Isosorbide Dinitrate

Isordil (isosorbide dinitrate) Titradose tablets are indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action of immediate-release oral isosorbide dinitrate is not sufficiently rapid for this product to be useful in aborting an acute anginal episode.

Amplification of the vasodilatory effects of Isordil by sildenafil can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriates upportive 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 immediate-release oral isosorbide dinitrate in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use isosorbide dinitrate in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Because the effects of oral isosorbide dinitrate are so difficult to terminate rapidly, this formulation is not recommended in these settings.

This is not a complete list of Isosorbide Dinitratedrug interactions. Ask your doctor or pharmacist for more information.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Isosorbide Dinitrate falls into category C:

In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

OR

There are no well-controlled studies that have been done in pregnant women. Isosorbide Dinitrate should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

OR

No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Isosorbide Dinitrate should be given to a pregnant woman only if clearly needed.

Isosorbide dinitrate is a nitrate that dilates (widens) blood vessels, making it easier for blood to flow through them and easier for the heart to pump.

Isosorbide dinitrate is used to treat or prevent attacks of chest pain (angina).

Only the sublingual tablet should be used to treat an angina attack that has already begun.

Isosorbide dinitrate regular and extended-release tablets are used to prevent angina attacks but will not treat an angina attack.

Isosorbide dinitrate may also be used for purposes not listed in this medication guide.

Usual Adult Dose for Angina Pectoris Prophylaxis:

SUBLINGUAL:
2.5 to 5 mg sublingually 15 minutes prior to activity likely to cause an anginal episode

Comments:
-No dosing regimen of this drug should be expected to provide more than 12 hours of antianginal efficacy per day; a nitrate-free interval of at least 14 hours is recommended to minimize tolerance.

Use: Prevention and treatment of angina pectoris due to coronary artery disease; not the drug of choice for aborting an acute anginal episode due to slower onset of action than sublingual nitroglycerin.


IMMEDIATE RELEASE:
Initial dose: 5 to 20 mg orally 2 or 3 times a day

Maintenance dose: 10 to 40 mg orally 2 or 3 times a day

Comments:
-Total daily doses have ranged from 30 to 480 mg in clinical trials.
-No dosing regimen of this drug should be expected to provide more than 12 hours of antianginal efficacy per day; a nitrate-free interval of at least 14 hours is recommended to minimize tolerance.
-Use at the lowest effective dose to achieve therapeutic efficacy and minimize adverse effects.

Use: Prevention of angina pectoris due to coronary artery disease; onset of action not sufficiently rapid for aborting an acute anginal episode.


EXTENDED RELEASE:
40 to 160 mg/day orally

Comments:
-No dosing regimen of this drug should be expected to provide more than 12 hours of antianginal efficacy per day; a nitrate-free interval greater than 18 hours is recommended to minimize tolerance.
-40 mg was administered twice daily in doses given 6 hours apart; after 4 weeks, this drug could not be distinguished from placebo.
-Use at the lowest effective dose to achieve therapeutic efficacy and minimize adverse effects.
-Swallow whole (do not crush or chew).

Use: Prevention of angina pectoris due to coronary artery disease; onset of action not sufficiently rapid for aborting an acute anginal episode.

Usual Adult Dose for Angina Pectoris:

SUBLINGUAL:
2.5 to 5 mg sublingually 15 minutes prior to activity likely to cause an anginal episode

Comments:
-No dosing regimen of this drug should be expected to provide more than 12 hours of antianginal efficacy per day; a nitrate-free interval of at least 14 hours is recommended to minimize tolerance.

Use: Prevention and treatment of angina pectoris due to coronary artery disease; not the drug of choice for aborting an acute anginal episode due to slower onset of action than sublingual nitroglycerin.


IMMEDIATE RELEASE:
Initial dose: 5 to 20 mg orally 2 or 3 times a day

Maintenance dose: 10 to 40 mg orally 2 or 3 times a day

Comments:
-Total daily doses have ranged from 30 to 480 mg in clinical trials.
-No dosing regimen of this drug should be expected to provide more than 12 hours of antianginal efficacy per day; a nitrate-free interval of at least 14 hours is recommended to minimize tolerance.
-Use at the lowest effective dose to achieve therapeutic efficacy and minimize adverse effects.

Use: Prevention of angina pectoris due to coronary artery disease; onset of action not sufficiently rapid for aborting an acute anginal episode.


EXTENDED RELEASE:
40 to 160 mg/day orally

Comments:
-No dosing regimen of this drug should be expected to provide more than 12 hours of antianginal efficacy per day; a nitrate-free interval greater than 18 hours is recommended to minimize tolerance.
-40 mg was administered twice daily in doses given 6 hours apart; after 4 weeks, this drug could not be distinguished from placebo.
-Use at the lowest effective dose to achieve therapeutic efficacy and minimize adverse effects.
-Swallow whole (do not crush or chew).

Use: Prevention of angina pectoris due to coronary artery disease; onset of action not sufficiently rapid for aborting an acute anginal episode.

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 anddecreasedexercise tolerance. The importance of these observations to the routine, clinical use of immediate-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 on 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.

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

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

Carcinogenesis and Mutagenesis and Impairment of Fertility

No long-term studies in animals have been performed to evaluate 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.

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. Controlled trials of single oral doses of Isosorbide Dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours. Anti-anginal activity is present about 1 hour after dosing.

Most controlled trials of multiple-dose oral Isosorbide Dinitrate taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing. Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400 and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above. The effects of the second and later doses have been smaller and shorter-lasting than the effect of the first.

From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from Isosorbide Dinitrate is about 12 hours. No dosing regimen for Isosorbide Dinitrate, however, has ever actually been shown to achieve this duration of effect. One study of 8 patients, who were administered a pretitrated dose (average 27.5 mg) of immediate-release Isosorbide Dinitrate at 0800, 1300, and 1800 hours for 2 weeks, revealed that significant anti-anginal effectiveness was discontinuous and totaled about 6 hours in a 24 hour period.

Manufactured by:

PAR PHARMACEUTICAL

Chestnut Ridge, NY 10977

Revised 02/2016

• ISD
• ISDN

Sublingual tablet: ~2 to 5 minutes; Oral tablet and capsule (includes extended-release formulations): ~1 hour

Angina pectoris, prevention: Prevention of angina pectoris due to coronary artery disease.

Note: Due to slower onset of action, isosorbide dinitrate is not the drug of choice to abort an acute anginal episode.

Blood pressure, heart rate