Ismo - Reddy Pharmaceuticals, LLC

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continu-ously 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 Ismo 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 same twice-daily regimen of Ismo 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.

In humans, isosorbide mononitrate is not subject to first pass metabolism in the liver. The absolute bioavailability of isosorbide mononitrate from Ismo tablets is nearly 100%. Maximum serum concentrations of isosorbide mononitrate are achieved 30 to 60 minutes after ingestion of Ismo. The volume of distribution of isosorbide mononitrate is approximately 0.6 L/kg, and less than 4% is bound to plasma proteins. It is cleared from the serum by denitration to isosorbide; glucuronidation to the mononitrate glucuronide; and denitration/hydration to sorbitol. None of these metabolites is vasoactive. Less than 1% of administered isosorbide mononitrate is eliminated in the urine. 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. In a single-dose study, the pharmacokinetics of isosorbide mononitrate were dose-proportional up to at least 60 mg.

Controlled trials of single doses of Ismo 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 placebo-controlled trials lasting 2 to 3 weeks, Ismo tablets were administered twice daily, in asymmetric regimens (with interdosing intervals of 7 and 17 hours) designed to avoid tolerance. One trial tested doses of 10 mg and 20 mg; one trial tested doses of 20 mg, 40 mg, and 60 mg; and three trials tested only doses of 20 mg. In each trial, the subjects were persons with known chronic stable angina, and the primary measure of efficacy was exercise tolerance on a standardized treadmill test. After initial dosing and for at least 3 weeks, exercise tolerance in patients treated with Ismo 20 mg tablets was significantly greater than that seen in patients treated with placebo, although there was some attenuation of effect with time. Treatment with Ismo tablets was superior to placebo for at least 12 hours after the first dose (i.e., 5 hours after the second dose) of each day. Significant tolerance and rebound phenomena were not observed. The 10-mg dose was not unequivocally superior to placebo, while the effect of the 40-mg dose was similar to that of the 20-mg dose. The 60-mg dose appeared to be less effective, and it was associated with a rebound phenomenon (early-morning worsening).

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 Ismo tablets can be maintained by carefully following the prescribed schedule of dosing (two doses taken 7 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 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.

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 carcinogenic effects were observed in mice exposed to oral isosorbide mononitrate for 104 weeks at doses of up to 900 mg/kg/day (102 X the human exposure comparing body surface area). Rats treated with 900 mg/kg/day for 26 weeks (225 X the human exposure comparing body surface area) and 500 mg/kg/day for the remaining 95 to 111 weeks (males and females, respectively) showed no evidence of tumors. No mutagenic activity was seen in a variety of in vitro and in vivo assays. No adverse effects on fertility were observed when isosorbide mononitrate was administered to male and female rats at doses of up to 500 mg/kg/day (125 X the human exposure comparing body surface area).

Isosorbide mononitrate has been shown to be associated with stillbirths and neonatal death in rats receiving 500 mg/kg/day of isosorbide mononitrate (125 X the human exposure comparing body surface area). At 250 mg/kg/day, no adverse effects on reproduction and development were reported. In rats and rabbits receiving isosorbide mononitrate at up to 250 mg/kg/day, no developmental abnormalities, fetal abnormalities, or other effects upon reproductive performance were detected; these doses are larger than the maximum recommended human dose by factors between 70 (body-surface-area basis in rabbits) and 310 (body-weight basis, either species). In rats receiving 500 mg/kg/day, there were small but statistically significant increases in the rates of prolonged gestation, prolonged parturition, stillbirth, and neonatal death; and there were small but statistically significant decreases in birth weight, live litter size, and pup survival.

There are no adequate and well-controlled studies in pregnant women. Isosorbide mononitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 Ismo^® 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, although age, renal, hepatic or cardiac dysfunction do not appear to have a clinically significant effect on the clearance of Ismo^®.

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 doses of 2000 mg/kg and 3000 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. In particular, dialysis is known to be ineffective in removing isosorbide mononitrate from the body. 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 to 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 to 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 pO₂. 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 to 2 mg/kg intravenously.