Product Elements:
Isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate fd&c red no. 40 lactose monohydrate magnesium stearate microcrystalline cellulose povidone k30 sodium starch glycolate type a potato light pink to pink 1148 isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate lactose monohydrate magnesium stearate microcrystalline cellulose povidone k30 sodium starch glycolate type a potato white to off white 1149 isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate d&c yellow no. 10 fd&c blue no. 1 lactose monohydrate magnesium stearate microcrystalline cellulose povidone k30 sodium starch glycolate type a potato light green to green 1150 isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate fd&c blue no. 1 lactose monohydrate magnesium stearate microcrystalline cellulose povidone k30 sodium starch glycolate type a potato light blue to blue 1151 isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate isosorbide dinitrate d&c yellow no. 10 fd&c blue no. 1 lactose monohydrate magnesium stearate microcrystalline cellulose povidone k30 sodium starch glycolate type a potato light green to green 1152
Drug Interactions:
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).
Indications and Usage:
Indications and usage isosorbide dinitrate 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.
Warnings:
Warnings amplification of the vasodilatory effects of isosorbide dinitrate 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 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.
Dosage and Administration:
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 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. as also noted under clinical pharmacology , the effects of the second and later doses have been smaller and shorter-lasting than the effects of the first. large controlled studies with other nitrates suggest that no dosing regimen with isosorbide dinitrate tablets should be expected to provide more than about 12 hours of continuous anti-anginal efficacy per day. as with all titratable drugs, it is important to administer the minimum dose which produces the desired clinical effect. the usual starting dose of isosorbide dinitrate tablet
Read more...s is 5 mg to 20 mg, two or three times daily. for maintenance therapy, 10 mg to 40 mg, two or three times daily is recommended. some patients may require higher doses. a daily dose-free interval of at least 14 hours is advisable to minimize tolerance. the optimal interval will vary with the individual patient, dose and regimen.
Contraindications:
Contraindications isosorbide dinitrate tablets are contraindicated in patients who are allergic to isosorbide dinitrate or any of its ingredients. do not use isosorbide dinitrate in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, or vardenafil. concomitant use can cause severe hypotension, syncope, or myocardial ischemia. do not use isosorbide dinitrate in patients who are taking the soluble guanylate cyclase stimulator riociguat. concomitant use can cause hypotension.
Adverse Reactions:
Adverse reactions adverse reactions to isosorbide dinitrate are generally dose-related, and almost all of these reactions are the result of isosorbide dinitrate's activity as a vasodilator. headache, which may be severe, is the most commonly reported side effect. headache may be recurrent with each daily dose, especially at higher doses. transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur. hypotension occurs infrequently, but in some patients it may be severe enough to warrant discontinuation of therapy. syncope, crescendo angina, and rebound hypertension have been reported but are uncommon. extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients. methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see overdosage ). data are not available to allow estimation of the frequency of adverse reactions during treatment with i
Read more...sosorbide dinitrate tablets. to report suspected adverse reactions, contact zydus pharmaceuticals (usa) inc. at 1-877-993-8779 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.
Drug Interactions:
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).
Pediatric Use:
Pediatric use safety and effectiveness in pediatric patients have not been established.
Geriatric Use:
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.
Overdosage:
Overdosage 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 (ld 50 ) 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 effects 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 b 5 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 (â¥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 mg/hr to 4.4 mg/hr (equivalent, in total administered dose of nitrate ions, to 4.8 mg 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 po 2 . 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 mg/kg to 2 mg/kg intravenously.
Description:
Description isosorbide dinitrate (isdn) is 1,4:3,6-dianhydro-d-glucitol 2,5-dinitrate, an organic nitrate whose structural formula is and whose molecular weight is 236.14. the organic nitrates are vasodilators, active on both arteries and veins. isosorbide dinitrate is a white, crystalline compound, has a melting point of 70°c and has an optical rotation of +140° (c=1, alcohol, 20°c). isosorbide dinitrate is very slightly soluble in water; very soluble in acetone and sparingly soluble in alcohol. each isosorbide dinitrate tablet, usp contains 5 mg, 10 mg, 20 mg, 30 mg or 40 mg of isosorbide dinitrate. the inactive ingredients in each tablet are lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate. the 5 mg dosage strength also contains fd&c red no. 40 aluminium lake. the 20 mg and 40 mg dosage strengths also contain fd&c blue no. 1 aluminium lake and d&c yellow no. 10 aluminium lake. the 30 mg dosage strength also contains fd&c blue no. 1 aluminium lake. fda approved dissolution test specifications differ from usp. image
Clinical Pharmacology:
Clinical pharmacology 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 t
Read more...he 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 l/kg to 4 l/kg, and this volume is cleared at the rate of 2 l/min 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.
Pharmacokinetics:
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 l/kg to 4 l/kg, and this volume is cleared at the rate of 2 l/min 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 isosor
Read more...bide, 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.
How Supplied:
How supplied isosorbide dinitrate tablets, usp are available as follows: isosorbide dinitrate tablets usp, 5 mg, light pink to pink colored, spotted, round shaped, biconvex, uncoated tablets debossed with "1148" on one side and score on other side. ndc 70710-1148-1 in bottles of 100 tablets ndc 70710-1148-0 in bottles of 1000 tablets isosorbide dinitrate tablets usp, 10 mg, white to off white colored, round shaped, biconvex, uncoated tablets debossed with "1149" on one side and score on other side. ndc 70710-1149-1 in bottles of 100 tablets ndc 70710-1149-0 in bottles of 1000 tablets isosorbide dinitrate tablets usp, 20 mg, light green to green colored, spotted, round shaped, biconvex, uncoated tablets debossed with "1150" on one side and score on other side. ndc 70710-1150-1 in bottles of 100 tablets ndc 70710-1150-0 in bottles of 1000 tablets isosorbide dinitrate tablets usp, 30 mg, light blue to blue colored, spotted, round shaped, biconvex, uncoated tablets debossed with "1151" on
Read more...one side and score on other side. ndc 70710-1151-1 in bottles of 100 tablets ndc 70710-1151-0 in bottles of 1000 tablets isosorbide dinitrate tablets usp, 40 mg, light green to green colored, spotted, round, biconvex, uncoated tablets, debossed with "1152" on one side and score on other side. ndc 70710-1152-1 in bottles of 100 tablets store at 20° to 25°c (68° to 77°f) [see usp controlled room temperature]. protect from light. dispense in a light-resistant, tight container. keep bottles tightly closed. manufactured by: cadila healthcare ltd., india distributed by: zydus pharmaceuticals (usa) inc. pennington, nj 08534 rev. 08/19
Information for Patients:
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 patien
Read more...ts who have also consumed alcohol.
Package Label Principal Display Panel:
Package label.principal display panel ndc 70710-1148-1 isosorbide dinitrate tablets, usp 5 mg 100 tablets ndc 70710-1149-1 isosorbide dinitrate tablets, usp 10 mg 100 tablets ndc 70710-1150-1 isosorbide dinitrate tablets, usp 20 mg 100 tablets ndc 70710-1151-1 isosorbide dinitrate tablets, usp 30 mg 100 tablets ndc 70710-1152-1 isosorbide dinitrate tablets, usp 40 mg 100 tablets figure figure figure figure figure