Isordil

Isordil*
(Isosorbide Dinitrate)

DESCRIPTlON
Isordil is a white, crystalline odorless compound. It is sparingly soluble in water and freely soluble in alcohol. The chemical name for isosorbide dinitrate is 1, 4, 3, 6 - dianhydro-sorbitol-2, 5- dinitrate.

CLINICAL PHARMACOLOGY
The exact mechanism of action of the nitrates in the relief of angina pectoris is not fully understood. They appear to relieve classic angina pectoris by reducing myocardial oxygen demand, i. e. by decreasing the heart's "afterload" and "preload: through dilatation of peripheral venous capacitance and, to a lesser extent, arteriolar resistance vessels Nitrates my cause a redistribution of coronary blood flow to ischemic areas by selectively dilating large coronary vessels or collateral vessels which may develop secondary to myocardial ischemia. After therapeutic doses of the drug, systemic arterial pressure is usually decreased: heart rate is unchanged or undergoes a slight compensatory increase. In the absence of heart failure. cardiac output transiently increases and then decreased. Pulmonary vascular resistance. and pulmonary pressure are decreased. The antianginal effects of sub-lingual Isordin generally occur within 2 - 5 minutes after administration and last for 1 - 2 hour. The hemodynamic effects of the oral tablets are observed within 20-60 minutes and last for 4-6 hours
Pharmacokinetics. Gastrointestinal absorption of Isordil tablets is rapid and complete, The drug undergoes an extensive first pass effects with some inter patient variation Isordil is metabolized to two monotritrates which subsequently undergo glucuronidation.
Less than 1 % of Isordil bound to plasma proteins, plasma concentrations of Isordil and mononitrates were compared after administrations of sublingual (2 x 5 mg) and oral (2 x 10 mg) tablets to volunteers. The sublingual dosage form was more rapidly absorbed than the oral formulation as evidenced by the earlier peak concentrations of the parent drug and the mononitrates The half-life of the parent drug was 0.2 and 0.5 hours for the sublingual and oral tablets respectively.
For 2-Isosorbide mononitrates the half-life was 20 hours for bath dosage forms. For 5- isosorbide mononitrates.the half-life of the sublingual tablets was 5.8 hours while that of the oral tablets was 4.5 hours. With chronic administration significant plasma accumulation of the parent compound occurs, presumably the result of saturation of the intrahepatic biotransformation process.
The elimination phase after bath acute and chronic administration of Isordil appears to be at least
biexponential. Essentially all of the drug is eliminated by the kidneys. principally as isosorbide glucuronide.

INDICATIONS
Angina Pectoris

Isordil Oral Tablets: For the prophylaxis of angina pectoris Isordil may reduce the frequency, duration and severity of anginal attacks. Exercise tolerance may be improved and the need for nitroglycerin may be reduced
The oral tablets are not indicated for acute prophylaxis of an anginal attack

Isordil Sublingual Tablets: For treatment of angina pectoris and for prophylaxis in situations likely to provoke an anginal attack

Congestive Cardiac failure
Acute and chronic congestive cardiac failure (including that associated with myocardial infarction). Based on current knowledge, Isordil should be considered only as adjunct to the more conventional modes of therapy (cardiac glycosides and diuretics)

CONTRAINDICATlONS
Hypersensitivity or idiosyncrasy to Isordil or related compounds.
Cardiogenic shock, marked hypotension and circulatory collapse.

WARNINGS AND PRECAUTIONS
Severe hypotensive response, particulary with upright posture. may occur with even small doses of Isordil. Paradoxical bradycardia and increased angina pectoris may accompany nitrate-induced hypotension. The drug should be used with caution in subjects who may have blood volume depletion from diuretic therapy or in subjects who have low systolic blood pressure (e.g. below 90 mm Hg)
In the treatment of acute or chronic cardiac failure, pulmonary capillary pressure should not be allowed to fall below 15 mm Hg or systolic blood pressure below the physiological range in normal or hypertensive patients Systolic pressure should be preserved in patients with pre-existing hypotension in the range of 90-100 mm Hg
As with other vasodilators, isordil may cause paradoxical side effects in sensitive patients, which may increase ischemia and may even lead to extension of myocardial damage and advanced congestive heart failure. if one elects to use organic nitrates in the early infarctions hemodynamic monitoring and frequent clinical assessment should be used because of the potential deleterious effects of hypotension
Marked symptomatic, orthostatic hypotension have been reported when calcium channel blockers and organic nitrates were used in combination
Dose adjustment of either class of agents may be necessary.
Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy
Tolerance of this drug and cross tolerance to other nitrates and nitrites may occur. The importance of tolerance to the appropriate use of isordil in the management of patients with angina pectoris has not been determined
In clinical trials in angina patients, there are reports of anginai attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal. It seems prudent, therefore, to gradually withdraw patients from isosorbide dinitrate when the therapy is being terminated, rather than stopping the drug abruptly
Carcinogenesis, Mutagenesis, Impairment of Fertility - No long term studies in animals have been performed to evaluate the carcinogenic potential of this drug. A modified two-litter reproduction study in rats fed isosorbide dinitrate at 25 or 100 mg/kg/day did not reveal any affects on fertility or gestation or any remakable growth pathology in any parent or offspring fed isosorbide dinitrate as compared with rats led basal-controlled diet

Patient with glaucoma - Use with caution

Use During Pregnancy - Isosorbide dinitrate has been shown to cause a dose-related increase in embryo toxicity (increase in mummified pups) in rabbits at oral doses 35 and 150 times the maximum recommended human daily dose. There are no-adequate and well-controlled studies in pregnant women. Isordil should be used during pregnancy only if the potential benefit justfies the potential risk to the fetus

Use During Lactation - It is not known if isordil is excreted in breast milk. Because many drugs are excreted in breast milk, a decision should be made whether to discontinue nursing or to discontinue Isordil, taking into account the importance of the drug to the mother and the potential risk to the infant
Use in Children - The safety and effectiveness of Isordil in children has not been estabilished

ADVERSE EFFECTS

1. Cutaneous vasodilation with flushing may occur
2. Vascular headache is common and may be severe and persistent. Headache is usually relieved by the use of suitable analgesics, or by a temporary reduction in dosage, and tends to disappear after the first week or two of use
3. Transient episodes of dizziness and weakness as well as other signs of cerebral ischemia associated with postural hypotension, may occasionally develop. Occasional individuals may exhibit marked sensitivity to the hypotensive effects of nitrates, even with the usual therapeutic dosage. Severe responses such as nausea, vomiting weakness, restlessness, pallor, perspiration, and collapse can be manifested. Alcohol may intensify this effect. Measures which fasilitate venous return (e.g. head- low or Trendelenburg position, deep breathing movement of extremities) will usually reverse the syndrome
4. Drug rash and/or exfoliative dermatitis may occasionally occur
5. Nausea and vomiting appear to be uncommon
6. Marked orthostatic hypotension and rarely syncope may occur

DRUG INTERACTIONS
Nitrates may cause hypotension as a result of peripheral vasodilatation. Alcohol may enhance this effect. Patients who are prescribed isordil should be cautioned accordingly
Patient receiving antihypertensive drugs, beta adrenergic blockers, or pnenothiazines with nitrates should be observed for possible additive hypotensive effects

DOSAGE AND ADMINISTRATION
The initial dose should be no more than 5 mg since a severe hypotensive response occasionally occurs

Angina Pectoris
Sublingual Tablets (Tablet dissolve within 20 seconds) 5 mg to 10 mg sublingually every 2 to 3 hours for the prophytaxis of acute angina. Adequate controlled clinical studies demonstrating the effectiveness of chronic maintenance therapy with these dosage forms have not been reported

Oral Tablets:

• For treatment of chronic stable angina pectoris the usual starting dose is 5 to 20 mg
• For maintenance therapy oral dose of 10 to 40 mg every 6 hours. In order to obtain optimal therapeutic effect, it is important that the dosage of sublingual and oral forms be individualized in accordance with each patient's needs, clinical response and tolerance

Congestive Heart Failure
In selected cases of chronic congestive heart failure both sublingual and oral forms as adjunct therapy may be used. The selection of sublingual or oral isordil should be made on the basis of duration of action rather than magnitude of response, since this is major difference observed for these dosage forms
Isordil therapy should begin with the lowest effective dose and further adjusted as necessary, based on the left ventricular performance. The initial dose really depends on the assessment of how severe the heart failure is. For the treatment of acute congestive heart failure the rapidly acting sublingual form of isordil is preferred and should first administered to stabilize the patients symtoms or to determine the magnitude of hemodynamic responce, then it should be followed by the oral form for maintenance therapy.
In refractory cases isordil may be used alone or concomitantly with other vasodilators. Haemodynamic monitoring of the patient under treatment is desirable and optimal dose regimens should be determined for individual cases depending on these results
The averange recommended doses for selected cases of acute and chronic congestive heart failure are the following

Acute Congestive Heart Failure
- Sublingual tablet: 5 to 10 mg every two hours or as needed
- Oral tablet: 10 to 40 mg four times daily or as needed

Chronic Congestive Heart Failure.
- Initial dosage sublingual tablet: 5 to 10 mg every two hours or as needed
- Maintenance dosage oral tablet: 20 to 40 mg four times daily or as needed

OVERDOSAGE
Symptoms of nitrate overdosage may include the following prompt fall in blood pressure, persistent and throbbing headache, vertigo, palpitation, visual disturbances, flushed and perspiring skin (later becoming cold and cyanotic, nausea and vomiting (possibly with colic and even bloody diarrhea), syncope(especially in the upright position) methemoglobinemia with cyanosis and anoxia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent, heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions and possibly death due to circulatory collapse
It is not known what dose of the drug is associated with symptoms of overdosing or what dose of the drug would be life-threatening. The acute oral LD 50 of isosorbide dinitrate in rats was found to be approximately 1100 mg/kg of body weight. These animal experiments indicate that approximately 500 times the usual therapeutic dose would be required to produce such toxic symptoms in humans. It is not known whether the drug is dialyzable.
Suggested treatment of overdosage Prompt removal of the ingested material bay gastric lavage, if ingestion was recent and the patient is conscious. Keep the patient recumbent in a shock position and comfortably warm. Passive movement of the extremities may did venous return. Administer oxygen and artificial respiration if necessary. If methemoglobinemia is present, administer methylen blue (1% solution), 1 to 2 mg/kg intravenously.
Epinephrine is ineffective in reversing the severe hypotensive events associated with overdose it and related compounds are contraindicated in this situation.

HOW SUPPLIED
Tablet Bottle of 60 tablets @ 10 mg
Reg. No. DKL9431802610A1

Sublingual Tablet Bottle of 60 tablets @ 5 MG
Reg. No. DKL9431802574A1

STORE IN A COOL DRY PLACE (15° - 25° C).

HARUS DENGAN RESEP DOKTER

Manufactured and sold by :
PT. SUNTHI SEPURI
Tangerang, Indonesia

Under License from
Wyeth-Ayerst laboratories
Philadelphia, PA 19101 USA.
* Registered Trademark

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