Amlodipine (Norvasc) Interactions
Alpha-blockers
- Amiodarone
Anti-retroviral protease inhibitors
Antihypertensive Agents
- Aprepitant
Barbiturates
Beta-blockers
- Bosentan
- Calcium Salts
- Carbamazepine
- Clarithromycin
- Conivaptan
- Dalfopristin; Quinupristin
- Delavirdine
- Efavirenz
- Ephedra, Ma Huang
- Erythromycin
- Ethanol
- Fluconazole
- Fluoxetine
- Fluvoxamine
- food
- Fosphenytoin
General Anesthetics
- Ginkgo, Ginkgo biloba
- Ginseng, Panax ginseng
- grapefruit juice
- Hawthorn, Crataegus laevigata
- Imatinib, STI-571
- Itraconazole
- Ketoconazole
Local Anesthetics
- Melatonin
- Mifepristone, RU-486
- Nefazodone
Nonsteroidal antiinflammatory drugs (NSAIDs)
Oral contraceptives
- Phenytoin
Photosensitizing Agents
- Rifabutin
- Rifampin
- Rifapentine
- St. John’s Wort, Hypericum perforatum
- Telithromycin
- Troleandomycin
- Voriconazole
- Yohimbine
- Zafirlukast
- Zileuton
Amlodipine (Norvasc) Interactions
NOTE: Amlodipine is a CYP3A4 substrate, and its metabolism may theoretically be affected by CYP3A4 inhibitors or inducers.
Edema has been reported in patients receiving itraconazole and dihydropyridine calcium-channel blockers concomitantly. Appropriate dose adjustment may be necessary. Calcium-channel blockers can have a negative inotropic effect that may be additive to that of itraconazole. In addition, because systemic azole antifungals (fluconazole, itraconazole, ketoconazole, IV miconazole, or voriconazole) inhibit CYP 3A4, they may inhibit the metabolism of calcium-channel blockers (CYP3A4 substrates). Therefore, exercise caution when coadministering systemic azole antifungals and calcium-channel blockers.
Diltiazem (CYP3A4 inhibitor) may increase the plasma level of amlodipine via CYP3A4 inhibition, and because both drugs reduce blood pressure, additive hypotensive effects may occur. Other examples of CYP3A4 inhibitors which theoretically may decrease the hepatic metabolism of amlodipine (a CYP3A4 substrate) include: amiodarone, anti-retroviral protease inhibitors, aprepitant, systemic azole antifungals, clarithromycin, dalfopristin; quinupristin, delavirdine, diltiazem, efavirenz (inducer or inhibitor), erythromycin, fluoxetine, fluvoxamine, mifepristone, RU-486, nefazodone, troleandomycin, verapamil, zafirlukast, and zileuton. This list is not inclusive of all CYP3A4 inhibitors. Coadministration of cimetidine (a nonspecific cytochrome P-450 inhibitor) with amlodipine does not change the pharmacokinetics of amlodipine. Caution should be used when CYP3A4 inhibitors are co-administered with calcium-channel blockers; monitor therapeutic response.
The net result of theoretical interactions between bosentan and calcium-channel blockers is unknown; monitor for possible additive vasodilatory effects or reduced efficacy. Bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Bosentan may increase the clearance of amlodipine (CYP3A4 substrate) and potentially lead to a reduction of efficacy; however, this interaction has not been studied. In addition, bosentan may contribute additive hypotensive effects when given with calcium-channel blockers. In clinical trials in patients with pulmonary hypertension, bosentan was added to other drug regimens which may have included other vasodilators such as ACE inhibitors or calcium-channel blockers.
Yohimbine is a selective central alpha 2-adrenoceptor antagonist. Yohimbine can increase blood pressure and therefore can antagonize the therapeutic action of antihypertensive drugs in general; one study in patients with essential hypertension (n=25) reported an average rise of 5 mmHg in mean blood pressure and a 66% increase in plasma norepinephrine (NE) concentrations following yohimbine administration (4 x 5.4 mg tablets PO). Use with particular caution in hypertensive patients with high or uncontrolled BP.
Conivaptan is a potent inhibitor of CYP3A4 and may increase plasma concentrations of drugs that are primarily metabolized by CYP3A4. Oral conivaptan 40 mg twice daily has resulted in a 2-fold increase in the AUC and half-life of amlodipine. According to the manufacturer, concomitant use of conivaptan with drugs that are primarily metabolized by CYP3A4 such as calcium-channel blockers should be closely monitored, or the combination should be avoided. If a clinical decision is made to discontinue concomitant drugs at recommended doses, allow an appropriate time interval following the conivaptan administration before resuming these drugs. In addition, certain calcium-channel blockers such as diltiazem and verapamil can theoretically inhibit CYP3A4 metabolism of conivaptan (CYP3A4 substrate) and should be coadministered with caution until further data are available. Based on the pharmacology of conivaptan, there is potential for additive hypotensive effects when coadministered with calcium-channel blockers. Intravenous infusion of conivaptan has been associated with orthostatic hypotension (see Adverse Reactions). Monitor blood pressure and fluid volume status closely in patients receiving conivaptan infusion.
Amlodipine can have additive hypotensive effects with other antihypertensive agents including alpha-blockers, other calcium-channel blockers, vasodilators, and diuretics. This additive effect can be desirable, but the patient should be monitored carefully and the dosage should be adjusted based on clinical response. The concomitant use of dihydropyridine calcium-channel blockers 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.
Rifampin, rifabutin, rifapentine, carbamazepine, barbiturates (e.g., phenobarbital or primidone), and phenytoin (or fosphenytoin which is metabolized to phenytoin) 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.
Ethanol interacts with antihypertensive agents by potentiating their hypotensive effect.
In vitro studies have not shown any effect of amlodipine on the protein binding of digoxin, phenytoin, warfarin and indomethacin. Coadministration of amlodipine with digoxin did not affect serum digoxin concentrations or digoxin renal clearance in normal volunteers. Prothrombin time is not altered when amlodipine is given to patients receiving warfarin therapy. Concurrent administration of amlodipine did not alter the pharmacokinetics of atorvastatin (80 mg/day) or ethanol. Coadministration of cimetidine or aluminum hydroxide; magnesium hydroxide with amlodipine did not change the pharmacokinetics of amlodipine. In clinical trials, amlodipine has been safely administered with warfarin, digoxin, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, antibiotics, oral hypoglycemic agents, thiazide diuretics, and beta-adrenergic blocking agents.
A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on amlodipine pharmacokinetics. The mean additional reduction on supine blood pressure (systolic, 8 mmHg; diastolic, 7 mmHg) was of a similar magnitude to that seen when sildenafil was administered alone to healthy volunteers.
Clinicians should be aware that grapefruit juice (food) interactions with some calcium channel blockers are possible. Grapefruit juice contains compounds (psoralen derivatives and possibly the flavonoid naringenin) that inhibit the cytochrome P-450 CYP3A4 isozyme in the gut wall. Grapefruit juice can increase the serum concentrations and oral bioavailability of most calcium-channel blockers (e.g., amlodipine, felodipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil); no significant effect on diltiazem bioavailability has been reported. Administration of grapefruit juice with oral amlodipine in healthy volunteers increases peak plasma concentrations by 115% and AUC by 116% (compared to water), with no significant differences in BP and HR. The relatively small increase in amlodipine bioavailability is most likely due to inhibition of the CYP3A4 isoenzyme, which reduces first-pass drug metabolism. While amlodipine may be administered with food, it is prudent to avoid grapefruit juice before or after drug administration to avoid potential increases in amlodipine bioavailability.
Preclinical data suggest that calcium-channel blockers could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Hawthorn, Crataegus laevigata may lower peripheral vascular resistance. Hawthorn use in combination with antihypertensive agents may lead to additional reductions in blood pressure in some individuals. Patients receiving hawthorn concurrently with antihypertensive medications should receive periodic blood pressure monitoring.
Calcium salts are used in the treatment of calcium channel blocker overdose. In general, high doses of calcium salts are needed to overcome the hypotensive effects of calcium channel blocker overdose. However, the exogenous administration of intravenous calcium salts in non-overdose situations may attenuate the pharmacodynamic response to calcium-channel antagonists. If patients receive intravenous calcium salts during concomitant calcium channel blocker therapy, therapeutic response should be monitored.
NSAIDs may alter the response to antihypertensive agents due to inhibition of vasodilatory prostaglandins. Among NSAIDs, indomethacin, naproxen, and piroxicam may have the greatest pressor effect, while the effects of sulindac and nabumetone may be significantly less
Imatinib, STI-571 inhibits cytochrome P450 3A4 and may result in increased levels of amlodipine.
Telithromycin, a ketolide antibiotic, can theoretically compete with amlodipine for metabolism by CYP3A4. This can result in increased concentrations of amlodipine if the two drugs are coadministered.
Melatonin may impair the efficacy of some calcium-channel blockers, and caution is advised with concurrent use. In one placebo-controlled study, melatonin ingestion led to significant increases in blood pressure throughout the day in patients taking nifedipine. The mechanism of this interaction is unclear. It may be prudent to avoid melatonin use during calcium-channel blocker therapy.
Ephedra, Ma huang can antagonize all types of antihypertensive agents. Blood pressure should be monitored closely in patients using antihypertensive agents with ephedra.
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.
St. John’s wort appears to induce the metabolism of the calcium-channel blockers, apparently by the induction of the CYP3A4 isoenzyme. A non-controlled pharmacokinetic study in healthy volunteers found that concurrent administration of St. John’s wort with nifedipine resulted in a 53% decrease in nifedipine peak concentrations. The metabolism of other calcium channel blockers may also be increased; it is assumed the reductions in calcium-channel blocker concentrations could reduce clinical efficacy.
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.
Local anesthetics may cause additive hypotension in combination with antihypertensive agents.
Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with oral contraceptives should be monitored to confirm that the desired antihypertensive effect is being obtained.
In addition to additive hypotension, the depression of cardiac contractility, conductivity, and automaticity associated with general anesthetics may be potentiated by calcium-channel blockers. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully to avoid excessive cardiovascular depression.
[ Last revised: 2/4/2006 7:03:00 PM ]
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