Nifedipine (Page 4 of 6)

Pregnancy

Nifedipine has been shown to produce teratogenic findings in rats and rabbits, including digital anomalies similar to those reported for phenytoin. Digital anomalies have been reported to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow.

Nifedipine administration was associated with a variety of embryotoxic, placentotoxic, and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits), and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). On a mg/kg basis, all of the doses associated with the teratogenic embryotoxic or fetotoxic effects in animals were higher (5 to 50 times) than the maximum recommended human dose of 120 mg/day. On a mg/m² basis, some doses were higher and some were lower than the maximum recommended human dose, but all are within an order of magnitude of it. The doses associated with placentotoxic effects in monkeys were equivalent to or lower than the maximum recommended human dose on a mg/m² basis.

There are no adequate and well-controlled studies in pregnant women. Nifedipine Extended-release Tablets should be used during pregnancy only if the potential benefit justifies the potential risk.

Lactation

Nifedipine is transferred through breast milk. Nifedipine Extended-release Tablets should be used during breast-feeding only if the potential benefit justifies the potential risk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Age appears to have a significant effect on the pharmacokinetics of nifedipine. The clearance is decreased resulting in a higher AUC in the elderly. These changes are not due to changes in renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

ADVERSE EXPERIENCES

Over 1000 patients from both controlled and open trials with Nifedipine Extended-release Tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during Nifedipine Extended-release Tablet therapy were tabulated independent of their causal relation to medication. The most common side effect reported with Nifedipine Extended-release Tablets was edema which was dose related and ranged in frequency from approximately 10% to about 30% at the highest dose studied (180 mg). Other common adverse experiences reported in placebo-controlled trials include:

	Nifedipine Extended-release Tablets (%)	Placebo (%)
Adverse Effect	(N=707)	(N=266)
Headache	15.8	9.8
Fatigue	5.9	4.1
Dizziness	4.1	4.5
Constipation	3.3	2.3
Nausea	3.3	1.9

Of these, only edema and headache were more common in Nifedipine Extended-release Tablet patients than placebo patients.

The following adverse reactions occurred with an incidence of less than 3.0%. With the exception of leg cramps, the incidence of these side effects was similar to that of placebo alone.

Body as a Whole/Systemic: asthenia, flushing, pain

Cardiovascular: palpitations

Central Nervous System: insomnia, nervousness, paresthesia, somnolence

Dermatologic: pruritus, rash

Gastrointestinal: abdominal pain, diarrhea, dry mouth, dyspepsia, flatulence

Musculoskeletal: arthralgia, leg cramps

Respiratory: chest pain (nonspecific), dyspnea

Urogenital: impotence, polyuria

Other adverse reactions were reported sporadically with an incidence of 1.0% or less. These include:

• Body as a Whole/Systemic: face edema, fever, hot flashes, malaise, periorbital edema, rigors
• Cardiovascular: arrhythmia, hypotension, increased angina, tachycardia, syncope
• Central Nervous System: anxiety, ataxia, decreased libido, depression, hypertonia, hypoesthesia, migraine, paroniria, tremor, vertigo
• Dermatologic: alopecia, increased sweating, urticaria, purpura
• Gastrointestinal: eructation, gastroesophageal reflux, gum hyperplasia, melena, vomiting, weight increase
• Musculoskeletal: back pain, gout, myalgias
• Respiratory: coughing, epistaxis, upper respiratory tract infection, respiratory disorder, sinusitis
• Special Senses: abnormal lacrimation, abnormal vision, taste perversion, tinnitus
• Urogenital/Reproductive: breast pain, dysuria, hematuria, nocturia

Adverse experiences which occurred in less than 1 in 1000 patients cannot be distinguished from concurrent disease states or medications.

The following adverse experiences, reported in less than 1% of patients, occurred under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain:

gastrointestinal irritation, gastrointestinal bleeding, gynecomastia.

Gastrointestinal obstruction resulting in hospitalization and surgery, including the need for bezoar removal, has occurred in association with Nifedipine Extended-release Tablets, even in patients with no prior history of gastrointestinal disease (see WARNINGS).

Cases of tablet adherence to the gastrointestinal wall with ulceration have been reported, some requiring hospitalization and intervention.

In multiple-dose U.S. and foreign controlled studies with nifedipine capsules 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 CAPSULES (%)(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
Palpitations	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 relatively common adverse events were similar in nature to those seen with Nifedipine Extended-release Tablets.

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 was 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, 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.