INDICATIONS AND USAGE I.

Vasospastic Angina 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 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.

II.

Chronic Stable Angina (Classical Effort-Associated Angina) Nifedipine 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 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 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 .

)

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.

Although patients have rarely experienced excessive hypotension on nifedipine alone, this may be more common in patients on concomitant beta blocker therapy.

Although not approved for this purpose, nifedipine capsules have been used (orally and sublingually) for acute reduction of blood pressure.

Several well-documented reports describe cases of profound hypotension, myocardial infarction, and death when immediate-release nifedipine was used in this way.

Nifedipine capsules should not be used for the acute reduction of blood pressure.

Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving nifedipine together with a beta-blocking agent 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 on starting nifedipine or at the time of dosage increase.

The mechanism of this effect is not established.

Several well-controlled, randomized trials studied the use of immediate-release nifedipine in patients who had just sustained myocardial infarctions.

In none of these trials did immediate-release nifedipine appear to provide any benefit.

In some of the trials, patients who received immediate-release nifedipine had significantly worse outcomes than patients who received placebo.

Nifedipine capsules should not be administered within the first week or two after myocardial infarction, and they should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent).

Use in Essential Hypertension Nifedipine and other immediate-release nifedipine capsules have also been used for the long-term control of essential hypertension, although nifedipine capsules have not been approved for this purpose and no properly controlled studies have been conducted to define an appropriate dose or dose interval for such treatment.

Nifedipine capsules should not be used for the control of essential hypertension.

Beta Blocker Withdrawal 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 might be expected to exacerbate it by provoking reflex catecholamine release.

There have been occasional reports of increased angina in a setting of beta blocker withdrawal and nifedipine initiation.

It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine.

Congestive Heart Failure Rarely, patients, usually those 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.

ADVERSE REACTIONS 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 2,100 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 1,000 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 Avet Pharmaceuticals Inc.

at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.