NIFEDIPINE

Nifedipine extended-release tablets are an extended-release tablet dosage form of the calcium channel blocker nifedipine. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2 - nitrophenyl)-, dimethyl ester. The molecular formula is C 17 H 18 N 2 O 6 and has the structural formula: Nifedipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 346.3. Nifedipine extended-release tablets contain 30 mg of nifedipine for once-a-day oral administration. In addition, each tablet contains the following inactive ingredients: ethylcellulose, ferric oxide yellow, hydroxyethyl cellulose, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyacrylic dispersion (copolymer of ethyl acrylate and methyl methacrylate), polyethylene glycol, silicon dioxide, sodium lauryl sulfate, talc, and titanium dioxide. Nifedipine extended-release tablets meet USP Dissolution Test 4 (using first derivative UV spectrophotometry at 245 nm for sample analysis).

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

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 to 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. Coadministration 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.

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.

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% 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.

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 coadministration 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 CYP3A inhibition), grapefruit, nefazodone, fluoxetine, saquinavir, indinavir, nelfinavir, and ritonavir may result in increased exposure to nifedipine when coadministered. 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 . Coadministration 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 coadministration of flecainide with nifedipine to recommend concomitant use. Calcium Channel Blockers Diltiazem: Pretreatment 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 coadministering 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 coadministration 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-release tablet was well tolerated when administered in combination with beta-blockers in 187 hypertensive patients in a placebo-controlled clinical trial. However, there have been occasional literature reports suggesting that the combination of nifedipine and beta-adrenergic blocking drugs may increase the likelihood of congestive heart failure, severe hypotension, or exacerbation of angina in patients with cardiovascular disease. Clinical monitoring is recommended, and a dose adjustment of nifedipine should be considered. Timolol: Hypotension is more likely to occur if dihydropryridine calcium antagonists such as nifedipine are coadministered with timolol. Central Alpha1-Blockers Doxazosin: Healthy volunteers participating in a multiple dose doxazosin-nifedipine interaction study received 2 mg doxazosin q.d. alone or combined with 20 mg nifedipine ER b.i.d. Coadministration of nifedipine resulted in a decrease in AUC and C max of doxazosin to 83% and 86% of the values in the absence of nifedipine, respectively. In the presence of doxazosin, AUC and C max of nifedipine were increased by factors of 1.13 and 1.23, respectively. Compared to nifedipine monotherapy, blood pressure was lower in the presence of doxazosin. Blood pressure should be monitored when doxazosin is coadministered with nifedipine and dose reduction of nifedipine considered. Digitalis Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced clearance resulting in an increase in plasma concentration of digoxin. Since there have been isolated reports of patients with elevated digoxin levels and there is a possible interaction between digoxin and nifedipine extended-release tablet, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine extended-release tablet to avoid possible over- or under-digitalization. Antithrombotics Coumarins: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom nifedipine was administered. However, the relationship to nifedipine therapy is uncertain. Platelet Aggregation Inhibitors Clopidogrel: No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with nifedipine. Tirofiban: Coadministration of nifedipine did not alter the exposure to tirofiban importantly. Other Diuretics, PDE5 inhibitors, alpha-methyldopa: Nifedipine may increase the blood pressure lowering effect of these concomitantly administered agents.