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` dilatrate®-SR
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` (isosorbide dinitrate)
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` Sustained Release Capsules
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` 40 mg
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`DESCRIPTION
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`Isosorbide dinitrate (ISDN) is 1,4:3,6-dianhydro-D-glucitol 2,5 dinitrate, an organic nitrate
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`whose structural formula is
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`and whose molecular weight is 236.14. The organic nitrates are vasodilators, active on both
`arteries and veins. Each dilatrate®-SR sustained release capsule contains 40 mg of isosorbide
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`dinitrate, in a microdialysis delivery system that causes the active drug to be released over an
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`extended period. Each capsule also contains ethylcellulose, lactose, pharmaceutical glaze, starch,
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`sucrose and talc. The capsule shells contain D&C Red 33, D&C Yellow 10, gelatin and titanium
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`dioxide.
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`CLINICAL PHARMACOLOGY
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`The principal pharmacological action of isosorbide dinitrate is relaxation of vascular smooth
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`muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation
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`of the veins promotes peripheral pooling of blood and decreases venous return to the heart,
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`thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure
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`(preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure,
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`and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The
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`relative importance of preload reduction, afterload reduction, and coronary dilatation remains
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`undefined.
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`Dosing regimens for most chronically used drugs are designed to provide plasma concentrations
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`that are continuously greater than a minimally effective concentration. This strategy is
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`inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise
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`testing to assess the antianginal efficacy of continuously-delivered nitrates. In the large majority
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`of these trials, active agents were no more effective than placebo after 24 hours (or less) of
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`continuous therapy. Attempts to overcome nitrate tolerance by dose escalation, even to doses far
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`Reference ID: 3648258
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`in excess of those used acutely, have consistently failed. Only after nitrates have been absent
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`from the body for several hours has their antianginal efficacy been restored.
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`Pharmacokinetics
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`The kinetics of absorption of isosorbide dinitrate from dilatrate®-SR sustained release capsules
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`have not been well studied. Studies of immediate-release formulations of ISDN have found
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`highly variable bioavailability (10 to 90%), with extensive first-pass metabolism in the liver.
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`Most such studies have observed progressive increases in bioavailability during chronic therapy;
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`it is not known whether similar increases in bioavailability appear during the course of chronic
`therapy with dilatrate®-SR sustained release capsules.
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`Once absorbed, the distribution volume of isosorbide dinitrate is 2-4 L/kg and this volume is
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`cleared at the rate of 2-4 L/min, so ISDN’s half-life in serum is about an hour. Since the
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`clearance exceeds hepatic blood flow, considerable extrahepatic metabolism must also occur.
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`Clearance is affected primarily by denitration to the 2-mononitrate (15 to 25%) and the
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`5-mononitrate (75 to 85%).
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`Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life
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`of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide;
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`glucuronidation to the 5-mononitrate glucuronide; and denitration/hydration to sorbitol. The
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`2-mononitrate has been less well studied, but it appears to participate in the same metabolic
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`pathways with a half-life of about 2 hours.
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`The interdosing interval sufficient to avoid tolerance to ISDN has not been well defined. Studies
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`of nitroglycerin (an organic nitrate with a very short half-life) have shown that dosing intervals
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`of 10-12 hours are usually sufficient to prevent or attenuate tolerance. Dosing intervals that have
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`succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate
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`release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with
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`the longer half-lives of ISDN and its active metabolites.
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`An interdosing interval sufficient to avoid tolerance with dilatrate®-SR has not been
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`demonstrated. In an eccentric dosing study, 40 mg capsules of dilatrate®-SR were administered
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`daily at 0800 and 1400 hours. After two weeks of this regimen, dilatrate®-SR was statistically
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`indistinguishable from placebo. Thus, the necessary interdosing interval sufficient to avoid
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`tolerance remains unknown, but it must be greater than 18 hours.
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`Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or
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`withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise
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`tolerance at the end of the daily interdosing interval than the parallel group receiving placebo.
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`The incidence, magnitude, and clinical significance of similar phenomena in patients receiving
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`ISDN have not been studied.
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`Clinical Trials
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`In clinical trials, extended-release oral isosorbide dinitrate has been administered in a variety of
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`regimens, with total daily doses ranging from 40 to 160 mg. A controlled trial using a single
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`40 mg sustained-release oral dose of isosorbide dinitrate (dilatrate®-SR) has demonstrated
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`effective reductions in exercise-related angina for up to 8 hours. Antianginal activity is present
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`about 1 hour after dosing.
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`Adequate multiple-dose trials of dilatrate®-SR sustained release capsules have not been
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`reported.
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`Most controlled trials of multiple-dose immediate-release oral ISDN taken every 12 hours (or
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`more frequently) for several weeks have shown statistically significant antianginal efficacy for
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`only 2 hours after dosing. Once-daily regimens, and regimens with one daily interdosing interval
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`of at least 14 hours (e.g., a regimen providing doses at 0800, 1400 and 1800 hours), have shown
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`efficacy after the first dose of each day that was similar to that shown in the single dose studies
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`cited above. The efficacy of subsequent doses has not been demonstrated. From large, well-
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`controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily
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`duration of antianginal effect from isosorbide dinitrate is about 12 hours. No dosing regimen for
`dilatrate®-SR sustained release capsules has actually been shown to achieve this duration of
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`effect.
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`INDICATIONS AND USAGE
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`dilatrate®-SR sustained release capsules are indicated for the prevention of angina pectoris due to
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`coronary artery disease. The onset of action of controlled-release oral isosorbide dinitrate is not
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`sufficiently rapid for this product to be useful in aborting an acute anginal episode.
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`CONTRAINDICATIONS
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`Isosorbide dinitrate is contraindicated in patients who are allergic to it.
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`Do not use dilatrate®-SR in patients who are taking certain drugs for erectile dysfunction
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`(phosphodiesterase inhibitors), such as sildenafil, tadalafil, vardenafil, or avanafil. Concomitant
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`use can cause severe hypotension, syncope, or myocardial ischemia.
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`Do not use dilatrate®-SR in patients who are taking the soluble guanylate cyclase stimulator
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`riociguat. Concomitant use can cause hypotension.
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`WARNINGS
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`Amplification of the vasodilatory effects of dilatrate®-SR by sildenafil can result in severe
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`hypotension. The time course and dose dependence of this interaction have not been
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`studied. Appropriate supportive care has not been studied, but it seems reasonable to treat
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`this as a nitrate overdose, with elevation of the extremities and with central volume
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`expansion.
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`The benefits of extended-release oral isosorbide dinitrate in patients with acute myocardial
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`infarction or congestive heart failure have not been established. If one elects to use isosorbide
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`dinitrate in these conditions, careful clinical or hemodynamic monitoring must be used to avoid
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`the hazards of hypotension and tachycardia. Because the effects of extended-release oral
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`isosorbide dinitrate are so difficult to terminate rapidly, this formulation is not recommended in
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`these settings.
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`PRECAUTIONS
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`General
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` Severe hypotension, particularly with upright posture, may occur with even small doses of
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` isosorbide dinitrate. This drug should therefore be used with caution in patients who may be
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` volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by
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` isosorbide dinitrate may be accompanied by paradoxical bradycardia and increased angina
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` pectoris.
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` Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
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` As tolerance to isosorbide dinitrate develops, the effect of sublingual nitroglycerin on exercise
` tolerance, although still observable, is somewhat blunted.
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` Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours
` of every 24-hour day. During the interdosing intervals in some of these trials, anginal attacks
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` have been more easily provoked than before treatment and patients have demonstrated
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` hemodynamic rebound and decreased exercise tolerance. The importance of these observations
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` to the routine, clinical use of controlled-release oral isosorbide dinitrate is not known.
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` 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
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` sudden death have occurred during temporary withdrawal of nitrates from these workers
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` demonstrating the existence of true physical dependence.
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` Information for Patients
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`Patients should be told that the antianginal efficacy of isosorbide dinitrate is strongly related to
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`its dosing regimen, so the prescribed schedule of dosing should be followed carefully. In
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`particular, daily headaches sometimes accompany treatment with isosorbide dinitrate. In patients
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`who get these headaches, the headaches are a marker of the activity of the drug. Patients should
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`resist the temptation to avoid headaches by altering the schedule of their treatment with
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`isosorbide dinitrate, since loss of headache may be associated with simultaneous loss of
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`antianginal efficacy. Aspirin and/or acetaminophen, on the other hand, often successfully relieve
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`isosorbide dinitrate-induced headaches with no deleterious effect on isosorbide dinitrate’s
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`antianginal efficacy.
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`Treatment with isosorbide dinitrate may be associated with lightheadedness on standing,
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`especially just after rising from a recumbent or seated position. This effect may be more frequent
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`in patients who have also consumed alcohol.
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`Drug Interactions
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`Concomitant use of dilatrate®-SR with phosphodiesterase inhibitors in any form is
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`contraindicated (see CONTRAINDICATIONS).
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`Concomitant use of dilatrate®-SR with riociguat, a soluble guanylate cyclase stimulator, is
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`contraindicated (see CONTRAINDICATIONS).
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`The vasodilating effects of isosorbide dinitrate may be additive with those of other vasodilators.
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`Alcohol, in particular, has been found to exhibit additive effects of this variety.
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`Carcinogenesis, Mutagenesis and Impairment of Fertility
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`No long-term studies in animals have been performed to evaluate the carcinogenic potential of
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`isosorbide dinitrate. In a modified two-litter reproduction study, there was no remarkable gross
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`pathology and no altered fertility or gestation among rats fed isosorbide dinitrate at 25 or
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`100 mg/kg/day.
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`Pregnancy Category C
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`At oral doses 35 and 150 times the daily Maximum Recommended Human Dose (MRHD),
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`isosorbide dinitrate has been shown to cause a dose related increase in embryotoxicity (increase
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`in mummified pups) in rabbits. There are no adequate, well-controlled studies in pregnant
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`women. Isosorbide dinitrate should be used during pregnancy only if the potential benefit
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`justifies the potential risk to the fetus.
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`Nursing Mothers
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`It is not known whether isosorbide dinitrate is excreted in human milk. Because many drugs are
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`excreted in human milk, caution should be exercised when isosorbide dinitrate is administered to
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`a nursing woman.
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`Pediatric Use
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`Safety and effectiveness in pediatric patients have not been established.
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`Geriatric Use
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` Clinical studies of dilatrate®-SR did not include sufficient numbers of subjects aged 65 and over
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` to determine whether they respond differently from younger subjects. Other reported clinical
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` experience has not identified differences in responses between the elderly and younger patients.
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` In general, dose selection for an elderly patient should be cautious, usually starting at the low end
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` of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac
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` function, and of concomitant disease or other drug therapy.
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`ADVERSE REACTIONS
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`Adverse reactions to isosorbide dinitrate are generally dose related, and almost all of these
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`reactions are the result of isosorbide dinitrate’s activity as a vasodilator. Headache, which may
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`be severe, is the most commonly reported side effect. Headache may be recurrent with each daily
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`dose, especially at higher doses. Transient episodes of lightheadedness, occasionally related to
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`blood pressure changes, may also occur. Hypotension occurs infrequently, but in some patients it
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`may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina, and
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`rebound hypertension have been reported but are uncommon.
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`Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-
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`seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of
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`its diagnosis and treatment is deferred (see OVERDOSAGE).
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`Data are not available to allow estimation of the frequency of adverse reactions during treatment
`with dilatrate®-SR sustained release capsules.
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`OVERDOSAGE
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`Hemodynamic Effects
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`The ill effects of isosorbide dinitrate overdose are generally the results of isosorbide dinitrate’s
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`capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension.
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`These hemodynamic changes may have protean manifestations, including increased intracranial
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`pressure, with any or all of persistent throbbing headache, confusion, and moderate fever;
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`vertigo; palpitations; visual disturbances; nausea and vomiting (possibly with colic and even
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`bloody diarrhea); syncope (especially in the upright posture); air hunger and dyspnea, later
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`followed by reduced ventilatory effort; diaphoresis, with the skin either flushed or cold and
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`clammy; heart block and bradycardia; paralysis; coma; seizures and death.
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`Laboratory determinations of serum levels of isosorbide dinitrate and its metabolites are not
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`widely available, and such determinations have, in any event, no established role in the
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`management of isosorbide dinitrate overdose.
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`There are no data suggesting what dose of isosorbide dinitrate is likely to be life-threatening in
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`humans. In rats, the median acute lethal dose (LD50) was found to be 1100 mg/kg.
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`No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of
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`the urine) that might accelerate elimination of isosorbide dinitrate and its active metabolites.
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`Similarly, it is not known which, if any, of these substances can usefully be removed from the
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`body by hemodialysis.
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`No specific antagonist to the vasodilator effects of isosorbide dinitrate is known, and no
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`intervention has been subject to controlled study as a therapy of isosorbide dinitrate overdose.
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`Because the hypotension associated with isosorbide dinitrate overdose is the result of
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`venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed
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`toward an increase in central fluid volume. Passive elevation of the patient’s legs may be
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`sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The
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`use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than
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`good.
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`In patients with renal disease or congestive heart failure, therapy resulting in central volume
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`expansion is not without hazard. Treatment of isosorbide dinitrate overdose in these patients may
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`be subtle and difficult, and invasive monitoring may be required.
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`Methemoglobinemia
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`Nitrate ions liberated during metabolism of isosorbide dinitrate can oxidize hemoglobin into
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`methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and
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`even assuming that the nitrate moieties of isosorbide dinitrate are quantitatively applied to
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`oxidation of hemoglobin, about 1 mg/kg of isosorbide dinitrate should be required before any of
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`these patients manifests clinically significant (≥ 10%) methemoglobinemia. In patients with
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`normal reductase function, significant production of methemoglobin should require even larger
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`doses of isosorbide dinitrate. In one study in which 36 patients received 2-4 weeks of continuous
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`nitroglycerin therapy at 3.1 to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to
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`4.8-6.9 mg of bioavailable isosorbide dinitrate per hour), the average methemoglobin level
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`measured was 0.2%; this was comparable to that observed in parallel patients who received
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`placebo.Notwithstanding these observations, there are case reports of significant
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`methemoglobinemia in association with moderate overdoses of organic nitrates. None of the
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`affected patients had been thought to be unusually susceptible. Methemoglobin levels are
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`available from most clinical laboratories. The diagnosis should be suspected in patients who
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`exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial
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`pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color
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`change on exposure to air.
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`When methemoglobinemia is diagnosed, the treatment of choice is methylene blue,
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`1-2 mg/kg intravenously.
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`DOSAGE AND ADMINISTRATION
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`As noted above (CLINICAL PHARMACOLOGY), multiple studies with ISDN and other
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`nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory
`tolerance. Every dosing regimen for organic nitrates including dilatrate®-SR must provide a daily
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`nitrate-free interval to avoid the development of tolerance. To achieve the necessary nitrate-free
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`interval with immediate-release oral ISDN, it appears that at least one of the daily interdose
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`7
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` intervals must be at least 14 hours long. The necessary interdose interval for dilatrate®-SR has
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` not been clearly identified, but it must be greater than 18 hours.
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`As noted under Clinical Pharmacology, only one trial has ever studied the use of extended-
`release isosorbide dinitrate for more than one dose. In that trial, 40 mg of dilatrate®-SR was
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`administered twice daily in doses given 6 hours apart. After 4 weeks, dilatrate®-SR could not be
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`distinguished from placebo.
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`Large controlled studies with other nitrates suggest that no dosing regimen with dilatrate®-SR
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`should be expected to provide more than about 12 hours of continuous antianginal efficacy per
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`day.
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`In clinical trials, immediate-release oral isosorbide dinitrate has been administered in a variety of
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`regimens, with total daily doses ranging from 30 to 480 mg.
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`Do not exceed 160 mg (4 capsules) per day.
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`HOW SUPPLIED
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`dilatrate®-SR (isosorbide dinitrate) 40 mg sustained release capsules are opaque pink and
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`colorless capsules with white beadlets and are imprinted “AP” and “0920”. They are supplied as
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`follows:
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`Bottles of 100
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`NDC 66887-005-10
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`Store at 20° - 25°C (68° - 77°F); excursions permitted between 15° - 30°C (59° - 86°F) [See USP
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`Controlled Room Temperature].
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`Manufactured for:
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`Auxilium Pharmaceuticals, Inc.
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`Chesterbrook, PA 19087
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`Revised 10/2014
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`PL-0714-001.a
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`Reference ID: 3648258
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