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Uses

Angina

Nifedipine is used in the management of Prinzmetal variant angina and chronic stable angina pectoris. Calcium-channel blocking agents (used alone or in combination with nitrates) are considered the drugs of choice for the management of Prinzmetal variant angina. β-Adrenergic blocking agents (β-blockers) are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; however, calcium-channel blockers may be substituted or added in patients who do not tolerate or respond adequately to β-blockers. In controlled clinical studies of up to 8 weeks' duration in patients with chronic stable angina, nifedipine reduced the frequency of attacks, allowed a decrease in sublingual nitroglycerin dosage, and increased exercise tolerance. All classes of calcium-channel blockers appear to be equally effective in reducing anginal episodes; however, choice of a specific agent should be individualized since the pharmacologic properties of these drugs differ. The potential risks of short-acting (conventional, immediate-release) nifedipine should be considered.(See Cautions.)

Calcium-channel blockers also have been used for the relief of ongoing or recurrent ischemia in patients with unstable angina; however, a nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) generally is recommended.

Concurrent use of nifedipine and a β-blocker may have beneficial effects in some patients with chronic stable angina (e.g., reduction of dihydropyridine-induced tachycardia through β-blockade).

Hypertension

Nifedipine is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Because of concerns about potentially serious adverse cardiovascular effects and increased mortality associated with short-acting (conventional, immediate-release) nifedipine (see Cautions), only extended-release formulations of the drug are recommended for the management of hypertension.

Calcium-channel blocking agents (e.g., nifedipine) are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

Calcium-channel blockers may be particularly useful in the management of hypertension in black patients ; these patients tend to have greater blood pressure response to calcium-channel blockers and thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists). Use of a calcium-channel blocker also may be beneficial in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina) and in geriatric patients, including those with isolated systolic hypertension.

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk of coronary heart disease. Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed. Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure. The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.

For additional information on the role of calcium-channel blockers in the management of hypertension, see . For information on overall principles and expert recommendations for treatment of hypertension, .

Hypertensive Crises

In the past, when oral therapy was considered preferable to parenteral therapy in selected patients, short-acting (conventional, immediate-release capsules) nifedipine had been used for rapidly reducing blood pressure in patients with hypertensive crises in whom reduction of blood pressure was considered urgent (hypertensive urgencies) or an emergency (hypertensive emergencies); however, most clinicians and the manufacturers now question the safety of short-acting nifedipine for this use because of occasional reports of poorly tolerated severe hypotension and the potential adverse cardiovascular consequences (e.g., cerebrovascular ischemia, stroke, myocardial ischemia and infarction, death). As a result of these and other (see Cautions) concerns and absence of substantial evidence clearly establishing superiority (both in terms of safety and efficacy) of nifedipine for this use, it is recommended that short-acting nifedipine no longer be used for the management of any form of hypertension, including hypertensive crises.

Patients with hypertensive emergencies (i.e., those rare situations requiring immediate blood pressure reduction, although not necessarily to normal ranges, in order to prevent or limit target organ damage) require hospitalization and are treated with an appropriate parenteral antihypertensive agent (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside). Hypertensive urgencies (i.e., situations in which there is severe elevation in blood pressure without progressive target organ damage) generally can be managed by intensification or reinstitution (e.g., following noncompliance) of the current antihypertensive regimen or with oral doses of short-acting antihypertensive agents (e.g., captopril, labetalol, clonidine) followed by several hours of observation. However, there is no evidence suggesting that failure to aggressively reduce blood pressure in these patients is associated with any short-term risk. In fact, overly aggressive management of severe elevations in blood pressure not associated with impending or progressing organ damage can sometimes lead to cumulative hypotensive effects. Excessive falls in blood pressure should be avoided in any hypertensive crisis since they may precipitate renal, cerebral, or coronary ischemia.

Hypertension During Pregnancy

Antihypertensive therapy is recommended in pregnant women with chronic hypertension who have persistent, severely elevated blood pressure (e.g., systolic blood pressure of 160 mm Hg or higher or diastolic blood pressure of 105 mm Hg or higher); it is less clear whether antihypertensive therapy should be initiated in women with mild to moderate chronic hypertension. If initiation of antihypertensive therapy is necessary in a pregnant woman, use of labetalol, nifedipine, or methyldopa is recommended by the American College of Obstetricians and Gynecologists (ACOG) and other experts. In women who are already receiving antihypertensive therapy prior to pregnancy, ACOG states there are insufficient data to make recommendations regarding the continuance or discontinuance of such therapy; treatment decisions should be individualized in these situations.

Nifedipine also has been used orally in the hospital setting for urgent lowering of blood pressure in severely hypertensive pregnant women, including those with preeclampsia. However, short-acting (conventional) formulations of nifedipine are not labeled by the US Food and Drug Administration (FDA) for acute reduction of blood pressure; cases of profound hypotension and other serious adverse cardiovascular consequences have been reported with the use of these preparations. (For additional information on the use of antihypertensive drugs in women with preeclampsia,

Raynaud's Phenomenon

Nifedipine has been used effectively in the management of Raynaud's phenomenon and is considered a drug of choice for the management of this condition. The drug has reduced the frequency, duration, and severity of attacks in patients with this condition. However, not all patients with this condition respond to nifedipine, and intolerable adverse effects (e.g., headache, flushing, orthostatic hypotension) may limit the usefulness of the drug in some other patients. Although most experience with nifedipine in the management of Raynaud's phenomenon had been with short-acting (conventional, immediate-release) formulations of the drug, recent concerns (e.g., risks of serious hypotension and associated cardiovascular consequences) about the safety of short-acting (conventional) nifedipine have prompted the manufacturers to warn against use of this preparation in conditions for which safety and efficacy have not been fully established.(See Cautions.) Therefore, while not studied as extensively as short-acting nifedipine, extended-release nifedipine (e.g., 30-60 mg daily) preferably should be used when the drug is indicated for the management of Raynaud's phenomenon. The extended-release preparation of nifedipine appears to be tolerated better than the short-acting preparation in patients with this condition. The principal troublesome adverse effect during long-term therapy in these patients appears to be peripheral (ankle) edema.

Preterm Labor

Nifedipine has been used in selected patients to inhibit uterine contractions in preterm labor (tocolysis) and thus prolong gestation when such prolongation of intrauterine life was expected to benefit pregnancy outcome. Current ACOG guidelines for management of preterm labor state that there is no clear first-line tocolytic agent because of conflicting results regarding efficacy in comparative trials. In addition, concerns about the safety of short-acting (conventional) nifedipine (e.g., risks of serious hypotension and associated cardiovascular consequences) have prompted the manufacturers to warn against use of this preparation in conditions for which safety and efficacy have not been fully established.(See Cautions.) However, an analysis of pooled data from a number of randomized, controlled studies suggests that calcium-channel blockers (principally nifedipine) may be more effective than, and preferable to, other agents (e.g., magnesium sulfate, β-adrenergic agonists) when tocolysis is deemed necessary. Results of this pooled analysis suggest that calcium-channel blockers are more effective in reducing births within 7 days of initiation of tocolytic treatment and before 34 weeks' gestation and are associated with improved neonatal outcomes (e.g., less neonatal respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, jaundice) and a reduced frequency of maternal adverse effects leading to treatment discontinuance compared with other tocolytic agents. A number of different dosages and dosage forms of nifedipine were used in these studies, and an optimal dosage regimen for the drug as a tocolytic has not been determined.

The main benefit currently derived from tocolytic therapy may be to forestall labor and provide time for patients to receive corticosteroids to increase fetal lung maturation and/or to be transferred to other (e.g., tertiary-care) facilities; any other potential benefits of prolonging pregnancy are unclear. For additional information, see Uses: Preterm Labor in

Acute Myocardial Infarction

Calcium-channel blocking agents have been used in the early treatment and secondary prevention of acute myocardial infarction (MI); although these drugs are effective anti-ischemic agents, they have not demonstrated mortality benefits and therefore are generally used as an alternative to β-blockers. A review of 28 randomized controlled studies involving 19,000 patients found no benefit with regard to infarct size, rate of reinfarction, or death when calcium-channel blockers were used during the acute or convalescent phase of ST-segment-elevation MI (STEMI).Calcium-channel blockers generally are used for their anti-ischemic and blood pressure-reducing properties in the MI setting, and only when β-blockers (which have been shown to reduce mortality after MI) are ineffective, not tolerated, or contraindicated.

Current expert guidelines state that a calcium-channel blocker may be used to relieve ischemic symptoms, lower blood pressure, or control rapid ventricular response associated with atrial fibrillation in patients with STEMI who are intolerant to β-blockers. A nondihydropyridine calcium-channel blocker (e.g., verapamil or diltiazem) may be used as an alternative to β-blockers for the relief of ongoing or recurring ischemia when β-blocker therapy is inadequate, not tolerated, or contraindicated in patients with non-ST-segment-elevation MI (NSTEMI) who do not have clinically important left ventricular dysfunction, increased risk of cardiogenic shock, or AV block.

The use of short-acting (conventional, immediate-release) nifedipine is generally contraindicated in patients with MI because of its negative inotropic effects and the reflex sympathetic activation, tachycardia, and hypotension associated with its use. Short-acting nifedipine may be particularly detrimental in patients with hypotension and/or tachycardia since the drug may induce a reduction in coronary perfusion pressure, disproportionate dilatation of coronary arteries adjacent to ischemic areas (''steal'' phenomenon), and/or reflex activation of the sympathetic nervous system, resulting in an increase in myocardial oxygen demands. These findings are based on numerous clinical trials, including the Nifedipine Angina Myocardial Infarction Trial (NAMIS), the Trial of Early Nifedipine Treatment in Acute Myocardial Infarction (TRENT), the Norwegian Nifedipine Multicenter Trial, and the Secondary Prevention Reinfarction Israeli Nifedipine Trial (SPRINT).

Dosage and Administration

Administration

Nifedipine is administered orally. The drug also has been administered sublingually or intrabuccally (e.g., for rapid reduction of blood pressure). When nifedipine is administered sublingually or intrabuccally, the conventional liquid-filled capsule must be punctured, chewed, and/or squeezed to express the liquid into the mouth. However, based on pharmacokinetic considerations (see Pharmacokinetics: Absorption), some clinicians recommend that when a relatively rapid response is desired the drug preferably be administered as conventional liquid-filled capsules that are bitten and then swallowed.

Nifedipine extended-release tablets should be swallowed intact and should not be chewed, crushed, or broken. The manufacturer of Adalat CC states that the extended-release nifedipine tablets should be taken on an empty stomach. Patients should be advised not to become alarmed if they notice a tablet-like substance in their stools; this is normal since the tablet containing the drug is designed to remain intact and slowly release the drug from a nonabsorbable shell during passage through the GI tract.

Whenever extended-release tablets of nifedipine are dispensed or administered, care should be taken to ensure that the extended-release dosage form actually was prescribed. The manufacturers recommend that dosage of extended-release nifedipine tablets should be decreased gradually with close clinical supervision when discontinuance of the drug is required.

The manufacturer of Adalat CC states that two 30-mg Adalat CC extended-release tablets may be interchanged with one 60-mg Adalat CC extended-release tablet; however, three 30-mg Adalat CC extended-release tablets should not be considered interchangeable with one 90-mg Adalat CC extended-release tablet (see Pharmacokinetics: Absorption).

Concomitant oral administration of 1,4-dihydropyridine-derivative calcium-channel blocking agents (e.g., nifedipine) with grapefruit juice usually should be avoided since potentially clinically important increases in hemodynamic effects may result.(See Grapefruit Juice under Drug Interactions: Drugs and Foods Affecting Hepatic Microsomal Enzymes.)

Dosage

Angina

The National Heart, Lung, and Blood Institute (NHLBI) states that, pending further accumulation of data, it seems prudent that conventional liquid-filled (short-acting) capsules of nifedipine, especially at high doses, be used in the management of angina with great caution, if at all.(See Cautions.)

If short-acting nifedipine is used for the management of Prinzmetal variant angina or chronic stable angina pectoris, the usual initial adult dosage of the drug as conventional liquid-filled capsules that are swallowed intact is 10 mg 3 times daily. Alternatively, nifedipine antianginal therapy can be initiated with extended-release tablets at a dosage of 30 or 60 mg once daily. Generally, dosage is gradually increased at 7- to 14-day intervals until optimum control of angina is obtained. If symptoms so warrant and the patient's tolerance and response to therapy are assessed frequently, dosage may be increased more rapidly to 90 mg daily in increments of 30 mg/day over a 3-day period using conventional liquid-filled capsules or after steady state is achieved (usually achieved on the second day of therapy with a given dose) using extended-release tablets. In hospitalized patients who are closely monitored, nifedipine dosage may be increased in 10-mg increments using conventional liquid-filled capsules at 4- to 6-hour intervals, as necessary to control pain and arrhythmias caused by ischemia. Single doses usually should not exceed 30 mg.

The usual adult maintenance dosage of nifedipine as conventional liquid-filled capsules is 10-20 mg 3 times daily. In some patients, especially those with evidence of coronary artery spasm, higher dosages (using conventional liquid-filled capsules or extended-release tablets) and/or more frequent administration (using conventional liquid-filled capsules only) are necessary. In such patients, the usual maintenance dosage is 20-30 mg 3 or 4 times daily using conventional liquid-filled capsules; rarely, more than 120 mg daily is necessary. Experience with antianginal dosages exceeding 90 mg once daily using the extended-release tablets is limited; therefore, higher dosages using this dosage form should be employed with caution and only when clinically necessary.

Dosage generally should not exceed 180 mg daily as conventional liquid-filled capsules or 120 mg daily as extended-release tablets, since the safety and efficacy of higher dosages have not been established. After anginal symptoms are controlled, dosage should be gradually reduced to the lowest level that will maintain relief of symptoms.

In patients whose angina is controlled with conventional liquid-filled capsules of nifedipine alone or in combination with other antianginal agents, extended-release tablets of nifedipine can be substituted for the conventional capsules at the nearest equivalent total daily dose. Thus, patients who are receiving a nifedipine dosage of 30 mg 3 times daily as conventional liquid-filled capsules can be switched to a dosage of 90 mg once daily as extended-release tablets. When the total daily dose as conventional liquid-filled capsules does not correspond exactly to the strength of a commercially available extended-release tablet, the nearest equivalent daily dose can be substituted; the extended-release tablets should not be divided in an attempt to exactly match total daily doses of conventional capsules. Subsequent titration to higher or lower dosages may be necessary and should be guided by the patient's clinical response and tolerance.

Hypertension

Dosage of nifedipine should be adjusted according to the patient's blood pressure response and tolerance.

Usual Dosage

For the management of hypertension in adults, the usual initial dosage of nifedipine as extended-release tablets is 30 or 60 mg once daily. Generally, dosage is increased gradually at 7- to 14-day intervals until optimum control of blood pressure is obtained. If symptoms so warrant and the patient's tolerance and response to therapy are assessed frequently, dosage may be increased more rapidly. Steady state usually is achieved during the second day of therapy with a given dose as extended-release tablets. The manufacturers state that dosages exceeding 90 mg once daily (Adalat CC) or 120 mg once daily (Procardia XL) as extended-release tablets are not recommended. Some experts recommend a usual dosage range of 30-60 mg once daily.

If nifedipine is used for the management of hypertension in children, some experts recommend a usual initial dosage of 0.25-0.5 mg/kg daily, administered as extended-release tablets once daily or in 2 divided doses daily. Dosage may be increased as necessary to a maximum dosage of 3 mg/kg (up to 120 mg), given once daily or in 2 divided doses. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Target dosages generally can be achieved within 2-4 weeks, but it may take up to several months. Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with nifedipine monotherapy, another antihypertensive agent with demonstrated benefit may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents at optimal dosages, a third drug may be added. In patients who experience intolerable adverse effects with nifedipine, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the calcium-channel blocker and switch to another class of antihypertensive agent.

Because of concerns about potential cardiovascular risks associated with conventional liquid-filled (short-acting) capsules of the drug, short-acting preparations of nifedipine are no longer recommended for use in the management of hypertension.

Although not labeled for use in this condition, short-acting nifedipine has been administered at an oral dose of 10-20 mg in pregnant women who require urgent reduction of blood pressure; the dose has been repeated after 30 minutes and then every 2-6 hours if necessary.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of nifedipine is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

Cautions

While serious adverse reactions requiring discontinuance of nifedipine therapy or dosage adjustments are uncommon, concerns about safety and efficacy of calcium-channel blocking agents (mainly conventional [short-acting] preparations of dihydropyridine derivatives) have been raised by findings of several studies. Results of a case-control study indicate dose-dependent increases in the risk of myocardial infarction (MI) (by about 60%) in hypertensive patients (with or without diagnosed cardiovascular disease, but excluding MI or heart failure) receiving a short-acting calcium-channel blocking agent (e.g., nifedipine, diltiazem, verapamil) compared with those receiving a diuretic or a β-adrenergic blocking agent (β-blocker). In addition, findings of several pooled analyses of studies indicate an increased risk of mortality (by about 16%) and reinfarction (by about 19%) in patients who have had an MI or in those with stable or unstable angina who were receiving dihydropyridine-derivative calcium-channel blocking agents (mainly conventional [short-acting] preparations of nifedipine) compared with those receiving placebo. Results of a pooled analysis of 16 studies indicate that the nifedipine-associated mortality may be dose dependent, especially in patients receiving short-acting nifedipine dosages of 80 mg or more daily when compared with those receiving placebo.

The National Heart, Lung, and Blood Institute (NHLBI) concluded from the apparent concordance of findings from observational studies in hypertensive patients and from randomized studies principally in acute MI and unstable angina patients that it seems prudent and consistent with current evidence to recommend that short-acting nifedipine, especially at high doses, be used in the management of hypertension, angina, or MI with great caution, if at all. In arriving at this conclusion, the NHLBI recognized the potential biases of observational studies. The NHLBI and some clinicians also state that while other calcium-channel blocking agents (e.g., diltiazem, verapamil) also were associated with increased risk of MI in the described case-control study, results of previous well-designed clinical studies indicate that the use of calcium-channel blocking agents was not associated with an increased risk of death; therefore, the adverse effects associated with short-acting nifedipine may not necessarily apply to other calcium-channel blocking agents, including other short-acting dihydropyridines (e.g., isradipine), or to long-acting preparations of nifedipine. Findings from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared long-term therapy with an ACE inhibitor (lisinopril) or dihydropyridine-derivative calcium-channel blocker (amlodipine) revealed no difference in the primary outcome of combined fatal coronary heart disease or nonfatal MI among these therapies.

The increased risk of MI and death in patients receiving short-acting calcium-channel blocking agents may be associated with the arrhythmogenic, proischemic, negative inotropic, and/or prohemorrhagic effects of these agents; proischemic effects may result from reflex increases in sympathetic activity or from a reduction of coronary perfusion pressure induced by short-acting calcium-channel blocking agents. However, some clinicians state that while current evidence indicates an increased relative risk of MI associated with calcium-channel blocking agents, the actual increased risk for an individual patient may be low. Therefore, patients should not discontinue such therapy independently, but instead should consult their clinician about possible alternatives based on full evaluation of their medical condition, since the known risks of uncontrolled hypertension may be far greater than the postulated but unproven hazards associated with calcium-channel blocking agents.

Cardiovascular Effects

Serious adverse reactions requiring discontinuance of nifedipine therapy or dosage adjustment are relatively rare. An increase in the frequency, intensity, and duration of angina, possibly resulting from hypotension, has occurred rarely during initiation of nifedipine therapy. Additional serious adverse effects including MI, congestive heart failure or pulmonary edema, and ventricular arrhythmia or conduction defects have reportedly occurred in 4%, 2%, and less than 0.5% of patients receiving conventional nifedipine capsules, respectively, but these have not been directly attributed to the drug. For additional information on potential serious cardiovascular effects associated with nifedipine, see the introductory discussion in Cautions and see also Cautions: Precautions and Contraindications.

Chest pain (nonspecific) has been reported in less than 3% of patients receiving extended-release nifedipine tablets in clinical trials. Adverse cardiovascular effects reported in up to 1% of patients receiving extended-release nifedipine tablets include substernal chest pain, arrhythmia, atrial fibrillation, bradycardia, tachycardia, cardiac arrest, extrasystole, hypotension, postural hypotension, syncope, increased angina, phlebitis, and cutaneous angiectases.

Most of the common adverse reactions to nifedipine result from its vasodilating action on vascular smooth muscle and include dizziness, lightheadedness, giddiness, flushing or heat sensation, and headache, reportedly occurring in up to 25% of patients, and less frequently, hypotension (usually mild to moderate and well tolerated), weakness, peripheral edema, and palpitation. The incidence and severity of syncope, peripheral (ankle) edema, and hypotension generally are dose related and occasionally may be obviated by a reduction in dosage. In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, transient hypotension occurred in about 2% of patients receiving less than 60 mg daily and in about 5% of patients receiving 120 mg or more daily. Nifedipine-induced peripheral edema of the lower extremities usually responds to diuretic therapy. The relatively common adverse effects reported with conventional liquid-filled (short-acting) nifedipine capsules are similar in nature to those reported with extended-release tablets of the drug. However, some evidence indicates that the risk of certain adverse effects may be increased with short-acting preparations of the drug, particularly at high doses.(See the introductory discussion in Cautions.)

Although the hypotensive effect of nifedipine is modest and well tolerated in most patients receiving the drug for angina, excessive and poorly tolerated hypotension occurs occasionally in such patients. Such excessive hypotension usually occurs during initial dosage titration or subsequent upward titration of dosage, and may be more likely in patients receiving a β-blocker concomitantly. Severe hypotension and/or increased fluid requirements also have been reported in patients who were receiving these drugs concomitantly and underwent coronary artery bypass surgery involving high-dose fentanyl anesthesia.(See Drug Interactions: Fentanyl.) Several cases of profound hypotension, cerebrovascular ischemia or stroke, myocardial ischemia or infarction, and/or death have been reported when conventional short-acting preparations of nifedipine were used for the management of hypertensive crises, and therefore, the manufacturers currently warn that short-acting preparations should not be used for acute reduction in blood pressure.(See Hypertensive Crises under Uses: Hypertension.) However, profound hypotension, myocardial ischemia or infarction, and/or death also have been reported occasionally in patients receiving conventional short-acting preparations of the drug for other uses (e.g., angina, pulmonary hypertension). The manufacturers also warn that short-acting preparations of nifedipine should not be used for the chronic management of hypertension.

The frequency of nifedipine-induced peripheral edema appears to be dose related and reportedly occurs in 10-30% of patients receiving the drug. The edema is localized and probably occurs secondary to vasodilation of dependent arterioles and small blood vessels rather than to left ventricular dysfunction or generalized fluid retention. Intolerable adverse effects associated with nifedipine-induced vasodilation (e.g., headache, flushing, orthostatic hypotension) may limit the usefulness of nifedipine in some patients receiving the drug for Raynaud's phenomenon. The extended-release preparations of nifedipine appear to be tolerated better than the short-acting preparation in patients with this condition. The principal troublesome adverse effect during long-term therapy in these patients appears to be peripheral (ankle) edema.

Erythromelalgia has been reported in about 0.5% of patients receiving nifedipine. Characteristic manifestations of erythromelalgia include burning pain, increased skin temperature, and erythema of the extremities, usually the feet and lower legs, and less commonly, the hands. Manifestations resolve following discontinuance of the drug.

Nervous System Effects

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, weakness was reported in 12% of patients, while tremor, nervousness, and mood changes occurred in about 7-8% of patients; fever and chills were reported in up to 2% of patients, and shakiness, jitteriness, disturbed sleep, and difficulty with postural balance occurred occasionally; mental depression and paranoid syndrome were reported rarely. In patients receiving extended-release nifedipine tablets, fatigue and asthenia were reported in about 4-6% of patients, pain occurred in less than 3% of patients, and paresthesia, vertigo, asthenia, insomnia, nervousness, and somnolence were reported in up to 3% of patients, while migraine, anxiety, confusion, ataxia, depression, hypertonia, hypoesthesia, paroniria, fever, and tremor were reported in up to 1% of patients. Chills occurred in less than 1% of patients.For nervous system effects associated with the vasodilating effect of nifedipine, see Cautions: Cardiovascular Effects.

GI Effects

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, nausea and heartburn occurred in 11% of patients, while diarrhea, constipation, cramps, and flatulence were reported occasionally, and gingival hyperplasia occurred rarely. In patients receiving extended-release nifedipine tablets, nausea and constipation were reported in about 2-3 and about 1-3%, respectively, while abdominal pain, diarrhea, dry mouth, dyspepsia, and flatulence occurred in less than 3% of patients, and dysphagia, eructation, gastroesophageal reflux, esophagitis, vomiting, melena, GI hemorrhage, gum hemorrhage, gum hyperplasia, gum disorder, unspecified GI disorder, and taste perversion were reported in up to 1% of patients. GI irritation and GI bleeding have been reported in less than 1% of patients receiving Procardia XL extended-release nifedipine tablets in open-label trials and during post-marketing experience, although a causal relationship to the drug has not been established.

Symptoms of GI obstruction have occurred in several patients with a history of GI strictures who were receiving extended-release tablets of the drug.(See Cautions: Precautions and Contraindications.) GI obstruction also has occurred in at least one patient with no preexisting abnormality who was receiving conventional capsules of the drug concomitantly with diltiazem; it was suggested that obstruction in this patient may have resulted from a pharmacologic effect on intestinal smooth muscle.

Dermatologic and Sensitivity Reactions

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, dermatitis, pruritus, urticaria, and sweating have been reported occasionally, while angioedema (principally oropharyngeal edema and occasionally breathing difficulty) occurred in less than 0.5% of patients. Exfoliative dermatitis, exfoliative or bullous skin reactions (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis), and photosensitivity reactions have been reported rarely.

In patients receiving extended-release nifedipine tablets, rash and pruritus have been reported in up to 3% of patients, while angioedema, allergic reaction, cellulitis, facial edema, periorbital edema, alopecia, sweating, urticaria, photosensitivity reactions, and petechial rash were reported in up to 1% of patients.

Anaphylactic reactions have been reported rarely in patients receiving nifedipine.

Respiratory Effects

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, dyspnea, cough, wheezing, nasal congestion, and sore throat occurred in 6% of patients, while chest congestion and shortness of breath have been reported in up to 2% of patients.

In patients receiving extended-release nifedipine tablets, dyspnea, epistaxis, and rhinitis were reported in up to 3% of patients, while cough, pharyngitis, sinusitis, upper respiratory tract infection, respiratory disorder, rales, and stridor were reported in up to 1% of patients.

Musculoskeletal Effects

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, muscle cramps occurred in 8% of patients, while musculoskeletal complaints of inflammation and joint stiffness have been reported occasionally, and myalgia and arthritis with increased antinuclear antibodies (ANA) have been reported rarely.

In patients receiving extended-release nifedipine tablets, arthralgia, leg pain, and leg cramps occurred in up to 3% of patients, while myalgia, arthritis, joint disorder, myasthenia, back pain, neck pain, and gout occurred in up to 1% of patients.

Genitourinary Effects

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, sexual difficulty has been reported occasionally, while gynecomastia, nocturia, and polyuria have been reported rarely.

In patients receiving extended-release nifedipine tablets, impotence, polyuria, and urinary frequency have been reported in up to 3% of patients, while decreased libido, breast pain, pelvic pain, dysuria, hematuria, and nocturia occurred in up to 1% of patients, and renal calculi, urogenital disorder, and breast engorgement were reported in less than 1% of patients. Gynecomastia has been reported in less than 1% of patients receiving Procardia XL extended-release nifedipine tablets in open-label trials and during postmarketing experience, although a causal relationship to the drug has not been established.

Hepatic Effects

Abnormal laboratory test results including mild to moderately increased serum concentrations of alkaline phosphatase, LDH, creatine kinase (CK, creatine phosphokinase, CPK), AST (SGOT), and ALT (SGPT) have been reported rarely in patients receiving nifedipine. Although a definite causal relationship of these laboratory test results to the drug has not been established, the relationship has been considered probable in several cases. In most cases, the laboratory test abnormalities were not associated with clinical symptoms; however, cholestasis (with or without jaundice) has been reported. Small increases (about 5%) in mean alkaline phosphatase concentrations have been reported in patients receiving extended-release nifedipine tablets; however, these increases were clinically asymptomatic, isolated incidents that rarely resulted in values outside the normal range. Increased γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP) concentrations have been reported in less than 1% of patients receiving Adalat CC extended-release nifedipine tablets. Allergic hepatitis has occurred rarely.

Renal Effects

In patients with preexisting chronic renal insufficiency receiving nifedipine, reversible increases in blood urea nitrogen (BUN) and serum creatinine concentrations have been reported rarely. Although a definite causal relationship of these laboratory test results to the drug has not been established, the relationship has been considered probable in several cases.

Ocular and Otic Effects

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, blurred vision has been reported occasionally, while transient blindness at peak serum nifedipine concentrations and transient unilateral loss of vision have been reported rarely.

In patients receiving extended-release nifedipine tablets, abnormal lacrimation and vision abnormalities have been reported in up to 1% of patients, while amblyopia, conjunctivitis, diplopia, eye disorder, and ocular hemorrhage have been reported in less than 1% of patients.

Tinnitus has been reported in up to 1% of patients receiving nifedipine.

Hematologic Effects

In patients receiving conventional liquid-filled (short-acting) nifedipine capsules, thrombocytopenia, anemia, leukopenia, and purpura have been reported rarely. In patients receiving extended-release nifedipine tablets, purpura occurred in up to 1% of patients, and eosinophilia and lymphadenopathy occurred in less than 1% of patients. Positive antiglobulin (Coombs') test results, with or without hemolytic anemia, have been reported in patients receiving nifedipine, but a causal relationship to the drug has not been established.

Like other calcium-channel blocking agents, nifedipine decreases platelet aggregation in vitro. A moderate decrease in platelet aggregation and increases in bleeding time, believed to be related to inhibition of calcium transport across the platelet membrane, have been reported in patients receiving nifedipine in a limited number of clinical studies; however, these findings were not considered to be clinically important.

Metabolic Effects

Weight gain has been reported in up to 1% of patients receiving Procardia XL extended-release nifedipine tablets, while weight loss has been reported in less than 1% of patients receiving Adalat CC extended-release nifedipine tablets.

Other Adverse Effects

In patients receiving extended-release nifedipine tablets, hot flushes (flashes), rigors, and malaise were reported in up to 1% of patients in clinical trials.

Precautions and Contraindications

Some findings concerning possible risks of calcium-channel blocking agents have raised concerns about the safety and efficacy of these agents (mainly conventional [short-acting] preparations of nifedipine). However, findings with amlodipine in the ALLHAT study have shown a beneficial effect of dihydropyridine-derivative calcium-channel blockers on fatal coronary heart disease and nonfatal MI in patients treated with the drug for hypertension.

Nifedipine shares the toxic potentials of the calcium-channel blocking agents, and the usual precautions of these agents should be observed.

Because nifedipine decreases peripheral vascular resistance and occasionally causes excessive and poorly tolerated hypotension, blood pressure should be monitored carefully, especially during initiation of therapy and titration or upward adjustment of dosage. In addition, the manufacturers warn that the frequency, duration, and severity of angina may increase during initiation of therapy or upward adjustment of dosage.

Nifedipine should be used with caution in patients with congestive heart failure or aortic stenosis, especially in those receiving concomitant β-blockers, because nifedipine may precipitate or worsen heart failure in these patients. Peripheral edema occurring during the course of nifedipine therapy should be investigated, especially in patients with congestive heart failure, since it may indicate deterioration in left ventricular function induced by the drug.

Patients with acute stroke or acute MI may be at particular risk for the negative cardiovascular effects (both direct and reflex) of rapid blood pressure reduction, and the manufacturers warn that short-acting nifedipine should not be used during the first 1-2 weeks after acute MI. Preexisting hypovolemia or recent antihypertensive therapy may increase the risk of severe hypotension as may repeated doses of nifedipine. In patients with coronary artery disease and/or myocardial ischemia, reflex sympathetic activity with resultant increases in myocardial contractility, heart rate, and workload may aggravate preexisting myocardial ischemia. The manufacturers warn that short-acting nifedipine should be avoided in patients with acute coronary syndrome when MI may be imminent. When nifedipine therapy is initiated in patients with angina, they should be warned that the drug may cause increased angina, especially if β-blocker therapy is withdrawn abruptly when nifedipine therapy is being initiated. (See Drug Interactions: β-Adrenergic Blocking Agents.)

As with other nondeformable material, extended-release nifedipine tablets should be used with caution in patients with underlying severe GI narrowing (pathologic or iatrogenic) since obstruction may occur.

Nifedipine is contraindicated in patients with known hypersensitivity to the drug.

Pediatric Precautions

Although safety and efficacy remain to be fully established in children younger than 18 years of age, some experts have recommended pediatric dosages for hypertension based on currently limited clinical experience.

Geriatric Precautions

Although a prolonged elimination half-life and an increase in peak plasma concentration and area under the plasma concentration-time curve (AUC) have been observed in pharmacokinetic studies in small numbers of patients (see Pharmacokinetics: Elimination), clinical studies of nifedipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. While other clinical experience generally has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range and adjusting dosage as necessary based on patient response. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.

Mutagenicity and Carcinogenicity

In vivo studies using nifedipine have not revealed evidence of mutagenicity. No evidence of carcinogenicity was observed in rats receiving oral nifedipine for 2 years.

Pregnancy, Fertility, and Lactation

Pregnancy

Nifedipine has been shown to be teratogenic in rats and rabbits. Digital anomalies similar to those reported with phenytoin also have been reported in the offspring of animals receiving nifedipine or other dihydropyridines; these anomalies may occur secondary to compromised uterine blood flow. Nifedipine administration in rats, mice, rabbits, and monkeys also has been associated with a variety of other embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). The dosages (on a mg/kg basis) of nifedipine associated with teratogenic, embryotoxic, or fetotoxic effects in animals were higher (3.5-42 times) than the maximum recommended human dosage (120 mg daily); however, such dosages were within one order of magnitude of the maximum recommended human dosage. The dosages of nifedipine associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dosage on a mg/m basis. There are no adequate and well-controlled studies using nifedipine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

Nifedipine caused decreased fertility when given to rats prior to mating at a dosage approximately 30 times the maximum recommended human dosage. A reversible reduction in the ability of human sperm to bind to and fertilize an ovum in vitro has been reported in a limited number of infertile men who were receiving usual dosages of nifedipine when the sperm was obtained.

Lactation

Nifedipine is distributed into milk. In one lactating woman who received 10, 20, and 30 mg of the drug every 8 hours as conventional capsules, peak milk concentrations of nifedipine occurred within 1 hour after a dose and ranged from about 13-53 ng/mL; the drug generally was not detectable during the hour prior to a dose. Because of the potential for serious adverse reactions to nifedipine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Metabolism of nifedipine is mediated by the cytochrome P-450 (CYP) microsomal enzyme system (principally the 3A isoenzyme) and concomitant use of nifedipine with inhibitors or inducers of CYP3A4 may be associated with altered nifedipine exposure resulting in favorable or adverse effects. In addition, in vitro and in vivo data indicate that nifedipine may inhibit metabolism of drugs that are substrates of CYP3A, thereby increasing exposure of other drugs. Nifedipine does not appear to affect the metabolism of CYP2D6 substrates.

Quinidine

Quinidine appears to be a substrate of the CYP isoenzyme system and has been shown to inhibit CYP3A in vitro. In a multiple-dose study in healthy individuals, concomitant use of quinidine sulfate (200 mg 3 times daily) and nifedipine (20 mg 3 times daily) increased the area under the plasma concentration-time curve (AUC) and peak plasma concentration values of nifedipine 2.3 and 1.37 times, respectively. Heart rate during the initial interval following drug administration increased by up to 17.9 beats per minute.Heart rate should be monitored and nifedipine dosage adjusted as needed in patients receiving concomitant therapy with quinidine and nifedipine.

Although exposure to quinidine was not substantially affected by nifedipine in the previous study, nifedipine may decrease serum quinidine concentrations in some patients. Reductions or increases in serum quinidine concentrations occasionally have been observed following initiation or discontinuance, respectively, of nifedipine. Such changes can be substantial and may manifest as therapeutic resistance to usual quinidine dosages during concomitant therapy and/or altered ECGs (e.g., prolongation in corrected QT interval following discontinuance of nifedipine). While it had been postulated that alterations in quinidine pharmacokinetics during concomitant nifedipine therapy may have resulted from changes in hemodynamics induced by the latter drug (e.g., reduced peripheral vascular resistance with resultantly increased quinidine volume of distribution) in some patients (e.g., those with left ventricular dysfunction), subsequent study failed to confirm left ventricular dysfunction as a predictor of this interaction. Therefore, the mechanism of this interaction remains to be established, and possible identification of patients at risk requires further study. The possibility of this interaction should be considered in any patient exhibiting unpredictably low serum quinidine concentrations during concomitant nifedipine therapy. Serum quinidine concentrations should be monitored whenever nifedipine is initiated or discontinued in patients maintained on the antiarrhythmic, and quinidine dosage adjusted accordingly.

Verapamil

Verapamil, an inhibitor of the isoenzyme CYP3A, may inhibit the metabolism of nifedipine. In patients receiving concomitant therapy with verapamil and nifedipine, blood pressure should be monitored, and nifedipine dosage reduction should be considered.

Diltiazem

Since metabolism of diltiazem also is mediated principally by the CYP3A isoenzyme, diltiazem may competitively inhibit CYP3A4-dependent metabolism of other drugs (e.g., nifedipine). Administration of diltiazem 30- or 90-mg doses 3 times daily followed by a single 20-mg dose of nifedipine in healthy individuals increased nifedipine AUC values by 2.2 or 3.1 times, respectively, and peak plasma nifedipine concentrations by 2 or 1.7 times, respectively.

Angiotensin II Receptor Antagonists

Nifedipine has been shown to inhibit the formation of oxidized metabolites of irbesartan in vitro; however, concomitant nifedipine therapy had no effect on irbesartan pharmacokinetics in clinical studies.

In addition, since candesartan is not substantially metabolized by the CYP isoenzyme system, no substantial drug interaction has been reported in individuals receiving nifedipine concomitantly with candesartan.

Antifungal Agents

Concomitant use of nifedipine with ketoconazole, itraconazole, or fluconazole may affect the pharmacokinetics of nifedipine, possibly secondary to the inhibition of the CYP3A isoenzyme, and increased exposure of nifedipine may occur. Blood pressure should be monitored, and a decrease in nifedipine dosage should be considered.

Antiretroviral Agents

Concomitant use of nifedipine with antiretroviral agents (HIV protease inhibitors [e.g., amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir, ritonavir] and nonnucleoside reverse transcriptase inhibitors [e.g., delavirdine]) may affect the pharmacokinetics of nifedipine, possibly secondary to the inhibition of the CYP3A isoenzyme, and may result in decreased nifedipine metabolism and increased nifedipine exposure. Caution is advised if nifedipine is administered concomitantly with these antiretroviral agents; patients should be monitored carefully.

Antituberculosis Agents

Rifamycin derivatives (e.g., rifampin, rifabutin) can induce certain cytochrome P-450 liver enzymes (e.g., CYP3A isoenzyme) responsible for the metabolism of nifedipine. Concomitant use of these rifamycin derivatives and nifedipine may result in decreased plasma concentrations of nifedipine. In healthy individuals, concomitant use of oral rifampin (600 mg daily) and oral nifedipine (20 mcg/kg) or IV nifedipine resulted in an 87 or 30% decrease in nifedipine exposure, respectively. Adjustment of nifedipine dosage may be needed in patients receiving nifedipine concomitantly with rifamycin derivatives.

Quinupristin and Dalfopristin

Concomitant use of nifedipine with quinupristin and dalfopristin may affect the pharmacokinetics of nifedipine, possibly secondary to the inhibition of the isoenzyme CYP3A. In healthy individuals, concomitant administration of repeated oral doses of nifedipine with IV quinupristin and dalfopristin increased the median peak plasma concentration and the AUC of nifedipine by 18 and 44%, respectively. In patients receiving nifedipine concomitantly with quinupristin and dalfopristin, blood pressure should be monitored and nifedipine dosage reduced if needed.

Erythromycin

Concomitant use of erythromycin (an inhibitor of the CYP3A4 isoenzyme) and nifedipine may result in inhibition of the metabolism of nifedipine and increased nifedipine exposure. Blood pressure should be monitored and nifedipine dosage reduced if necessary in patients in whom erythromycin is used concomitantly with nifedipine.

Histamine H2-Receptor Antagonists

Concomitant use of nifedipine (single 10-mg doses and 40-60 mg daily) with cimetidine (up to 1 g daily) in healthy individuals increased peak plasma nifedipine concentrations by approximately 60-102% and AUC of nifedipine by approximately 52-101%; plasma clearance of nifedipine was decreased by approximately 40%. Increases in the effect of nifedipine on blood pressure also have been observed in hypertensive patients receiving concomitant therapy with cimetidine (1 g daily) and nifedipine (10 mg daily). Peak plasma concentrations and AUCs of nifedipine also have increased with concomitant nifedipine and ranitidine therapy, but to a lesser degree than with cimetidine. Although the precise mechanism of these interactions is not known, cimetidine-induced inhibition of the cytochrome P-450 mixed-function oxidase system (the enzyme system that is probably responsible for the first-pass metabolism of nifedipine) may play a role. Pending further accumulation of data, cautious dosage titration of nifedipine is recommended in patients receiving cimetidine; a reduction in nifedipine dosage may be necessary in some patients previously stabilized on the drug when cimetidine therapy is initiated.

Since ranitidine interacts with the hepatic cytochrome P-450 (microsomal) enzyme system differently than does cimetidine, ranitidine appears to only minimally inhibit hepatic metabolism of some drugs. Results of several studies indicate that concomitant use of ranitidine with nifedipine did not affect exposure of nifedipine and no effects on blood pressure or heart rate have been observed when these drugs were used concomitantly in healthy individuals or hypertensive patients.

Anticonvulsant Agents

Concomitant use of phenytoin with nifedipine may affect the pharmacokinetics of nifedipine. Phenytoin is an inducer of the CYP3A4 isoenzyme and may cause decreased nifedipine exposure. Concomitant use of nifedipine (as a 10-mg capsule or a 60-mg extended-release tablet) with phenytoin decreased (by about 70%) the AUC and peak plasma concentrations of nifedipine. Phenytoin toxicity has occurred within 4 weeks after initiating nifedipine in a patient stabilized on phenytoin. Manifestations of phenytoin toxicity (e.g., headaches, nystagmus, tremors, slurred speech, ataxia, mental depression) resolved and plasma concentrations of the drug decreased within 2 weeks after discontinuance of nifedipine. While the mechanism of this interaction has not been elucidated, it was suggested that nifedipine may have reduced the metabolism of phenytoin.

Phenytoin toxicity also reportedly has occurred in at least one patient with subarachnoid hemorrhage receiving nimodipine, another 1,4-dihydropyridine calcium-channel blocker. Whether this effect represented an actual drug interaction between phenytoin and nimodipine has not been determined to date. However, most patients with subarachnoid hemorrhage receiving nimodipine also received concomitant therapy with phenytoin or barbiturates reportedly with no apparent evidence of drug interactions.

Pending further accumulation of data, patients and plasma phenytoin concentrations should be monitored carefully whenever therapy with a 1,4-dihydropyridine calcium-channel blocker is initiated or withdrawn from a patient receiving phenytoin. Blood pressure should be monitored and nifedipine dosage adjusted as needed in patients receiving concomitant nifedipine and phenytoin therapy.

Phenobarbital and carbamazepine also may decrease exposure to nifedipine by inducing the CYP3A isoenzyme. In patients receiving nifedipine concomitantly with phenobarbital or carbamazepine, adjustment of nifedipine dosage may be needed. Conversely, nifedipine exposure may be increased in patients receiving valproic acid concomitantly with nifedipine; blood pressure should be monitored, and a reduction in nifedipine dosage should be considered in these patients.

Immunosuppressive Agents

Because nifedipine may inhibit metabolism of tacrolimus, a substrate of CYP3A4, concomitant use of nifedipine and tacrolimus may result in increased tacrolimus exposure. In patients who underwent transplantation and received such concomitant therapy, tacrolimus dosage reductions of 26-38% were required; tacrolimus blood concentrations should be monitored, and a reduction in tacrolimus dosage should be considered in these patients.

Although sirolimus is a substrate for the isoenzyme 3A4, no clinically important pharmacokinetic interactions were observed in patients receiving nifedipine (a single 60-mg dose) concomitantly with oral sirolimus (a single 10-mg dose).

Dolasetron

Although hydrodolasetron (the main active metabolite of dolasetron) is extensively metabolized, principally via the CYP system, including the 2D6 and 3A4 isoenzymes, concomitant use of IV or oral dolasetron with nifedipine did not alter the clearance of the metabolite.

Other Drugs Affecting Hepatic Microsomal Enzymes

Ethanol can increase the oral bioavailability of nifedipine, possibly via inhibition of hepatic cytochrome P-450 microsomal metabolism. In one study in healthy adults, concomitant administration of ethanol with a single 20-mg oral dose of nifedipine capsules resulted in a 54% increase in the AUC of nifedipine.

Nefazodone, an inhibitor of the CYP3A isoenzyme, may inhibit the metabolism of nifedipine and increase nifedipine exposure; blood pressure should be monitored, and a reduction of nifedipine dosage should be considered in patients receiving nefazodone concomitantly with nifedipine.

St. John's wort may decrease nifedipine exposure by inducing the CYP3A4 isoenzyme. Adjustment of nifedipine dosage may be necessary in patients receiving nifedipine concomitantly with St. John's wort.

Grapefruit Juice

Concomitant oral administration of grapefruit juice with nifedipine has been reported to increase bioavailability of the drug. Peak plasma concentrations and AUC values of nifedipine have been reported to increase by approximately twofold (with no change in elimination half-life) when the drug is administered with grapefruit juice. The interaction between grapefruit juice and the oral bioavailability of some 1,4-dihydropyridine-derivative calcium-channel blocking agents appears to result from inhibition, probably prehepatic, of the cytochrome P-450 enzyme system by some constituent(s) in the juice. Following oral administration of nifedipine, such prehepatic inhibition of drug metabolism by grapefruit juice appears mainly to involve the CYP3A4 isoenzyme, principally within the wall of the small intestine (e.g., in the jejunum), thus increasing systemic availability of the drug. Concomitant oral administration of grapefruit juice and nifedipine should be avoided. Consumption of grapefruit juice should be discontinued at least 3 days prior to initiating nifedipine therapy.

β-Adrenergic Blocking Agents

Although concomitant therapy usually is well tolerated, the risk of severe hypotension, exacerbation of angina, congestive heart failure, and arrhythmia may be increased when nifedipine is used concomitantly with a β-adrenergic blocking agent (β-blocker) (e.g., propranolol, timolol), as compared with nifedipine alone. One manufacturer states that clinical monitoring is recommended in patients receiving nifedipine concomitantly with a β-blocker, and adjustment of nifedipine dosage should be considered. Exacerbation of anginal pain also has been observed when β-blocker therapy was being withdrawn concurrently with initiation of nifedipine therapy; gradual reduction of β-blocker dosage instead of abrupt withdrawal may minimize the risk of this effect.

Fentanyl

Severe hypotension has occurred during surgery in patients receiving nifedipine, a β-blocker, and fentanyl concomitantly. The manufacturers recommend temporarily withholding nifedipine for at least 36 hours before surgery in which use of high-dose fentanyl is contemplated, if the patient's condition permits.

Digoxin

Most evidence indicates that nifedipine does not substantially affect the pharmacokinetics of digoxin when the drugs are administered concomitantly; however, some data suggest that serum digoxin concentrations may increase by about 15-45% during concomitant therapy. Further evaluation of this potential interaction is needed. Since there have been isolated reports of increased serum digoxin concentrations during concomitant administration, serum digoxin concentrations should be monitored when nifedipine therapy is initiated or discontinued or dosage of nifedipine is adjusted in patients receiving digoxin. Patients receiving the drugs concomitantly should be monitored for signs and symptoms of digoxin toxicity and dosage of the cardiac glycoside reduced if necessary.

Antidiabetic Agents

Since nifedipine may produce hyperglycemia which may lead to loss of glycemic control, glucose concentrations should be carefully monitored and adjustment of nifedipine dosage should be considered in patients receiving concomitant therapy with nifedipine and acarbose.

Nifedipine appears to enhance absorption of metformin. In healthy individuals, concomitant use of nifedipine with metformin was associated with 20 and 9% increases in peak plasma concentrations and AUC of metformin, respectively.

Omeprazole

Administration of omeprazole 20 mg daily for 8 days followed by a single 10-mg dose of nifedipine in healthy individuals increased AUC of nifedipine by 26% and decreased peak plasma concentrations of nifedipine by 13% when compared with placebo followed by a single 10-mg dose of nifedipine. Concomitant use of omeprazole and nifedipine did not alter the effects of nifedipine on blood pressure or heart rate. The effect of omeprazole on nifedipine pharmacokinetics is unlikely to be clinically important.

Hypotensive Agents

Concomitant administration of nifedipine with hypotensive agents (e.g., methyldopa, hydralazine, captopril, doxazosin) may increase the incidence of severe hypotension. When nifedipine is added to an existing antihypertensive therapy regimen, the patient should be observed closely for severe hypotension, especially during initial titration or upward adjustment of nifedipine dosage.

Attenuation of the tachycardic effect of nifedipine has been observed in patients receiving concomitant benazepril.

Anticoagulants

Increased prothrombin time has been reported rarely in patients receiving concomitant therapy with nifedipine and coumarin anticoagulants; however, a causal relationship to nifedipine has not been established.

Platelet-aggregation Inhibitors

No clinically important interactions have been reported in patients receiving nifedipine concomitantly with clopidogrel or tirofiban.

Other Drugs

The manufacturer of Adalat CC extended-release nifedipine tablets states that clinical experience is insufficient to recommend concomitant use of nifedipine with flecainide.

Pharmacokinetics

Absorption

Approximately 90% of an oral dose of nifedipine is rapidly absorbed from the GI tract following oral administration of the drug as conventional capsules. Only about 45-75% of an oral dose as conventional capsules reaches systemic circulation as unchanged drug since nifedipine is metabolized on first pass through the liver. Peak serum concentrations usually are reached within 0.5-2 hours after oral administration as conventional capsules. Food appears to decrease the rate but not the extent of absorption of nifedipine as conventional capsules.

The manufacturer states that relative oral bioavailability differs little if conventional nifedipine capsules are swallowed intact, bitten and swallowed, or bitten and held sublingually. However, some data indicate that the rate and extent of absorption of nifedipine following sublingual administration may be decreased substantially. In several studies, peak plasma concentrations of nifedipine appeared to be delayed and decreased following sublingual administration. In one crossover study in healthy adults in which a 10-mg conventional capsule of the drug was bitten and held sublingually for 20 minutes or bitten and swallowed, the bioavailability following sublingual administration was 17% (range: 7-28%) of that following oral administration of a bitten capsule; on average, 86% of the dose remained in the mouth at the end of the 20-minute sublingual retention period. In this study, peak serum nifedipine concentrations following sublingual or oral administration of a bitten capsule occurred within 50 (range: 20-99) or 30 (range: 15-49) minutes, respectively, and averaged 10 (range: 5-17) or 82 (range: 44-146) ng/mL, respectively. Oral bioavailability of nifedipine may be increased up to twofold in patients with liver cirrhosis.

The commercially available extended-release tablets of nifedipine (Procardia XL) contain the drug in an oral osmotic delivery system formulation (elementary osmotic pump, gastrointestinal therapeutic system [GITS]). The osmotic delivery system consists of an osmotically active core (comprised of a layer containing the drug and a layer containing osmotically active but pharmacologically inert components) that is surrounded by a semipermeable membrane with a laser-drilled delivery orifice and is designed to deliver the drug at an approximately constant rate over a 24-hour period (approximately zero-order delivery). When exposed to water in the GI tract, water is drawn osmotically into the core at a controlled rate that is determined by the permeability of the outer membrane and the osmotic pressure of the core formulation; as water enters the formulation, a resulting suspension of the drug is pushed out the delivery orifice of the membrane into the GI tract. Delivery of nifedipine from the formulation depends on the existence of an osmotic gradient between the fluid in the GI tract and the osmotically active core of the tablet, with drug delivery remaining approximately constant as long as the gradient is maintained and then declining parabolically to zero as the concentration inside the tablet falls below saturation. The rate of nifedipine delivery in the GI tract is independent of pH over the range of 1.2-7.5 and probably GI motility. The inert tablet ingredients remain intact and are eliminated in feces.

Extended-release tablets (Procardia XL) labeled as containing 30, 60, or 90 mg of nifedipine reportedly deliver the drug into the GI tract at an approximately constant rate of 1.7, 3.4, and 5.1 mg/hour, respectively, throughout the 24-hour dosing period. Following oral administration of a single dose of the drug as extended-release tablets, plasma nifedipine concentrations increase gradually, reaching a peak at approximately 6 hours, and bioavailability is approximately 55-65% of that achieved with the same doses administered orally as conventional capsules. Following multiple doses, oral bioavailability from the extended-release tablets increases to approximately 75-86% of that achieved with the same doses administered as conventional capsules. Administration of Procardia XL nifedipine extended-release tablets with food can increase the early rate of GI absorption but reportedly does not affect overall bioavailability.

The commercially available extended-release tablets of nifedipine (Adalat CC) are composed of a slow-release outer coat and an immediate-release core. The bioavailability of nifedipine as Adalat CC extended-release tablets relative to conventional nifedipine capsules is about 84-89%. Following oral administration of Adalat CC in fasting individuals, peak plasma concentrations occur within 2.5-5 hours, with a small second peak (or ''shoulder'') occurring within 6-12 hours. Following oral administration of Adalat CC extended-release nifedipine 30-mg tablets over a dosage range of 30-90 mg, the area under the plasma-concentration time curve (AUC) was proportional to the dose administered; however, peak plasma concentrations of the 90-mg dose (three 30-mg tablets) were 29% greater than that predicted from the 30- and 60-mg doses. Once-daily dosing of Adalat CC extended-release tablets, under fasting conditions, resulted in less fluctuation in plasma nifedipine concentrations when compared with 3-times-daily dosing with conventional nifedipine capsules. Following administration of a single Adalat CC 90-mg extended-release tablet under fasting conditions, mean peak plasma nifedipine concentration of about 115 ng/mL were reported. Administration of Adalat CC extended-release tablets immediately after a high-fat meal increases peak plasma nifedipine concentrations by 60% and delays the time to peak plasma concentrations; however, no substantial changes in AUC occur. Peak plasma concentrations of nifedipine following administration of Adalat CC extended-release tablets after a high-fat meal are slightly lower compared with those occurring after administration of the same daily dosage given in 3 divided doses as the conventional nifedipine capsules; this difference may be attributed to the lower bioavailability of Adalat CC extended-release tablets compared with that of conventional nifedipine capsules.

Following oral administration of Adalat CC extended-release nifedipine tablets in healthy geriatric individuals (older than 60 years of age), the mean peak plasma concentrations and average plasma concentrations of nifedipine increased by 36 and 70%, respectively, compared with those observed in younger adults.

With another extended-release tablet formulation (Adalat L, not commercially available in the US), both the rate and extent (over 12 hours) of absorption of a single dose of nifedipine were increased by administration with food. Because orally administered nifedipine undergoes extensive metabolism on first pass through the liver, bioavailability of the drug from extended-release tablets is increased substantially in patients with liver cirrhosis and may be particularly increased in those with portacaval shunts. Substantial reductions in GI retention time for prolonged periods (e.g., in patients with short-bowel syndrome) can result in decreased absorption of nifedipine from extended-release tablets.

Distribution

Binding of nifedipine to plasma proteins is concentration dependent and ranges from 92-98%. Protein binding may be reduced in patients with renal or hepatic (e.g., liver cirrhosis) impairment.

Elimination

In patients with normal renal and hepatic function, the plasma half-life of nifedipine is about 2 hours when administered as conventional capsules, and about 7 hours when administered as extended-release tablets (Adalat CC). The drug is extensively metabolized in the liver (to highly water-soluble, inactive metabolites) by the cytochrome P-450 microsomal enzyme system, including CYP3A. Approximately 60-80% of an oral dose of nifedipine is excreted as metabolites in the urine, with only traces (less than 0.1%) of an oral dose being excreted in urine as unchanged drug. The remainder of a dose is excreted in the feces as metabolites, possibly via biliary elimination. Nifedipine appears to be negligibly removed by hemodialysis or hemoperfusion.

Adalat CC extended-release tablets should be used with caution in patients with renal impairment because absorption of the drug may be altered in such patients. In patients with hepatic impairment, elimination of the drug may be altered. The elimination half-life of nifedipine has been reported to increase to 7 hours in patients with liver cirrhosis; oral bioavailability of the drug also is increased in such patients.

Following IV administration of nifedipine, body clearance of the drug is 519 and 348 mL/minute in young adults and geriatric individuals, respectively.