Isosorbide Mononitrate

ISOSORBIDE MONONITRATE- isosorbide mononitrate tablet
Actavis Pharma, Inc.

DESCRIPTION

Isosorbide mononitrate (diluted), USP, an organic nitrate, is a vasodilator with effects on both arteries and veins. The molecular formula is C₆ H₉ NO₆ and the molecular weight is 191.14. The chemical name for isosorbide mononitrate is 1,4:3,6-Dianhydro-D-glucitol 5-nitrate and the compound has the following structural formula:

Isosorbide mononitrate tablets, USP, for oral administration, contain 10 mg or 20 mg of isosorbide mononitrate (diluted), USP. In addition, each tablet contains the following inactive ingredients: calcium stearate, colloidal silicon dioxide, corn starch, FD&C Blue #1HT Aluminum Lake, lactose monohydrate, microcrystalline cellulose, and talc.

CLINICAL PHARMACOLOGY

Isosorbide mononitrate is the major active metabolite of isosorbide dinitrate (ISDN), and most of the clinical activity of the dinitrate is attributable to the mononitrate.

The principal pharmacological action of isosorbide mononitrate is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction and coronary dilatation remains undefined.

Pharmacodynamics

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored.

The drug-free interval sufficient to avoid tolerance to isosorbide mononitrate has not been completely defined. In the only regimen of twice-daily isosorbide mononitrate that has been shown to avoid development of tolerance, the two doses of isosorbide mononitrate tablets are given 7 hours apart, so there is a gap of 17 hours between the second dose of each day and the first dose of the next day. Taking account of the relatively long half-life of isosorbide mononitrate this result is consistent with those obtained for other organic nitrates.

The asymmetric twice-daily regimen of isosorbide mononitrate tablets successfully avoided significant rebound/withdrawal effects. The incidence and magnitude of such phenomena have appeared, in studies of other nitrates, to be highly dependent upon the schedule of nitrate administration.

Pharmacokinetics

Isosorbide mononitrate is rapidly and completely absorbed from the gastrointestinal tract. In humans, isosorbide mononitrate is not subject to first pass metabolism in the liver. The absolute bioavailability of isosorbide mononitrate from isosorbide mononitrate tablets is nearly 100%. Peak plasma concentrations usually occur in about 30 to 60 minutes. Isosorbide mononitrate exhibits dose proportionality over the recommended dose range. Food does not significantly affect the absorption or bioavailability of isosorbide mononitrate. Metoprolol coadministration did not change the pharmacokinetics of isosorbide mononitrate. The volume of distribution is approximately 0.6 L/kg. Plasma protein binding of isosorbide mononitrate was found to be less than 5%.

When radiolabelled isosorbide mononitrate was administered to humans in order to elucidate the metabolic fate, about half of the dose was found denitrated and renally excreted as isosorbide and sorbitol. One quarter of the dose was accounted for as conjugates of the parent drug in the urine. None of these metabolites is vasoactive. Only 2% of the dose was excreted as unchanged drug.

The overall elimination half-life of isosorbide mononitrate is about 5 hours. The rate of clearance is the same in healthy young adults, in patients with various degrees of renal, hepatic or cardiac dysfunction and in the elderly. When radiolabelled isosorbide mononitrate was administered to humans, 93% of the dose was excreted within 48 hours into the urine. Renal excretion was virtually complete after 5 days; fecal excretion amounted to only 1% of the dose.

Isosorbide mononitrate has no known effect on renal and hepatic function. In patients with varying degrees of renal failure, dosage adjustment does not appear necessary. In patients with liver cirrhosis, the pharmacokinetic parameters after a single dose of isosorbide mononitrate were similar to the values found in healthy volunteers.

Isosorbide mononitrate is significantly removed from the blood during hemodialysis; however, an additional dose to compensate for drug lost is not necessary. In patients undergoing continuous ambulatory peritoneal dialysis, blood levels are similar to patients not on dialysis.

Clinical Trials

The acute and chronic antianginal efficacy of isosorbide mononitrate has been confirmed in clinical trials. The clinical efficacy of isosorbide mononitrate was studied in 21 stable angina pectoris patients. After single dose administration of isosorbide mononitrate, 20 mg, the exercise capacity was increased by 42.7% after one hour, 29.6% after 6 hours, and by 25% after eight hours when compared to placebo. Controlled trials of single doses of isosorbide mononitrate tablets have demonstrated that antianginal activity is present about 1 hour after dosing, with peak effect seen from 1 to 4 hours after dosing.

In one multicenter placebo-controlled trial, isosorbide mononitrate was found to be safe and effective during acute and chronic (3 weeks) treatment of angina pectoris. Two hundred fourteen (214) patients were enrolled in the trial; 54 patients were randomized to receive placebo and 106 patients were randomized to receive 10 or 20 mg of isosorbide mononitrate twice daily seven hours apart. The largest effect of isosorbide mononitrate, compared to placebo, was on day one — dose one. Although 14 hours after the first dose of day 14, the increase in exercise tolerance due to isosorbide mononitrate was statistically significant, the increase was about half of that seen 2 hours after the first dose of day one. On day 21, two hours after the first dose the effect of isosorbide mononitrate was 60 to 70% of that seen on day one.

INDICATIONS AND USAGE

Isosorbide mononitrate tablets, USP are indicated for the prevention and treatment 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 is contraindicated in patients who are allergic to it.

Do not use isosorbide mononitrate in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia.

Do not use isosorbide mononitrate in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.

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 isosorbide mononitrate 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.