Isosorbide Mononitrate

INDICATIONS & USAGE Isosorbide mononitrate extended-release tablets are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of oral isosorbide mononitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

DOSAGE & ADMINISTRATION The recommended starting dose of Isosorbide Mononitrate Extended-Release Tablets, USP is 30 mg (given as a single 30 mg tablet or as 1/2 of a 60 mg tablet) or 60 mg (given as a single tablet) once daily. After several days, the dosage may be increased to 120 mg (given as a single 120 mg tablet or as two 60 mg tablets) once daily. Rarely, 240 mg may be required. The daily dose of Isosorbide Mononitrate Extended-Release Tablets, USP should be taken in the morning on arising. Isosorbide Mononitrate Extended-Release Tablets, USP should not be chewed or crushed and should be swallowed together with a half-glassful of fluid. Do not break the 30 mg tablet.

WARNINGS Amplification of the vasodilatory effects of isosorbide mononitrate by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion. The benefits of ISMN in patients with acute myocardial infarction or congestive heart failure have not been established; because the effects of isosorbide mononitrate are difficult to terminate rapidly, this drug is not recommended in these settings. If isosorbide mononitrate is used in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.

CONTRAINDICATIONS Isosorbide mononitrate extended-release tablets are contraindicated in patients who have shown hypersensitivity or idiosyncratic reactions to other nitrates or nitrites.

DRUG INTERACTIONS The vasodilating effects of isosorbide mononitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety. Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary.

PREGNANCY Teratogenic effects Pregnancy Category B In studies designed to detect effects of isosorbide mononitrate on embryo-fetal development, doses of up to 240 or 248 mg/kg/day, administered to pregnant rats and rabbits, were unassociated with evidence of such effects. These animal doses are about 100 times the maximum recommended human dose (120 mg in a 50 kg woman) when comparison is based on body weight; when comparison is based on body surface area, the rat dose is about 17 times the human dose and the rabbit dose is about 38 times the human dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, isosorbide mononitrate extended-release tablets should be used during pregnancy only if clearly needed. Nonteratogenic effects Neonatal survival and development and incidence of stillbirths were adversely affected when pregnant rats were administered oral doses of 750 (but not 300) mg isosorbide mononitrate/kg/day during late gestation and lactation. This dose (about 312 times the human dose when comparison is based on body weight and 54 times the human dose when comparison is based on body surface area) was associated with decreases in maternal weight gain and motor activity and evidence of impaired lactation.

NURSING MOTHERS It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ISMN is administered to a nursing mother.

ADVERSE REACTIONS The table below shows the frequencies of the adverse events that occurred in >5% of the subjects in three placebo-controlled North American studies in which patients in the active treatment arm received 30 mg, 60 mg, 120 mg, or 240 mg of isosorbide mononitrate extended-release tablets once daily. In parentheses, the same table shows the frequencies with which these adverse events were associated with the discontinuation of treatment. Overall, 8% of the patients who received 30 mg, 60 mg, 120 mg, or 240 mg of isosorbide mononitrate in the three placebo-controlled North American studies discontinued treatment because of adverse events. Most of these discontinued because of headache. Dizziness was rarely associated with withdrawal from these studies. Since headache appears to be a dose-related adverse effect and tends to disappear with continued treatment, it is recommended that isosorbide mononitrate extended-release tablets treatment be initiated at low doses for several days before being increased to desired levels. FREQUENCY AND ADVERSE EVENTS (DISCONTINUED) a Three Controlled North American Studies Dose Placebo 30 mg 60 mg 120 mg* 240 mg* Patients 96 60 102 65 65 Headache 15% (0%) 38% (5%) 51% (8%) 42% (5%) 57% (8%) Dizziness 4% (0%) 8% (0%) 11% (1%) 9% (2%) 9% (2%) a Some individuals discontinued for multiple reasons. * Patients were started on 60 mg and titrated to their final dose. In addition, the three North American trials were pooled with 11 controlled trials conducted in Europe. Among the 14 controlled trials, a total of 711 patients were randomized to isosorbide mononitrate extended-release tablets. When the pooled data were reviewed, headache and dizziness were the only adverse events that were reported by >5% of patients. Other adverse events, each reported by ≤5% of exposed patients, and in many cases of uncertain relation to drug treatment, were: Autonomic Nervous System Disorders : Dry mouth, hot flushes. Body as a Whole : Asthenia, back pain, chest pain, edema, fatigue, fever, flu-like symptoms, malaise, rigors. Cardiovascular Disorders, General : Cardiac failure, hypertension, hypotension. Central and Peripheral Nervous System Disorders : Dizziness, headache, hypoesthesia, migraine, neuritis, paresis, paresthesia, ptosis, tremor, vertigo. Gastrointestinal System Disorders : Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gastric ulcer, gastritis, glossitis, hemorrhagic gastric ulcer, hemorrhoids, loose stools, melena, nausea, vomiting. Hearing and Vestibular Disorders : Earache, tinnitus, tympanic membrane perforation. Heart Rate and Rhythm Disorders : Arrhythmia, arrhythmia atrial, atrial fibrillation, bradycardia, bundle branch block, extrasystole, palpitation, tachycardia, ventricular tachycardia. Liver and Biliary System Disorders : SGOT increase, SGPT increase. Metabolic and Nutritional Disorders : Hyperuricemia, hypokalemia. Musculoskeletal System Disorders : Arthralgia, frozen shoulder, muscle weakness, musculoskeletal pain, myalgia, myositis, tendon disorder, torticollis. Myo-, Endo-, Pericardial and Valve Disorders : Angina pectoris aggravated, heart murmur, heart sound abnormal, myocardial infarction, Q wave abnormality. Platelet, Bleeding and Clotting Disorders : Purpura, thrombocytopenia. Psychiatric Disorders : Anxiety, concentration impaired, confusion, decreased libido, depression, impotence, insomnia, nervousness, paroniria, somnolence. Red Blood Cell Disorder : Hypochromic anemia. Reproductive Disorders, Female : Atrophic vaginitis, breast pain. Resistance Mechanism Disorders : Bacterial infection, moniliasis, viral infection. Respiratory System Disorders : Bronchitis, bronchospasm, coughing, dyspnea, increased sputum, nasal congestion, pharyngitis, pneumonia, pulmonary infiltration, rales, rhinitis, sinusitis. Skin and Appendages Disorders : Acne, hair texture abnormal, increased sweating, pruritus, rash, skin nodule. Urinary System Disorders : Polyuria, rena…