 7.5 mg/46 mg per day should not be exceeded in patients with moderate renal impairment (i.e., CrCl 30 to 49 mL/minute). Accumulation of phentermine; topiramate occurs in severe renal impairment (i.e., CrCl less than 30 mL/min) and use of the drug should be avoided in this population. Phentermine; topiramate should not be used in patients with end-stage renal failure.[62881]

    Nephrolithiasis

    Phentermine; topiramate should be used with caution in patients with a history of kidney stones (nephrolithiasis). Topiramate is a carbonic anhydrase inhibitor and promotes kidney stone formation by reducing urinary citrate excretion and by increasing urinary pH. During clinical trials of topiramate for epilepsy, 1.3% to 1.5% of topiramate-treated patients developed kidney stones; this incidence is about 2 to 4 times that expected in a similar, untreated population and was higher in men.[31428] The concomitant use of topiramate with other carbonic anhydrase inhibitors or in patients on a ketogenic diet may create a physiological environment that increases the risk of kidney stone formation, and should, therefore, be avoided. Patients who are receiving phentermine; topiramate, especially those who have a history of kidney stones, should be instructed to maintain adequate fluid intake to reduce the formation of nephrolithiasis.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate should be avoided in patients with recent nephrolithiasis as calcium phosphate stone formation is possible. Caution should be exercised when using phentermine; topiramate in patients with a history of nephrolithiasis.[62881]

    Hepatic disease

    Use phentermine; topiramate with caution in patients with hepatic disease. Exposure to phentermine was higher in patients with mild or moderate (Child-Pugh Class A and B) hepatic impairment. A 7.5 mg/46 mg daily dose should not be exceeded in patients with moderate hepatic impairment. Phentermine; topiramate has not been studied in patients with severe hepatic disease (Child-Pugh Class C); avoid use in this patient population. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, all weight loss medications should be used cautiously in patients with hepatic impairment and should be avoided in severe liver impairment (i.e., Child-Pugh score greater than 9). In patients with moderate hepatic impairment, the AACE/ACE guidelines recommend that the dose of phentermine; topiramate not exceed 7.5 mg/46 mg per day. Close monitoring for cholelithiasis is recommended in any obese patients undergoing weight loss therapy, regardless of modality, due to a proven association between these conditions.

    Chronic obstructive pulmonary disease (COPD), diarrhea, emphysema, hypokalemia, metabolic acidosis, status asthmaticus, status epilepticus, surgery

    Phentermine; topiramate has been associated with metabolic acidosis. Topiramate is a carbonic anhydrase inhibitor that can promote metabolic acidosis and also hypokalemia. Conditions that may predispose patients to acidosis [i.e., renal disease, diarrhea, ketogenic diet, severe pulmonary disease (chronic obstructive pulmonary disease (COPD), emphysema, status asthmaticus), surgery, status epilepticus or administration with other bicarbonate-lowering drugs] may have an additive risk for this complication. Metabolic acidosis may manifest as fatigue and anorexia, or more severely, cardiac arrhythmias or stupor. Chronic, untreated metabolic acidosis may increase the risk for nephrolithiasis or nephrocalcinosis and may also result in osteomalacia (rickets) and/or osteoporosis with an increased fracture risk. In pediatric patients, chronic metabolic acidosis may also reduce growth rates. Measurement of baseline and periodic serum bicarbonate and potassium, along with other serum chemistries, is recommended during therapy. In clinical trials, the peak reduction in serum bicarbonate occurred by week 4, and in most subjects there was a correction of bicarbonate by week 56, without any change to study drug. However, if persistent metabolic acidosis develops, reduce the dose or taper to discontinue the dose. Hypokalemia risk may be aggravated by the use of diuretic therapy.

    Diabetes mellitus

    Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and insulin secretagogues (e.g., sulfonylureas). Phentermine; topiramate has not been studied in combination with insulin. Blood glucose monitoring is warranted in patients with type 2 diabetes before starting and during phentermine; topiramate treatment. Dosage adjustments of anti-diabetic medications should be considered. If a patient develops hypoglycemia during treatment, adjust the anti-diabetic drug regimen accordingly.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, weight loss medications such as phentermine; topiramate should be considered as an adjunct to lifestyle therapy in all patients with type 2 diabetes as needed for weight loss sufficient to improve glycemic control, lipids, and blood pressure. During controlled trial evaluation of phentermine; topiramate as an adjunct to lifestyle therapy versus lifestyle therapy alone for diabetes prevention, a more significant weight loss and more profound reductions in incident diabetes occurred with medication plus lifestyle therapy than lifestyle therapy alone.[62881]

    Ambient temperature increase, anticholinergic medications, hyperthermia, strenuous exercise

    Topiramate has been associated with oligohidrosis and hyperthermia, infrequently resulting in hospitalization; most reports have been in pediatric patients. Decreased sweating and an elevation in body temperature above normal characterized these cases. Some of the cases have been reported with topiramate after exposure to elevated environmental temperatures. Therefore, patients taking phentermine; topiramate should be instructed to limit exposure to ambient temperature increase (i.e., elevated environmental temperature) or other temperature extremes that might aggravate temperature regulation. Proper hydration to help prevent oligohidrosis and hyperthermia is suggested before and during strenuous exercise or exposure to warm temperatures. Use caution when prescribing with other drugs that predispose patients to heat-related disorders, such as anticholinergic medications and other carbonic anhydrase inhibitors.[51256]

    Anorexia nervosa, bariatric surgery, bulimia nervosa

    Similar to other weight loss products,  phentermine; topiramate use is not likely to be appropriate in patients with eating disorders such as anorexia nervosa or bulimia nervosa. The AACE/ACE) Obesity Clinical Practice Guidelines state that there are insufficient data on the use of phentermine; topiramate in overweight or obese patients with binge eating disorder (BED); however, there is a possible benefit in BED based on studies with topiramate, and approved medications containing topiramate may be considered along with non-medication interventions (i.e., behavioral/lifestyle program, psychotherapy). The AACE/ACE Obesity Guidelines state that there are limited data available on the benefits of the use of phentermine; topiramate in patients following bariatric surgery.[62881]

    Abrupt discontinuation, seizures

    Abrupt discontinuation of phentermine; topiramate, particularly at a dose of 15 mg/92 mg once daily, should be avoided since the withdrawal of topiramate has been associated with seizures, even in individuals without a history of seizures or epilepsy. If immediate discontinuation is medically necessary in any patient, careful monitoring and symptom management is warranted. Patients discontinuing higher-dose therapy due to a lack of efficacy should follow recommended tapering (e.g., every other day dosing for 1 week) to avoid precipitating a seizure.[51256]

    Geriatric

    Clinical studies of phentermine; topiramate did not include sufficient numbers of elderly subjects to determine whether they respond differently from younger subjects. In those studied, no age-related differences were observed. Nevertheless, use caution when selecting a dose for a geriatric patient, given their propensity to have concurrent disease states that may influence drug tolerability, usually starting at the low end of the dosing range. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, there are limited data on the use of phentermine; topiramate for weight reduction in the elderly and extra caution is advisable in this population. Elderly patients selected for weight loss therapy should have structured lifestyle interventions including reduced calorie meal plans and exercise, clear health-related goals including blood pressure reduction, diabetes prevention in high risk patients with pre-diabetes, and improvements in osteoarthritis, mobility, and physical functioning. Overweight or obese elderly patients being considered for a weight loss medication should be evaluated for osteopenia and sarcopenia.

    Contraception requirements, labor, obstetric delivery, pregnancy, pregnancy testing, reproductive risk

    Phentermine; topiramate is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Further, data from pregnancy registries and epidemiology studies indicate increased reproductive risk with the use of topiramate; a risk in oral clefts (cleft lip with or without cleft palate) with first-trimester exposure to topiramate is noted. Females of reproductive potential should have negative pregnancy testing before starting therapy and then monthly after that. Females of reproductive potential should be advised of the contraception requirements to use adequate contraception during therapy. If phentermine; topiramate is inadvertently used during pregnancy, or if a patient becomes pregnant while on therapy, discontinue treatment immediately and inform the patient of the potential hazard to the fetus. The Qsymia Pregnancy Surveillance Program is a maternal-fetal outcomes program which monitors pregnancies that occur during therapy; healthcare professional and patients are encouraged to report pregnancies to the program by calling 1-888-998-4887. The effect of phentermine; topiramate on labor and obstetric delivery in humans is unknown. However, metabolic acidosis has been reported in patients treated with phentermine; topiramate and metabolic acidosis in pregnancy can cause decreased fetal growth, decreased fetal oxygenation, and fetal death, and may affect the ability of the fetus to tolerate labor.[51256] According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, phentermine; topiramate must not be used during pregnancy. Women of childbearing potential should use contraception and discontinue the drug if pregnancy occurs. Monthly pregnancy testing is necessary during treatment to identify early pregnancy due to the risk of cleft lip/palate.[62881]

    Breast-feeding

    Both topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue phentermine; topiramate, taking into account the importance of therapy to the mother. During lactation, first line weight loss strategies include a healthy diet and exercise, if appropriate. Sufficient calories and nutrition are important for proper lactation. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, the use of phentermine; topiramate in breast-feeding women is not recommended.

    Growth inhibition

    Phentermine; topiramate is associated with a reduction in height velocity in obese pediatric patients 12 to 17 years. The potential for growth inhibition in pediatric patients should be periodically monitored during phentermine; topiramate therapy. Patients who are not growing or gaining weight as expected may need to have their treatment interrupted.

    Tartrazine dye hypersensitivity

    Phentermine; topiramate contains tartrazine dye; use with caution in patients with tartrazine dye hypersensitivity. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    pemphigus / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 7.9-16.1
    impaired cognition / Early / 2.1-7.6
    blurred vision / Early / 4.0-6.3
    depression / Delayed / 2.0-4.0
    palpitations / Early / 0.8-2.4
    nephrolithiasis / Delayed / 0.2-1.2
    hypertension / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    psychosis / Early / Incidence not known
    euphoria / Early / Incidence not known
    myopia / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    metabolic acidosis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    hyperammonemia / Delayed / Incidence not known
    hypokalemia / Delayed / Incidence not known
    physiological dependence / Delayed / Incidence not known
    psychological dependence / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    growth inhibition / Delayed / Incidence not known

    Mild

    paresthesias / Delayed / 2.0-19.9
    xerostomia / Early / 6.7-19.1
    infection / Delayed / 12.2-15.8
    pharyngitis / Delayed / 9.4-12.5
    headache / Early / 7.0-10.6
    dysgeusia / Early / 1.3-9.4
    metallic taste / Early / 1.3-9.4
    insomnia / Early / 5.0-9.0
    dizziness / Early / 2.0-8.6
    sinusitis / Delayed / 6.8-7.8
    influenza / Delayed / 2.0-7.5
    nausea / Early / 3.6-7.2
    back pain / Delayed / 5.4-6.6
    diarrhea / Early / 5.0-6.4
    fatigue / Early / 3.0-5.9
    cough / Delayed / 3.3-4.8
    anxiety / Delayed / 2.0-4.0
    irritability / Delayed / 2.0-4.0
    arthralgia / Delayed / 2.0-4.0
    fever / Early / 2.0-4.0
    alopecia / Delayed / 2.1-3.7
    hypoesthesia / Delayed / 0.8-3.7
    gastroesophageal reflux / Delayed / 0.8-3.2
    musculoskeletal pain / Early / 0.8-3.0
    abdominal pain / Early / 3.0-3.0
    muscle cramps / Delayed / 2.8-2.9
    dyspepsia / Early / 2.1-2.8
    rash / Early / 1.7-2.6
    xerophthalmia / Early / 0.8-2.5
    ocular pain / Early / 2.1-2.2
    dysmenorrhea / Delayed / 0.4-2.1
    nasal congestion / Early / 1.2-2.0
    restlessness / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    tremor / Early / Incidence not known
    libido decrease / Delayed / Incidence not known
    libido increase / Delayed / Incidence not known
    hypothermia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    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: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Aspirin; Diphenhydramine: (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.
    Acetaminophen; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants. (Moderate) Concomitant use of dihydrocodeine with topiramate can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If topiramate is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Topiramate is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Acetaminophen; Caffeine; Pyrilamine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (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.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (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.
    Acetaminophen; Dextromethorphan; Doxylamine: (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.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (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.
    Acetaminophen; Dextromethorphan; Phenylephrine: (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.
    Acetaminophen; Diphenhydramine: (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.
    Acetaminophen; Guaifenesin; Phenylephrine: (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.
    Acetaminophen; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Aclidinium; Formoterol: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Albiglutide: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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) Monitor blood pressure and heart rate during concomitant albuterol and phentermine use. Concomitant use may potentiate sympathetic effects.
    Aliskiren; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Alogliptin; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Alogliptin; Pioglitazone: (Moderate) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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.
    Alpha-blockers: (Moderate) Monitor for desired antihypertensive effect of alpha-blockers when administered with phentermine, Sympathomimetics like phentermine 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) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Ambrisentan: (Major) Sympathomimetics, such as phentermine, can antagonize the effects of vasodilators such as ambrisentan when administered concomitantly. Patients should be monitored for reduced efficacy if taking ambrisentan with a sympathomimetic.
    Amifampridine: (Major) Carefully consider the need for concomitant treatment with phentermine and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Phentermine may increase the risk of seizures.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Amitriptyline: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation and for increased amitriptyline-related adverse events during concomitant topiramate use. Concomitant use resulted in an increase in amitriptyline exposure by 12% and may increase the risk for additive CNS depression.
    Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Celecoxib: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amoxapine: (Moderate) Use phentermine and amoxapine together with caution and close clinical monitoring. Regularly assess blood pressure, heart rate, the efficacy of weight loss treatment, and the emergence of sympathomimetic/adrenergic adverse events. Carefully adjust dosages as clinically indicated. Amoxapine has pharmacologic activity similar to tricylclic antidepressant agents. Phentermine is a sympathomimetic agent related to the amphetamines and may cause additive sympathomimetic effects when combined with amoxapine. CNS effects, such as dizziness, are also possible.
    Amphetamine: (Major) Avoid coadministration of phentermine and other medications for weight loss, such as amphetamines. The safety and efficacy of combination therapy have not been established.
    Amphetamine; Dextroamphetamine: (Major) Avoid coadministration of phentermine and other medications for weight loss, such as amphetamines. The safety and efficacy of combination therapy have not been established.
    Amphetamines: (Major) Avoid coadministration of phentermine and other medications for weight loss, such as amphetamines. The safety and efficacy of combination therapy have not been established. (Moderate) Monitor for amphetamine-related adverse events if coadministered with topiramate. Concurrent use may increase amphetamine concentrations, resulting in potentiation of the action of amphetamines.
    Angiotensin II: (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.
    Anticholinergics: (Moderate) Monitor for decreased sweating and increased body temperature, especially in hot weather, during concomitant use of topiramate and other drugs that predispose persons to heat-related disorders, such as anticholinergic medications. Concomitant use increases the risk for oligohidrosis and hyperthermia.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) Although not specifically studied, coadministration of CNS depressant drugs (e.g., anxiolytics, sedatives, and hypnotics) with topiramate may potentiate CNS depression such as dizziness or cognitive adverse reactions, or other centrally mediated effects of these agents. Monitor for increased CNS effects if coadministering.
    Apixaban: (Moderate) Concurrent use of topiramate and anticoagulants, such as apixaban, may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if topiramate and aprepitant, fosaprepitant are used concurrently and monitor for a possible decrease in the efficacy of aprepitant for several days after administration of a multi-day aprepitant regimen. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer; aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold. The manufacturer of aprepitant recommends avoidance of administration with strong CYP3A4 inducers, but does not provide guidance for weak-to-moderate inducers. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions.
    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 unusal drowsiness and excessive sedation during concomitant aripiprazole and topiramate use due to the risk for additive CNS depression.
    Articaine; Epinephrine: (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.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Aspirin, ASA; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with topiramate as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Atazanavir is a substrate of CYP3A4.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with topiramate as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Atazanavir is a substrate of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Atenolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Atenolol; Chlorthalidone: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Atomoxetine: (Moderate) Use atomoxetine with caution and monitor blood pressure in patients receiving concomitant phentermine due to potential effects on blood pressure.
    Atovaquone; Proguanil: (Minor) Proguanil is metabolized to cycloguanil by CYP2C19. Potential interactions between proguanil or cycloguanil and other drugs that are CYP2C19 inhibitors are unknown. Use caution when combining atovaquone; proguanil with CYP2C19 inhibitors, such as topiramate.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Azilsartan; Chlorthalidone: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Barbiturates: (Moderate) Although topiramate is not extensively metabolized (70% renally eliminated), an interaction with barbiturates via hepatic isoenzyme activity is possible. In patients receiving either phenobarbital or primidone in combination with topiramate, there was a < 10% change in phenobarbital or primidone plasma concentrations; the effects on topiramate plasma concentrations were not evaluated. Barbiturates may cause additive sedation or other CNS depressive effects when used concurrently with topiramate. When topiramate is combined with phentermine for the treatment of obesity, a greater risk of CNS depression exists. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as the barbiturates, may also increase the risk of bleeding; monitor patients appropriately.
    Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of topiramate with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and topiramate is a CYP2C19 inhibitor.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Bendroflumethiazide; Nadolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Benzodiazepines: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Benzphetamine: (Major) Avoid coadministration of phentermine and other medications for weight loss, such as amphetamines. The safety and efficacy of combination therapy have not been established.
    Beta-blockers: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Betaxolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Bethanechol: (Moderate) Bethanechol offsets the effects of sympathomimetics at sites where sympathomimetic and cholinergic receptors have opposite effects.
    Bisoprolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug. (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    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.
    Brexpiprazole: (Moderate) Because brexpiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as topiramate may result in decreased plasma concentrations of brexpiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in brexpiprazole efficacy. An increase in brexpiprazole dosage may be clinically warranted in some patients. Similar precautions apply to combination products containing topiramate such as phentermine; topiramate.
    Brimonidine; Timolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Bromocriptine: (Moderate) The combination of bromocriptine with phentermine may cause headache, tachycardia, other cardiovascular abnormalities, seizures, and other serious effects. Concurrent use of bromocriptine and phentermine should be approached with caution.
    Brompheniramine; Carbetapentane; Phenylephrine: (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.
    Brompheniramine; Dextromethorphan; Phenylephrine: (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.
    Brompheniramine; Phenylephrine: (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.
    Budesonide; Formoterol: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Bumetanide: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Bupivacaine; Epinephrine: (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.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Bupropion: (Moderate) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as stimulants including phentermine. Use low initial doses of bupropion and increase the dose gradually.
    Bupropion; Naltrexone: (Moderate) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as stimulants including phentermine. Use low initial doses of bupropion and increase the dose gradually.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Caffeine: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Caffeine; Sodium Benzoate: (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) Because phentermine is a sympathomimetic and anorexic agent, it should not be used in combination with other psychostimulants.
    Canagliflozin: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Carbamazepine: (Moderate) A topiramate dosage adjustment may be needed during concomitant carbamazepine use. Concomitant administration of topiramate with carbamazepine resulted in a clinically significant decrease (40%) in plasma topiramate concentrations.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (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.
    Carbetapentane; Diphenhydramine; Phenylephrine: (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.
    Carbetapentane; Guaifenesin; Phenylephrine: (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.
    Carbetapentane; Phenylephrine: (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.
    Carbetapentane; Phenylephrine; Pyrilamine: (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.
    Carbinoxamine; Phenylephrine: (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.
    Carbonic anhydrase inhibitors: (Major) Avoid concurrent use of acetazolamide or methazolamide with topiramate. Topiramate is a weak carbonic anhydrase inhibitor. Concomitant use of topiramate with acetazolamide or methazolamide may create a physiological environment that increases the risk of renal stone formation associated with topiramate use. Additionally, through an additive effect, the use of topiramate with agents that may increase the risk for heat-related disorders (acetazolamide and methazolamide), may lead to oligohidrosis, hyperthermia and heat stroke.
    Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as topiramate, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
    Carteolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Carvedilol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Celecoxib; Tramadol: (Moderate) Reserve concomitant prescribing of opioids and other CNS depressants, such as topiramate, 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. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
    Chlordiazepoxide: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Chlordiazepoxide; Amitriptyline: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation and for increased amitriptyline-related adverse events during concomitant topiramate use. Concomitant use resulted in an increase in amitriptyline exposure by 12% and may increase the risk for additive CNS depression. (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Chlordiazepoxide; Clidinium: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Chlorothiazide: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Moderate) Topiramate is a carbonic anhydrase inhibitor. Concurrent use of topiramate with non-potassium sparing diuretics (e.g., thiazide diuretics) may potentiate the potassium-wasting action of these diuretics. Monitor baseline and periodic potassium concentrations during coadministration.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (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.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (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) Concomitant use of dihydrocodeine with topiramate can decrease dihydrocodeine levels, resulting in less metabolism by CYP2D6 and decreased dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If topiramate is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs or respiratory depression and sedation. Topiramate is a weak inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
    Chlorpheniramine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Chlorpheniramine; Phenylephrine: (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.
    Chlorpromazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Chlorthalidone: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Chlorthalidone; Clonidine: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Cilostazol: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as cilostazol may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. In addition, cilostazol is metabolized by the cytochrome P450 CYP2C19 hepatic isoenzyme and may interact with medications that are inhibitors of CYP2C19, including topiramate.
    Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with topiramate. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation. Citalopram is a sensitive CYP2C19 substrate; topiramate is a weak inhibitor of CYP2C19.
    Clomipramine: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant clomipramine and topiramate use due to the risk for additive CNS depression.
    Clonazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Clonidine: (Moderate) Sympathomimetics can antagonize the antihypertensive effects of clonidine when administered concomitantly. Patients should be monitored for loss of blood pressure control.
    Clorazepate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and topiramate is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and topiramate is a weak inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
    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; Phenylephrine; Promethazine: (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 unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Codeine; Promethazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Colchicine: (Minor) The response to sympathomimetics may be enhanced by colchicine.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Dapagliflozin: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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 tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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: (Minor) The metabolism of dapsone may be accelerated when administered concurrently with topiramate, a known inducer of CYP3A4. Coadministration is expected to decrease the plasma concentration of dapsone and increase the formation of dapsone hydroxylamine (a metabolite associated with hemolysis). If these drugs must be administered together, closely monitor for a reduction in dapsone efficacy and signs of hemolytic anemia.
    Darunavir: (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Desflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Desipramine: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant desipramine and topiramate use due to the risk for additive CNS depression.
    Desogestrel; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Desvenlafaxine: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Dextroamphetamine: (Major) Avoid coadministration of phentermine and other medications for weight loss, such as amphetamines. The safety and efficacy of combination therapy have not been established.
    Dextromethorphan; Bupropion: (Moderate) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as stimulants including phentermine. Use low initial doses of bupropion and increase the dose gradually.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (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.
    Dextromethorphan; Guaifenesin; Phenylephrine: (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.
    Diazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and topiramate, another carbonic anhydrase inhibitor, together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Dienogest; Estradiol valerate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Digoxin: (Moderate) Serum digoxin AUC was decreased by 12% when coadministered with topiramate. Although the clinical relevance has not been determined, the clinician should be aware that serum digoxin concentrations may be affected when digoxin and topiramate are used concomitantly.
    Dihydroergotamine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Diltiazem: (Moderate) Monitor for loss of diltiazem efficacy and an increase in topiramate-related adverse events during coadministration. Concomitant use of diltiazem (240 mg) with topiramate (150 mg/day) resulted in a 10% decrease in Cmax and a 25% decrease in diltiazem AUC, a 27% decrease in Cmax and an 18% decrease in desacetyl diltiazem AUC, and no effect on N-desmethyl diltiazem. Co-administration of topiramate with diltiazem resulted in a 16% increase in Cmax and a 19% increase in AUC of topiramate.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors. 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: (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.
    Diphenhydramine; Ibuprofen: (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.
    Diphenhydramine; Naproxen: (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.
    Diphenhydramine; Phenylephrine: (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.
    Dolutegravir: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Lamivudine: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme.
    Dolutegravir; Rilpivirine: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Dolutegravir is partially metabolized by this isoenzyme. (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Dopamine: (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.
    Doravirine: (Minor) Concurrent administration of doravirine and topiramate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Minor) Concurrent administration of doravirine and topiramate may result in decreased doravirine exposure, resulting in potential loss of virologic control. Doravirine is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
    Dorzolamide; Timolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Doxazosin: (Moderate) Monitor for desired antihypertensive effect of alpha-blockers when administered with phentermine, Sympathomimetics like phentermine can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Doxepin: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant doxepin and topiramate use due to the risk for additive CNS depression.
    Doxorubicin Liposomal: (Major) Topiramate is a mild CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of topiramate and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Doxorubicin: (Major) Topiramate is a mild CYP3A4 inducer; doxorubicin is a major substrate of CYP3A4. Inducers of CYP3A4 may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of topiramate and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
    Doxylamine: (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.
    Doxylamine; Pyridoxine: (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.
    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 topiramate is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate; topiramate is a weak inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. Topiramate induces CYP3A4. Coadministration of CYP3A4 inducers, such as topiramate, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
    Droperidol: (Major) 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. Monitor for increased CNS effects if coadministering.
    Drospirenone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Estetrol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Droxidopa: (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.
    Dulaglutide: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    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.
    Elagolix; Estradiol; Norethindrone acetate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Elbasvir; Grazoprevir: (Moderate) Caution is advised when administering elbasvir with topiramate. Topiramate is a mild CYP3A inducer, while elbasvir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of elbasvir and could result in decreased virologic response. (Moderate) Caution is advised when administering elbasvir; grazoprevir with topiramate. Topiramate is a mild CYP3A inducer, while grazoprevir is a substrate of CYP3A. Use of these drugs together may decrease the plasma concentrations of grazoprevir and could result in decreased virologic response.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when elvitegravir is administered with topiramate as there is a potential for decreased elvitegravir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Elvitegravir is a CYP3A4 substrate.
    Empagliflozin: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Ephedrine: (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.
    Ephedrine; Guaifenesin: (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.
    Epinephrine: (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.
    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) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Ergoloid Mesylates: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Ergonovine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Ergot alkaloids: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Ergotamine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Ergotamine; Caffeine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable. (Moderate) Caffeine is a CNS-stimulant and such actions are expected to be additive when coadministered with other CNS stimulants or psychostimulants.
    Ertugliflozin: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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 tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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.
    Esketamine: (Major) Closely monitor blood pressure during concomitant use of esketamine and phentermine. Coadministration of psychostimulants, such as phentermine, with esketamine may increase blood pressure.
    Esmolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Estazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Estradiol Cypionate; Medroxyprogesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Levonorgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Norgestimate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estradiol; Progesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and topiramate should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed topiramate, especially for patients receiving topiramate doses greater than 200 mg per day. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of topiramate. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on topiramate, with dose adjustments made based on clinical efficacy. Concurrent administration may increase estrogen elimination.
    Ethacrynic Acid: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking topiramate. Topiramate is a CNS depressant. Concomitant administration of topiramate with alcohol can result in significant CNS depression. Trokendi XR is contraindicated with recent alcohol use (i.e., within 6 hours before and 6 hours after use). In the presence of alcohol, the pattern of topiramate release from Trokendi XR is significantly altered. As a result, plasma concentrations of topiramate may be markedly higher soon after dosing and subtherapeutic later in the day. (Major) Avoid alcohol with topiramate. Topiramate is a CNS depressant. Concomitant administration of topiramate with alcohol can result in significant CNS depression. Trokendi XR is contraindicated with recent alcohol use (i.e., within 6 hours before and 6 hours after use). In the presence of alcohol, the pattern of topiramate release from Trokendi XR is significantly altered. As a result, plasma concentrations of topiramate may be markedly higher soon after dosing and subtherapeutic later in the day.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethinyl Estradiol; Norelgestromin: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethinyl Estradiol; Norethindrone Acetate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethinyl Estradiol; Norgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Ethiodized Oil: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Ethynodiol Diacetate; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Etonogestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Etonogestrel; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Exenatide: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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.
    Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if concurrent use of topiramate is necessary. If topiramate is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a CYP3A4 inducer like topiramate with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression.
    Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and CYP3A4 inducers, such as topiramate is not recommended.
    Fluphenazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Flurazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Fluticasone; Salmeterol: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and phentermine use. Concomitant use may potentiate sympathetic effects.
    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.
    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.
    Formoterol: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Formoterol; Mometasone: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Furosemide: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Gefitinib: (Moderate) Monitor for clinical response of gefitinib if used concomitantly with topiramate. Gefitinib is metabolized significantly by CYP3A4 and topiramate is a weak CYP3A4 inducer; coadministration may increase gefitinib metabolism and decrease gefitinib concentrations. This also applies to combination products containing topiramate, such as phentermine; topiramate. While the manufacturer has provided no guidance regarding the use of gefitinib with mild or moderate CYP3A4 inducers, administration of a single 500 mg gefitinib dose with a concurrent strong CYP3A4 inducer (rifampin) resulted in reduced mean AUC of gefitinib by 83%.
    Glimepiride; Rosiglitazone: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Glyburide: (Minor) Coadministration of glyburide with topiramate may decrease systemic exposure to glyburide. A pharmacokinetic drug interaction study evaluated the combination of topiramate and glyburide. Reductions in AUC and Cmax were noted for glyburide and the active metabolites.
    Glyburide; Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Minor) Coadministration of glyburide with topiramate may decrease systemic exposure to glyburide. A pharmacokinetic drug interaction study evaluated the combination of topiramate and glyburide. Reductions in AUC and Cmax were noted for glyburide and the active metabolites.
    Glycopyrrolate; Formoterol: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and formoterol use. Concomitant use may potentiate sympathetic effects.
    Green Tea: (Major) Some, but not all, green tea products contain caffeine. Additive CNS stimulant effects are likely to occur when caffeine is coadministered with other CNS stimulants or psychostimulants. Caffeine should be avoided or used cautiously with phentermine.
    Guaifenesin; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Guaifenesin; Phenylephrine: (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.
    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: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Homatropine; Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydantoins: (Moderate) A dosage adjustment may be needed during coadministration of topiramate and hydantoins, closely monitor patients appropriately for increased adverse effects or altered clinical response to therapy. Serum phenytoin concentration may be needed for optimal dosage adjustments. Hydantoins have been shown to reduce topiramate serum concentrations.Topiramate may increase phenytoin concentrations through its inhibitory effects on CYP2C19. In some patients receiving phenytoin concurrently with topiramate, plasma concentrations of phenytoin were increased by 25% and topiramate plasma concentrations were decreased by 48%. These patients were generally receiving dosage regimens of phenytoin twice-daily. Other patients experienced a change of less than 10% in phenytoin plasma concentrations. A similar reaction would be expected with fosphenytoin.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as methyldopa. Concomitant use of phentermine with methyldopa may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications. (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Hydrocodone: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Ibuprofen: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydrocodone; Pseudoephedrine: (Moderate) Monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of hydrocodone as needed. If topiramate is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Hydroxychloroquine: (Moderate) Monitor persons with epilepsy for seizure activity during concomitant topiramate and hydroxychloroquine use. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Hydroxyzine: (Moderate) Monitor for increased CNS effects if topiramate is coadministered with hydroxyzine. 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.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    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: (Moderate) Imatinib is a potent inhibitors of cytochrome P450 2C9 and might decrease topiramate metabolism leading to increased topiramate serum concentrations and a risk of adverse reactions.
    Imipramine: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant imipramine and topiramate use due to the risk for additive CNS depression.
    Incretin Mimetics: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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 tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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 tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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.
    Insulins: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking insulin. 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.
    Iodixanol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Iohexol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Iomeprol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Iopamidol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Iopromide: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Ioversol: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Ipratropium; Albuterol: (Moderate) Monitor blood pressure and heart rate during concomitant albuterol and phentermine use. Concomitant use may potentiate sympathetic effects.
    Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Isavuconazonium: (Moderate) Caution and close monitoring are warranted when isavuconazonium is administered with topiramate as there is a potential for decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of this enzyme.
    Isocarboxazid: (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 the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    Isosulfan Blue: (Major) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Ketamine: (Moderate) Closely monitor vital signs when ketamine and phentermine are coadministered; consider dose adjustment individualized to the patient's clinical situation. Phentermine may enhance the sympathomimetic effects of ketamine.
    Labetalol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., topiramate), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
    Lamotrigine: (Moderate) Monitor for loss of topiramate efficacy and/or an increase in topiramate-related adverse events during coadministration. Coadministration has resulted in both a 13% decrease and 15% increase in topiramate concentrations.
    Leuprolide; Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Levalbuterol: (Moderate) Monitor blood pressure and heart rate during concomitant albuterol and phentermine use. Concomitant use may potentiate sympathetic effects.
    Levamlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Levobetaxolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Levobunolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Levomilnacipran: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Levonorgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Levonorgestrel; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Levothyroxine: (Moderate) Monitor hemodynamic parameters during concomitant sympathomimetic agent and thyroid hormone use; dosage adjustments may be necessary. Concomitant use may increase the effects of sympathomimetics or thyroid hormone.
    Levothyroxine; Liothyronine (Porcine): (Moderate) Monitor hemodynamic parameters during concomitant sympathomimetic agent and thyroid hormone use; dosage adjustments may be necessary. Concomitant use may increase the effects of sympathomimetics or thyroid hormone.
    Levothyroxine; Liothyronine (Synthetic): (Moderate) Monitor hemodynamic parameters during concomitant sympathomimetic agent and thyroid hormone use; dosage adjustments may be necessary. Concomitant use may increase the effects of sympathomimetics or thyroid hormone.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Lidocaine; Epinephrine: (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) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and topiramate may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; topiramate induces CYP3A4.
    Linagliptin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
    Linagliptin; Metformin: (Major) Inducers of CYP3A4 (e.g., topiramate) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Linezolid: (Major) Phentermine should not be administered during or within 14 days following the use of linezolid. Linezolid is an antibiotic that is also a weak, reversible nonselective inhibitor of monoamine oxidase (MAO). Drugs that possess MAO-inhibiting activity, such as linezolid, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine which may invoke a hypertensive reaction. Additonally, phentermine has a weak ability to dose-dependently raise serotonin levels. Linezolid has the potential for interaction with serotonergic agents, which may increase the risk for serotonin syndrome. If coadministration is necessary, closely monitor for increased blood pressure and signs of serotonin syndrome.
    Liothyronine: (Moderate) Monitor hemodynamic parameters during concomitant sympathomimetic agent and thyroid hormone use; dosage adjustments may be necessary. Concomitant use may increase the effects of sympathomimetics or thyroid hormone.
    Liraglutide: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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.
    Lisdexamfetamine: (Major) Avoid coadministration of phentermine and other medications for weight loss, such as amphetamines. The safety and efficacy of combination therapy have not been established.
    Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Lithium: (Moderate) Monitor serum lithium concentrations during concomitant high-dose topiramate use. Lithium concentrations were unaffected during treatment with topiramate 200 mg/day; however, there was an observed increase in systemic exposure of lithium (26%) after topiramate doses up to 600 mg/day.
    Lixisenatide: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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.
    Loop diuretics: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Lorazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Lorcaserin: (Major) The safety and efficacy of coadministration of lorcaserin with other products intended for weight loss including prescription drugs (e.g., phentermine, fenfluramine, dexfenfluramine, orlistat, phendimetrazine, amphetamines), over-the-counter drugs (e.g., orlistat, phenylpropanolamine, ephedrine), and herbal preparations (ephedra, Ma huang) have not been established. Some of these agents (fenfluramine, dexfenfluramine) are known to increase the risk for cardiac valvulopathy and pulmonary hypertension. Coadministration of sibutramine with other serotonergic medications is contraindicated due to the risk for serotonin-related adverse effects, such as serotonin syndrome.
    Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Lumateperone: (Major) Avoid coadministration of lumateperone and topiramate as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; topiramate is a weak CYP3A4 inducer.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, decreased plasma concentrations of lurasidone may theoretically occur when the drug is co-administered with inducers of CYP3A4 such as topiramate.
    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) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy. (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.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with topiramate is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and topiramate is a CYP3A4 inducer. Monitor for a decrease in maraviroc efficacy with concomitant use.
    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.
    Medroxyprogesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Mefloquine: (Moderate) Topiramate induces CYP3A4 and may increase the metabolism of mefloquine if coadministered. Use may reduce the clinical efficacy of mefloquine, increasing the risk of Plasmodium falciparum resistance during treatment of malaria. Coadministration of mefloquine and anticonvulsants may also result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of drug concentrations (if therapeutic monitoring is advised for the anticonvulsant) is recommended. When topiramate is used for other conditions, monitor for clinical efficacy. Mefloquine may additionally cause CNS side effects that may cause seizures or alter moods or behaviors.
    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.
    Meperidine; Promethazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Mestranol; Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    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.
    Metformin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Metformin; Repaglinide: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Metformin; Rosiglitazone: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Metformin; Sitagliptin: (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known.
    Methamphetamine: (Major) Avoid coadministration of phentermine and other medications for weight loss, such as amphetamines. The safety and efficacy of combination therapy have not been established.
    Methenamine: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Acid Phosphate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methenamine; Sodium Salicylate: (Moderate) Carbonic anhydrase inhibiting drugs, such as topiramate (a weak carbonic anhydrase inhibitor) can alkalinize the urine, thereby decreasing the effectiveness of methenamine by inhibiting the conversion of methenamine to formaldehyde.
    Methyclothiazide: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Methyldopa: (Major) Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as methyldopa. Concomitant use of phentermine with methyldopa may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Methylergonovine: (Major) Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.
    Metolazone: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Metoprolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug. (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Midazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Midodrine: (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.
    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) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Mirtazapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed during co-administration of mirtazapine with other drugs that have serotonergic properties. As a drug related to the amphetamines, phentermine has the potential to cause serotonin syndrome when combined with serotonergic agents. Patients receiving this combination should be monitored for the emergence of serotonin syndrome.
    Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
    Monoamine oxidase inhibitors: (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.
    Nabilone: (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: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Nanoparticle Albumin-Bound Sirolimus: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of topiramate; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; topiramate is a weak CYP3A inducer.
    Nebivolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Nebivolol; Valsartan: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Nirmatrelvir; Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with topiramate due to decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Coadministration with a strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
    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) Phentermine lowers the seizure threshold and should be discontinued at least 48 hours before and for at least 24 hours after intrathecal use of contrast media.
    Norepinephrine: (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.
    Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norethindrone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norethindrone; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norgestimate; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Norgestrel: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Nortriptyline: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant nortriptyline and topiramate use due to the risk for additive CNS depression.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly. (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Orlistat: (Moderate) The safety and efficacy of coadministration of phentermine with other products intended for weight loss has not been established.
    Oxazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of oxycodone as needed. If topiramate is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Ozanimod: (Contraindicated) Coadministration of ozanimod with phentermine is contraindicated. Allow at least 14 days between discontinuation of ozanimod and initiation of phentermine. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. Sympathomimetics such as phentermine 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 during coadministration of sympathomimetic medications and other selective or nonselective MAO inhibitors.
    Pazopanib: (Moderate) Coadministration of pazopanib and topiramate may cause a decrease in systemic concentrations of pazopanib. Use caution when administering these drugs concomitantly. Pazopanib is a substrate for CYP3A4. Topiramate in a weak CYP3A4 inducer.
    Penbutolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Perampanel: (Moderate) During clinical trials, co-administration of topiramate and perampanel to patients led to a 20% decrease in the AUC of perampanel compared to patients not taking enzyme-inducing antiepileptic drugs. Topiramate is an inducer of CYP3A4, while perampanel is a substrate of this enzyme. Patients taking topiramate who begin treatment with perampanel should be closely monitored for adverse effects and receive a higher initial dose of perampanel. Addition or withdrawal of enzyme-inducing antiepileptic drugs may require a perampanel dose adjustment.
    Perindopril; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Perphenazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Perphenazine; Amitriptyline: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression. (Moderate) Monitor for unusual drowsiness or excess sedation and for increased amitriptyline-related adverse events during concomitant topiramate use. Concomitant use resulted in an increase in amitriptyline exposure by 12% and may increase the risk for additive CNS depression.
    Phendimetrazine: (Contraindicated) Phendimetrazine is a phenylalkaline sympathomimetic agent. All sympathomimetics and psychostimulants, including other anorexiants, should be used cautiously or avoided in patients receiving phendimetrazine. The safety of phendimetrazine when used with other anorexiants such as phentermine is controversial and concurrent use should be avoided. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmia. Similarly, phendimetrazine should not be used in combination with OTC preparations and herbal products that may contain ephedra alkaloids or Ma huang.
    Phenelzine: (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.
    Phenothiazines: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Phenoxybenzamine: (Moderate) Monitor for desired antihypertensive effect of alpha-blockers when administered with phentermine, Sympathomimetics like phentermine can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Phentolamine: (Moderate) Monitor for desired antihypertensive effect of alpha-blockers when administered with phentermine, Sympathomimetics like phentermine can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Phenylephrine: (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.
    Pindolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Pioglitazone: (Moderate) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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) A decrease in the exposures of pioglitazone and its active metabolites were observed in a clinical trial during concurrent use of topiramate. The clinical significance is unknown; however, results of routine blood glucose monitoring should be carefully followed during coadministration of pioglitazone and topiramate to ensure adequate glucose control. (Moderate) Consider more frequent monitoring of patients receiving metformin and concomitant topiramate due to increased risk for lactic acidosis. Carbonic anhydrase inhibitors, such as topiramate, frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. In healthy volunteers, metformin Cmax and AUC increased by 17% and 25%, respectively, when topiramate was added, and oral plasma clearance of topiramate appears to be reduced when administered with metformin. The clinical significance of the effect on the pharmacokinetics of metformin or topiramate are not known. (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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.
    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.
    Prazosin: (Moderate) Monitor for desired antihypertensive effect of alpha-blockers when administered with phentermine, Sympathomimetics like phentermine can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Pregabalin: (Moderate) Monitor for respiratory depression and sedation during concomitant topiramate and pregabalin use; consider starting pregabalin at a low dose. Concomitant use increases the risk for additive CNS depression.
    Prilocaine; Epinephrine: (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.
    Probenecid: (Minor) Probenecid may increase the renal clearance of topiramate resulting in lower topiramate concentrations. Although not evaluated in humans, animal studies using probenecid along with topiramate showed a significant increase in renal clearance of topiramate. This suggests that topiramate may undergo renal tubular reabsorption. Probenecid may block renal tubular reabsorption of topiramate, thus increasing the renal clearance of the drug.
    Probenecid; Colchicine: (Minor) Probenecid may increase the renal clearance of topiramate resulting in lower topiramate concentrations. Although not evaluated in humans, animal studies using probenecid along with topiramate showed a significant increase in renal clearance of topiramate. This suggests that topiramate may undergo renal tubular reabsorption. Probenecid may block renal tubular reabsorption of topiramate, thus increasing the renal clearance of the drug. (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.
    Prochlorperazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Progesterone: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Progestins: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Promethazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Promethazine; Dextromethorphan: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Promethazine; Phenylephrine: (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 unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Propranolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug. (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Protriptyline: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant protriptyline and topiramate use due to the risk for additive CNS depression.
    Quazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Ramelteon: (Major) 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. Monitor for increased CNS effects if coadministering.
    Rasagiline: (Moderate) The concomitant use of rasagiline and sympathomimetics was not allowed in clinical studies; therefore, caution is advised during concurrent use of rasagiline and sympathomimetics including stimulants for ADHD and weight loss, non-prescription nasal, oral, and ophthalmic decongestants, and weight loss dietary supplements containing Ephedra. Although sympathomimetics are contraindicated for use with other non-selective monoamine oxidase inhibitors (MAOIs), hypertensive reactions generally are not expected to occur during concurrent use with rasagiline because of the selective monoamine oxidase-B (MAO-B) inhibition of rasagiline at manufacturer recommended doses. One case of elevated blood pressure has been reported in a patient during concurrent use of the recommended dose of rasagiline and ophthalmic tetrahydrozoline. One case of hypertensive crisis has been reported in a patient taking the recommended dose of another MAO-B inhibitor, selegiline, in combination with ephedrine. It should be noted that the MAO-B selectivity of rasagiline decreases in a dose-related manner as increases are made above the recommended daily dose and interactions with sympathomimetics may be more likely to occur at these higher doses.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Remimazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Reserpine: (Major) Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as reserpine. Concomitant use of phentermine with reserpine may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
    Rilpivirine: (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
    Riociguat: (Major) Avoid use of sympathomimetic agents with riociguat. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including riociguat. 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.
    Ritonavir: (Moderate) Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Coadministration of a CYP3A4 inducer, like topiramate, may decrease systemic concentrations of romidepsin. Use caution when concomitant administration of these agents is necessary.
    Rosiglitazone: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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.
    Safinamide: (Moderate) Severe hypertensive reactions, including hypertensive crisis, have been reported in patients taking monoamine oxidase inhibitors (MAOIs), such as safinamide, and sympathomimetic medications, such as phentermine. If concomitant use of safinamide and phentermine is necessary, monitor for hypertension and hypertensive crisis.
    Salmeterol: (Moderate) Monitor blood pressure and heart rate during concomitant salmeterol and phentermine use. Concomitant use may potentiate sympathetic effects.
    Segesterone Acetate; Ethinyl Estradiol: (Moderate) Topiramate may reduce the efficacy of progestins used in contraception or hormone replacement therapies. Reduced contraceptive efficacy can occur even in the absence of breakthrough bleeding. Dosages of hormone replacement products may need adjustment. Different or additional forms of contraception (e.g., non-hormonal contraceptives) may also be needed. In a pharmacokinetic interaction study, a combination oral contraceptive (containing norethindrone and ethinyl estradiol) administered with only topiramate at doses of 50 to 200 mg/day did not result in clinically significant alterations of AUC for either component of the oral contraceptive. Norethindrone pharmacokinetics were not significantly affected. Pregnancy has been reported in patients who are using hormonal-containing contraceptives and hepatic enzyme inducers.
    Selective serotonin reuptake inhibitors: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SSRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Selegiline: (Contraindicated) The product label for phentermine contraindicates use with monoamine oxidase inhibitors (MAOIs) due to the risk of hypertensive crisis. Phentermine should generally not be used concurrently with MAOIs or within 14 days before or after their use. The manufacturers of selegiline products recommend caution and monitoring of blood pressure during concurrent use with sympathomimetics.
    Selexipag: (Major) Avoid use of sympathomimetic agents with selexipag. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including selexipag. 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.
    Semaglutide: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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.
    Serotonin norepinephrine reuptake inhibitors: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Sevoflurane: (Major) Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.
    SGLT2 Inhibitors: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking SGLT2 inhibitors. 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.
    Sibutramine: (Contraindicated) Sibutramine is contraindicated in patients taking other centrally-acting appetite suppressant drugs, such as phentermine. In addition, many of these agents enhance central serotonergic activity by various mechanisms. Concurrent use of sibutramine with other serotonergic agents may increase the potential for serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Simeprevir: (Major) Avoid concurrent use of simeprevir and topiramate. Induction of CYP3A4 by topiramate may significantly reduce the plasma concentrations of simeprevir, resulting in treatment failure.
    Sirolimus: (Moderate) Monitor for loss of efficacy of sirolimus during coadministration of topiramate; a sirolimus dose adjustment may be necessary. Monitor sirolimus serum concentrations as appropriate. Sirolimus is a sensitive CYP3A substrate with a narrow therapeutic range; topiramate is a weak CYP3A inducer.
    Sodium Oxybate: (Contraindicated) Because phentermine is a sympathomimetic and anorexic agent, it should not be used in combination with other psychostimulants.
    Sofosbuvir; Velpatasvir: (Major) Use caution when administering velpatasvir with topiramate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; topiramate is a weak inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Use caution when administering velpatasvir with topiramate. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; topiramate is a weak inducer of CYP3A4.
    Solifenacin: (Moderate) Through an additive effect, the use of topiramate with agents that may increase the risk for heat related disorders, such as solifenacin, may lead to oligohidrosis, hyperthermia, and/or heat stroke.
    Solriamfetol: (Moderate) Monitor blood pressure and heart rate during coadministration of solriamfetol, a norepinephrine and dopamine reuptake inhibitor, and phentermine, a CNS stimulant. Concurrent use of solriamfetol and other medications that increase blood pressure and/or heart rate may increase the risk of such effects. Coadministration of solriamfetol with other drugs that increase blood pressure or heart rate has not been evaluated.
    Sotalol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    St. John's Wort, Hypericum perforatum: (Moderate) The concomitant use of St. John's Wort with phentermine may increase the risk for serotonin syndrome. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if topiramate must be administered. Monitor for reduced efficacy of sufentanil injection and signs of opioid withdrawal if coadministration with topiramate is necessary; consider increasing the dose of sufentanil injection as needed. If topiramate is discontinued, consider a dose reduction of sufentanil injection and frequently monitor for signs or respiratory depression and sedation. Sufentanil is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
    Sulfonylureas: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking sulfonylureas. 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.
    Tedizolid: (Moderate) Caution is warranted with the concurrent use of tedizolid and phentermine. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO which could potentially prolong and intensify the cardiac stimulation and vasopressor effects of phentermine. Phentermine should not be administered during or within 14 days following the use of drugs with MAO-inhibiting activity.
    Telithromycin: (Moderate) Caution is warranted when topiramate is administered with telithromycin as there is a potential for decreased telithromycin concentrations and loss of efficacy. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Telithromycin is a substrate of CYP3A4.
    Telmisartan; Amlodipine: (Minor) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as topiramate, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Temazepam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Terazosin: (Moderate) Monitor for desired antihypertensive effect of alpha-blockers when administered with phentermine, Sympathomimetics like phentermine can antagonize the effects of antihypertensives such as alpha-blockers when administered concomitantly.
    Terbinafine: (Moderate) Caution is advised when administering terbinafine with topiramate. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP2C19 and CYP3A4; topiramate is an inducer of CYP3A4 and an inhibitor of CYP2C19. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
    Terbutaline: (Moderate) Concomitant use of sympathomimetics with beta-agonists might result in additive cardiovascular effects such as increased blood pressure and heart rate.
    Theophylline, Aminophylline: (Moderate) Concurrent administration of theophylline or aminophylline with some sympathomimetics can produce excessive stimulation and effects such as nervousness, irritability, or insomnia. Seizures or cardiac arrhythmias are also possible. (Moderate) Concurrent administration of theophylline or aminophylline with sympathomimetics can produce excessive stimulation manifested by skeletal muscle activity, agitation, and hyperactivity.
    Thiazide diuretics: (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Thiazolidinediones: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking thiazolidinediones. 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.
    Thiethylperazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Thioridazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Thyroid hormones: (Moderate) Monitor hemodynamic parameters during concomitant sympathomimetic agent and thyroid hormone use; dosage adjustments may be necessary. Concomitant use may increase the effects of sympathomimetics or thyroid hormone.
    Timolol: (Moderate) Monitor hemodynamic parameters and for loss of efficacy during concomitant sympathomimetic agent and beta-blocker use; dosage adjustments may be necessary. Concomitant use may antagonize the cardiovascular effects of either drug.
    Tirzepatide: (Moderate) Sympathomimetic agents tend to increase blood glucose concentrations when administered systemically. Monitor for loss of glycemic control when sympathomimetics are administered to patients taking incretin mimetics. 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.
    Tolterodine: (Moderate) Through an additive effect, the use of topiramate (a weak carbonic anhydrase inhibitor) with agents that may increase the risk for heat-related disorders, such as antimuscarinics, may lead to oligohidrosis, hyperthermia and/or heat stroke.
    Torsemide: (Moderate) Monitor potassium concentration before and during concomitant topiramate and loop diuretic use due to risk for additive hypokalemia. Topiramate can increase the risk of hypokalemia through its inhibition of carbonic anhydrase activity and concomitant use with loop diuretics may further potentiate potassium-wasting.
    Tramadol: (Moderate) Reserve concomitant prescribing of opioids and other CNS depressants, such as topiramate, 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. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
    Tramadol; Acetaminophen: (Moderate) Reserve concomitant prescribing of opioids and other CNS depressants, such as topiramate, 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. If concomitant use is necessary, consider prescribing naloxone for the emergency treatment of opioid overdose. Concomitant use can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
    Tranylcypromine: (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.
    Treprostinil: (Major) Avoid use of sympathomimetic agents with treprostinil. Sympathomimetics counteract the medications used to stabilize pulmonary hypertension, including treprostinil. 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.
    Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Triazolam: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
    Tricyclic antidepressants: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain.
    Trifluoperazine: (Moderate) Monitor for unusual drowsiness and excess sedation during coadministration of phenothiazines and topiramate due to the risk for additive CNS depression.
    Trimipramine: (Moderate) Monitor blood pressure and heart rate during concomitant phentermine and tricyclic antidepressant use. Adjust doses or use alternative therapy based on clinical response. Concomitant use increases the risk for potentiation of cardiovascular effects. Amphetamines may enhance the activity of tricyclic antidepressants causing significant and sustained increases in amphetamine concentrations in the brain. (Moderate) Monitor for unusual drowsiness or excess sedation during concomitant trimipramine and topiramate use due to the risk for additive CNS depression.
    Trospium: (Moderate) Oligohidrosis and hyperthermia have been reported in post-marketing experience with topiramate. Use caution when topiramate is prescribed with agents known to predispose patients to similar heat-related disorders such as trospium.
    Ulipristal: (Major) Avoid administration of ulipristal with drugs that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and topiramate is a mild CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
    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.
    Valproic Acid, Divalproex Sodium: (Moderate) Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. In addition, concomitant administration of topiramate and valproic acid has been associated with hypothermia with or without hyperammonemia in patients who have tolerated either drug alone. Assessment of blood ammonia levels may be advisable in patients presenting with symptoms of hypothermia. Concurrent use of topiramate and drugs that cause thrombocytopenia, such as valproic acid, may also increase the risk of bleeding; monitor patients appropriately. In several case reports, children with localized epilepsy have presented with somnolence, seizure exacerbation, behavioral alteration, decline in speech and cognitive abilities, and ataxia while being treated with a combination of valproate and topiramate. Previously, the children tolerated valproic acid with other antiepileptic drugs. Children presented with elevated serum ammonia, normal or elevated LFTs, and generalized slowing of EEG background activity during encephalopathy, which promptly reverted to normal along with clinical improvement following withdrawal of valproate. The possible mechanism is topiramate-induced aggravation of all the known complications of valproic acid monotherapy; it is not due to a pharmacokinetic interaction. This condition is reversible with cessation of either valproic acid or topiramate.
    Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum potassium concentrations and for increased topiramate-related adverse effects during concomitant hydrochlorothiazide use. Concomitant use has been shown to increase topiramate exposure by 29% and may potentiate the potassium-wasting action of hydrochlorothiazide. (Moderate) Sympathomimetics can antagonize the effects of antihypertensives when administered concomitantly.
    Vasodilators: (Moderate) Use sympathomimetic agents with caution in patients receiving therapy for hypertension. Patients should be monitored to confirm that the desired antihypertensive effect is achieved. Sympathomimetics can increase blood pressure and heart rate, and antagonize the antihypertensive effects of vasodilators when administered concomitantly. Anginal pain may be induced when coronary insufficiency is present.
    Vasopressin, ADH: (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.
    Vasopressors: (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.
    Vemurafenib: (Major) Concomitant use of vemurafenib and topiramate may result in decreased concentrations of vemurafenib. Vemurafenib is a CYP3A4 substrate and topiramate is a weak CYP3A4 inducer. Use caution and monitor patients for therapeutic effects.
    Venlafaxine: (Moderate) Use phentermine and serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution due to a potential for serotonin syndrome. Monitor weight, cardiovascular status, and for potential serotonergic adverse effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome when combined with serotonergic agents. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses and some large controlled clinical studies have allowed patients to start phentermine-based therapy for obesity along with their SNRI as long as the antidepressant dose had been stable for at least 3 months prior. Such therapy was generally well-tolerated, especially at lower phentermine doses. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Vilazodone: (Moderate) Use phentermine and vilazodone together with caution; use together might be efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report describes adverse reactions with phentermine and the antidepressant fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with extended-release phentermine or extended-release phentermine combinations for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal therapies.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and topiramate. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with topiramate, a mild inducer of CYP3A4 in vitro. In addition, concurrent use of topiramate and drugs that affect platelet function such as platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (23%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Vortioxetine: (Moderate) Use phentermine and vortioxetine together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and the antidepressant fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with topiramate is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy; increased bleeding is also possible with the combination. Topiramate is a weak CYP3A4 inducer and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zonisamide: (Moderate) Monitor for the appearance or worsening of metabolic acidosis if zonisamide is given concomitantly with topiramate. Concomitant use of zonisamide with another carbonic anhydrase inhibitor, like topiramate, may increase the severity of metabolic acidosis and may also increase the risks of hyperammonemia, encephalopathy, and kidney stone formation. Monitor serum ammonia concentrations if signs or symptoms of encephalopathy occur. Hyperammonemia resulting from zonisamide resolves when zonisamide is discontinued and may resolve or decrease in severity with a decrease of the daily dose.

    PREGNANCY AND LACTATION

    Pregnancy

    Both topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue phentermine; topiramate, taking into account the importance of therapy to the mother. During lactation, first line weight loss strategies include a healthy diet and exercise, if appropriate. Sufficient calories and nutrition are important for proper lactation. According to the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Obesity Clinical Practice Guidelines, the use of phentermine; topiramate in breast-feeding women is not recommended.

    MECHANISM OF ACTION

    Phentermine; topiramate are two medications, that when combined, are used for chronic weight management. The exact mechanism of action responsible for weight reduction with this combination is not known.
     
    Phentermine: Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic. Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of methamphetamine itself. The effect of phentermine on chronic weight management is likely mediated by release of catecholamines in the hypothalamus and limbic region, resulting in reduced appetite and decreased food consumption, but other metabolic effects may also be involved. The exact mechanism of action is not known. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Other clinical effects include CNS stimulation and potential elevation of blood pressure. Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased.
    Topiramate: The mechanism of action of topiramate on chronic weight management is not known. Its effect on obesity may be due to its effects on both appetite suppression and satiety enhancement, induced by a combination of pharmacologic effects including augmenting the activity of the neurotransmitter gamma-aminobutyrate, modulation of voltage-gated ion channels, inhibition of AMPA/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase.

    PHARMACOKINETICS

    Phentermine; topiramate extended-release is administered orally.
     
    Phentermine: Phentermine is 17.5% plasma protein bound. Phentermine has 2 metabolic pathways, p-hydroxylation on the aromatic ring and N-oxidation on the alipthatic side chain. Although not extensively metabolized, CYP3A4 accounts for the primary mode of metabolism. Approximately 70% to 80% of the parent drug remains unchanged in the urine. Population pharmacokinetic analysis estimates oral clearance (CL/F) at 8.79 L/hour. The mean phentermine terminal half-life is about 20 hours.
    Topiramate: Topiramate is 15% to 41% plasma protein bound over the blood concentration range of 0.5 to 250 mcg/mL; as blood concentration increases, the bound fraction of topiramate decreases. Topiramate is not metabolized to a great extent. Six metabolites have been identified and are formed via hydroxylation, hydrolysis, and glucuronidation. None of these metabolites constitutes more than 5% of an administered dose. About 70% of an administered dose is eliminated as unchanged drug in the urine. Population pharmacokinetic analysis estimates oral clearance CL/F is 1.17 L/hour. The mean topiramate terminal half-life is approximately 65 hours.

    Oral Route

    Phentermine: After oral administration of a single phentermine; topiramate extended-release (15 mg/92 mg) dose, the Cmax, Tmax, and AUC for phentermine are 49.1 ng/mL, 6 hours, and 1,990 to 2,000 ng x hour/mL, respectively. A high fat meal does not affect exposure. Phentermine exhibits approximately dose-proportional pharmacokinetics throughout the recommended dosing range. Upon dosing phentermine; topiramate to steady state, the mean phentermine accumulation ratios for AUC and Cmax are both approximately 2.5.
    Topiramate: After oral administration of a single phentermine; topiramate extended-release (15 mg/92 mg) dose, the Cmax, Tmax, and AUC for topiramate are 1,020 ng/mL, 9 hour, and 61,600 to 68,000 ng x hour/mL, respectively. A high fat meal does not affect exposure. Topiramate exhibits approximately dose-proportional pharmacokinetics throughout the recommended dosing range. Upon dosing to steady state, the mean topiramate accumulation ratios for AUC and Cmax are both approximately 4.