Ismo

Ismo (isosorbide mononitrate) tablets, 20 mg, are available in bottles of 100 (NDC 67857-702-01). Each orange, round, film-coated tablet is engraved "ISMO (isosorbide mononitrate) 20" on one side and scored on the reverse side.

Store at 20 - 25° C (68 -77° F). Dispense in tight container.

Manufactured by: West-ward Pharmaceutical Corp. Eatontown, NJ 07724. Manufactured for: Reddy Pharmaceuticals, LLC. Bridgewater, NJ 08807

Ismo (isosorbide mononitrate) 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.

(SEE INDICATIONS AND USAGE)

The recommended regimen of Ismo (isosorbide mononitrate) tablets is 20 mg (one tablet) twice daily, with the two doses given 7 hours apart. For most patients, this can be accomplished by taking the first dose on awakening and the second dose 7 hours later. Dosage adjustments are not necessary for elderly patients or patients with altered renal or hepatic function. As noted above (CLINICAL PHARMACOLOGY), multiple studies of organic nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. The dosing regimen for Ismo (isosorbide mononitrate) tablets provides a daily nitrate-free interval to avoid the development of this tolerance. As also noted under CLINICAL PHARMACOLOGY, well-controlled studies have shown that tolerance to Ismo (isosorbide mononitrate) tablets is avoided when using the twice-daily regimen in which the two doses are given 7 hours apart. This regimen has been shown to have antianginal efficacy beginning 1 hour after the first dose and lasting at least 5 hours after the second dose. The duration (if any) of antianginal activity beyond 12 hours has not been studied; large controlled studies with other nitrates suggest that no dosing regimen should be expected to provide more than about 12 hours of continuous antianginal efficacy per day.

In clinical trials, Ismo (isosorbide mononitrate) tablets have been administered in a variety of regimens. Single doses less than 20 mg have not been adequately studied, while single doses greater than 20 mg have demonstrated no greater efficacy than doses of 20 mg.

Allergic reactions to organic nitrates are extremely rare, but they do occur. Isosorbide mononitrate is contraindicated in patients who are allergic to it.

WARNINGS

Amplification of the vasodilatory effects of Ismo (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 hemo-dynamic 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

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).

Pregnancy Category C

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.

Nursing Mothers

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.

Pediatric Use

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

Geriatric Use

Clinical studies of Ismo (isosorbide mononitrate) 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 (isosorbide mononitrate) ®.

SIDE EFFECTS

The table below shows the frequencies of the adverse reactions observed in more than 1% of the subjects (a) in 6 placebo-controlled domestic studies in which patients in the active-treatment arm received 20 mg of isosorbide mononitrate twice daily, and (b) in all studies in which patients received isosorbide mononitrate in a variety of regimens. In parentheses, the same table shows the frequencies with which these adverse reactions led to discontinuation of treatment. Overall, 11% of the patients who received isosorbide mononitrate in the six controlled U.S. studies discontinued treatment because of adverse reactions. Most of these discontinued because of headache. "Dizziness" and nausea were also frequently associated with withdrawal from these studies.

Other adverse reactions, each reported by fewer than 1% of exposed patients, and in many cases of uncertain relation to drug treatment, were::

Cardiovascular: angina pectoris, arrhythmias, atrial fibrillation, hypotension, palpitations, postural hypotension, premature ventricular contractions, supraventricular tachycardia, syncope.

Dermatologic: pruritus, rash.

Gastrointestinal: abdominal pain, diarrhea, dyspepsia, tenesmus, tooth disorder, vomiting.

Genitourinary: dysuria, impotence, urinary frequency.

Miscellaneous: asthenia, blurred vision, cold sweat, diplopia, edema, malaise, neck stiffness, rigors.

Musculoskeletal: arthralgia.

Neurological: agitation, anxiey, confusion, dyscoordination, hypoesthesia, hypokinesia, increased appetite, insomnia, nervousness, nightmares.

Respiratory: bronchitis, pneumonia, upper-respiratory tract infection.

Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients; for futher discussion of its diagnosis and treatment see under OVERDOSAGE.

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.

The table below shows the frequencies of the adverse reactions observed in more than 1% of the subjects (a) in 6 placebo-controlled domestic studies in which patients in the active-treatment arm received 20 mg of isosorbide mononitrate twice daily, and (b) in all studies in which patients received isosorbide mononitrate in a variety of regimens. In parentheses, the same table shows the frequencies with which these adverse reactions led to discontinuation of treatment. Overall, 11% of the patients who received isosorbide mononitrate in the six controlled U.S. studies discontinued treatment because of adverse reactions. Most of these discontinued because of headache. "Dizziness" and nausea were also frequently associated with withdrawal from these studies.

Other adverse reactions, each reported by fewer than 1% of exposed patients, and in many cases of uncertain relation to drug treatment, were::

Cardiovascular: angina pectoris, arrhythmias, atrial fibrillation, hypotension, palpitations, postural hypotension, premature ventricular contractions, supraventricular tachycardia, syncope.

Dermatologic: pruritus, rash.

Gastrointestinal: abdominal pain, diarrhea, dyspepsia, tenesmus, tooth disorder, vomiting.

Genitourinary: dysuria, impotence, urinary frequency.

Miscellaneous: asthenia, blurred vision, cold sweat, diplopia, edema, malaise, neck stiffness, rigors.

Musculoskeletal: arthralgia.

Neurological: agitation, anxiey, confusion, dyscoordination, hypoesthesia, hypokinesia, increased appetite, insomnia, nervousness, nightmares.

Respiratory: bronchitis, pneumonia, upper-respiratory tract infection.

Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients; for futher discussion of its diagnosis and treatment see under OVERDOSAGE.

Hemodynamic Effects

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

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.

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 (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 same twice-daily regimen of Ismo (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.

In humans, isosorbide mononitrate is not subject to first pass metabolism in the liver. The absolute bioavailability of isosorbide mononitrate from Ismo (isosorbide mononitrate) 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.