Isordil Titradose

In the U.S.

• Dilatrate-SR
• Isochron
• IsoDitrate
• Isordil Titradose

In Canada

• Apo-Isdn
• Isordil

Available Dosage Forms:

• Tablet, Chewable
• Tablet
• Capsule, Extended Release
• Tablet, Extended Release

Therapeutic Class: Antianginal

Chemical Class: Nitrate

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Bluish-colored lips, fingernails, or palms
• dark urine
• difficulty with breathing
• dizziness or lightheadedness
• fever
• headache
• pale skin
• rapid heart rate
• sore throat
• unusual bleeding or bruising
• unusual tiredness or weakness

• Arm, back, or jaw pain
• blurred vision
• chest pain or discomfort
• chest tightness or heaviness
• confusion
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast or irregular heartbeat
• sweating

Get emergency help immediately if any of the following symptoms of overdose occur:

• Blurred or loss of vision
• bulging soft spot on the head of an infant
• change in consciousness
• change in the ability to see colors, especially blue or yellow
• cold, clammy skin
• convulsions
• disturbed color perception
• double vision
• fast, irregular, pounding, or racing heartbeat or pulse
• feeling of constant movement of self or surroundings
• halos around lights
• headache, severe and throbbing
• increased sweating
• loss of appetite
• loss of consciousness
• nausea
• night blindness
• overbright appearance of lights
• paralysis
• sensation of spinning
• slow heartbeat
• tunnel vision
• vomiting

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

• It is used to prevent chest pain.
• It may be given to you for other reasons. Talk with the doctor.

Use Isordil Titradose as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Do not stop taking this medicine all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop Isordil Titradose, you will want to slowly stop it as ordered by your doctor.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Isordil Titradose or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Isordil Titradose. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

The principal pharmacological action of isosorbide dinitrate is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined.

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously 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 anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attempts to overcome nitrate 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 anti-anginal efficacy been restored.

Pharmacokinetics

Absorption of isosorbide dinitrate after oral dosing is nearly complete, but bioavailability is highly variable (10% to 90%), with extensive first-pass metabolism in the liver. Serum levels reach their maxima about an hour after ingestion. The average bioavailability of ISDN is about 25%; most studies have observed progressive increases in bioavailability during chronic therapy.

Once absorbed, the volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN's half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extra hepatic metabolism must also occur. Clearance is affected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%).

Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours.

The daily dose-free interval sufficient to avoid tolerance to organic nitrates has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of ISDN and its active metabolites.

Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise tolerance at the end of the daily dose-free interval than the parallel group receiving placebo. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have not been studied.

Clinical Trials

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 ISDN 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 ISDN 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.

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 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 Isordil Titradose with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS).

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

Carcinogenesis, Mutagenesis, 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

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 Isordil (isosorbide dinitrate) Titradose 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.

Isordil® (isosorbide dinitrate) Oral Titradose® Tablets are available as follows:

5 mg, round, pink tablets imprinted "BPI 152" on one side and deeply scored on reverse side:

NDC 0187-0152-01, bottles of 100.

40 mg, round, light green tablets imprinted "BPI 192" on one side and deeply scored on reverse side:

NDC 0187-0192-01, bottles of 100.

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30° (59° to 86°F) [see USP Controlled Room Temperature].

Protect from light.

Keep bottles tightly closed.

Dispense in a light-resistant, tight container.

Keep out of reach of children.

Manufactured for:
Valeant Pharmaceuticals North America LLC
Bridgewater, NJ 08807 USA

By:
MEDA Manufacturing GmbH
Cologne, Germany D-51063

©Valeant Pharmaceuticals North America LLC
®/™ are trademarks of Valeant Pharmaceuticals International, Inc. or its affiliates.

9434501 20001629

Rev. 10/2016

NDC 0187-0152-01

Rx only

Isordil®5
(isosorbide dinitrate)

5 mg

TITRADOSE®

100 Tablets

Valeant