CYP3A inhibitors such as ketoconazole, fluconazole, itraconazole, clarithromycin, erythromycin (Azithromycin, although structurally related to the class of macrolide antibiotic is void of clinically relevant CYP3A4 inhibition), grapefruit, nefazodone, fluoxetine, saquinavir, indinavir, nelfinavir, and ritonavir may result in increased exposure to nifedipine when co-administered. Careful monitoring and dose adjustment may be necessary; consider initiating nifedipine at the lowest dose available if given concomitantly with these medications.
Strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, and St. John’s Wort reduce the bioavailability and efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (See CONTRAINDICATIONS).
Quinidine: Quinidine is a substrate of CYP3A and has been shown to inhibit CYP3A in vitro. Co-administration of multiple doses of quinidine sulfate, 200 mg t.i.d., and nifedipine, 20 mg t.i.d., increased C max and AUC of nifedipine in healthy volunteers by factors of 2.30 and 1.37, respectively. The heart rate in the initial interval after drug administration was increased by up to 17.9 beats/minute. The exposure to quinidine was not importantly changed in the presence of nifedipine. Monitoring of heart rate and adjustment of the nifedipine dose, if necessary, are recommended when quinidine is added to a treatment with nifedipine.
Flecainide: There has been too little experience with the co-administration of Tambocor with nifedipine to recommend concomitant use.
Calcium Channel Blockers
Diltiazem: Pre-treatment of healthy volunteers with 30 mg or 90 mg t.i.d. diltiazem p.o. increased the AUC of nifedipine after a single dose of 20 mg nifedipine by factors of 2.2 and 3.1, respectively. The corresponding C max values of nifedipine increased by factors of 2.0 and 1.7, respectively. Caution should be exercised when co-administering diltiazem and nifedipine and a reduction of the dose of nifedipine should be considered.
Verapamil: Verapamil, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.
Benazepril: In healthy volunteers receiving single dose of 20 mg nifedipine ER and benazepril 10 mg, the plasma concentrations of benazeprilat and nifedipine in the presence and absence of each other were not statistically significantly different. A hypotensive effect was only seen after co-administration of the two drugs. The tachycardic effect of nifedipine was attenuated in the presence of benazepril.
Irbesartan: In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites by nifedipine. However, in clinical studies, concomitant nifedipine had no effect on irbesartan pharmacokinetics.
Candesartan: No significant drug interaction has been reported in studies with candesartan cilexitil given together with nifedipine. Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effect on cytochrome P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.
Nifedipine extended-release tablets were well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended and a dose adjustment of nifedipine should be considered.
Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are co-administered with timolol.
Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Co-administration of nifedipine resulted in a decrease in AUC and C max of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and C max of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is co-administered with nifedipine, and dose reduction of nifedipine considered.
Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced clearance resulting in an increase in plasma concentrations of digoxin. Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine extended-release tablets, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablets, to avoid possible over- or under- digitalization.
Coumarins: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However the relationship to nifedipine therapy is uncertain.
Platelet Aggregation Inhibitors
Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidrogrel was co-administered with nifedipine.
Tirofiban: Co-administration of nifedipine did not alter the exposure to tirofiban importantly.
Diuretics, PDE5 inhibitors, alpha-methyldopa: Nifedipine may increase the blood pressure lowering effect of these concomitantly administered agents.
Ketoconazole, itraconazole and fluconazole are CYP3A inhibitors and can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.
Omeprazole: In healthy volunteers receiving a single dose of 10 mg nifedipine, AUC and C max of nifedipine after pretreatment with omeprazole 20 mg q.d. for 8 days were 1.26 and 0.87 times those after pre-treatment with placebo. Pretreatment with or co-administration of omeprazole did not impact the effect of nifedipine on blood pressure or heart rate. The impact of omeprazole on nifedipine is not likely to be of clinical relevance.
Pantoprazole: In healthy volunteers the exposure to neither drug was changed significantly in the presence of the other drug.
Ranitidine: Five studies in healthy volunteers investigated the impact of multiple ranitidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of co-administered ranitidine on blood pressure in hypertensive subjects on nifedipine. Co-administration of ranitidine did not have relevant effects on the exposure to nifedipine that affected the blood pressure or heart rate in normotensive or hypertensive subjects.
Cimetidine: Five studies in healthy volunteers investigated the impact of multiple cimetidine doses on the single or multiple dose pharmacokinetics of nifedipine. Two studies investigated the impact of co-administered cimetidine on blood pressure in hypertensive subjects on nifedipine. In normotensive subjects receiving single doses of 10 mg or multiple doses of up to 20 mg nifedipine t.i.d. alone or together with cimetidine up to 1000 mg/day, the AUC values of nifedipine in the presence of cimetidine were between 1.52 and 2.01 times those in the absence of cimetidine. The C max values of nifedipine in the presence of cimetidine were increased by factors ranging between 1.60 and 2.02. The increase in exposure to nifedipine by cimetidine was accompanied by relevant changes in blood pressure or heart rate in normotensive subjects. Hypertensive subjects receiving 10 mg q.d. nifedipine alone or in combination with cimetidine 1000 mg q.d. also experienced relevant changes in blood pressure when cimetidine was added to nifedipine. The interaction between cimetidine and nifedipine is of clinical relevance and blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Cisapride: Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.
Quinupristin/Dalfopristin: In vitro drug interaction studies have demonstrated that quinupristin/dalfopristin significantly inhibits the CYP3A metabolism of nifedipine. Concomitant administration of quinupristin/dalfopristin and nifedipine (repeated oral dose) in healthy volunteers increased AUC and C max for nifedipine by factors of 1.44 and 1.18, respectively, compared to nifedipine monotherapy. Upon co-administration of quinupristin/dalfopristin with nifedipine, blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Erythromycin: Erythromycin, a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and reduction of the dose of nifedipine considered.
Rifampin: Strong CYP3A inducers, such as rifampin, rifapentin, and rifabutin reduce the bioavailability of nifedipine which may reduce the efficacy of nifedipine; therefore nifedipine should not be used in combination with strong CYP3A inducers such as rifampin (See CONTRAINDICATIONS). The impact of multiple oral doses of 600 mg rifampin on the pharmacokinetics of nifedipine after a single oral dose of 20 mg nifedipine capsule was evaluated in a clinical study. Twelve healthy male volunteers received a single oral dose of 20 mg nifedipine capsule on study Day 1. Starting on study Day 2, the subjects received 600 mg rifampin once daily for 14 days. On study Day 15, a second single oral dose of 20 mg nifedipine capsule was administered together with the last dose of rifampin. Compared to study Day 1, 14 days pretreatment with rifampin reduced C max and AUC of concomitantly administered nifedipine on average by 95% and 97%, respectively.
Amprenavir, atanazavir, delavirine, fosamprinavir, indinavir, nelfinavir and ritonavir , as CYP3A inhibitors, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine. Caution is warranted and clinical monitoring of patients recommended.
Nefazodone , a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Fluoxetine , a CYP3A inhibitor, can inhibit the metabolism of nifedipine and increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a reduction of the dose of nifedipine considered.
Valproic acid may increase the exposure to nifedipine during concomitant therapy. Blood pressure should be monitored and a dose reduction of nifedipine considered.
Phenytoin, Phenobarbital, and Carbamazepine: Nifedipine is metabolized by CYP3A. Co-administration of nifedipine 10 mg capsule and 60 mg nifedipine coat-core tablet with phenytoin, an inducer of CYP3A, lowered the AUC and C max of nifedipine by approximately 70%. Phenobarbital and carbamazepine are also inducers of CYP3A. Alternative antihypertensive therapy should be considered in patients taking phenytoin, phenobarbital, and carbamazepine.
Dolasetron: In patients taking dolasetron by the oral or intravenous route and nifedipine, no effect was shown on the clearance of hydrodolasetron.
Tacrolimus: Tacrolimus has been shown to be metabolized via the CYP3A system. Nifedipine has been shown to inhibit the metabolism of tacrolimus in vitro. Transplant patients on tacrolimus and nifedipine required from 26% to 38% smaller doses than patients not receiving nifedipine. Nifedipine can increase the exposure to tacrolimus. When nifedipine is co-administered with tacrolimus the blood concentrations of tacrolimus should be monitored and a reduction of the dose of tacrolimus considered.
Sirolimus: A single 60 mg dose of nifedipine and a single 10 mg dose of sirolimus oral solution were administered to 24 healthy volunteers. Clinically significant pharmacokinetic drug interactions were not observed.
Glucose Lowering Drugs
Pioglitazone: Co-administration of pioglitazone for 7 days with 30 mg nifedipine ER administered orally q.d. for 4 days to male and female volunteers resulted in least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73-0.95) for C max and 0.88 (0.80-0.96) for AUC relative to nifedipine monotherapy. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
Rosiglitazone: Co-administration of rosiglitazone (4 mg b.i.d.) was shown to have no clinically relevant effect on the pharmacokinetics of nifedipine.
Metformin: A single dose metformin-nifedipine interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma metformin C max and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in urine. T max and half-life were unaffected. Nifedipine appears to enhance the absorption of metformin.
Miglitol: No effect of miglitol was observed on the pharmacokinetics and pharmacodynamics of nifedipine.
Repaglinide: Co-administration of 10 mg nifedipine with a single dose of 2 mg repaglinide (after 4 days nifedipine 10 mg t.i.d. and repaglinide 2 mg t.i.d.) resulted in unchanged AUC and C max values for both drugs.
Acarbose: Nifedipine tends to produce hyperglycemia and may lead to loss of glucose control. If nifedipine is co-administered with acarbose, blood glucose levels should be monitored carefully and a dose adjustment of nifedipine considered.
Drugs Interfering with Food Absorption
Orlistat: In 17 normal-weight subjects receiving orlistat 120 mg t.i.d. for 6 days, orlistat did not alter the bioavailability of 60 mg nifedipine (extended release tablets).
Grapefruit Juice: In healthy volunteers, a single dose co-administration of 250 mL double strength grapefruit juice with 10 mg nifedipine increased AUC and C max by factors of 1.35 and 1.13, respectively. Ingestion of repeated doses of grapefruit juice (5 x 200 mL in 12 hours) after administration of 20 mg nifedipine ER increased AUC and C max of nifedipine by a factor of 2. Grapefruit juice should be avoided by patients on nifedipine. The intake of grapefruit juice should be stopped at least 3 days prior to initiating patients on nifedipine.
St. John’s Wort: St. John’s Wort is an inducer of CYP3A and may decrease exposure to nifedipine. Alternative antihypertensive therapy should be considered in patients in whom St. John’s Wort therapy is necessary.
CYP2D6 Probe Drug
Debrisoquine: In healthy volunteers, pretreatment with nifedipine 20 mg t.i.d. for 5 days did not change the metabolic ratio of hydroxydebrisoquine to debrisoquine measured in urine after a single dose of 10 mg debrisoquine. Thus, it is improbable that nifedipine inhibits in vivo the metabolism of other drugs that are substrates of CYP2D6.
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