Isopen-20

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Each tablet contains Isosorbide-5-mononitrate (INN: Isosorbide mononitrate) 20 mg.

Pharmacology: Pharmacodynamics: Isosorbide-5-mononitrate, an organic nitrate, forms free radical nitric oxide (NO). In smooth muscle, NO activates guanylate cyclase which increases guanosine 3' 5' monophosphate (cGMP) concentration leading to dephosphorylation of myosin light chains and smooth muscle relaxation. Produces a vasodilator effect on the peripheral veins and arteries with more prominent effects on the veins. Primarily reduces cardiac oxygen demand by decreasing preload; may modestly reduce afterload; dilates coronary arteries and improves collateral flow to ischemic regions.
Pharmacokinetics: Absorption: Isosorbide-5-mononitrate is rapidly absorbed from the GI tract with peak plasma concentration within 30 to 60 minutes. Because Isosorbide-5-mononitrate does not undergo first-pass hepatic metabolism, the bioavailability of Isosorbide-5-mononitrate conventional tablets is approximately 100%. The onset of action occurs within 20 minutes. Food delays the rate but not the extent of absorption (less than 10%).
Distribution: Isosorbide-5-mononitrate is distributed into blood cells, saliva and tissue with an apparent volume of distribution of approximately 0.6-0.7 L/kg in adults. The distribution half-life is 8.6 minutes. Isosorbide-5-mononitrate is approximately 4-5% bound to plasma protein.
Metabolism: Isosorbide-5-mononitrate is metabolized principally in the liver, but it does not undergo first-pass hepatic metabolism. Isosorbide-5-mononitrate undergoes denitration to form Isosorbide, glucuronidation to form 5-isosorbide mononitrate glucuronide and denitration/dehydration to form sorbitol. These metabolites apparently do not have pharmacologic activity.
Excretion: Isosorbide-5-mononitrate and metabolites are excreted mainly via urine (96% and 2% as unchanged drug) and in feces (1%) within 5 days (excretion about 93% occurs within 48 hours). Elimination half-life is approximately 5 hours. Renal clearance accounts only for about 4% of total body clearance. Isosorbide-5-mononitrate significantly removes from the blood during hemodialysis but not the peritoneal dialysis. The rate of clearance does not appear to be affected by age, cardiac disease, or renal or hepatic impairment.

Isosorbide-5-mononitrate is used for the long-term treatment of coronary heart disease (CHD), prophylaxis of angina pectoris, treatment of pulmonary hypertension, treatment of chronic heart failure which is concomitantly being treated with glycosides and/or diuretics.

Standard dosage: 1 tablet twice daily if necessary up to 1 tablet three times daily.
Initial dosage: ¼-½ tablet twice daily (first and second day), then 1 tablet twice daily for the next 2 days.
Slow increase of the dose at the beginning of treatment is advisable to prevent or minimize possible occurrence of headaches.
The tablets should be swallowed unchewed with plenty of fluid after the meals. If required, 1 tablet can be taken shortly before going to sleep.

Symptoms of intoxication: The primary symptoms of intoxication are headache, a fall in blood pressure with orthostatic hypotension and reflex tachycardia.
High doses may cause methemoglobinemia with cyanosis, dyspnea and tachypnea, due to the formation of the nitrite ions.
Very high doses of Isosorbide-5-mononitrate may lead to increased intracranial pressure with cerebral symptoms.
Therapy of intoxication: Therapeutic measures should aim the normalization of blood pressure, which may be achieved in mild cases by keeping the patient recumbent in the shock position (put the patient in horizontal position with legs up and lower the head).
In the case of severe intoxication, the general guidelines for treatment of poisoning and shock should be followed.
Volume substitution may be necessary in the case of severe hypotension. Sympathomimetic drugs (e.g. norepinephrine, dopamine) may be used in exceptional cases.
Epinephrine is ineffective in reversing the severe hypotensive events associated with Isosorbide-5-mononitrate overdosage and should therefore not be used.
If methemoglobinemia is present, the following antidotes are recommended, depending on the severity of intoxication: Vitamin C, 1 g orally or I.V. as the sodium salt.
Methylene blue (I.V. only): up to 50 mL of a 1% methylene blue solution.
Toluidine blue (I.V. only): initially 2-4 mg/kg body weight, repeated hourly administrations of 2 mg/kg body weight, if necessary.
Oxygen should be administered, if necessary, as well as hemodialysis or exchange transfusion.

Isosorbide-5-mononitrate must not be used in: Hypersensitivity to Isosorbide-5-mononitrate, other nitrates or nitrites or any component of the formulation.
Concurrent use with phosphodiesterase-5 (PDE-5) inhibitors (sildenafil, tadalafil or vardenafil) or riociguat since it may lead to serious and often treatment-resistant hypotension.
Marked hypotension (systolic blood pressure <90 mmHg), circulatory collapse, shock, myocardial infarction with low ventricular filling pressure or cardiogenic shock unless sufficient end-diastolic pressure is maintained e.g. by the use of positive inotropic drugs or intra-aortic balloon counterpulsation.

Avoid use in hypertrophic cardiomyopathy with outflow tract obstruction. Nitrates may reduce preload, exacerbating obstruction and cause hypotension or syncope and/or worsening of heart failure.
Not recommended for use in patients with acute myocardial infarction or heart failure (has not been studied).
Avoid use in patients who marked bradycardia or tachycardia, and right ventricular MI. Because the effects of Isosorbide-5-mononitrate are so difficult to terminate rapidly, this product is not recommended in these settings.
Since a rebound phenomenon cannot be excluded, therapy with Isosorbide-5-mononitrate should be terminated gradually rather than stopping abruptly.
Severe hypotension can occur, paradoxical bradycardia and increased angina pectoris can accompany hypotension.
Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.
Tolerance development and occurrence of cross-tolerance with other nitrate compounds have been described. In order to avoid any attenuation or loss of effect, high continuous dosing regimens should be avoided.

Pregnancy: Animal studies have shown no adverse effects on the foetus. Isosorbide-5-mononitrate was fetotoxic at maternally toxic doses in the rat. Available evidence is inconclusive or inadequate for determining fetal risk when used in pregnant women. Isosorbide-5-mononitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known if Isosorbide-5-mononitrate is excreted in breast milk. Caution be exercised when administering Isosorbide-5-mononitrate to breast-feeding women. Isosorbide-5-mononitrate should be used during lactation only if the potential benefit justifies the potential risk to the infant.

Hematology: Possible formation of methemoglobin, in particular in patients with methemoglobin reductase deficiency as well as in patients with diaphorase deficiency and abnormal hemoglobin structure.
Gastrointestinal system: Occasionally, especially when first used, nausea and/or vomiting.
Cardiovascular system: Occasionally, especially at the beginning of treatment, postural hypotension, tachycardia or flush, which normally improve on continuation of therapy, rarely collapse, in some instances accompanied by bradyarrhythmias and syncope, or intensified symptoms of angina pectoris if there is a significant drop in blood pressure.
Administration of Isosorbide-5-mononitrate may produce transient hypoxemia as a result of redistribution of blood flow with a relative increase in perfusion of poorly ventilated areas of the lung. This may cause ischemia in patients with coronary heart disease.
Central nervous system: Frequently, particularly at the start of treatment, transient "nitrate headache" may occur, which normally subsides after some days of continued treatment, occasionally, particularly when first used, slight states of dizziness or feeling of weakness may occur, which normally improve during treatment.
Skin: Rarely allergic skin reactions.

Isosorbide-5-mononitrate may enhance the hypotensive effect of other vasodilators, antihypertensives (e.g., ACE-inhibitors, angiotensin-II receptor antagonists, beta-blockers, calcium channel blockers, diuretics), neuroleptics, tricyclic antidepressants and alcohol.
Isosorbide-5-mononitrate may increase the serum concentration of ergot derivatives by increasing its oral availability that can enhance the hypertensive effect (i.e., increase standing systolic blood pressure).
Phosphodiesterase-5 inhibitors (e.g., avanafil, sildenafil, tadalafil, vardenafil) may enhance vasodilatory effect of Isosorbide-5-mononitrate. Use of phosphodiesterase-5 inhibitors during treatment with Isosorbide-5-mononitrate is contraindicated.

Store in a tight, light resistant container below 30°C.

Anti-Anginal Drugs

C01DA14 - isosorbide mononitrate ; Belongs to the class of organic nitrate vasodilators. Used in the treatment of cardiac disease.

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