Caduet

HMG-CoA Reductase Inhibitors (Statins) and Other Cardiovascular Agent Combinations

 
NOTE: Patients receiving amlodipine; atorvastatin therapy should also be placed on a standard cholesterol-lowering diet, and this diet should be continued throughout therapy. Serum lipoprotein concentrations should be determined periodically and dosage adjusted according to individual response and established NCEP treatment guidelines.

Oral Administration

May be administered without regard to meals.

Severe

bradycardia / Rapid / 0-1.0
ventricular tachycardia / Early / 0-1.0
atrial fibrillation / Early / 0-1.0
arrhythmia exacerbation / Early / 0-1.0
vasculitis / Delayed / 0-1.0
hepatic failure / Delayed / 0-1.0
hepatic necrosis / Delayed / 0-1.0
rhabdomyolysis / Delayed / 0-1.0
immune-mediated necrotizing myopathy / Delayed / 0-1.0
erythema multiforme / Delayed / 0-1.0
pancreatitis / Delayed / Incidence not known
cirrhosis / Delayed / Incidence not known
myoglobinuria / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
angioedema / Rapid / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
muscle paralysis / Delayed / Incidence not known
stroke / Early / Incidence not known
myasthenia gravis / Delayed / Incidence not known

Moderate

edema / Delayed / 1.8-10.8
palpitations / Early / 0.7-4.5
dyspnea / Early / 0-2.0
orthostatic hypotension / Delayed / 0-1.0
gingival hyperplasia / Delayed / 0-1.0
chest pain (unspecified) / Early / 0-1.0
sinus tachycardia / Rapid / 0-1.0
constipation / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
leukopenia / Delayed / 0-1.0
elevated hepatic enzymes / Delayed / 0.7-0.7
angina / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
peripheral vasodilation / Rapid / Incidence not known
hypotension / Rapid / Incidence not known
cholestasis / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
myopathy / Delayed / Incidence not known
myasthenia / Delayed / Incidence not known
bullous rash / Early / Incidence not known
peripheral neuropathy / Delayed / Incidence not known
dysphagia / Delayed / Incidence not known
dysarthria / Delayed / Incidence not known
diabetes mellitus / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
memory impairment / Delayed / Incidence not known
confusion / Early / Incidence not known
amnesia / Delayed / Incidence not known
interstitial lung disease / Delayed / Incidence not known

Mild

diarrhea / Early / 0-14.1
pharyngitis / Delayed / 4.2-12.9
arthralgia / Delayed / 0-11.7
gynecomastia / Delayed / 1.0-10.0
headache / Early / 7.3-7.3
nausea / Early / 2.9-7.1
dyspepsia / Early / 0-6.0
fatigue / Early / 4.5-4.5
dizziness / Early / 1.1-3.4
flushing / Rapid / 0.7-2.6
pruritus / Rapid / 0-2.0
rash / Early / 0-2.0
abdominal pain / Early / 1.6-1.6
drowsiness / Early / 1.4-1.4
paresthesias / Delayed / 0-1.0
anorexia / Delayed / 0-1.0
hypoesthesia / Delayed / 0-1.0
vertigo / Early / 0-1.0
syncope / Early / 0-1.0
tremor / Early / 0-1.0
flatulence / Early / 0-1.0
vomiting / Early / 0-1.0
back pain / Delayed / 0-1.0
diaphoresis / Early / 0-1.0
purpura / Delayed / 0-1.0
maculopapular rash / Early / 0-1.0
fever / Early / Incidence not known
myalgia / Early / Incidence not known
malaise / Early / Incidence not known
weakness / Early / Incidence not known
urticaria / Rapid / Incidence not known
Co-Enzyme Q-10 deficiency / Delayed / Incidence not known

Caduet

Rx

Combination calcium-channel blocker and HMG-CoA reductase inhibitor; used for HTN or angina with hyperlipidemia in patients who were previously receiving the individually titrated drug components

For the treatment of hypertension or coronary artery disease including angina (chronic stable angina or variant angina) in patients with coexisting hyperlipoproteinemia (hypercholesterolemia, type IV hypertriglyceridemia, or type III hyperlipoproteinemia) and/or patients at risk for complications of coronary artery disease (stroke prophylaxis, myocardial infarction prophylaxis).
NOTE: The combination product (Caduet) is indicated in patients for whom treatment with both amlodipine and atorvastatin are appropriate (see separate monographs for more specific information regarding indications for each component).
Oral dosage Adults

The recommended dosage range for amlodipine is 5—10 mg/day. For hypertension, titration should proceed over 7—14 days. Most patients require 10 mg/day for adequate treatment of angina. For atorvastatin, the initial dosage is 10—20 mg PO once daily; may start at 40 mg PO once daily in patients requiring > 45% LDL-reduction. The atorvastatin dosage range is 10—80 mg PO once daily (mean LDL reduction range: 43—60% LDL). After dosage initiation or titration, lipid concentrations should be analyzed within 2—4 weeks. Adjust dosage to attain the target LDL and lipid goals based on the NCEP guidelines.

Geriatric and Debilitated patients

The initial starting dosage for amlodipine should be reduced to 2.5 mg PO once daily. The dosage may be increased to 5 mg PO once daily. Maximum 5—10 mg/day amlodipine (based on tolerance and clinical response). For initiation of atorvastatin, see adult dosage. In general, elderly patients may have an increased cholesterol-lowering response to HMG-CoA reductase inhibitors. The degree of LDL-cholesterol reduction at a given atorvastatin dosage is greater than that seen in younger patient populations.

Children and Adolescents >= 10 years (females must be  postmenarchal)

The FDA-approved amlodipine dosage range for hypertension is 2.5—5 mg PO once daily. The maximum dosage studied is 5 mg/day PO. Amlodipine has not been shown to be safe and effective for the treatment of angina in adolescents or children. Atorvastatin should be started at 10 mg PO once daily. Maximum dosage is 20 mg PO once daily. Atorvastatin is FDA-approved for heterozygous familial hypercholesterolemia in adolescent boys and postmenarchal females. Adjust dosage at intervals >= 4 weeks to attain the target LDL and lipid goals.

Hepatic Impairment

Not recommended in patients with hepatic disease.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
 
Intermittent hemodialysis
Amlodipine and atorvastatin are highly protein bound, and are not likely to be significantly removed by hemodialysis.

Abrocitinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with abrocitinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; abrocitinib is a P-gp inhibitor.
Acebutolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with amlodipine may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of amlodipine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If amlodipine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Amlodipine is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Isometheptene has sympathomimetic properties. Patients taking antihypertensive agents may need to have their therapy modified. Careful blood pressure monitoring is recommended.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like amlodipine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amlodipine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Acetaminophen; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Acetaminophen; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Acrivastine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Adagrasib: (Major) Coadministration of atorvastatin with adagrasib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with adagrasib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Adenosine: (Moderate) Use adenosine with caution in the presence of calcium-channel blockers due to the potential for additive or synergistic depressant effects on the sinoatrial and atrioventricular nodes.
Aldesleukin, IL-2: (Moderate) Calcium channel blockers may potentiate the hypotension seen with aldesleukin, IL 2.
Alemtuzumab: (Moderate) Alemtuzumab may cause hypotension. Careful monitoring of blood pressure and hypotensive symptoms is recommended especially in patients with ischemic heart disease and in patients on antihypertensive agents.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with weak CYP3A4 inhibitors like amlodipine can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If amlodipine is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Aliskiren: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of atorvastatin resulted in an approximate 50% increase in aliskiren Cmax and AUC after multiple doses; the pharmacokinetics of atorvastatin were not affected. Monitor blood pressure in patients taking both of these medications.
Alogliptin; Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Alprazolam: (Major) Avoid coadministration of alprazolam and amlodipine due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with amlodipine, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Alprostadil: (Minor) The concomitant use of systemic alprostadil injection and antihypertensive agents, like calcium channel blockers, may cause additive hypotension. Caution is advised with this combination. Systemic drug interactions with the urethral suppository (MUSE) or alprostadil intracavernous injection are unlikely in most patients because low or undetectable amounts of the drug are found in the peripheral venous circulation following administration. In those men with significant corpora cavernosa venous leakage, hypotension might be more likely. Use caution with in-clinic dosing for erectile dysfunction (ED) and monitor for the effects on blood pressure. In addition, the presence of medications in the circulation that attenuate erectile function may influence the response to alprostadil. However, in clinical trials with alprostadil intracavernous injection, anti-hypertensive agents had no apparent effect on the safety and efficacy of alprostadil.
Amifostine: (Major) Patients receiving calcium-channel blockers should be closely monitored during amifostine infusions due to additive effects. Patients receiving amifostine at doses recommended for chemotherapy should have antihypertensive therapy interrupted 24 hours preceding administration of amifostine. If the antihypertensive cannot be stopped for 24 hours before chemotherapy doses of amifostine, patients should not receive amifostine.
Aminolevulinic Acid: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Amiodarone: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with amiodarone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; amiodarone is a P-gp inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with amiodarone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and amiodarone is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Amobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Amphetamine; Dextroamphetamine Salts: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Apalutamide: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with apalutamide is necessary. Amlodipine is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for decreased efficacy of atorvastatin if coadministration with apalutamide is necessary. Atorvastatin is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased atorvastatin exposure by 80% if the doses were separated, but increased the exposure of atorvastatin by 30% with simultaneous administration.
Apomorphine: (Moderate) Use of calcium-channel blockers and apomorphine together can increase the hypotensive effects of apomorphine. Monitor blood pressure regularly during use of this combination.
Apraclonidine: (Minor) Apraclonidine had minimal effects on heart rate and blood pressure during clinical studies in patients with glaucoma. However, it is theoretically possible that additive blood pressure reductions could occur when apraclonidine is combined with the use of antihypertensive agents. Use caution during concurrent use, especially in patients with severe, uncontrolled cardiovascular disease, including hypertension.
Aprepitant, Fosaprepitant: (Moderate) Use caution if amlodipine and a multi-day regimen of oral aprepitant are used concurrently; monitor for an increase in amlodipine-related adverse effects for several days after administration. Amlodipine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of amlodipine. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. (Moderate) Use caution if atorvastatin and a multi-day regimen of oral aprepitant are used concurrently; monitor for an increase in atorvastatin-related adverse effects for several days after administration. Atorvastatin is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of atorvastatin. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions and hypotension during concomitant use of amlodipine. Patients receiving both a CYP2D6 inhibitor plus amlodipine may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Additionally, aripiprazole may enhance the hypotensive effects of antihypertensive agents such as amlodipine. Aripiprazole is a CYP3A and CYP2D6 substrate; amlodipine is a weak CYP3A inhibitor.
Armodafinil: (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 armodafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Articaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
Asenapine: (Moderate) Secondary to alpha-blockade, asenapine can produce vasodilation that may result in additive effects during concurrent use of antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of asenapine and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Aspirin, ASA; Butalbital; Caffeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like amlodipine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amlodipine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and atazanavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Atazanavir; Cobicistat: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and atazanavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Atenolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Atenolol; Chlorthalidone: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Avanafil: (Moderate) Monitor blood pressure closely during concomitant use of avanafil and amlodipine as coadministration may increase the risk of additive hypotension. Avanafil is a substrate of CYP3A and amlodipine is a CYP3A inhibitor. Coadministration with amlodipine increased the AUC of avanafil by approximately 70% and the half-life was prolonged to approximately 10 hours. A mean maximum decrease in supine systolic blood pressure of 1.2 mmHg (compared to placebo), accompanied by a mean maximum increase in pulse rate of 1 beat per minute was observed.
Baclofen: (Moderate) Baclofen has been associated with hypotension. Concurrent use with baclofen and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
Barbiturates: (Major) Barbiturates may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine, and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers; monitor blood pressure closely.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with amlodipine may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of amlodipine in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If amlodipine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Amlodipine is a weak inhibitor of CYP3A4.
Benzphetamine: (Minor) Benzphetamine might increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Berotralstat: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with berotralstat is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; berotralstat is a P-gp inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with berotralstat is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Beta-blockers: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Betaxolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Bexarotene: (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 bexarotene, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Bisoprolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Bortezomib: (Moderate) Patients on antihypertensive agents receiving bortezomib treatment may require close monitoring of their blood pressure and dosage adjustment of their medication. During clinical trials of bortezomib, hypotension was reported in roughly 12 percent of patients. (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like HMG-CoA reductase inhibitors; the risk of peripheral neuropathy may be additive.
Bosentan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with bosentan is necessary. Amlodipine is a CYP3A4 substrate and bosentan is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Brigatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with brigatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate. Brigatinib is a P-gp inhibitor in vitro and may have the potential to increase concentrations of P-gp substrates.
Brimonidine; Timolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Brompheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Brompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Bupivacaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
Bupivacaine; Meloxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Butabarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Acetaminophen: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Acetaminophen; Caffeine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations. (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations. (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Cabergoline: (Moderate) Cabergoline should be used cautiously with antihypertensive agents, including amlodipine. Cabergoline has been associated with hypotension. Initial doses higher than 1 mg may produce orthostatic hypotension. It may be advisable to monitor blood pressure.
Calcium: (Minor) Monitor blood pressure during concurrent use of calcium and calcium-channel blockers. Concomitant use may reduce the response to calcium-channel blockers.
Cannabidiol: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with cannabidiol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; cannabidiol is a P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions including myopathy and rhabdomyolysis if coadministration with capmatinib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and a substrate of the efflux transporter BCRP. Capmatinib is a P-gp and BCRP inhibitor. If coadministration is unavoidable, consider a decrease in the atorvastatin dosage in accordance with the approved atorvastatin prescribing information and clinical goals for the patient.
Carbamazepine: (Moderate) Carbamazepine, which is a CYP3A4 inducer, may decrease the efficacy of HMG-Co-A reductase inhibitors which are CYP3A4 substrates, such as atorvastatin. (Moderate) Monitor carbamazepine concentrations and blood pressure closely during coadministration of amlodipine; carbamazepine dose adjustments may be needed. Concomitant use may increase carbamazepine concentrations. Carbamazepine is a CYP3A substrate and strong inducer and amlodipine is CYP3A substrate and inhibitor. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Carbidopa; Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Carbidopa; Levodopa; Entacapone: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Carteolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Carvedilol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis. (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with carvedilol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; carvedilol is a P-gp inhibitor.
Celecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist. (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Cenobamate: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with cenobamate is necessary. Amlodipine is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Ceritinib: (Major) Consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness) if coadministration of atorvastatin with ceritinib is required, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ceritinib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration of ceritinib with atorvastatin may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ceritinib is necessary; adjust the dose of amlodipine as clinically appropriate. Ceritinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Cetirizine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chloramphenicol: (Moderate) Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as chloramphenicol, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when chloramphenicol is coadministered with amlodipine; therapeutic response should be monitored.
Chloroprocaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
Chlorpheniramine; Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with amlodipine may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of amlodipine could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If amlodipine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Amlodipine is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Chlorpheniramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Chlorpheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Cimetidine: (Moderate) Use HMG-CoA reductase inhibitors with caution with concomitant drugs that may decrease the levels or activity of endogenous steroids, such as cimetidine. Evaluate patients with signs and symptoms of endocrine dysfunction appropriately. HMG-CoA reductase inhibitors interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production.
Ciprofloxacin: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking ciprofloxacin. Coadministration of ciprofloxacin, a moderate CYP3A4 inhibitor, with atorvastatin, a CYP3A4 substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ciprofloxacin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ciprofloxacin is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Cisapride: (Moderate) Use caution when administering amlodipine with cisapride. Taking these drugs together may increase cisapride plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; cisapride is a substrate of CYP3A4 with a narrow therapeutic index.
Clarithromycin: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Clobazam: (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 clobazam, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Clopidogrel: (Moderate) Monitor for reduced therapeutic response to clopidogrel when it is coadministered with amlodipine. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that calcium channel blocker (CCB)-induced inhibition of CYP3A4 reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Because amlodipine has represented the largest subgroup of CCB studied, it is unknown whether this is a class effect. It has been theorized that CCBs that inhibit P-glycoprotein (P-gp) decrease the intestinal efflux of clopidogrel, thereby increasing its plasma concentrations and counteracting the effect of CCB-induced CYP3A4 inhibition. Amlodipine is not a P-gp inhibitor.
Clozapine: (Moderate) Clozapine used concomitantly with the antihypertensive agents can increase the risk and severity of hypotension by potentiating the effect of the antihypertensive drug.
Cobicistat: (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting

dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Cocaine: (Major) Use of cocaine with antihypertensive agents may increase the antihypertensive effects of the antihypertensive medications or may potentiate cocaine-induced sympathetic stimulation.
Codeine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Codeine; Guaifenesin: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Codeine; Phenylephrine; Promethazine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations. (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Codeine; Promethazine: (Moderate) Monitor for an increase in codeine-related adverse reactions including sedation and respiratory depression if coadministration with amlodipine is necessary; adjust the dose of codeine if necessary. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Amlodipine is a weak CYP3A4 inhibitor. Concomitant use may result in an increase in codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and increased morphine concentrations.
Co-Enzyme Q10, Ubiquinone: (Moderate) Co-enzyme Q10, ubiquinone (CoQ10) may lower blood pressure. CoQ10 use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients who choose to take CoQ10 concurrently with antihypertensive medications should receive periodic blood pressure monitoring. Patients should be advised to inform their prescriber of their use of CoQ10.
Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
Colestipol: (Moderate) Coadministration of atorvastatin with colestipol resulted in approximately 25% lower plasma concentrations of atorvastatin. However, LDL-cholesterol reduction was greater when atorvastatin and colestipol were administered together than when either drug was given alone.
Conivaptan: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with conivaptan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; conivaptan is a P-gp inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with conivaptan is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; conivaptan is a moderate CYP3A inhibitor. Concomitant use of amlodipine and oral conivaptan doubled amlodipine's overall exposure in a drug interaction study.
Conjugated Estrogens; Bazedoxifene: (Minor) In clinical evaluation, atorvastatin 20 mg was given once with bazedoxifene 40 mg in 30 postmenopausal women. Co-administration decreased the Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%. The clinical effect of this change is not known. Monitor patients for loss of efficacy and increased side effects during conjugated estrogens; bazedoxifene therapy. In addition, bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration decreased the Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively. The possibility of reduced anti-lipemic efficacy should be considered; however, the clinical relevance of this interaction has not been determined, since the AUC (exposure) of atorvastatin remained unchanged.
Crizotinib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with crizotinib is necessary; adjust the dose of amlodipine as clinically appropriate. Crizotinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Cyclosporine: (Major) FDA-approved labeling recommends avoiding coadministration of atorvastatin and cyclosporine. However, guidelines recommend limiting the atorvastatin dose to 10 mg/day in patients receiving cyclosporine. Concomitant administration increases the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate for OATP1B1 transporter; cyclosporine is an inhibitor of this transporter. Concomitant administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a significantly higher atorvastatin AUC (8.7-fold higher) compared to that of atorvastatin alone. (Moderate) Caution should be used when cyclosporine is coadministered with amlodipine; therapeutic response should be monitored, including cyclosporine levels as necessary. Amlodipine may increase cyclosporine concentrations. In one study, whole blood cyclosporine trough concentrations increased from 140.2 +/- 18.2 to 200 +/- 21.9 mcg/L after amlodipine addition. In another study, the systemic exposure (AUC) of cyclosporine increased following the addition of amlodipine, and was decreased in the absence of the drug. The postulated mechanism is the inhibitory effect of amlodipine on the P-glycoprotein-mediated efflux of cyclosporine from intestinal epithelial cells. In addition, amlodipine is a weak inhibitor of CYP3A4; cyclosporine is a substrate with a narrow therapeutic index. Also, amlodipine is a CYP3A4 substrate and theoretically, cyclosporine, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals.
Dabrafenib: (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 dabrafenib, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Daclatasvir: (Moderate) Caution and close monitoring is advised if daclatasvir is administered with HMG-CoA reductase inhibitors (Statins). Use of these drugs together may result in elevated Statin serum concentrations, potentially resulting in adverse effects such as myopathy and rhabdomyolysis.
Dalfopristin; Quinupristin: (Moderate) Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
Danazol: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as danazol , are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required. (Moderate) The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with atorvastatin. Danazol is a CYP3A4 inhibitor and may inhibit the metabolism of atorvastatin, a CYP3A4 substrate. Until more data are available, danazol should be used very cautiously, if at all, in patients receiving statins which are CYP3A4 substrates.
Dantrolene: (Moderate) Concurrent use with skeletal muscle relaxants and antihypertensive agents may result in additive hypotension. Dosage adjustments of the antihypertensive medication may be required.
Daptomycin: (Major) Temporarily suspend HMG-CoA reductase inhibitors in patients taking daptomycin as cases of rhabdomyolysis have been reported with concomitant use. Both agents can cause myopathy and rhabdomyolysis when given alone and the risk may be increased when given together.
Darolutamide: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with darolutamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; darolutamide is a BCRP and OATP1B1/3 inhibitor.
Darunavir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Darunavir; Cobicistat: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Deferasirox: (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 deferasirox, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Delavirdine: (Major) The risk of myopathy, including rhabdomyolysis, may be increased when delavirdine is given in combination with HMG-CoA reductase inhibitors. Coadminister delavirdine and atorvastatin cautiously; use the lowest possible dose of atorvastatin. Delavirdine is a potent inhibitor of CYP3A4. Atorvastatin is a substrate of CYP3A4. If these drugs are coadministered, carefully monitor the patient. If treatment with an HMG-CoA reductase inhibitor is necessary, pravastatin should also be considered, since it is not significantly metabolized by CYP3A4 or CYP2C9 isoenzymes. (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as delavirdine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when delavirdine is coadministered with amlodipine; therapeutic response should be monitored.
Desloratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Desogestrel; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Dexbrompheniramine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Dexmedetomidine: (Moderate) Concomitant administration of dexmedetomidine and calcium-channel blockers could lead to additive hypotension and bradycardia; use together with caution. Dexmedetomidine can produce bradycardia or AV block and should be used cautiously in patients who are receiving antihypertensive drugs that may lower the heart rate such as calcium-channel blockers.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Dextromethorphan; Quinidine: (Moderate) Monitor for increased quinidine adverse reactions if coadministered with amlodipine. Taking these drugs together may increase quinidine plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; quinidine is a substrate of CYP3A4 with a narrow therapeutic index. In addition, quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
Diazoxide: (Moderate) Additive hypotensive effects can occur with the concomitant administration of diazoxide with other antihypertensive agents. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly. The manufacturer advises that IV diazoxide should not be administered to patients within 6 hours of receiving other antihypertensive agents.
Diclofenac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Diclofenac; Misoprostol: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Diethylpropion: (Major) Diethylpropion has vasopressor effects and may limit the benefit of calcium-channel blockers. Although leading drug interaction texts differ in the potential for an interaction between diethylpropion and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.
Diflunisal: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Digoxin: (Major) Measure serum digoxin concentrations before initiating atorvastatin. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Coadministration of digoxin and atorvastatin increases the serum concentration and AUC of digoxin by 22% and 15%, respectively. Digoxin and atorvastatin are both substrates for P-glycoprotein (P-gp).
Diltiazem: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with diltiazem is necessary. Atorvastatin is a CYP3A substrate; diltiazem is a CYP3A inhibitor. Concomitant use has been shown to increase atorvastatin overall exposure by 1.5-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with diltiazem is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and diltiazem is a moderate CYP3A inhibitor. Coadministration with diltiazem in elderly hypertensive patients increased systemic exposure to amlodipine by 60%.
Diphenhydramine; Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Diphenhydramine; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Diphenhydramine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with amlodipine is necessary. Amlodipine is a weak CYP3A4 inhibitor. Dofetilide is a minor CYP3A4 substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dorzolamide; Timolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with amlodipine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; amlodipine is a weak inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A and is an inhibitor of CYP3A, CYP2D6, and P-gp. Atorvastatin is a substrate for CYP3A4 and P-gp. Monitor for signs and symptoms of myopathy in patients receiving dronedarone concurrently with atorvastatin. (Moderate) Monitor for evidence of hypotension and edema if amlodipine is coadministered with dronedarone; an amlodipine dose adjustment may be necessary due to increased amlodipine exposure. Dronedarone is a moderate CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate.
Drospirenone; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Duloxetine: (Moderate) Orthostatic hypotension and syncope have been reported during duloxetine administration. The concurrent administration of antihypertensive agents and duloxetine may increase the risk of hypotension. Monitor blood pressure if the combination is necessary.
Dutasteride; Tamsulosin: (Moderate) The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
Duvelisib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with duvelisib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and duvelisib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Efavirenz: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution. (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution. (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Efavirenz has the potential to induce CYP3A4 isoenzymes according to in vivo studies with other CYP3A4 substrates. Until data with HMG-CoA reductase inhibitors are available, efavirenz should be coadministered with atorvastatin with caution. (Moderate) Monitor blood pressure if amlodipine and efavirenz are used concomitantly. Amlodipine is a CYP3A4 substrate; efavirenz induces CYP3A4. In addition, monitor for an increase in efavirenz-related adverse reactions if coadministration with amlodipine is necessary. Efavirenz is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor; concomitant use may increase plasma concentrations of efavirenz.
Elacestrant: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elacestrant is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a substrate of BCRP and P-gp; elacestrant inhibits BCRP and P-gp.
Elagolix: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with elagolix is necessary. Amlodipine is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Elagolix; Estradiol; Norethindrone acetate: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with elagolix is necessary. Amlodipine is a CYP3A4 substrate and elagolix is a weak to moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Elbasvir; Grazoprevir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with grazoprevir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a substrate for the hepatic enzymes CYP3A; grazoprevir is a weak CYP3A inhibitor. (Moderate) Administering elbasvir; grazoprevir with amlodipine may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Amlodipine is a substrate and weak inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with elexacaftor is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is an OATP1B1/3 substrate; elexacaftor is an OATP1B1/3 inhibitor.
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of amlodipine and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Amlodipine is a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients. (Moderate) Coadministration of atorvastatin and eliglustat may result in increased plasma concentrations of atorvastatin. Monitor patients closely for atorvastatin-related adverse effects including myalgia, myopathy, myasthenia, and/or rhabdomyolysis; if appropriate, consider reducing the atorvastatin dosage and titrating to clinical effect. Atorvastatin is a P-glycoprotein (P-gp) substrate; eliglustat is a P-gp inhibitor.
Eltrombopag: (Moderate) Eltrombopag is an inhibitor of the transporter OATP1B1. Drugs that are substrates for this transporter, such as atorvastatin, may exhibit an increase in systemic exposure if coadministered with eltrombopag; monitor patients for adverse reactions if these drugs are coadministered.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Empagliflozin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Empagliflozin; Linagliptin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Empagliflozin; Linagliptin; Metformin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Empagliflozin; Metformin: (Moderate) Administer antidiabetic agents with caution in patients receiving calcium-channel blockers. These drugs may cause hyperglycemia leading to a temporary loss of glycemic control in patients receiving antidiabetic agents. Close observation and monitoring of blood glucose is necessary to maintain adequate glycemic control.
Enasidenib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with enasidenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp, BCRP, and OATP1B1/3 substrate; enasidenib is a P-gp, BCRP, and OATP1B1/3 inhibitor.
Encorafenib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with encorafenib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a substrate of OATP1B1/3 and BCRP; encorafenib is an OATP1B1/3 and BCRP inhibitor.
Enzalutamide: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with enzalutamide is necessary. Amlodipine is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Ephedrine: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
Ephedrine; Guaifenesin: (Major) The cardiovascular effects of sympathomimetics, such as ephedrine, may reduce the antihypertensive effects produced by calcium-channel blockers. Blood pressure and heart rates should be monitored closely to confirm that the desired antihypertensive effect is achieved.
Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
Epirubicin: (Moderate) Close cardiac monitoring is recommended throughout therapy in patients receiving concomitant therapy with epirubicin and calcium-channel blockers. Individuals receiving these medications together are at increased risk of developing heart failure.
Eplerenone: (Moderate) Amlodipine can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Epoprostenol: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Erythromycin: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with erythromycin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and erythromycin is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with erythromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a CYP3A and OATP1B1/3 substrate; erythromycin is a moderate CYP3A and OATP1B1/3 inhibitor.
Eslicarbazepine: (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as amlodipine, may result in decreased serum concentrations of the substrates. Monitor for potential reduced cholesterol-lowering and hypotensive efficacy when these drugs are coadministered with eslicarbazepine. Appropriate dose adjustments may be necessary. (Minor) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atorvastatin, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atorvastatin if coadministered with eslicarbazepine. Adjust the dose of atorvastatin if clinically significant alterations in serum lipids are noted.
Esmolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Estradiol: (Minor) Estrogens can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with hormonal contraceptives should be monitored for antihypertensive effectiveness.
Ethinyl Estradiol; Norelgestromin: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Ethinyl Estradiol; Norgestrel: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Ethosuximide: (Moderate) Monitor for increased ethosuximide adverse reactions if coadministered with amlodipine. Taking these drugs together may increase ethosuximide plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; ethosuximide is a substrate of CYP3A4 with a narrow therapeutic index.
Ethotoin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Etodolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Etomidate: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Etonogestrel; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Etravirine: (Moderate) Concomitant use of etravirine and atorvastatin decreases atorvastatin serum concentrations and increases concentrations of the metabolite, 2-OH-atorvastatin. Atorvastatin may be a substrate of the CYP3A4 isoenzyme and etravirine induces the CYP3A4 isoenzyme. According to the manufacturer of etravirine, atorvastatin can be given without any dose adjustments, although its dose may need to be altered based on clinical response. The risk of myopathy, including rhabdomyolysis, may be increased when antiretrovirals are given in combination with HMG-CoA reductase inhibitors. (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 etravirine, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Everolimus: (Moderate) Carefully weigh the benefits of combined use of everolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Although FDA-approved labeling for everolimus state that dosage adjustments are not necessary, guidelines recommend maximum atorvastatin doses of 10 mg/day unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. In a drug interaction study in healthy subjects, the pharmacokinetics of atorvastatin were not significantly altered by single dose administration of everolimus.
Ezetimibe; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Fedratinib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fedratinib is necessary; adjust the dose of amlodipine as clinically appropriate. Fedratinib is a moderate CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Fenofibrate: (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with fenofibrate is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Fenofibric Acid: (Moderate) Use caution and the lowest atorvastatin dose necessary if coadministration with fenofibric acid is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
Fenoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If amlodipine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fexofenadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or amlodipine; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
Fluconazole: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with fluconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a CYP3A substrate; fluconazole is a CYP3A inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with fluconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and fluconazole is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Flurbiprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Flutamide: (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 flutamide, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Fluvoxamine: (Moderate) A dose reduction of amlodipine may be required during coadministration of fluvoxamine. Administering amlodipine with CYP3A4 inhibitors, such as fluvoxamine, may increase plasma concentrations of amlodipine, which might lead to hypotension and peripheral edema in some individuals.
Fosamprenavir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with fosamprenavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Fosphenytoin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Fostemsavir: (Moderate) Use the lowest possible starting dose for atorvastatin when administered concurrently with fostemsavir and monitor for signs of atorvastatin-associated adverse events, such as rhabdomyolysis. Use of these drugs together may increase the systemic exposure of atorvastatin. Atorvastatin is a substrate for the transporters OATP1B1/3 and fostemsavir is an inhibitor of OATP1B1/3.
Futibatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with futibatinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; futibatinib is a P-gp and BCRP inhibitor.
Gemfibrozil: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with gemfibrozil is necessary due to an increased risk of myopathy and rhabdomyolysis. Clinical practice guidelines state the concurrent use of gemfibrozil and atorvastatin is acceptable if clinically indicated and fenofibrate or fenofibric acid is not an option. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy.
General anesthetics: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Gilteritinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with gilteritinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; gilteritinib is a P-gp and BCRP inhibitor.
Ginkgo, Ginkgo biloba: (Moderate) Ginkgo biloba appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginkgo with nifedipine resulted in a 53% increase in nifedipine peak concentrations. More study is needed regarding ginkgo's effects on CYP3A4 and whether clinically significant drug interactions result.
Ginseng, Panax ginseng: (Moderate) Ginseng appears to inhibit the metabolism of calcium-channel blockers, perhaps by inhibiting the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that the concurrent administration of ginseng with nifedipine resulted in a 30% increase in nifedipine peak concentrations. More study is needed regarding ginseng's effects on CYP3A4 and whether clinically significant drug interactions result.
Glecaprevir; Pibrentasvir: (Major) Avoid the concurrent use of atorvastatin and glecaprevir due to an increased risk of myopathy/rhabdomyolysis. Coadministration may increase the plasma concentrations of atorvastatin. Atorvastatin is a substrate of the drug transporters P-glycoprotein (P-gp) and OATP1B1/3; glecaprevir is an inhibitor of these transporters. In drug interaction studies, coadministration of atorvastatin with glecaprevir; pibrentasvir resulted in an approximately 8-fold increase in the AUC of atorvastatin. (Major) Avoid the concurrent use of atorvastatin and pibrentasvir due to an increased risk of myopathy/rhabdomyolysis. Coadministration may increase the plasma concentrations of atorvastatin. Atorvastatin is a substrate of the drug transporters P-glycoprotein (P-gp) and OATP1B1; pibrentasvir is an inhibitor of these transporters. In drug interaction studies, coadministration of atorvastatin with glecaprevir; pibrentasvir resulted in an approximately 8-fold increase in the AUC of atorvastatin.
Grapefruit juice: (Major) Avoid grapefruit juice quantities greater than 1.2 L daily in patients taking atorvastatin to avoid the potential for drug accumulation and toxicity (i.e., myopathy and rhabdomyolysis), Grapefruit juice contains a compound that inhibits the CYP3A4 isozyme in the gut wall. In one pharmacokinetic study, coadministration of 240 mL grapefruit juice once daily with a single 40 mg dose of atorvastatin resulted in a 37% increase in the AUC and a 16% increase in Cmax of atorvastatin. Excessive consumption of grapefruit juice (i.e., 750 mL to 1.2 L/day) has been reported to result in an up to 2.5-fold increase in AUC and/or a 71% increase in Cmax of atorvastatin.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guaifenesin; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Guaifenesin; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Haloperidol: (Moderate) In general, antipsychotics like haloperidol should be used cautiously with antihypertensive agents due to the possibility of additive hypotension.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydantoins: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for a decrease in atorvastatin efficacy if concomitant use with phenytoin is necessary. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and phenytoin is a strong CYP3A inducer.
Hydralazine; Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like amlodipine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If amlodipine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Ibuprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ibuprofen; Famotidine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like amlodipine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amlodipine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ibuprofen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Idelalisib: (Major) Coadministration of idelalisib with atorvastatin may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Idelalisib is a strong CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate. (Moderate) Coadministration of idelalisib with amlodipine may increase the systemic exposure of amlodipine resulting in amlodipine-related adverse events. Consider an amlodipine dose reduction if these agents are administered together and monitor for symptoms of hypotension and edema.
Iloperidone: (Moderate) Secondary to alpha-blockade, iloperidone can produce vasodilation that may result in additive effects during concurrent use with antihypertensive agents. The potential reduction in blood pressure can precipitate orthostatic hypotension and associated dizziness, tachycardia, and syncope. If concurrent use of iloperidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Iloprost: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Imatinib: (Major) The risk of developing myopathy during therapy with atorvastatin, a CYP3A4 substrate, is increased if coadministered with imatinib, STI-571, a CYP3A4 inhibitor. When possible, avoid concurrent use of HMG-reductase inhibitors with drugs known to increase the risk of developing rhabdomyolysis or acute renal failure. The serious risk of myopathy or rhabdomyolysis should be weighed carefully versus the benefits of combined atorvastatin and imatinib, STI-571 therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as imatinib, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when imatinib is coadministered with amlodipine; therapeutic response should be monitored.
Indinavir: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with indinavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with CYP3A4 inhibitors such as indinavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and protease inhibitor therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Indomethacin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Intravenous Lipid Emulsions: (Moderate) High doses of fish oil supplements may produce a blood pressure lowering effect. It is possible that additive reductions in blood pressure may be seen when fish oils are used in a patient already taking antihypertensive agents.
Isavuconazonium: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with isavuconazonium is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Isavuconazole, the active moiety of isavuconazonium, inhibits the CYP3A4-mediated metabolism and P-glycoprotein (P-gp)-mediated transport of atorvastatin. (Moderate) Concomitant use of isavuconazonium with amlodipine may result in increased serum concentrations of amlodipine. Amlodipine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
Isoflurane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Coadministration of atorvastatin with rifampin may result in variable decreases in atorvastatin exposures, with the potential for reduced antilipemic efficacy. If concomitant use of these drugs is required, atorvastatin and rifampin should be simultaneously administered. Atorvastatin is a CYP3A4 and OATP1B1 substrate. Rifampin is a strong CYP3A4 inducer and OATP1B1 inhibitor. As a result of the dual interaction mechanisms, delayed administration of atorvastatin after rifampin administration has been associated with a significant reduction in atorvastatin plasma concentrations. To evaluate this interaction, monitor serum lipid concentrations during coadministration. (Moderate) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of calcium-channel blockers. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Isoniazid, INH; Rifampin: (Moderate) Coadministration of atorvastatin with rifampin may result in variable decreases in atorvastatin exposures, with the potential for reduced antilipemic efficacy. If concomitant use of these drugs is required, atorvastatin and rifampin should be simultaneously administered. Atorvastatin is a CYP3A4 and OATP1B1 substrate. Rifampin is a strong CYP3A4 inducer and OATP1B1 inhibitor. As a result of the dual interaction mechanisms, delayed administration of atorvastatin after rifampin administration has been associated with a significant reduction in atorvastatin plasma concentrations. To evaluate this interaction, monitor serum lipid concentrations during coadministration. (Moderate) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of calcium-channel blockers. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Isoproterenol: (Moderate) The pharmacologic effects of isoproterenol may cause an increase in blood pressure. If isoproterenol is used concomitantly with antihypertensives, the blood pressure should be monitored as the administration of isoproterenol can compromise the effectiveness of antihypertensive agents.
Isosorbide Dinitrate, ISDN: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Isosorbide Mononitrate: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Istradefylline: (Moderate) Monitor for atorvastatin-related adverse reactions (i.e., myopathy/rhabdomyolysis) if coadministration of istradefylline 40 mg daily is necessary as atorvastatin exposure may be increased. Atorvastatin is a CYP3A4 and P-gp substrate; istradefylline administered as 40 mg daily is a weak inhibitor of CYP3A4 and P-gp. Coadministration of atorvastatin and istradefylline 40 mg daily increased the atorvastatin exposure by 1.5-fold.
Itraconazole: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with itraconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Itraconazole inhibits the CYP3A4 metabolism of atorvastatin. Itraconazole increases the AUC of atorvastatin by 2.5 to 3.3-fold, which is substantially less than the effect of itraconazole on the AUC of simvastatin and lovastatin (increased 19-fold and 20-fold, respectively). (Moderate) Calcium-channel blockers can have a negative inotropic effect that may be additive to those of itraconazole. In addition, itraconazole may increase amlodipine serum concentrations via inhibition of CYP3A4 with the potential for amlodipine toxicity. Edema has been reported in patients receiving concomitantly itraconazole and amlodipine, therefore, caution is recommended when administering these medications in combination. A dosage reduction of the calcium-channel blocker may be appropriate.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of amlodipine is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Ketamine: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Ketoconazole: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with ketoconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Ketoconazole inhibits the CYP3A and P-gp-mediated metabolism of atorvastatin. In addition, HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis and should be used with caution when given concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Ketoprofen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Ketorolac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Labetalol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction, such as calcium-channel blockers, 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.
Lanreotide: (Moderate) Concomitant administration of bradycardia-inducing drugs (e.g., calcium-channel blockers) may have an additive effect on the reduction of heart rate associated with lanreotide. Adjust the calcium-channel blocker dose if necessary.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Lanthanum Carbonate: (Major) To limit absorption problems, HMG-CoA reductase inhibitors ("statins") should not be taken within 2 hours of dosing with lanthanum carbonate. Oral drugs known to interact with cationic antacids, like statin cholesterol treatments, may also be bound by lanthanum carbonate. Separate the times of administration appropriately. Monitor the patient's lipid profile to ensure the appropriate response to statin therapy is obtained.
Lasmiditan: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with lasmiditan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; lasmiditan is a P-gp inhibitor. (Moderate) Monitor heart rate if lasmiditan is coadministered with calcium-channel blockers as concurrent use may increase the risk for bradycardia. Lasmiditan has been associated with lowering of heart rate. In a drug interaction study, addition of a single 200 mg dose of lasmiditan to another heart rate lowering drug decreased heart rate by an additional 5 beats per minute.
Ledipasvir; Sofosbuvir: (Moderate) Caution and close monitoring of adverse reactions, such as myopathy and rhabdomyolysis, is advised with concomitant administration of atorvastatin and ledipasvir; sofosbuvir. Concurrent use may result in increased atorvastatin exposure. Atorvastatin is a substrate of the drug transporter P-glycoprotein (P-gp); ledipasvir is a P-gp inhibitor.
Lefamulin: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with oral lefamulin is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and oral lefamulin is a moderate CYP3A4 inhibitor; an interaction is not expected with intravenous lefamulin. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Leflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of leflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Lenacapavir: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with lenacapavir is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; lenacapavir is a P-gp and BCRP inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with lenacapavir is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; lenacapavir is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Leniolisib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with leniolisib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; leniolisib is an inhibitor of BCRP and OATP1B1/3.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of amlodipine; monitor blood pressure closely. Amlodipine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of amlodipine; monitor blood pressure closely. Amlodipine is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Major) Do not exceed an atorvastatin dosage of 20 mg daily and closely monitor for myopathy and rhabdomyolysis if coadministration with letermovir is necessary. Concurrent use is not recommended for patients who are also receiving cyclosporine, as the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of atorvastatin may occur during concurrent administration with letermovir. Atorvastatin is a substrate of CYP3A4 and the organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1/3). Both letermovir and cyclosporine are moderate inhibitors of CYP3A4 and inhibitors of OATP1B1; letermovir is also an OATP1B3 inhibitor. Coadministration of letermovir increased the AUC and Cmax of atorvastatin by 3.29-fold and 2.17-fold, respectively. The combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Amlodipine dose reductions may be required during concurrent administration with letermovir; monitor for symptoms of hypotension and edema to determine the need for dose adjustment. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Administering these drugs together may increase amlodipine concentration and risk for adverse events. Amlodipine is a substrate of CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Concurrent administration with a moderate CYP3A inhibitor increased amlodipine exposure by 60%; however, another moderate inhibitor did not significantly change amlodipine exposure. Strong CYP3A4 inhibitors may increase amlodipine exposure to a greater extent.
Levobunolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Levodopa: (Moderate) Concomitant use of antihypertensive agents with levodopa can result in additive hypotensive effects.
Levoketoconazole: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with ketoconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Ketoconazole inhibits the CYP3A and P-gp-mediated metabolism of atorvastatin. In addition, HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis and should be used with caution when given concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as ketoconazole. The clinical relevance of these potential interactions has not been established. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ketoconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Levonorgestrel; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
Lidocaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine. (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and amlodipine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; amlodipine inhibits CYP3A4.
Lisdexamfetamine: (Minor) Lisdexamfetamine might increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Lithium: (Moderate) Monitor for neurologic adverse reactions during concomitant use of lithium and calcium channel blockers. Concomitant use may increase the risk of neurologic adverse reactions, such as ataxia, tremors, nausea, vomiting, diarrhea, and/or tinnitus.
Lomitapide: (Major) Concomitant use of lomitapide and amlodipine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Amlodipine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors. (Major) Concomitant use of lomitapide and atorvastatin may result in increased lomitapide concentrations. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Atorvastatin is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Lonafarnib: (Contraindicated) Coadministration of atorvastatin and lonafarnib is contraindicated according to the manufacturer of lonafarnib. The manufacturer of atorvastatin recommends that if concomitant use of these drugs is required, a lower starting and maintenance dose of atorvastatin should be considered; monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 and P-gp substrate and lonafarnib is a strong CYP3A4 inhibitor and P-gp inhibitor. (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Lopinavir; Ritonavir: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with lopinavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); lopinavir is an OATP1B1 inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Loratadine; Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Lorlatinib: (Moderate) Monitor blood pressure if coadministration of amlodipine with lorlatinib is necessary. Amlodipine is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Concomitant use may decrease amlodipine plasma concentrations, decreasing efficacy.
Lovastatin: (Moderate) Carefully weigh the benefits of combined use of amlodipine and lovastatin against the potential risks. Lovastatin exposure may increase resulting in increased risk of myopathy/rhabdomyolysis. Although FDA-approved labeling for amlodipine or lovastatin do not suggest dose adjustments, guidelines recommend limiting the dose of lovastatin to 20 mg/day if combined with amlodipine. Lovastatin is a CYP3A4 substrate; amlodipine is a weak CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of atorvastatin; if used together, monitor serum lipid concentrations. Atorvastatin is a substrate of CYP3A4 and the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggests lumacaftor; ivacaftor may also induce and/or inhibit P-gp. While the induction of atorvastatin through the CYP3A pathway may lead to decreased plasma concentrations of atorvastatin, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of amlodipine. If used together, monitor blood pressure closely; the dosage requirements of amlodipine may be increased. Amlodipine is a CYP3A substrate. Lumacaftor is a strong CYP3A inducer.
Lurasidone: (Moderate) Due to the antagonism of lurasidone at alpha-1 adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents. If concurrent use of lurasidone and antihypertensive agents is necessary, patients should be counseled on measures to prevent orthostatic hypotension, such as sitting on the edge of the bed for several minutes prior to standing in the morning and rising slowly from a seated position. Close monitoring of blood pressure is recommended until the full effects of the combination therapy are known.
Maralixibat: (Minor) Maralixibat may reduce the oral absorption of HMG-CoA reductase inhibitors, also known as statins, which may reduce their efficacy. This risk is greatest with maralixibat doses greater than 4.75 mg. Monitor statin therapy and adjust the dose as needed based on clinical response. Maralixibat is a OATP2B1 inhibitor and statins are OATP2B1 substrates.
Maraviroc: (Minor) Use caution if coadministration of maraviroc with amlodipine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and amlodipine is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
Maribavir: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with maribavir is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; maribavir is a P-gp and BCRP inhibitor.
Mavacamten: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with mavacamten is necessary. Amlodipine is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Meclofenamate Sodium: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Mefenamic Acid: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Melatonin: (Moderate) Monitor blood pressure during concomitant calcium-channel blocker and melatonin use. Melatonin may impair the efficacy of calcium-channel blockers. In a placebo-controlled study, melatonin evening ingestion led to significant increases in blood pressure (6.5 mmHg systolic and 4.9 mmHg diastolic) and heart rate (3.9 bpm) throughout the day in patients taking a calcium channel blocker Melatonin appeared to antagonize the antihypertensive effects of the calcium channel blocker.
Meloxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Methadone: (Moderate) Frequently monitor for respiratory depression and sedation if concurrent use of amlodipine is necessary; consider reducing the dose of methadone if clinically appropriate. If amlodipine is discontinued, monitor for evidence of opioid withdrawal; consider increasing the methadone dose if needed. Methadone is a CYP3A4 substrate; coadministration with a weak CYP3A4 inhibitor like amlodipine can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory de pression, particularly when an inhibitor is added to a stable dose of methadone. If amlodipine is discontinued, methadone plasma concentrations may decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to methadone.
Methamphetamine: (Minor) Amphetamines increase both systolic and diastolic blood pressure and may counteract the activity of some antihypertensive agents, like calcium-channel blockers. Close monitoring of blood pressure is advised.
Methohexital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Methoxsalen: (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Methylergonovine: (Moderate) Be alert for symptoms of ergot toxicity if using methylergonovine and amlodipine together is medically necessary. An ergot alkaloid dose reduction may be necessary if these drugs are used together. Concomitant use of amlodipine, a weak CYP3A4 inhibitor, and methylergonovine, a CYP3A4 substrate, may result in increased ergot alkaloid levels.
Methylphenidate Derivatives: (Moderate) Periodic evaluation of blood pressure is advisable during concurrent use of methylphenidate derivatives and antihypertensive agents, particularly during initial coadministration and after dosage increases of methylphenidate derivatives. Methylphenidate derivatives can reduce the hypotensive effect of antihypertensive agents, including calcium-channel blockers.
Metoprolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Midostaurin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with midostaurin is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP and OATP1B1/3 substrate; midostaurin is a dual BCRP/OATP1B1 inhibitor.
Mifepristone: (Major) Coadministration of atorvastatin with mifepristone may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with mifepristone is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Milrinone: (Moderate) Concurrent administration of antihypertensive agents could lead to additive hypotension when administered with milrinone. Titrate milrinone dosage according to hemodynamic response.
Mitapivat: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with mitapivat is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; mitapivat is a P-gp inhibitor.
Mitotane: (Major) Use caution if mitotane and atorvastatin are used concomitantly, and monitor for decreased efficacy of atorvastatin and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and atorvastatin is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of atorvastatin. (Moderate) Use caution if mitotane and amlodipine are used concomitantly, and monitor for decreased efficacy of amlodipine and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and amlodipine is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of amlodipine.
Modafinil: (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 modafinil are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Nabumetone: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Nadolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Nafcillin: (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 nafcillin, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor. (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment.
Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Naproxen; Esomeprazole: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Naproxen; Pseudoephedrine: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease. (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Nebivolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Nebivolol; Valsartan: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Nefazodone: (Major) Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. There have been reports of rhabdomyolysis and myopathy when nefazodone has been administered to patients receiving statins metabolized by CYP3A4. Consider alternative therapy. Since pravastatin and rosuvastatin are not substantially metabolized and fluvastatin is a minor CYP3A4 substrate (20%), these statins are less likely to be significantly affected by CYP3A4 inhibitors such as nefazodone. (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as nefazodone, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when nefazodone is coadministered with amlodipine; therapeutic response should be monitored.
Nelfinavir: (Major) Do not exceed 40 mg/day of atorvastatin if coadministration with nelfinavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Neratinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with neratinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; neratinib is a P-gp inhibitor.
Nesiritide, BNP: (Major) The potential for hypotension may be increased when coadministering nesiritide with antihypertensive agents.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as netupitant, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine; valsartan may be required.
Neuromuscular blockers: (Moderate) Concomitant use of neuromuscular blockers and calcium-channel blockers may prolong neuromuscular blockade.
Nevirapine: (Moderate) Monitor for reduced cholesterol-lowering efficacy of atorvastatin if coadministration with nevirapine is necessary; a dose adjustment may be needed. Concomitant use may decrease atorvastatin exposure. Atorvastatin is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Niacin, Niacinamide: (Major) There is no clear indication for routine use of niacin in combination with atorvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with atorvastatin. Carefully weigh the potential benefits and risk of combined therapy. If coadministered, use the lowest atorvastatin dose necessary and closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Discontinue atorvastatin immediately if myopathy is diagnosed or suspected. (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Niacin; Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold. (Major) There is no clear indication for routine use of niacin in combination with atorvastatin. The addition of niacin to a statin has not been shown to reduce cardiovascular morbidity or mortality. In addition, lipid-modifying doses (1 g/day or more) of niacin increase the risk of myopathy and rhabdomyolysis when combined with atorvastatin. Carefully weigh the potential benefits and risk of combined therapy. If coadministered, use the lowest atorvastatin dose necessary and closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Discontinue atorvastatin immediately if myopathy is diagnosed or suspected. (Moderate) Cutaneous vasodilation induced by niacin may become problematic if high-dose niacin is used concomitantly with other antihypertensive agents, especially calcium-channel blockers. This effect is of particular concern in the setting of acute myocardial infarction, unstable angina, or other acute hemodynamic compromise.
Nicardipine: (Moderate) Monitor for evidence of myopathy if nicardipine is coadministered with atorvastatin. Nicardipine is an inhibitor of CYP3A4 isoenzymes. Coadministration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including atorvastatin.
Nilotinib: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as nilotinib, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required. (Moderate) Monitor for evidence of myopathy if atorvastatin is coadministered with nilotinib. Concurrent use may result in increased atorvastatin exposure. Nilotinib is a moderate CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate.
Nirmatrelvir; Ritonavir: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. (Major) Consider temporary discontinuation of atorvastatin during treatment with ritonavir-boosted nirmatrelvir; if this is not feasible, consider an alternative COVID-19 therapy. Atorvastatin does not need to be held prior to or after completing ritonavir-boosted nirmatrelvir. Coadministration may increase atorvastatin exposure resulting in increased toxicity. Atorvastatin is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Nitrates: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Nitroglycerin: (Moderate) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as calcium-channel blockers. Patients should be monitored more closely for hypotension if nitroglycerin, including nitroglycerin rectal ointment, is used concurrently with a calcium-channel blocker.
Nitroprusside: (Moderate) Additive hypotensive effects may occur when nitroprusside is used concomitantly with other antihypertensive agents. Dosages should be adjusted carefully, according to blood pressure.
Nonsteroidal antiinflammatory drugs: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Norethindrone; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Norgestimate; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Olanzapine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olanzapine; Fluoxetine: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Olanzapine; Samidorphan: (Moderate) Olanzapine may induce orthostatic hypotension and thus enhance the effects of antihypertensive agents.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Omeprazole; Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
Oritavancin: (Moderate) Amlodipine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of amlodipine may be reduced if these drugs are administered concurrently. (Moderate) Atorvastatin is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of atorvastatin may be reduced if these drugs are administered concurrently.
Oteseconazole: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with oteseconazole is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP substrate; oteseconazole is a BCRP inhibitor.
Oxaprozin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Oxcarbazepine: (Moderate) Monitor for potential reduced cholesterol-lowering efficacy when oxcarbazepine is coadministered with atorvastatin. Oxcarbazepine, which is a CYP3A4 inducer, may decrease the efficacy of atorvastatin, a CYP3A4 substrate. (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 oxcarbazepine, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like amlodipine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If amlodipine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Oxymetazoline: (Major) The vasoconstricting actions of oxymetazoline, an alpha adrenergic agonist, may reduce the antihypertensive effects produced by calcium-channel blockers. If these drugs are used together, closely monitor for changes in blood pressure.
Pacritinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pacritinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pacritinib is a P-gp and BCRP inhibitor.
Paliperidone: (Moderate) Paliperidone may cause orthostatic hypotension, thereby enhancing the hypotensive effects of antihypertensive agents. Orthostatic vital signs should be monitored in patients receiving paliperidone and calcium-channel blockers who are susceptible to hypotension.
Pasireotide: (Major) Pasireotide may cause a decrease in heart rate. Closely monitor patients who are also taking drugs associated with bradycardia such as calcium-channel blockers. Dose adjustments of calcium-channel blockers may be necessary.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and amlodipine, a CYP3A4 substrate, may cause an increase in systemic concentrations of amlodipine. Use caution when administering these drugs concomitantly. (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and atorvastatin, a CYP3A4 substrate, may cause an increase in systemic concentrations of atorvastatin. Use caution when administering these drugs concomitantly.
Pentobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Pentoxifylline: (Moderate) Pentoxifylline has been used concurrently with antihypertensive drugs (beta blockers, diuretics) without observed problems. Small decreases in blood pressure have been observed in some patients treated with pentoxifylline; periodic systemic blood pressure monitoring is recommended for patients receiving concomitant antihypertensives. If indicated, dosage of the antihypertensive agents should be reduced.
Perampanel: (Moderate) 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 perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Pexidartinib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with pexidartinib is necessary. Amlodipine is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with atorvastatin. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Phenelzine: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider.
Phenobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Phentermine; Topiramate: (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.
Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Phenytoin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with hydantoins is necessary. Amlodipine is a CYP3A4 substrate and hydantoins are strong CYP3A4 inducers. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Photosensitizing agents (topical): (Minor) Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Pindolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Pioglitazone: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Pioglitazone; Glimepiride: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Pioglitazone; Metformin: (Minor) Concentrations of atorvastatin may be decreased with concomitant use of pioglitazone. The effect of pioglitazone capistration on the systemic exposure of atorvastatin was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with atorvastatin 80 mg daily for 7 days resulted in a 14% and 23% reduction in atorvastatin AUC and Cmax, respectively. In addition, coadministration resulted in a 24% and 31% reduction in pioglitazone AUC and Cmax, respectively. Patients should be evaluated more frequently with respect to glycemic control and lipid therapy.
Piroxicam: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Pirtobrutinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pirtobrutinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pirtobrutinib is a P-gp and BCRP inhibitor.
Posaconazole: (Contraindicated) The concurrent use of posaconazole and atorvastatin is contraindicated due to the risk of myopathy, rhabdomyolysis, and acute renal failure. If treatment with posaconazole is unavoidable, a brief suspension of atorvastatin therapy can be considered. Coadministration of these drugs may result in elevated atorvastatin plasma concentrations, causing an increased risk for adverse events. Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme responsible for atorvastatin metabolism. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with posaconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Posaconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Prazosin: (Moderate) Prazosin is well-known to produce a 'first-dose' phenomenon. Some patients develop significant hypotension shortly after administration of the first dose. The first dose response (acute postural hypotension) of prazosin may be exaggerated in patients who are receiving beta-adrenergic blockers, diuretics, or other antihypertensive agents. Concomitant administration of prazosin with other antihypertensive agents is not prohibited, however. This can be therapeutically advantageous, but lower dosages of each agent should be used. The use of alpha-blockers with verapamil can lead to excessive hypotension; In addition, verapamil has been reported to increase the AUC and Cmax of prazosin.
Pretomanid: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with pretomanid is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; pretomanid is a P-gp and BCRP inhibitor.
Prilocaine; Epinephrine: (Moderate) Antihypertensives, including calcium-channel blockers, antagonize the vasopressor effects of parenteral epinephrine.
Primidone: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Probenecid; Colchicine: (Major) Use caution and the lowest HMG-CoA reductase inhibitor dose necessary if coadministration with colchicine is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that period monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Case reports exist describing the development of myotoxicity with the concurrent administration of colchicine and HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, fluvastatin, lovastatin, pravastatin).
Procainamide: (Moderate) Procainamide can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents. Intravenous administration of procainamide is more likely to cause hypotensive effects.
Promethazine; Phenylephrine: (Moderate) Phenylephrine's cardiovascular effects may reduce the antihypertensive effects of calcium-channel blockers. Well-controlled hypertensive patients receiving decongestant sympathomimetics at recommended doses do not appear to be at high risk for significant elevations in blood pressure; however, increased blood pressure (especially systolic hypertension) has been reported in some patients.
Propafenone: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with propafenone is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; propafenone is a P-gp inhibitor.
Propofol: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Propranolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Protease inhibitors: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Pseudoephedrine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Pseudoephedrine; Triprolidine: (Moderate) The cardiovascular effects of pseudoephedrine may reduce the antihypertensive effects produced by calcium-channel blockers. Monitor blood pressure and heart rate.
Quinidine: (Moderate) Monitor for increased quinidine adverse reactions if coadministered with amlodipine. Taking these drugs together may increase quinidine plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; quinidine is a substrate of CYP3A4 with a narrow therapeutic index. In addition, quinidine can decrease blood pressure and should be used cautiously in patients receiving antihypertensive agents due to the potential for additive hypotension.
Quinine: (Moderate) Coadministration of CYP3A4 inhibitors with amlodipine can theoretically decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inhibitors, such as quinine, are coadministered with calcium-channel blockers. Monitor therapeutic response; a dose reduction of amlodipine may be required. (Moderate) Patients receiving concomitant atorvastatin and quinine should be monitored closely for muscle pain or weakness. Lower starting doses of atorvastatin should be considered while patients are receiving quinine. Atorvastatin is a CYP3A4 substrate; therefore, quinine has the potential to inhibit the metabolism of atorvastatin leading to an increased potential of rhabdomyolysis.
Raltegravir: (Moderate) Raltegravir use has been associated with elevated creatinine kinase concentrations; myopathy and rhabdomyolysis have been reported. Use raltegravir cautiously with drugs that increase the risk of myopathy or rhabdomyolysis such as HMG-CoA reductase inhibitors (Statins).
Ranolazine: (Moderate) Ranolazine inhibits CYP3A isoenzymes and P-glycoprotein transport. Although not studied, ranolazine may theoretically increase plasma concentrations of CYP3A4 and/or P-glycoprotein substrates such as atorvastatin. Monitor serum lipid profile and for signs and symptoms of myopathy during coadministration.
Rasagiline: (Moderate) Additive hypotensive effects may be seen when monoamine oxidase inhibitors (MAOIs) are combined with antihypertensives. Careful monitoring of blood pressure is suggested during concurrent therapy of MAOIs with calcium-channel blockers. Patients should be instructed to rise slowly from a sitting position, and to report syncope or changes in blood pressure or heart rate to their health care provider during concurrent use of an MAOI and a calcium-channel blocker.
Red Yeast Rice: (Contraindicated) Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, red yeast rice should not be used in combination with HMG-CoA reductase inhibitors. The administration of more than one HMG-CoA reductase inhibitor at one time would be duplicative therapy and perhaps increase the risk of drug-related toxicity including myopathy and rhabdomyolysis.
Remifentanil: (Moderate) The risk of significant hypotension and/or bradycardia during therapy with remifentanil may be increased in patients receiving calcium-channel blockers due to additive hypotensive effects.
Ribociclib: (Major) If concomitant use of atorvastatin with ribociclib is necessary, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ribociclib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Ribociclib; Letrozole: (Major) If concomitant use of atorvastatin with ribociclib is necessary, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Ribociclib is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ribociclib is necessary; adjust the dose of amlodipine as clinically appropriate. Ribociclib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Rifabutin: (Moderate) Rifabutin may induce the CYP3A4 metabolism of calcium-channel blockers such as amlodipine and thereby reduce their oral bioavailability. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Rifampin: (Moderate) Coadministration of atorvastatin with rifampin may result in variable decreases in atorvastatin exposures, with the potential for reduced antilipemic efficacy. If concomitant use of these drugs is required, atorvastatin and rifampin should be simultaneously administered. Atorvastatin is a CYP3A4 and OATP1B1 substrate. Rifampin is a strong CYP3A4 inducer and OATP1B1 inhibitor. As a result of the dual interaction mechanisms, delayed administration of atorvastatin after rifampin administration has been associated with a significant reduction in atorvastatin plasma concentrations. To evaluate this interaction, monitor serum lipid concentrations during coadministration. (Moderate) Rifampin is a potent inducer of the cytochrome P450 hepatic enzyme system and can reduce the plasma concentrations and possibly the efficacy of calcium-channel blockers. The dosage requirements of amlodipine may be increased in patients receiving concurrent enzyme inducers.
Rifapentine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with rifapentine is necessary. Amlodipine is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and atorvastatin. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Risperidone: (Moderate) Risperidone has been associated with orthostatic hypotension and may enhance the hypotensive effects of antihypertensive agents. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medications. Lower initial doses or slower dose titration of risperidone may be necessary in patients receiving antihypertensive agents concomitantly.
Ritlecitinib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with ritlecitinib is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; ritlecitinib is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Ritonavir: (Major) Coadministration of atorvastatin and ritonavir may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Saquinavir: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with saquinavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Sarilumab: (Moderate) Utilize caution with concomitant use of sarilumab and CYP3A4 substrate drugs, such as atorvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by sarilumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping sarilumab. A 45% decrease in exposure to another "statin" was noted in a drug interaction study. In vitro, sarilumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Atorvastatin is a CYP3A4 substrate.
Secobarbital: (Minor) CYP3A4 inducers like the barbiturates may decrease the efficacy of atorvastatin, a CYP3A4 substrate. Monitor for potential reduced cholesterol-lowering efficacy when these drugs are co-administered.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. These increases should be considered when administering atorvastatin and oral contraceptives concomitantly. (Minor) Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients.
Selpercatinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with selpercatinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; selpercatinib is a P-gp inhibitor.
Sevoflurane: (Major) The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with general anesthetics may be potentiated by calcium-channel blockers. Alternatively, general anesthetics can potentiate the hypotensive effects of calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
Sildenafil: (Moderate) Monitor for additive hypotension if amlodipine is administered concurrently with sildenafil, as both agents act independently to reduce blood pressure. When sildenafil 100 mg was co-administered with amlodipine (5 mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure (SBP) was 8 mmHg systolic and 7 mmHg diastolic.
Silodosin: (Moderate) Monitor for adverse effects if silodosin is coadministered with amlodipine. The incidence of dizziness and orthostatic hypotension were increased in patients also receiving antihypertensive medications in clinical trials.
Siltuximab: (Moderate) Caution is warranted in patients receiving siltuximab who are taking CYP3A4 substrates, such as atorvastatin, in which a decreased effect would be undesirable. Monitor the patient's lipid profile as clinically indicated and adjust treatment as necessary. Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli, including cytokines such as interleukin-6 (IL-6). Inhibition of IL-6 signaling by siltuximab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. The effect of siltuximab on CYP450 enzyme activity can persist for several weeks after stopping therapy.
Simvastatin: (Major) Do not exceed a simvastatin dose of 20 mg/day in patients taking amlodipine due to increased risk of myopathy, including rhabdomyolysis. For patients chronically receiving simvastatin 80 mg/day who need to be started on amlodipine, consider switching to an alternative statin with less potential for interaction. Carefully weigh the benefits of combined use of amlodipine and simvastatin against the potential risks. Amlodipine increases the simvastatin exposure by approximately 1.5-fold.
Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by calcium-channel blockers. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of results.
Sirolimus: (Moderate) Carefully weigh the benefits of combined use of sirolimus and atorvastatin against the potential risks. The risk of myopathy/rhabdomyolysis may increase with concurrent use. Guidelines recommend limiting the dose of atorvastatin to 10 mg/day when combined with sirolimus unless there is close monitoring of creatinine kinase and symptoms of muscle-related toxicity. However, FDA-approved labeling for sirolimus states that no clinically significant drug-drug interaction was observed with atorvastatin in drug interaction studies and the two drugs may be administered without dose adjustment. (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of amlodipine. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Sodium Bicarbonate: (Moderate) Concomitant administration of atorvastatin with antacids reduced the plasma concentrations of atorvastatin by approximately 35 percent. However, LDL-cholesterol reduction was not altered.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with taurursodiol is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; taurursodiol is a P-gp and BCRP inhibitor.
Sofosbuvir; Velpatasvir: (Major) Monitor patients closely when atorvastatin is coadministered with velpatasvir as this may significantly increase the serum concentrations of atorvastatin, which may increase the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate of the P-glycoprotein (P-gp) and OATP1B1 transporters as well as CYP3A4, while velpatasvir inhibits P-gp, OATP1B1, and CYP3A4. (Moderate) Use caution when administering velpatasvir with amlodipine. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Monitor patients closely when atorvastatin is coadministered with velpatasvir as this may significantly increase the serum concentrations of atorvastatin, which may increase the risk of myopathy and rhabdomyolysis. Atorvastatin is a substrate of the P-glycoprotein (P-gp) and OATP1B1 transporters as well as CYP3A4, while velpatasvir inhibits P-gp, OATP1B1, and CYP3A4. (Moderate) Caution is advised when administering voxilaprevir with atorvastatin. Taking these drugs together may increase atorvastatin plasma concentrations; thereby increasing th e risk for adverse events, such as myopathy or rhabdomyolysis. Initiate atorvastatin at the lowest approved dose. If higher doses are needed, use the lowest necessary dose based on risk and benefit assessment. Atorvastatin is a substrate of P-glycoprotein (P-gp) and Organic Anion Transporting Polypeptides 1B1 (OATP1B1). Voxilaprevir is an inhibitor of both P-gp and OATP1B1. (Moderate) Use caution when administering velpatasvir with amlodipine. Taking these drugs together may increase velpatasvir plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; velpatasvir is a substrate of CYP3A4.
Sorafenib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sorafenib is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and sorafenib is a P-gp inhibitor in vitro. Sorafenib may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sotalol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Sotorasib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with sotorasib is necessary. Amlodipine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sotorasib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; sotorasib is a P-gp and BCRP inhibitor.
Sparsentan: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with sparsentan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; sparsentan is a P-gp and BCRP inhibitor.
Spironolactone: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
Spironolactone; Hydrochlorothiazide, HCTZ: (Minor) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends that caution should be exercised when atorvastatin is administered concomitantly with drugs that may decrease the concentrations or activity of endogenous hormones, such as spironolactone. The clinical relevance of these potential interactions has not been established.
St. John's Wort, Hypericum perforatum: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Coadministration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including atorvastatin.
Streptogramins: (Moderate) Dalfopristin; quinupristin has been shown to inhibit CYP3A4 and may decrease the elimination of atorvastatin, a CYP3A4 substrate.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if amlodipine must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of amlodipine is necessary. If amlodipine is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like amlodipine can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If amlodipine is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulindac: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Sumatriptan; Naproxen: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Tacrolimus: (Moderate) Carefully weigh the benefits of combined use of tacrolimus and atorvastatin against the potential risk of statin-induced myopathy/rhabdomyolysis. Guidelines recommend lower doses of statins in combination with tacrolimus. Atorvastatin doses above 10 mg/day are not recommended without close monitoring of creatinine kinase and symptoms of muscle-related toxicity. (Moderate) Monitor for increased tacrolimus adverse reactions if coadministered with amlodipine. Taking these drugs together may increase tacrolimus plasma concentrations, potentially resulting in adverse events. Amlodipine is a weak CYP3A4 inhibitor; tacrolimus is a substrate of CYP3A4 with a narrow therapeutic index.
Tamsulosin: (Moderate) The concomitant administration of tamsulosin with other antihypertensive agents can cause additive hypotensive effects. In addition, diltiazem, nicardipine, and verapamil may increase tamsulosin plasma concentrations via CYP3A4 inhibition. This interaction can be therapeutically advantageous, but dosages must be adjusted accordingly.
Temsirolimus: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions if coadministration with temsirolimus is necessary. Atorvastatin is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of atorvastatin. (Moderate) Monitor for signs and symptoms of angioedema if temsirolimus is administered concomitantly with amlodipine. Angioedema has been reported in patients taking mammalian target of rapamycin (mTOR) inhibitors in combination with amlodipine.
Tepotinib: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with tepotinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; tepotinib is a P-gp inhibitor.
Teriflunomide: (Major) Consider reducing the dose of HMG-CoA reductase inhibitors ("Statins" including atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin) during use of teriflunomide and monitor patients closely for signs and symptoms of myopathy. For a patient taking teriflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Teriflunomide is an inhibitor of the organic anion transporting polypeptide OATP1B1, and some statins are substrates for the OATP transporters. Teriflunomide may increase the exposure (AUC) of these statins. Increased concentrations of the statins increases the risk for myopathy and other statin-related side effects.
Tetrabenazine: (Moderate) Tetrabenazine may induce orthostatic hypotension and thus enhance the hypotensive effects of antihypertensive agents. Lower initial doses or slower dose titration of tetrabenazine may be necessary in patients receiving antihypertensive agents concomitantly.
Tetracaine: (Moderate) Local anesthetics may cause additive hypotension in combination with antihypertensive agents. Use extreme caution with the concomitant use of tetracaine and antihypertensive agents.
Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as calcium-channel blockers should be used cautiously due to the potential for additive bradycardia.
Thiothixene: (Moderate) Thiothixene should be used cautiously in patients receiving antihypertensive agents. Additive hypotensive effects are possible.
Timolol: (Moderate) Coadministration of amlodipine and beta-blockers can reduce angina and improve exercise tolerance. When these drugs are given together, however, hypotension and impaired cardiac performance can occur, especially in patients with left ventricular dysfunction, cardiac arrhythmias, or aortic stenosis.
Tipranavir: (Major) Avoid the concurrent use of atorvastatin and tipranavir used in combination with ritonavir due to the increased risk of developing myopathy/rhabdomyolysis. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Tocilizumab: (Moderate) Utilize caution with concomitant use of tocilizumab and CYP3A4 substrate drugs, such as atorvastatin, where a decrease in effectiveness is undesirable. Monitor lipid panels and adjust therapy as indicated. Inhibition of IL-6 signaling by tocilizumab may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates as compared to metabolism prior to treatment. This effect on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. A 57% decrease in the exposure of another "statin" was noted 1 week after a single tocilizumab dose. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Atorvastatin is a CYP3A4 substrate.
Tolmetin: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Topiramate: (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.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with amlodipine is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of amlodipine, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking verapamil. Coadministration of verapamil, a P-gp inhibitor, with atorvastatin, a P-gp substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Tranylcypromine: (Major) Avoid concomitant use of calcium-channel blockers and tranylcypromine due to the risk of additive hypotension. Potential for this interaction persists for up to 10 days after discontinuation of tranylcypromine (or 4 to 5 half-lives after discontinuation of the calcium-channel blocker). If a medication-free interval is not feasible, initiate therapy at the lowest appropriate dose and monitor blood pressure closely.
Trazodone: (Minor) Due to additive hypotensive effects, patients receiving antihypertensive agents concurrently with trazodone may have excessive hypotension. Decreased dosage of the antihypertensive agent may be required when given with trazodone.
Treprostinil: (Moderate) Calcium-channel blockers can have additive hypotensive effects with other antihypertensive agents. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with amlodipine and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and amlodipine is a weak CYP3A inhibitor.
Trofinetide: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with trofinetide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor.
Tucatinib: (Major) Coadministration of atorvastatin with tucatinib may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher doses of atorvastatin. If concomitant use of these drugs is required, consider a lower starting and maintenance dose of atorvastatin and monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Tucatinib is a strong CYP3A4 inhibitor; atorvastatin is a CYP3A4 substrate. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with tucatinib is necessary; adjust the dose of amlodipine as clinically appropriate. Tucatinib is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Valdecoxib: (Moderate) If nonsteroidal anti-inflammatory drugs (NSAIDs) and an antihypertensive drug are concurrently used, carefully monitor the patient for signs and symptoms of renal insufficiency and blood pressure control. Doses of antihypertensive medications may require adjustment in patients receiving concurrent NSAIDs. NSAIDs, to varying degrees, have been associated with an elevation in blood pressure. This effect is most significant in patients receiving concurrent antihypertensive agents and long-term NSAID therapy. NSAIDs cause a dose-dependent reduction in prostaglandin formation, which may result in a reduction in renal blood flow leading to renal insufficiency and an increase in blood pressure that are often accompanied by peripheral edema and weight gain. Patients who rely upon renal prostaglandins to maintain renal perfusion may have acute renal blood flow reduction with NSAID usage. Elderly patients may be at increased risk of adverse effects from combined long-term NSAID therapy and antihypertensive agents, especially diuretics, due to age-related decreases in renal function and an increased risk of stroke and coronary artery disease.
Valproic Acid, Divalproex Sodium: (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 valproic acid, divalproex sodium, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
Vemurafenib: (Moderate) Concomitant use of vemurafenib and atorvastatin may result in altered concentrations of atorvastatin and increased concentrations of vemurafenib. Vemurafenib is a substrate/inhibitor of P-glycoprotein (P-gp) and an inducer of CYP3A4. Atorvastatin is a substrate of P-gp and CYP3A4 and an inhibitor of P-gp. Use caution and monitor patients for toxicity and efficacy. (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as amlodipine, could be expected with concurrent use. Use caution, and monitor therapeutic effects of amlodipine when coadministered with vemurafenib.
Verapamil: (Moderate) Closely monitor for signs and symptoms of myopathy and rhabdomyolysis and consider atorvastatin dosage adjustment in patients also taking verapamil. Coadministration of verapamil, a P-gp inhibitor, with atorvastatin, a P-gp substrate, may increase atorvastatin exposure resulting in atorvastatin-related toxicity; the risk may be increased with higher statin doses. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with verapamil is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and verapamil is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A4 inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with calcium channel blockers is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use with calcium channel blockers could enhance the rate of verteporfin uptake by the vascular endothelium, resulting in enhanced photosensitivity.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with amlodipine is necessary. Vinorelbine is a CYP3A4 substrate and amlodipine is a weak CYP3A4 inhibitor.
Voclosporin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with voclosporin is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and OATP1B1 substrate; voclosporin is a P-gp and OATP1B1 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of clarithromycin and amlodipine, particularly in geriatric patients, due to an increased risk of hypotension and acute kidney injury. If the use of a macrolide antibiotic is necessary in a patient receiving amlodipine therapy, azithromycin is the preferred agent. If coadministration is unavoidable, monitor for symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. A retrospective, case crossover study, found the risk of hospitalization due to hypotension or shock to be significantly increased in geriatric patients exposed to clarithromycin during concurrent calcium-channel blocker therapy (OR 3.7, 95% CI 2.3-6.1). Concurrent use of azithromycin was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8-2.8). (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with clarithromycin is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Clarithromycin inhibits the CYP3A4 metabolism of atorvastatin.
Voriconazole: (Major) Use caution and the lowest atorvastatin dose necessary if coadministration with voriconazole is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Voriconazole inhibits the CYP3A4-mediated metabolism of atorvastatin. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voriconazole is necessary; adjust the dose of amlodipine as clinically appropriate. Voriconazole is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent.
Voxelotor: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with voxelotor is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate; voxelotor is a moderate CYP3A inhibitor. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with amlodipine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Amlodipine is a weak CYP3A4 inhibitor 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. (Moderate) Per the manufacturer of atorvastatin, a clinically significant effect on the prothrombin time when atorvastatin is administered to patients receiving chronic warfarin therapy has not been documented. In a study by the manufacturer, patients chronically maintained on warfarin were administered atorvastatin (80 mg/day) for 2 weeks. Mean prothrombin times decreased slightly, but only for the first few days of treatment. Per prescribing information for warfarin sodium (Coumadin), however, all HMG-CoA reductase inhibitors (statins), including atorvastatin, have been associated with potentiation of warfarin's clinical effect. In patients taking atorvastatin, it may be prudent to monitor the INR at baseline, at initiation of atorvastatin, and after subsequent dosage changes. Adjust warfarin dosage based on INR and clinical response. Once a stable INR is documented, the INR can be monitored at the intervals otherwise recommended based on the indication for anticoagulation and co-existing conditions.
Zafirlukast: (Minor) Zafirlukast is a CYP3A4 inhibitor which theoretically may decrease the hepatic metabolism of amlodipine, a CYP3A4 substrate.
Ziprasidone: (Minor) Ziprasidone is a moderate antagonist of alpha-1 receptors and may cause orthostatic hypotension with or without tachycardia, dizziness, or syncope. Additive hypotensive effects are possible if ziprasidone is used concurrently with antihypertensive agents.
Zonisamide: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with zonisamide is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp substrate; zonisamide is a P-gp inhibitor.

Amlodipine Besylate, Atorvastatin Calcium/Amlodipine, Atorvastatin/Caduet Oral Tab: 10-10mg, 10-20mg, 10-40mg, 10-80mg, 2.5-10mg, 2.5-20mg, 2.5-40mg, 5-10mg, 5-20mg, 5-40mg, 5-80mg

Adults

10 mg/day PO amlodipine and 80 mg/day PO atorvastatin.

Elderly

5—10 mg/day amlodipine (based on tolerance and clinical response) and 80 mg/day PO atorvastatin.

Adolescents

5 mg/day PO amlodipine and 20 mg/day PO atorvastatin.

Children

>= 10 years: 5 mg/day PO amlodipine and 20 mg/day PO atorvastatin.
< 10 years: Safety and efficacy have not been established.

•Amlodipine: Amlodipine inhibits the influx of extracellular calcium across cardiac muscle and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. The decrease in intracellular calcium inhibits the contractility of smooth muscle cells resulting in dilation of coronary and systemic arteries. This dilation results in decreased vascular resistance and increased coronary blood flow and oxygen delivery to myocardial tissue. Myocardial oxygen consumption is also reduced. As with other dihydropyridine class calcium-channel blockers, amlodipine exerts its effects mainly on arteriolar vasculature. It has no significant effect on sinus node function or cardiac conduction, nor does it possess negative inotropic effects at clinical doses. Unlike other peripheral vasodilators, amlodipine has a gradual onset and reflex tachycardia does not occur. Amlodipine therapy usually does not affect hemodynamic parameters in patients with normal ventricular function. In general, calcium-channel blockers exert favorable effects on LVH, and do not worsen insulin resistance or exert detrimental effects on the lipid profile.
 
•Atorvastatin: Atorvastatin is a selective, competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is the rate-limiting hepatic enzyme responsible for converting HMG-CoA to mevalonate, a precursor of sterols including cholesterol. Inhibition of HMG-CoA reductase lowers the amount of mevalonate and subsequently reduces cholesterol levels in hepatic cells. This, in turn, results in up-regulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation. Atorvastatin ultimately reduces the levels of circulating total cholesterol, LDL-cholesterol, and serum triglycerides. Drug dosage rather than systemic drug concentration correlates better with LDL-cholesterol reduction. As with other HMG-CoA reductase inhibitors, atorvastatin exhibits no effects on antipyrine hepatic metabolism.
 
HMG-CoA reductase inhibitors have been reported to decrease endogenous CoQ10 serum concentrations; the clinical significance of these effects is unknown.

Amlodipine; atorvastatin is administered orally.
Amlodipine: Like other calcium-channel blockers, amlodipine is primarily metabolized by CYP3A4 isoenzymes. The drug is approximately 93% bound to plasma proteins, but drug interactions secondary to displacement from binding sites have not been documented. Amlodipine is extensively metabolized to inactive compounds, and 10% of the parent compound and 60% of the inactive metabolites are excreted in the urine. The terminal half-life is about 30—50 hours, which is significantly longer than other dihydropyridines that are currently available. Steady-state plasma concentrations are reached after 7 to 8 days of consecutive daily dosing.
Atorvastatin: Atorvastatin is >= 98% bound to plasma proteins. A blood:plasma ratio of 0.25 indicates poor drug penetration into red blood cells. Animal data reveal that atorvastatin is likely to be secreted in human milk. Atorvastatin undergoes extensive metabolism to active ortho- and para-hydroxylated metabolites that account for approximately 70% of the circulating HMG-CoA reductase inhibitory activity. Based on in vitro studies, CYP3A4 may also contribute to metabolism. In animals, the ortho-hydroxy metabolite is further metabolized by glucuronidation. Elimination of atorvastatin and its metabolites occurs primarily in bile following hepatic and/or extrahepatic metabolism. It does not appear that the drug undergoes enterohepatic recirculation, and less than 2% of a dose is recovered in the urine. The mean plasma elimination half-life is approximately 14 hours, however, the half-life of HMG-CoA reductase inhibitory activity is 20—30 hours because of the active metabolites.
 
Affected cytochrome P450 isoenzymes and drug transporter: CYP3A4, P-gp
Atorvastatin is a substrate and inhibitor of the P-glycoprotein (P-pg) transport system. Amlodipine and atorvastatin are CYP3A4 substrates, and their metabolism may theoretically be affected by CYP3A4 inhibitors or inducers.

Oral Route

Amlodipine: Amlodipine is administered orally and is slowly but almost completely absorbed. Oral bioavailability ranges from 64—90%. Peak plasma concentrations are achieved between 6—12 hours post-dose, and maximum hypotensive effects are correspondingly delayed. Food does not appear to influence these parameters.
Atorvastatin: Following oral administration, atorvastatin is rapidly absorbed with peak plasma concentrations occurring within 1—2 hours. The extent of absorption increases in proportion to the dose of atorvastatin. The absolute bioavailability is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. Pre-systemic clearance and/or hepatic first-pass metabolism accounts for the low systemic bioavailability. Food decreases the rate and extent of atorvastatin absorption by approximately 25% and 9%, respectively, however, LDL-cholesterol reduction is similar whether the drug is given with or without food. Similarly, atorvastatin plasma concentrations are lower following evening doses compared with morning dosing and LDL-cholesterol reduction is the same regardless of the time of day the drug is administered.

Pregnancy

Atorvastatin; amlodipine is contraindicated for use in pregnant females. Cholesterol and other products of cholesterol biosynthesis are important for fetal development including synthesis of steroids and cell membranes. Because atorvastatin decreases cholesterol synthesis, the drug may cause fetal harm. Other HMG-CoA reductase inhibitors have been shown to cause malformations of vertebrae and ribs in fetal rats when given in high doses. Atorvastatin should be administered to females of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. Discontinue atorvastatin; amlodipine as soon as pregnancy is recognized. In animal reproduction studies.

Amlodipine; atorvastatin is contraindicated in women who are breast-feeding. Amlodipine is present in human breastmilk, although no adverse effects of amlodipine on the breast-fed infant have been observed. There is no information on the effect of amlodipine on milk production in breast-feeding women. In a study of thirty-one lactating women with pregnancy-induced hypertension, the median relative infant dose (RID) of amlodipine in human milk was 4.2% (interquartile range, 3.12% to 7.25%) and the maximum RID was 15.2%. No adverse effects of amlodipine on the breast-fed infant have been observed.[64369] In another study that enrolled eight lactating women, the average RID for amlodipine was 3.4% (range, 1.56% to 4.32%).[64368] It is not known if atorvastatin is present in human milk, but another drug in its class can be excreted in human milk. Cholesterol and other products of cholesterol biosynthesis are essential components for infant development; atorvastatin may also have other adverse effects on the nursing infant. If the drug is absolutely necessary to the mother, nursing should be discontinued. Otherwise, since atherosclerosis and its complications are a chronic health issue, discontinuation of atorvastatin for some time in order to allow for nursing of an infant would be expected to have little effect on the long-term outcomes associated with hypercholesterolemia. If pharmacotherapy is necessary in the nursing mother, a nonabsorbable resin such as cholestyramine, colesevelam, or colestipol should be considered. These agents do not enter the bloodstream and thusly will not be excreted during lactation. However, resins bind fat-soluble vitamins and prolonged use may result in deficiencies of these vitamins in the mother and her nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.