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PAR PHARM.
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49884002101

isosorbide dn 10 mg tablet

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Uses

Angina

Isosorbide dinitrate and isosorbide mononitrate share the actions of the other nitrates and nitrites. The drugs are used for the acute relief of angina pectoris, for prophylactic management in situations likely to provoke angina attacks, and for long-term prophylactic management of angina pectoris.

Heart Failure

Isosorbide dinitrate is used in fixed combination with hydralazine (BiDil) as an adjunct to standard therapy for the treatment of heart failure in self-identified black patients to improve survival, decrease rate of hospitalization for worsened heart failure, and improve patient-reported functional status. Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-adrenergic blocking agents [β-blockers], aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. ( and .) The combination of isosorbide dinitrate and hydralazine is recommended by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) for self-identified black patients with New York Heart Association (NYHA) functional class III or IV heart failure and reduced ejection fraction who are receiving optimal therapy with ACE inhibitors and β-blockers (unless contraindicated). ACCF and AHA also state that combined therapy with isosorbide dinitrate and hydralazine may be considered in patients with current or prior symptomatic heart failure and reduced ejection fraction who cannot receive an ACE inhibitor or angiotensin II receptor antagonist because of drug intolerance, hypotension, or renal insufficiency.

Diffuse Esophageal Spasm

In a limited number of patients with diffuse esophageal spasm without gastroesophageal reflux, isosorbide dinitrate has been used effectively to relieve pain, dysphagia, and spasm.

Dosage and Administration

Administration

Isosorbide Dinitrate

Isosorbide dinitrate is administered sublingually, intrabuccally, or orally. The possibility that sublingual or intrabuccal nitrates may be inadequately absorbed, with resultant decreased efficacy, in patients with dry oral mucous membranes (e.g., xerostomia) should be considered. Chewable tablets (no longer commercially available in the US) should be chewed thoroughly before swallowing. Extended-release preparations should not be chewed. The patient should be sitting immediately after administration of isosorbide dinitrate sublingually or as a chewable tablet.

Isosorbide Mononitrate

Isosorbide mononitrate is administered orally. Isosorbide mononitrate extended-release tablets can be administered as whole or halved tablets, but these should be swallowed intact and not chewed or crushed. In addition, isosorbide extended-release tablets should be administered with adequate amounts of fluid (e.g., 120 mL) on arising in the morning.

Dosage

Dosage of isosorbide dinitrate and isosorbide mononitrate must be carefully adjusted according to the patient's requirements and response and the smallest effective dosage should be used.

When isosorbide dinitrate is used in fixed combination with hydralazine, the cautions, precautions, and contraindications associated with hydralazine must be considered in addition to those associated with isosorbide dinitrate ( and ).

Clinical studies of isosorbide dinitrate alone or in fixed combination with hydralazine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Although other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered. Elimination of isosorbide dinitrate and its metabolites may occur more slowly in geriatric patients than in younger adults.

Clinical studies of isosorbide mononitrate did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. Other clinical experience has not identified any differences in responses between geriatric and younger patients. One manufacturer of isosorbide mononitrate states that if isosorbide mononitrate is used in geriatric patients, dosage of the drug should be selected with caution, usually initiating therapy at the low end of the dosage range, although age, renal, hepatic, and cardiovascular dysfunction do not appear to have a significant effect on the clearance of the drug.

Angina

Acute Symptomatic Relief and Prophylactic Management

For the acute relief of angina pectoris or for prophylactic management in situations likely to provoke angina attacks in patients who fail to respond to nitroglycerin lingual or sublingual preparations, 2.5-5 mg of isosorbide dinitrate is administered sublingually, intrabuccally, or as a chewable tablet (no longer commercially available in the US). If relief is not attained after a single dose during an acute attack, additional doses may be given at 5- to 10-minute intervals; no more than 3 doses should be given in a 15- to 30- minute period.

For the prophylactic management in situations likely to provoke angina attacks in patients who fail to respond to sublingual nitroglycerin, 2.5-5 mg of isosorbide dinitrate should be placed under the tongue approximately 15 minutes prior to engaging in such activities.

Since the onset of action of extended-release preparations containing isosorbide dinitrate or any preparation containing isosorbide mononitrate is not sufficiently rapid to be efficacious in aborting an acute anginal episode, such preparations are not indicated for use in the management of acute relief of angina or in the prophylactic management in situations likely to provoke angina attacks.

Long-term Prophylactic Management

For long-term prophylactic management of angina pectoris, the usual initial dosage of oral isosorbide dinitrate conventional tablets (e. g., Isordil Titradose) is 5-20 mg administered 2 or 3 times daily. The usual recommended maintenance dosage is 10-40 mg 2 or 3 times daily, although some patients may require higher dosages. Some clinicians recommend that such dosages be administered at 7 a.m., 12 p.m., and 5 p.m. in most patients with chronic stable angina or at 7 a.m. and 12 p.m. in patients with less severe symptoms of angina in order to allow for a nitrate-free interval of 10-14 hours. Patients who arise earlier than 7 a.m. may need to adjust this schedule since early morning angina is common. There is some evidence that less frequent administration of isosorbide dinitrate in patients with angina pectoris may reduce the development of tolerance to the drug's antianginal effects . In addition, the manufacturer of isosorbide dinitrate extended-release capsules (Dilatrate-SR) states that results of the only multiple-dose study performed using an extended-release preparation of isosorbide dinitrate indicate that when these extended-release capsules were given twice daily (6 hours apart), the antianginal efficacy of the drug after 4 weeks of therapy was comparable to that of placebo. This manufacturer also states that an interdosing interval sufficient to avoid tolerance with these extended-release capsules is not known, but it must exceed 18 hours. The maximum daily dosages of Dilatrate should not exceed 160 mg (4 capsules).

Alternatively, conventional or extended-release tablets of isosorbide mononitrate may be used for long-term prophylactic management of angina. The usual initial dosage of conventional isosorbide mononitrate tablets (e.g., Ismo, Monoket) is 20 mg twice daily, with the 2 doses administered 7 hours apart. Patients of particularly small stature may receive initial dosages of 5 mg (administered as one-half of a 10-mg tablet) twice daily, but since such a lower dosage is only effective (as determined by exercise tolerance) on the first day of therapy, the dosage should be increased to at least 10 mg twice daily by the second or third day of therapy. The recommended initial dosage of the extended-release isosorbide mononitrate tablets (e.g., Imdur) is 30 (administered as a single 30-mg tablet or as one-half of a 60-mg tablet) or 60 mg (administered as a single 60-mg tablet) once daily. Dosage may be increased to 120 mg (administered as a single 120-mg tablet or as two 60-mg tablets) once daily after several days of therapy; dosages of 240 mg of these extended-release tablets are rarely needed.

Heart Failure

For the adjunctive treatment of heart failure in self-identified black patients, the recommended initial dosage of the fixed-combination preparation is 20 mg of isosorbide dinitrate and 37.5 mg of hydralazine hydrochloride (1 tablet of BiDil) 3 times daily. The dosage may be titrated to a maximum tolerated dosage, not to exceed 2 tablets (a total of 40 mg of isosorbide dinitrate and 75 mg of hydralazine hydrochloride) 3 times daily. Although rapid titration (over 3-5 days) of dosage can be undertaken, slower titration may be needed in some patients who experience adverse effects. In patients who experience intolerable adverse effects, the dosage may be decreased to as little as one-half of the fixed-combination tablet 3 times daily; however, an attempt should be made to titrate the dosage up once the adverse effects subside.

If the drugs are administered separately in the treatment of heart failure, an initial dosage of isosorbide dinitrate 20-30 mg 3 or 4 times daily, given concomitantly with hydralazine hydrochloride 25-50 mg 3 or 4 times daily, is recommended by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA). Dosages of the drugs should be titrated to levels similar to those recommended for the fixed-combination preparation and administered at least 3 times daily. The maximum recommended dosages are isosorbide dinitrate 120 mg daily and hydralazine hydrochloride 300 mg daily.

Diffuse Esophageal Spasm

In a limited number of patients with diffuse esophageal spasm without gastroesophageal reflux, 10-30 mg of isosorbide dinitrate has been given orally 4 times daily.

Pharmacokinetics

Absorption

Isosorbide dinitrate is readily (and almost completely) absorbed from the GI tract and oral mucosa, but considerable variations in the bioavailability of the drug (10-90%) have been reported as a result of extensive first-pass metabolism in the liver. The bioavailability of isosorbide dinitrate, as unchanged drug, following oral administration of conventional tablets (25%) generally appears to be about half that following sublingual administration (40-50%); however, in one study, systemic bioavailability of the drug was similar (about 29%) for both oral conventional tablets and sublingual tablets. It has been suggested that the reduced bioavailability of sublingual tablets of isosorbide dinitrate may result from swallowing a portion of the drug dissolved from such tablets, possibly because absorption of the drug is slow relative to the time that a sublingual dose might reasonably be retained in the mouth. Although multiple-dose studies of isosorbide dinitrate sublingual tablets have not been conducted, multiple-dose studies of isosorbide dinitrate oral conventional tablets indicate that progressive increases in bioavailability may occur during chronic therapy.

Although some evidence suggests that systemic bioavailability of isosorbide dinitrate from extended-release oral tablets is similar but slightly less than that from conventional oral tablets, other evidence suggests that considerable variability exists for various extended-release preparations and that some preparations may be substantially less bioavailable than conventional tablets. Because pharmacologic effects of the drug also depend on serum concentrations of active metabolites (e.g., isosorbide-5-mononitrate, isosorbide-2-mononitrate), comparisons should extend beyond systemic bioavailability of unchanged drug alone. Unfortunately, many studies do not specify or provide incomplete data on these metabolites. In addition, although most studies have employed single doses, the pharmacokinetics and/or bioavailability of the drug may be affected substantially during multiple dosing because the metabolites may decrease the metabolic clearance of isosorbide dinitrate; therefore, predictions based on single-dose studies are uncertain.

Although food may decrease substantially mean peak plasma concentrations of isosorbide dinitrate, total bioavailability of the drug does not seem to be affected.

Considerable interindividual variations (approximately 5- to 11-fold) in peak plasma concentrations attained have been reported with a specific oral dose of isosorbide dinitrate. Following administration of isosorbide dinitrate as sublingual or conventional oral tablets, peak plasma isosorbide dinitrate concentrations are reached in 10-15 or 60 minutes, respectively. Elevated blood concentrations of isosorbide dinitrate have been observed in patients with cirrhosis.

Isosorbide mononitrate also is readily absorbed from the GI tract. Because isosorbide mononitrate, unlike isosorbide dinitrate, does not undergo first-pass hepatic metabolism, the bioavailability of isosorbide mononitrate conventional or extended-release tablets is approximately 100 or 77-80%, respectively.

In general, food was found to delay the rate but not the extent of absorption (less than 10%) of conventional or extended-release isosorbide mononitrate tablets. Following oral administration of conventional or extended-release isosorbide mononitrate tablets, peak plasma concentrations of isosorbide mononitrate are achieved within 0.5-1 or about 3-4.5 hours, respectively. In one study, following oral administration of a 40-mg conventional isosorbide mononitrate tablet in fasted healthy individuals, mean peak plasma concentrations of about 930 ng/mL were achieved within about 1 hour. In addition, in another study, following oral administration of a 60- or 120-mg extended-release tablet of isosorbide mononitrate in healthy individuals, peak plasma concentrations of about 557 or 1151 ng/mL were achieved within about 3 hours, respectively.

Following oral administration of a single 40-mg dose of isosorbide dinitrate given in fixed combination with 75 mg of hydralazine hydrochloride (2 tablets of BiDil) in a limited number of healthy adults, peak plasma isosorbide concentrations of 76 ng/mL per 65 kg were reached in 1 hour. The effect of food on the bioavailability of isosorbide dinitrate when administered in fixed combination with hydralazine hydrochloride is not known.

Although optimal therapeutic plasma concentrations have not been determined, it has been suggested that the therapeutic plasma concentration of isosorbide mononitrate (both for the management of angina and heart failure) is 100 ng/mL. In addition, evidence from clinical studies of isosorbide dinitrate and isosorbide mononitrate have shown that dosing regimens that result in plasma isosorbide mononitrate concentrations that fall below 100 ng/L prior to the administration of the next dose may be associated with a lower risk of developing tolerance.

The approximate onset and duration of action of various dosage forms of isosorbide dinitrate (ISDN) and isosorbide mononitrate (ISMN) are shown in Table 1 and Table 2.

Table 1. Antianginal Effects
Dosage Form Onset Duration
sublingual ISDN within 3 min 2 h
chewable ISDN within 3 min 2-2.5 h
oral ISDN 1 h up to 8 h
oral ISMN 1 h 5-7 h
extended-release ISDN 1 h 8 h
extended-release ISMN 1 h 12 h
Table 2. Hemodynamic Effects
Dosage Form Onset Duration
sublingual ISDN within 15-30 min 1.5-4 h
chewable ISDN 5 min 2-3 h
oral ISDN within 20-60 min 4-6 h
oral ISMN 10-30 min at least 6 h
extended-release ISDN within 2 h up to 12 h
extended-release ISMN 20-30 min at least 6 h

The onset and duration of action following intrabuccal administration are probably similar to those after sublingual administration of isosorbide dinitrate; however, no studies are available.

Distribution

Distribution of isosorbide dinitrate or isosorbide mononitrate into human body tissues and fluids has not been fully characterized. Once absorbed, isosorbide dinitrate is widely distributed into body tissues and fluids including smooth muscle cells of blood vessels with the apparent volume of distribution reported to be 2-4 L/kg in adults. Under steady-state conditions, substantial accumulation (relative to simultaneous plasma concentrations) of isosorbide dinitrate may occur in the pectoral muscle and saphenous vein walls. Following IV administration, isosorbide mononitrate is distributed into total body water in about 9 minutes with an apparent volume of distribution of approximately 0.6-0.7 L/kg in adults. Isosorbide mononitrate also is distributed into blood cells and saliva.

Isosorbide dinitrate and isosorbide mononitrate are approximately 28 and 4-5% bound to plasma proteins, respectively.

Although isosorbide dinitrate reportedly was detected in milk, it currently is not known if isosorbide dinitrate and isosorbide mononitrate are distributed into milk in humans.

Elimination

The elimination half-life of isosorbide dinitrate is approximately 1 hour (although a longer half-life [about 2 hours] has been reported when administered in fixed combination with hydralazine hydrochloride). Isosorbide mononitrate has an elimination half-life of about 5 hours.

Isosorbide dinitrate is metabolized (denitrated) extensively; about 15-25 and 75-85% of a dose is metabolized to isosorbide-2-mononitrate and isosorbide-5-mononitrate (referred to simply as isosorbide mononitrate), respectively. Both metabolites are pharmacologically active, especially the isosorbide mononitrate.

Isosorbide mononitrate is metabolized principally in the liver, but unlike isosorbide dinitrate, it does not undergo first-pass metabolism. About 50% of a dose of isosorbide mononitrate undergoes denitration to form isosorbide, followed by partial dehydration to form sorbitol. Isosorbide mononitrate also appears to undergo glucuronidation to form the 5-mononitrate glucuronide. These metabolites apparently do not have pharmacologic activity.

After a single oral dose of isosorbide dinitrate, 80-100% of the amount is excreted in urine within 24 hours, chiefly as metabolites. Isosorbide mononitrate also is excreted mainly in the urine; compounds recovered in urine after isosorbide mononitrate administration have included isosorbide, sorbitol, and conjugates; only 2% of a dose is excreted as unchanged drug. About 96% of an administered dose of isosorbide mononitrate is excreted in urine and about 1% in feces within 5 days; most excretion (about 93%) occurs within 48 hours.

The plasma clearance of isosorbide dinitrate reportedly is 2-4 L/minute. Since plasma clearance exceeds hepatic blood flow, it appears that the drug also is metabolized at extrahepatic sites.

Renal clearance of isosorbide mononitrate accounts only for about 4% of total body clearance. Plasma clearance of isosorbide mononitrate does not appear to be affected by age, cardiac disease, or renal or hepatic impairment. Isosorbide mononitrate is substantially removed by hemodialysis.

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