In multiple-dose U.S. 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 PROCARDIA.

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 PROCARDIA 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 PROCARDIA with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of PROCARDIA (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.

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 PROCARDIA 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: PROCARDIA 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 PROCARDIA was administered. However, the relationship to PROCARDIA 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.

Other Interactions

Grapefruit Juice: Co-administration of nifedipine with grapefruit juice resulted in approximately a 2-fold increase in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations are most likely due to inhibition of CYP 3A4 related first-pass metabolism. Co-administration of nifedipine with grapefruit juice is to be avoided.

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