isosorbide mononitrate 60 MG 24 HR Extended Release Oral Tablet
Generic Name: ISOSORBIDE MONONITRATE
Brand Name: isosorbide mononitrate
- Substance Name(s):
- ISOSORBIDE MONONITRATE
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.
DRUG INTERACTIONS
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.
OVERDOSAGE
Hemodynamic Effects The ill effects of isosorbide mononitrate overdose are generally the result 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 (eg, 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 manifest 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 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, 1-2 mg/kg intravenously.
DESCRIPTION
Isosorbide mononitrate (ISMN), an organic nitrate and the major biologically active metabolite of isosorbide dinitrate (ISDN), is a vasodilator with effects on both arteries and veins.
Each tablet, for oral administration, contains either 30 mg, 60 mg or 120 mg of isosorbide mononitrate in an extended-release formulation.
In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose and talc.
The molecular formula of ISMN is C6H9NO6 and the molecular weight is 191.14.
The chemical name for ISMN is 1,4:3,6-dianhydro-,D-glucitol 5-nitrate; the compound has the following structural formula: ISMN is a white, crystalline, odorless compound which is stable in air and in solution, has a melting point of about 90°C, and an optical rotation of +144° (2% in water, 20°C).
Isosorbide mononitrate is freely soluble in water, ethanol, methanol, chloroform, ethyl acetate, and dichloromethane.
Structural Formula
HOW SUPPLIED
Isosorbide Mononitrate Extended-Release Tablets, USP 30 mg are white, capsule-shaped tablets scored on one side and engraved “KU 128” on the unscored side.
They are supplied as follows: Bottles of 30 NDC 54868-4416-0 Bottles of 60 NDC 54868-4416-1 Bottles of 90 NDC 54868-4416-4 Bottles of 100 NDC 54868-4416-3 Isosorbide Mononitrate Extended-Release Tablets, USP 60 mg are white, capsule-shaped tablets scored on one side and engraved “KU 119” on the unscored side.
They are supplied as follows: Bottles of 30 NDC 54868-4417-0 Bottles of 60 NDC 54868-4417-1 Bottles of 100 NDC 54868-4417-2 Store at 20°-30°C (68°-86°F) [See USP].
Distributed by: Kremers Urban Pharmaceuticals Inc.
Princeton, NJ 08540, USA L3958L Rev.
4E 01/2011 Relabeling and Repackaging by: Physicians Total Care, Inc.
Tulsa, Oklahoma 74146
GERIATRIC USE
Geriatric use Clinical studies of isosorbide mononitrate extended-release tablets did not include sufficient information on patients age 65 and over to determine whether they respond differently from younger patients.
Other reported clinical experience for isosorbide mononitrate extended-release tablets has not identified differences in response between elderly and younger patients.
Clinical experience for organic nitrates reported in the literature identified a potential for severe hypotension and increased sensitivity to nitrates in the elderly.
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.
Elderly patients may have reduced baroreceptor function and may develop severe orthostatic hypotension when vasodilators are used.
Isosorbide Mononitrate Extended-Release Tablets should therefore be used with caution in elderly patients who may be volume depleted, on multiple medications or who, for whatever reason, are already hypotensive.
Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.
Elderly patients may be more susceptible to hypotension and may be at a greater risk of falling at therapeutic doses of nitroglycerin.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the elderly.
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.
PEDIATRIC USE
Pediatric use The safety and effectiveness of ISMN in pediatric patients have not been established.
PREGNANCY
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.
NUSRING MOTHERS
Nursing mothers It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk, caution should be exercised when ISMN is administered to a nursing mother.
INFORMATION FOR PATIENTS
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 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.
DOSAGE AND ADMINISTRATION
The recommended starting dose of Isosorbide Mononitrate Extended-Release Tablets is 30 mg (given as a single 30 mg tablet or as 1/2 of a 60 mg tablet) or 60 mg (given as a single tablet) once daily.
After several days, the dosage may be increased to 120 mg (given as a single 120 mg tablet or as two 60 mg tablets) once daily.
Rarely, 240 mg may be required.
The daily dose of Isosorbide Mononitrate Extended-Release Tablets should be taken in the morning on arising.
Isosorbide Mononitrate Extended-Release Tablets should not be chewed or crushed and should be swallowed together with a half-glassful of fluid.
Do not break the 30 mg tablet.