General

Severe hypotension, particularly with upright posture, may occur with even small doses of Isosorbide dinitrate. 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 dinitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

As tolerance to Isosorbide dinitrate develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.

Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of every 24-hour day. During the daily dose-free interval in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and decreased exercise tolerance. The importance of these observations to the routine, clinical use of controlled-release oral Isosorbide dinitrate is not known.

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.

Information for Patients

Patients should be told that the anti-anginal efficacy of Isosorbide dinitrate is strongly related to its dosing regimen, so the prescribed schedule of dosing should be followed carefully. In particular, daily headaches sometimes accompany treatment with Isosorbide dinitrate. 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 dinitrate, since loss of headache may be associated with simultaneous loss of anti-anginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully relieve Isosorbide dinitrate-induced headaches with no deleterious effect an Isosorbide dinitrate's anti-anginal efficacy.

Treatment with Isosorbide dinitrate 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.

Drug Interactions

The vasodilating effects of Isosorbide dinitrate may be additive with those of other vasodilators. Alcohol, in particular, has been found to exhibit additive effects of this variety.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term studies in animals have been performed to eva luate the carcinogenic potential of Isosorbide dinitrate. In a modified two-litter reproduction study, there was no remarkable gross pathology and no altered fertility or gestation among rats fed Isosorbide dinitrate at 25 or 100 mg/kg/day.

Pregnancy Category C

At oral doses 35 and 150 times the maximum recommended human daily dose, Isosorbide dinitrate has been shown to cause a dose-related increase in embryotoxicity (increase in mummified pups) in rabbits. There are no adequate, well-controlled studies in pregnant women. Isosorbide dinitrate  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 dinitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Isosorbide dinitrate is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Isosorbide dinitrate 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.

Hemodynamic Effects

The ill effects of Isosorbide dinitrate overdose are generally the results of Isosorbide dinitrate'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 dinitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Isosorbide dinitrate overdose.

There are no data suggesting what dose of Isosorbide dinitrate is likely to be life-threatening in humans. In rats, the median acute lethal dose (LD50) was found to be 1100 mg/kg.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Isosorbide dinitrate and its active metabolites. Similarly, it is not known which, if any, of these substances can usefully be removed from the body by hemodialysis.

No specific antagonist to the vasodilator effect of Isosorbide dinitrate is known, and no intervention has been subject to controlled studies as a therapy for Isosorbide dinitrate overdose. Because the hypotension associated with Isosorbide dinitrate overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward 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 dinitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Nitrate ions liberated during metabolism of Isosorbide dinitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moieties of Isosorbide dinitrate are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of Isosorbide dinitrate 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 dinitrate. 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 4.8 to 6.9 mg of bioavailable Isosorbide dinitrate 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.

Isosorbide Dosage and Administration

As noted under “CLINICAL PHARMACOLOGY”, multiple-dose studies with ISDN and other nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. Every dosing regimen for Isosorbide dinitrate extended-release tablets must provide a daily dose-free interval to minimize the development of this tolerance. With immediate-release ISDN, it appears that one daily dose-free interval must be at least 14 hours long. The necessary dose-free interval for Isosorbide dinitrate extended-release tablets has not been clearly identified, but is presumably somewhat longer.

As also noted under “CLINICAL PHARMACOLOGY”, only one trial has ever studied the use of controlled-release Isosorbide dinitrate for more than one dose. In that trial, 40 mg of a different formulation of controlled-release ISDN was administered twice daily in doses given 6 hours apart. After 4 weeks, active treatment could not be distinguished from placebo.

Large controlled studies with other nitrates suggest that no dosing regimen with Isosorbide dinitrate extended-release tablets should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per day.

In clinical trials, immediate-release oral Isosorbide dinitrate has been administered in a variety of regimens, with total daily doses ranging from    30 mg to 480 mg.

How is Isosorbide Supplied

Isosorbide dinitrate extended-release tablets USP, 40 mg are available as white, round, scored compressed tablets, debossed cor above the bisect and 183 below the bisect and the other side is plain. They are supplied as follows:

Bottles of 100        (NDC 64720-183-10)

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight container as defined in the USP.

KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN.

Manufactured and Distributed by:
CorePharma LLC
Middlesex, NJ 08846

LB#  465-02       
Rev. January, 2011