monoket ® (isosorbide mononitrate tablets, USP) Rx Only

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 monoket^® 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 monoket^® 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.

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

monoket^® 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 monoket^® 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.

The acute and chronic antianginal efficacy of monoket^® has been confirmed in clinical trials. The clinical efficacy of monoket^® was studied in 21 stable angina pectoris patients. After single dose administration of monoket^®, 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 monoket^® tablets have demonstrated that antianginal activity is present about 1 hour after dosing, with peak effect seen from 1-4 hours after dosing.

In one multicenter placebo-controlled trial, monoket^® 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 monoket^® twice daily seven hours apart. The largest effect of monoket^®, 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 monoket^® 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 monoket^® was 60 to 70% of that seen on day one.

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.

Patients should be told that the antianginal efficacy of monoket^® tablets can be maintained by carefully following the prescribed schedule of dosing (two doses taken seven hours apart). For most patients, this can be accomplished by taking the first dose on awakening and the second dose 7 hours later.

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 and/or acetaminophen, on the other hand, often successfully relieve isosorbide mononitrate-induced headaches with no deleterious effect on isosorbide mononitrate's antianginal efficacy.

Treatment with isosorbide mononitrate may be associated with light-headedness 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.

Concomitant use of monoket® with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS). 

Concomitant use of isosorbide mononitrate with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS).

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.

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 six 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 mutagenicity was seen in vitro in the Salmonella test (Ames test), in human peripheral lymphocytes, in Chinese hamster cells (V79) or, in vivo in the rat micronucleus test. In a study on the fertility and breeding capacity of two generations of rats, monoket^® had no adverse effects on fertility or general reproductive performance with oral doses up to 120 mg/kg/day. A dose of 360 mg/kg/day was associated with increased mortality in treated males and females and a reduced fertility index. (See table at end of Pregnancy section for animal-to-human dosage comparisons.)

It is not known whether isosorbide mononitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide mononitrate is administered to a nursing woman.

Safety and effectiveness of isosorbide mononitrate in pediatric patients have not been established.

Clinical studies of monoket^® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The ill effects of isosorbide mononitrate overdose are generally the results of isosorbide mononitrate's capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures and death.

Laboratory determinations of serum levels of isosorbide mononitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of isosorbide mononitrate overdose.

There are no data suggesting what dose of isosorbide mononitrate is likely to be life-threatening in humans. In rats and mice, there is significant lethality at oral doses of 1965 mg/kg and 2581 mg/kg, respectively.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of isosorbide mononitrate. Isosorbide mononitrate is significantly removed from the blood during hemodialysis.

No specific antagonist to the vasodilator effects of isosorbide mononitrate is known, and no intervention has been subject to controlled study as a therapy of isosorbide mononitrate overdose. Because the hypotension associated with isosorbide mononitrate overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward an increase in central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of isosorbide mononitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia has been reported in patients receiving other organic nitrates, and it probably could also occur as a side effect of isosorbide mononitrate. Certainly nitrate ions liberated during metabolism of isosorbide mononitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moiety of isosorbide mononitrate is quantitatively applied to oxidation of hemoglobin, about 2 mg/kg of isosorbide mononitrate should be required before any of these patients manifests clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of isosorbide mononitrate. In one study in which 36 patients received 2-4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 7.8-11.1 mg of isosorbide mononitrate per hour), the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial p02. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1-2 mg/kg intravenously.

Store at controlled room temperature 20°-30°C (68°-86°F) [See USP].

Keep tightly closed.