Nifedipine

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 Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines.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 nifedipine extended-release tablets. 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 nifedipine extended-release tablets 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 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 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: 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 3.0%. 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. 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 capsules with concomitant beta blocker therapy, the pattern and incidence of adverse experiences was not different from that of the entire group of nifedipine capsules-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. To report SUSPECTED ADVERSE REACTIONS, please call Ingenus Pharmaceuticals, LLC toll-free at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 02 03