ISOSORBIDE MONONITRATE (Page 2 of 4)

Food Effects

The influence of food on the bioavailability of ISMN after single-dose administration of isosorbide mononitrate extended-release tablets 60 mg was evaluated in three different studies involving either a “light” breakfast or a high-calorie, high-fat breakfast. Results of these studies indicate that concomitant food intake may decrease the rate (increase in Tmax ) but not the extent (AUC) of absorption of ISMN.

Clinical Trials

Controlled trials with isosorbide mononitrate extended-release tablets have demonstrated antianginal activity following acute and chronic dosing. Administration of isosorbide mononitrate extended-release tablets once daily, taken early in the morning on arising, provided at least 12 hours of antianginal activity.

In a placebo-controlled parallel study, 30, 60, 120 and 240 mg isosorbide mononitrate extended-release tablets were administered once daily for up to 6 weeks. Prior to randomization, all patients completed a 1- to 3-week single-blind placebo phase to demonstrate nitrate responsiveness and total exercise treadmill time reproducibility. Exercise tolerance tests using the Bruce Protocol were conducted prior to and at 4 and 12 hours after the morning dose on days 1, 7, 14, 28 and 42 of the double-blind period. Isosorbide mononitrate extended-release tablets 30 and 60 mg (only doses evaluated acutely) demonstrated a significant increase from baseline in total treadmill time relative to placebo at 4 and 12 hours after the administration of the first dose. At day 42, the 120 and 240 mg dose of isosorbide mononitrate extended-release tablets demonstrated a significant increase in total treadmill time at 4 and 12 hours post dosing, but by day 42, the 30 and 60 mg doses no longer were differentiable from placebo. Throughout chronic dosing, rebound was not observed in any isosorbide mononitrate extended-release treatment group.

Pooled data from two other trials, comparing isosorbide mononitrate extended-release tablets 60 mg once daily, ISDN 30 mg QID, and placebo QID in patients with chronic stable angina using a randomized, double-blind, three-way crossover design found statistically significant increases in exercise tolerance times for isosorbide mononitrate extended-release tablets compared to placebo at hours 4, 8 and 12 and to ISDN at hour 4. The increases in exercise tolerance on day 14, although statistically significant compared to placebo, were about half of that seen on day 1 of the trial.

INDICATIONS AND 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.

CONTRAINDICATIONS

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

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.

PRECAUTIONS

General

Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide mononitrate. This drug should, therefore, be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence. The importance of these observations to the routine, clinical use of oral isosorbide mononitrate is not known.

Information for Patients

Patients should be told that the antianginal efficacy of isosorbide mononitrate extended-release tablets can be maintained by carefully following the prescribed schedule of dosing. For most patients, this can be accomplished by taking the dose on arising.

As with other nitrates, daily headaches sometimes accompany treatment with isosorbide mononitrate. In patients who get these headaches, the headaches are a marker of the activity of the drug. Patients should resist the temptation to avoid headaches by altering the schedule of their treatment with isosorbide mononitrate, since loss of headache may be associated with simultaneous loss of antianginal efficacy. Aspirin or acetaminophen often successfully relieves isosorbide mononitrate-induced headaches with no deleterious effect on isosorbide mononitrate’s antianginal efficacy.

Treatment with isosorbide mononitrate may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol.

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.

Drug/Laboratory Test Interactions

Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction, causing falsely low readings in serum cholesterol determinations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was observed in rats exposed to isosorbide mononitrate in their diets at doses of up to 900 mg/kg/day for the first 6 months and 500 mg/kg/day for the remaining duration of a study in which males were dosed for up to 121 weeks and females were dosed for up to 137 weeks. No evidence of carcinogenicity was observed in mice exposed to isosorbide mononitrate in their diets for up to 104 weeks at doses of up to 900 mg/kg/day.

Isosorbide mononitrate did not produce gene mutations (Ames test, mouse lymphoma test) or chromosome aberrations (human lymphocyte and mouse micronucleus tests) at biologically relevant concentrations.

No effects on fertility were observed in a study in which male and female rats were administered doses of up to 750 mg/kg/day beginning, in males, 9 weeks prior to mating, and in females, 2 weeks prior to mating.

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.

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