Procardia nifedipine 90 mg Tablet, Film Coated, Extended Release, 100-count

WARNINGS Excessive Hypotension Although in most angina 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, and may be more likely in patients on concomitant beta blockers. 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.

The following information should be taken into account in those patients who are being treated for hypertension as well as angina: 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. Beta Blocker Withdrawal It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning nifedipine.

Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines.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 on occasion has been reported to increase it. Congestive Heart Failure Rarely, patients, usually 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, owing to the fixed impedance to flow across the aortic valve in these patients. Gastrointestinal Obstruction Requiring Surgery There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of PROCARDIA XL. Bezoars can occur in very rare cases and may require surgical intervention.

Cases of serious gastrointestinal obstruction have been identified in patients with no known gastrointestinal disease, including the need for hospitalization and surgical intervention. Risk factors for a gastrointestinal obstruction identified from post-marketing reports of PROCARDIA XL (GITS tablet formulation) include alteration in gastrointestinal anatomy (e.g., severe gastrointestinal narrowing, colon cancer, small bowel obstruction, bowel resection, gastric bypass, vertical banded gastroplasty, colostomy, diverticulitis, diverticulosis, and inflammatory bowel disease), hypomotility disorders (e.g., constipation, gastroesophageal reflux disease, ileus, obesity, hypothyroidism, and diabetes) and concomitant medications (e.g., H 2 -histamine blockers, opiates, nonsteroidal anti-inflammatory drugs, laxatives, anticholinergic agents, levothyroxine, and neuromuscular blocking agents).

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

ADVERSE EXPERIENCES Over 1000 patients from both controlled and open trials with PROCARDIA XL Extended Release Tablets in hypertension and angina were included in the evaluation of adverse experiences. All side effects reported during PROCARDIA XL Extended Release Tablet therapy were tabulated independent of their causal relation to medication. The most common side effect reported with PROCARDIA XL 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 PROCARDIA XL (%) (N=707) Placebo (%) (N=266) Headache 15.8

9.8Fatigue 5.9

4.1Dizziness 4.1

4.5Constipation 3.3

2.3Nausea 3.3

1.9Of these, only edema and headache were more common in PROCARDIA XL 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 PROCARDIA XL, 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 PROCARDIA 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 co…

Drug Interactions Beta-adrenergic blocking agents (see INDICATIONS AND USAGE and WARNINGS ) Experience in over 1400 patients with PROCARDIA 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.