Nifedipine

INDICATIONS AND USAGE Nifedipine extended-release tablets are indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

DOSAGE AND ADMINISTRATION Dosage should be adjusted according to each patient’s needs. It is recommended that nifedipine extended-release tablet be administered orally once daily on an empty stomach. Nifedipine extended-release tablet is an extended-release dosage form and tablets should be swallowed whole, not bitten or divided. In general, titration should proceed over a 7-14 day period starting with 30 mg once daily. Upward titration should be based on therapeutic efficacy and safety. The usual maintenance dose is 30 mg to 60 mg once daily. Titration to doses above 90 mg daily is not recommended. If discontinuation of nifedipine extended-release tablets is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Co-administration of nifedipine with grapefruit juice is to be avoided (See CLINICAL PHARMACOLOGY and PRECAUTIONS ). Care should be taken when dispensing nifedipine extended-release tablets to assure that the extended-release dosage form has been prescribed.

WARNINGS Excessive Hypotension Although in most patients the hypotensive effect of nifedipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients using concomitant beta-blockers. Severe hypotension and/or increased fluid volume requirements have been reported in patients who received immediate-release capsules together with a beta-blocking agent and who underwent coronary artery bypass surgery using high-dose fentanyl anesthesia. The interaction with high-dose fentanyl appears to be due to the combination of nifedipine and a beta-blocker, but the possibility that it may occur with nifedipine alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In nifedipine-treated patients where surgery using high-dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient’s condition permits, sufficient time (at least 36 hours) should be allowed for nifedipine to be washed out of the body prior to surgery. Increased Angina and/or Myocardial Infarction Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well-documented increased frequency, duration and/or severity of angina or acute myocardial infarction upon starting nifedipine or at the time of dosage increase. The mechanism of this effect is not established. Beta-Blocker Withdrawal When discontinuing a beta-blocker it is important to taper its dose, if possible, rather than stopping abruptly before beginning nifedipine. Patients recently withdrawn from beta-blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of nifedipine treatment will not prevent this occurrence and on occasion has been reported to increase it. Congestive Heart Failure Rarely, patients (usually while receiving a beta-blocker) have developed heart failure after beginning nifedipine. Patients with tight aortic stenosis may be at greater risk for such an event, as the unloading effect of nifedipine would be expected to be of less benefit to these patients, owing to their fixed impedance to flow across the aortic valve.

CONTRAINDICATIONS Concomitant administration with strong P450 inducers, such as rifampin, are contraindicated since the efficacy of nifedipine tablets could be significantly reduced. (See PRECAUTIONS, Drug Interactions. ) Nifedipine must not be used in cases of cardiogenic shock. Nifedipine extended-release tablets are contraindicated in patients with a known hypersensitivity to any component of the tablet.

Drug Interactions Nifedipine is mainly eliminated by metabolism and is a substrate of CYP3A. Inhibitors and inducers of CYP3A can impact the exposure to nifedipine and consequently its desirable and undesirable effects. In vitro and in vivo data indicate that nifedipine can inhibit the metabolism of drugs that are substrates of CYP3A, thereby increasing the exposure to other drugs. Nifedipine is a vasodilator, and co-administration of other drugs affecting blood pressure may result in pharmacodynamic interactions. CYP3A Inhibitors 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 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 ). Cardiovascular Drugs Antiarrhythmics 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. ACE Inhibitors 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. Angiotensin-II Blockers 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. Beta-Blockers Nifedipine extended-…

Pregnancy Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women. Pregnancy Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin. From the clinical evidence available, a specific prenatal risk has not been identified. However, an increase in perinatal asphyxia, caesarean delivery, prematurity and intrauterine growth retardation have been reported. Careful monitoring of blood pressure must be exercised in pregnant women, when administering nifedipine in combination with IV magnesium sulfate due to the possibility of an excessive fall in blood pressure which could harm the mother and fetus. There are no adequate and well-controlled studies in pregnant women. Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentotoxic, teratogenic and fetotoxic effects, including stunted fetuses (rats, mice and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within an order of magnitude of it. The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar t…

Nursing Mothers Nifedipine is excreted in human milk. Nursing mothers are advised not to breastfeed their babies when taking the drug.

ADVERSE EXPERIENCES The incidence of adverse events during treatment with nifedipine extended-release tablets in doses up to 90 mg daily were derived from multi-center placebo-controlled clinical trials in 370 hypertensive patients. Atenolol 50 mg once daily was used concomitantly in 187 of the 370 patients on nifedipine extended-release tablets and in 64 of the 126 patients on placebo. All adverse events reported during nifedipine extended-release tablets therapy were tabulated independently of their causal relationship to medication. The most common adverse event reported with nifedipine extended-release tablets was peripheral edema. This was dose related, and the frequency was 18% on nifedipine extended-release tablets 30 mg daily, 22% on nifedipine extended-release tablets 60 mg daily, and 29% on nifedipine extended-release tablets 90 mg daily versus 10% on placebo. Other common adverse events reported in the above placebo-controlled trials include: Adverse Event NIFEDIPINE EXTENDED-RELEASE TABLETS (%) (n=370) PLACEBO (%) (n=126) Headache 19 13 Flushing/heat sensation 4 0 Dizziness 4 2 Fatigue/asthenia 4 4 Nausea 2 1 Constipation 1 0 Where the frequency of adverse events with nifedipine extended-release tablets and placebo is similar, causal relationship cannot be established. The following adverse events were reported with an incidence of 3% or less in daily doses up to 90 mg: Body as a Whole/Systemic: chest pain, leg pain Central Nervous System: paresthesia, vertigo Dermatologic: rash Gastrointestinal: constipation Musculoskeletal: leg cramps Respiratory: epistaxis, rhinitis Urogenital: impotence, urinary frequency Other adverse events reported with an incidence of less than 1.0% were: Body as a Whole/Systemic: allergic reaction, asthenia, cellulitis, substernal chest pain, chills, facial edema, lab test abnormal, malaise, neck pain, pelvic pain, pain, photosensitivity reaction Cardiovascular: atrial fibrillation, bradycardia, cardiac arrest, extrasystole, hypotension, migraine, palpitations, phlebitis, postural hypotension, tachycardia, cutaneous angiectases Central Nervous System: anxiety, confusion, decreased libido, depression, hypertonia, hypesthesia, insomnia, somnolence Dermatologic: angioedema, petechial rash, pruritus, sweating Gastrointestinal: abdominal pain, diarrhea, dry mouth, dysphagia, dyspepsia, eructation, esophagitis, flatulence, gastrointestinal disorder, gastrointestinal hemorrhage, GGT increased, gum disorder, gum hemorrhage, vomiting Hematologic: eosinophilia, lymphadenopathy Metabolic: gout, weight loss Musculoskeletal: arthralgia, arthritis, joint disorder, myalgia, myasthenia Respiratory: dyspnea, increased cough, rales, pharyngitis, stridor Special Senses: abnormal vision, amblyopia, conjunctivitis, diplopia, eye disorder, eye hemorrhage, tinnitus Urogenital/Reproductive: dysuria, kidney calculus, nocturia, breast engorgement, polyuria, urogenital disorder, erectile dysfunction (ED) The following adverse events have been reported rarely in patients given nifedipine in coat core or other formulations: allergenic hepatitis, alopecia, anaphylactic reaction, anemia, arthritis with ANA (+), depression, erythromelalgia, exfoliative dermatitis, fever, gingival hyperplasia, gynecomastia, hyperglycemia, jaundice, leukopenia, mood changes, muscle cramps, nervousness, paranoid syndrome, purpura, shakiness, sleep disturbances, Stevens-Johnson syndrome, syncope, taste perversion, thrombocytopenia, toxic epidermal necrolysis, transient blindness at the peak of plasma level, tremor and urticaria. To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.