NIFEDIPINE

Nifedipine capsules, USP (nifedipine) is an antianginal drug belonging to a class of pharmacological agents, the calcium channel blockers. Nifedipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, dimethyl ester, 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 capsules, USP are formulated as soft gelatin capsules for oral administration each containing 20 mg nifedipine. Inert ingredients in the formulations are: glycerin, peppermint oil, polyethylene glycol, saccharin sodium, gelatin, FD&C Yellow #6, FD&C Red #40, titanium dioxide, ink white opacode (WB) NSP- 78-18022 (comprises of: polyethylene glycol/macrogol, polyvinyl acetate phthalate, titanium dioxide, propylene glycol) and water. Chem Structure

Vasospastic Angina Nifedipine capsules, USP (nifedipine) is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine capsules, USP may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta-blockers. Chronic Stable Angina (Classical Effort-Associated Angina) Nifedipine capsules, USP is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents. In chronic stable angina (effort-associated angina), nifedipine capsules, USP has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients are incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine capsules, USP and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely since severe hypotension can occur from the combined effects of the drugs. ( See WARNINGS ). Vasospastic Angina Nifedipine capsules, USP (nifedipine) is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. Nifedipine capsules, USP may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta-blockers. Chronic Stable Angina (Classical Effort-Associated Angina) Nifedipine capsules, USP is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents. In chronic stable angina (effort-associated angina), nifedipine capsules, USP has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long-term safety in these patients are incomplete. Controlled studies in small numbers of patients suggest concomitant use of nifedipine capsules, USP and beta-blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely since severe hypotension can occur from the combined effects of the drugs. ( See WARNINGS ).

The dosage of nifedipine needed to suppress angina and that can be tolerated by the patient must be established by titration. Excessive doses can result in hypotension. Therapy should be initiated with the 10 mg capsule. The starting dose is one 10 mg capsule, swallowed whole, 3 times/day. The usual effective dose range is 10 to 20 mg three times daily. Some patients, especially those with evidence of coronary artery spasm, respond only to higher doses, more frequent administration, or both. In such patients, doses of 20 to 30 mg three or four times daily may be effective. Doses above 120 mg daily are rarely necessary. More than 180 mg per day is not recommended. In most cases, nifedipine titration should proceed over a 7 to 14 day period so that the physician can assess the response to each dose level and monitor the blood pressure before proceeding to higher doses. If symptoms so warrant, titration may proceed more rapidly provided that the patient is assessed frequently. Based on the patient’s physical activity level, attack frequency, and sublingual nitroglycerin consumption, the dose of nifedipine may be increased from 10 mg t.i.d. to 20 mg t.i.d. and then to 30 mg t.i.d. over a three-day period. In hospitalized patients under close observation, the dose may be increased in 10 mg increments over four- to six-hour periods as required to control pain and arrhythmias due to ischemia. A single dose should rarely exceed 30 mg. Avoid co-administration of nifedipine with grapefruit juice (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Other Interactions ). No “rebound effect” has been observed upon discontinuation of nifedipine. However, if discontinuation of nifedipine is necessary, sound clinical practice suggests that the dosage should be decreased gradually with close physician supervision. Co-Administration with other Antianginal Drugs Sublingual nitroglycerin may be taken as required for the control of acute manifestations of angina, particularly during nifedipine titration. See PRECAUTIONS , Drug Interactions , for information on co-administration of nifedipine with beta-blockers or long-acting nitrates.

Known hypersensitivity reaction to nifedipine.

In multiple-dose United States and foreign controlled studies in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of nifedipine. Adverse Effect Nifedipine (%) (N=226) Placebo (%) (N=235) Dizziness, lightheadedness, giddiness 27 15 Flushing, heat sensation 25 8 Headache 23 20 Weakness 12 10 Nausea, heartburn 11 8 Muscle cramps, tremor 8 3 Peripheral edema 7 1 Nervousness, mood changes 7 4 Palpitation 7 5 Dyspnea, cough, wheezing 6 3 Nasal congestion, sore throat 6 8 There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The most common adverse events were: Incidence Approximately 10% Cardiovascular: peripheral edema Central Nervous System: dizziness or lightheadedness Gastrointestinal: nausea Systemic: headache and flushing, weakness Incidence Approximately 5% Cardiovascular: transient hypotension Incidence 2% or Less Cardiovascular: palpitation Respiratory: nasal and chest congestion, shortness of breath Gastrointestinal: diarrhea, constipation, cramps, flatulence Musculoskeletal: inflammation, joint stiffness, muscle cramps Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties Incidence Approximately 0.5% Cardiovascular: syncope (mostly with initial dosing and/or an increase in dose), erythromelalgia Incidence Less Than 0.5% Hematologic: thrombocytopenia, anemia, leukopenia, purpura Gastrointestinal: allergic hepatitis Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia CNS: depression, paranoid syndrome Special Senses: transient blindness at the peak of plasma level, tinnitus Urogenital: nocturia, polyuria Other: arthritis with ANA (+), exfoliative dermatitis, gynecomastia Musculoskeletal: myalgia Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day or more. Transient hypotension, generally of mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more. Very rarely, introduction of nifedipine therapy was associated with an increase in anginal pain, possibly due to associated hypotension. Transient unilateral loss of vision has also occurred. In addition, more serious adverse events were observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients. In a subgroup of over 1000 patients receiving nifedipine with concomitant beta-blocker therapy, the pattern and incidence of adverse experiences were not different from that of the entire group of nifedipine treated patients (See PRECAUTIONS ). In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina pectoris (about 10% of the total patient population), dizziness or lightheadedness, peripheral edema, headache, or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150. In post-marketing experience, there have been rare reports of exfoliative dermatitis caused by nifedipine. There have been rare reports of exfoliative or bullous skin adverse events (such as erythema multiforme, Stevens-Johnson Syndrome, and toxic epidermal necrolysis) and photosensitivity reactions. Acute generalized exanthematous pustulosis also has been reported. To report SUSPECTED ADVERSE REACTIONS, contact Leading Pharma, LLC at 1-844-740-7500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Beta-adrenergic blocking agents: (See INDICATIONS AND USAGE and WARNINGS ). Experience in over 1400 patients in a non-comparative clinical trial has shown that concomitant administration of nifedipine and beta-blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina. Long-acting nitrates: Nifedipine may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination. Digitalis: Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over- or under-digitalization. Quinidine: There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine). Coumarin anticoagulants: 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. Cimetidine: A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%) after a one week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised. Nifedipine is metabolized by CYP3A4. Co-administration of nifedipine with phenytoin, an inducer of CYP3A4, lowers the systemic exposure to nifedipine by approximately 70%. Avoid co-administration of nifedipine with phenytoin or any known CYP3A4 inducer or consider an alternative antihypertensive therapy. CYP3A inhibitors such as fluconazole, itraconazole, clarithromycin, erythromycin, nefazodone, fluoxetine, saquinavir, indinavir, and nelfinavir 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.