Nifedipine (Page 3 of 4)

Drug Interactions

Beta-adrenergic blocking agents: (see INDICATIONS AND USAGE and WARNINGS.) Experience in over 1400 patients with nifedipine capsules in a noncomparative 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: Administration of nifedipine with digoxin increased digoxin levels in nine of twelve normal volunteers. The average increase was 45%. Another investigator found no increase in digoxin levels in thirteen patients with coronary artery disease. In an uncontrolled study of over two hundred patients with congestive heart failure during which digoxin blood levels were not measured, digitalis toxicity was not observed. Since there have been isolated reports of patients with elevated digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing nifedipine to avoid possible over-or under-digitalization.

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.

Other Interactions

Grapefruit Juice: Co-administration of nifedipine with grapefruit juice resulted in approximately a doubling in nifedipine AUC and Cmax with no change in half-life. The increased plasma concentrations most likely result from inhibition of CYP 3A4 related first-pass metabolism. Avoid ingestion of grapefruit and grapefruit juice should be avoided while taking nifedipine.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 5 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.

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/kg2 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 tablets therapy were tabulated independent of their causal relation to medication. The most common side effect reported with nifedipine extended-release tablet 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:

Adverse Effect Nifedipine Extended-Release Tablets (%) Placebo (%)
(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 tablets patients than placebo patients.

The following adverse reactions occurred with an incidence of less than 3%. 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% 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, light headedness, 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 light headedness, 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 FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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