Felodipineside effects

In controlled studies in the United States and overseas, approximately 3000 patients were treated with felodipine as either the extended-release or the immediate-release formulation. The most common clinical adverse events reported with felodipine extended-release administered as monotherapy at the recommended dosage range of 2.5 mg to 10 mg once a day were peripheral edema and headache. Peripheral edema was generally mild, but it was age and dose related and resulted in discontinuation of therapy in about 3% of the enrolled patients. Discontinuation of therapy due to any clinical adverse event occurred in about 6% of the patients receiving felodipine extended-release tablets, principally for peripheral edema, headache, or flushing. Adverse events that occurred with an incidence of 1.5% or greater at any of the recommended doses of 2.5 mg to 10 mg once a day (felodipine extended-release tablets, N = 861; Placebo, N = 334), without regard to causality, are compared to placebo and are listed by dose in the table below. These events are reported from controlled clinical trials with patients who were randomized to a fixed dose of felodipine extended-release tablets or titrated from an initial dose of 2.5 mg or 5 mg once a day. A dose of 20 mg once a day has been evaluated in some clinical studies. Although the antihypertensive effect of felodipine extended-release tablets is increased at 20 mg once a day, there is a disproportionate increase in adverse events, especially those associated with vasodilatory effects (see DOSAGE AND ADMINISTRATION ). Percent of Patients with Adverse Events in Controlled Trials* of Felodipine Extended-Release Tablets (N = 861) as Monotherapy without Regard to Causality (Incidence of discontinuations shown in parentheses) Body System Adverse Events Placebo N=334 2.5 mg N=255 5 mg N=581 10 mg N= 408 Body as a whole Peripheral Edema 3.3 2.0 8.8 17.4 Asthenia 3.3 3.9 3.3 2.2 Warm Sensation 0.0 0.0 0.9

1.5 Cardiovascular

Palpitation 2.4 0.4 1.4

2.5 Digestive

Nausea 1.5 1.2 1.7 1.0 Dyspepsia 1.2 3.9 0.7 0.5 Constipation 0.9 1.2 0.3

1.5 Nervous

Headache 10.2 10.6 11.0 14.7 Dizziness 2.7 2.7 3.6 3.7 Paresthesia 1.5 1.6 1.2

1.2 Respiratory

Upper Respiratory Infection 1.8 3.9 1.9 0.7 Cough 0.3 0.8 1.2 1.7 Rhinorrhea 0.0 1.6 0.2 0.2 Sneezing 0.0 1.6 0.0 0.0 Skin Rash 0.9 2.0 0.2 0.2 Flushing 0.9 3.9 5.3 6.9 *Patients in titration studies may have been exposed to more than one dose level of felodipine extended-release tablets. Adverse events that occurred in 0.5 up to 1.5% of patients who received felodipine extended-release tablets in all controlled clinical trials at the recommended dosage range of 2.5 mg to 10 mg once a day, and serious adverse events that occurred at a lower rate, or events reported during marketing experience (those lower rate events are in italics) are listed below. These events are listed in order of decreasing severity within each category, and the relationship of these events to administration of felodipine extended-release tablets are uncertain: Body as a Whole: Chest pain, facial edema, flu-like illness Cardiovascular: Myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia, tachycardia, premature beats Digestive: Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation Endocrine: Gynecomastia Hematologic: Anemia Metabolic: ALT (SGPT) increased Musculoskeletal: Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain Nervous/Psychiatric: Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido Respiratory: Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis Special Senses: Visual disturbances Urogenital: Impotence, urinary frequency, urinary urgency, dysuria, polyuria.

Gingival Hyperplasia: Gingival hyperplasia, usually mild, occurred in < 0.5% of patients in controlled studies. This condition may be avoided or may regress with improved dental hygiene. (See PRECAUTIONS, Information for Patients.) Clinical Laboratory Test Findings Serum Electrolytes - No significant effects on serum electrolytes were observed during short- and long-term therapy (see CLINICAL PHARMACOLOGY:Renal/Endocrine Effects ). Serum Glucose - No significant effects on fasting serum glucose were observed in patients treated with felodipine extended-release tablets in the U.S. controlled study. Liver Enzymes - 1 of 2 episodes of elevated serum transaminases decreased once drug was discontinued in clinical studies; no follow-up was available for the other patient. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.