NIFEdipine 10 mg Capsule, 100-count

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 and other immediate-release 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 immediaterelease 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 capsules 10 mg 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…

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 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…

Drug Interactions 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.