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Isosorbide mononitrate as:
60mg tablet: A yellow, film-coated oval tablet of 13mm length scored on both sides.
Isosorbide mononitrate is an active metabolite of isosorbide dinitrate and exerts qualitatively similar effects. Isosorbide mononitrate reduces the workload of the heart by producing venous and arterial dilatation. By reducing the end diastolic pressure and volume, isosorbide mononitrate lowers intramural pressure, hence leading to an improvement in the subendocardial blood flow. The net effect when administering isosorbide mononitrate is therefore a reduced workload for the heart and an improvement in the oxygen supply/demand balance of myocardium.
Nitrates are highly effective in the prophylaxis of symptomatic and asymptomatic myocardial ischaemia. Nitrates dilate coronary arteries not only in pre- and poststenotic vessels, but also in eccentric lesions. The natural initiator of vascular relaxation is thought to be endothelium derived relaxing factor (EDRF), which has both the clinical and biological characteristics of nitric oxide. Organic nitrates are metabolised to nitric oxide in the muscle cell via a sulfhydryl dependent mechanism. They are therefore thought to be the physiological substitute for EDRF.
In placebo controlled studies, isosorbide mononitrate tablets have been shown to significantly increase exercise capacity in patients with angina pectoris taking no other chronic treatment, as well as in patients taking concomitant β-blocker therapy.
It is known that the clinical effects may be attenuated during repeated administration with nitrates in high doses and/or frequent administration. However, the pharmacokinetic characteristics of IMTRATE tablets produce a nitrate low period following once daily dosage. No development of tolerance with respect to antianginal effect has been detected when isosorbide mononitrate tablets are given at a dose of one or two tablets (60 or 120mg) once daily. The drug is not recommended for twice daily administration.
IMTRATE tablets provide a sustained release presentation of isosorbide mononitrate, with approximately 85% bioavailability. Administration of IMTRATE tablets results in a gradual, non-pH dependent release of the active substance, which is completed after approximately 10 hours. Compared to ordinary tablets, the absorption phase is prolonged and the duration of effect is extended. Drug particles close to the tablet surface are released relatively rapidly, but those incorporated more deeply are released more slowly. The absorption of IMTRATE tablets has been shown not to be influenced by food intake.
After repeated once daily administration of IMTRATE tablets 60mg, the maximum plasma level (about 480ng/ml) of isosorbide mononitrate is achieved at about 4 hours. The plasma concentration remains above 260 to 290 ng/ml for approximately 10 hours, dropping to under 95ng/ml by the end of the dosage interval (24 hours after dose). This nitrate low period minimises the possibility of nitrate tolerances developing during prolonged treatment with IMTRATE tablets.
Isosorbide mononitrate is less than 5% plasma protein bound. The distribution volume of isosorbide mononitrate is about 0.6 L/kg, indicating that it is mainly distributed into total body water. Elimination takes place predominantly by denitrification and conjugation in the liver. The metabolites are excreted mainly via the kidneys, with only about 2% of the dose being excreted intact. Isosorbide mononitrate has an elimination half-life of around 5 hours.
IMTRATE is indicated for the prophylactic treatment of angina pectoris. IMTRATE tablets are not recommended for the management of acute attacks of angina pectoris (see Precautions).
IMTRATE tablets should be administered as one (1) tablet once daily. That dose may be increased to two (2) tablets daily, both tablets taken at the same time.
IMTRATE tablets should not be administered twice daily.
If headache occurs, the initial dose may be reduced to half a tablet daily until the headache disappears. Patients with severe renal impairment may require dosage reduction to half a tablet given once daily.
IMTRATE tablets should not be chewed or crushed, and should be swallowed whole with half a glass of fluid. If care is taken to avoid crushing or chewing the tablet, half tablet doses may be administered without affecting the sustained release properties of IMTRATE tablets.
Known hypersensitivity to nitrates.
Acute Angina: IMTRATE tablets are not indicated for the relief of acute attacks of angina.
Concomitant administration of sildenafil (Viagra) and IMTRATE is contraindicated due to an increase in the hypotensive effect of IMTRATE. This may result in severe side effects such as syncope or myocardial infarction.
There is a risk of developing tolerance to the haemodynamic and antianginal effects if higher doses (more than 120mg/day) and/or more frequent doses (eg. twice daily) of IMTRATE tablets are administered. It is, therefore, important that IMTRATE tablets are administered once a day in order to ensure that intervals with low nitrate concentrations are achieved each day, reducing the risk of the development of tolerance.
Caution should be observed if IMTRATE tablets are administered to patients with: severe cerebral arteriosclerosis, pronounced mitral stenosis, hypertrophic cardiomyopathy, hypotension or cardiogenic shock.
Impaired Renal Function: The elimination of isosorbide mononitrate following administration of an immediate release tablet has been investigated in patients with severe renal impairment, but not using the sustained release tablet. Renal impairment makes no therapeutically important difference to the pharmacokinetics of isosorbide mononitrate administered as an immediate release tablet, although two single dose studies did indicate a prolonged half-life in these patients with severe renal impairment. One of these studies also showed a higher plasma concentration. In view of the lack of data regarding the use of the tablet presentation in patients with severe renal impairment, the possibility of accumulation should be borne in mind when administering IMTRATE tablets to such patients, in whom a reduced dosage may be appropriate.
Acute Myocardial Infarction & Congestive Cardiac Failure: The benefits of isosorbide mononitrate in patients with acute myocardial infarction or congestive cardiac failure have not been established. Because the effects of isosorbide mononitrate are difficult to terminate rapidly, the medicine is not recommended in these settings. If isosorbide mononitrate is used in these conditions, careful clinical and haemodynamic monitoring is necessary to avoid the hazards of hypotension and tachycardia.
Hypotension: Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide mononitrate. Hypotension and light-headedness on standing may be more frequent in patients who have consumed alcohol. The drug should be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate may be accompanied by paradoxical bradycardia and increased angina pectoris.
Hypertrophic Cardiomyopathy: Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
Industrial workers: Tolerance develops in industrial workers who have had long-term exposure to high doses of organic nitrates. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.
Impaired Hepatic Function: Isosorbide mononitrate has been shown to cause a significant decrease in portal pressure in patients with cirrhosis and portal hypertension during long-term therapy (see Interactions, Propranolol).
Abrupt Withdrawal: Although no clear cut, rebound phenomena were seen upon abrupt withdrawal of isosorbide mononitrate sustained release tablets, such withdrawal is not recommended because of the possibility of severe exacerbation of anginal symptoms.
Use in Pregnancy: The safety of isosorbide mononitrate in pregnancy has not been established. In the absence of Segment I and III studies with isosorbide mononitrate, the drug should only be administered to pregnant women if, in the opinion of the physician, the clinical benefits outweigh the potential risks.
Use in Lactation: At present there is no documentation about the passage of isosorbide mononitrate into breast milk, therefore its use in women who are breastfeeding is not recommended.
Use in Children: Due to lack of data, the use of IMTRATE tablets cannot be recommended in children.
Use in Elderly: No dose reduction is necessary in elderly patients unless they have severe renal impairment.
Adverse effects associated with the vascular activity of the drug are common and as expected with all nitrate preparations. They occur mainly in the early stages of treatment. Headache predominates (up to 30%), but the incidence reduces rapidly as treatment continues. Only 2 to 3% of patients withdrew during clinical trials due to this adverse effect.
Hypotension (4%) with symptoms such as dizziness and nausea have been reported. These symptoms generally disappear during long-term treatment.
The adverse reactions which follow have been reported in studies with isosorbide mononitrate.
Cardiovascular: Hypotension (4 to 5%), tachycardia.
Central Nervous System: Headache, vertigo.
Gastrointestinal: Poor appetite (2.5%), nausea (1%), vomiting, diarrhoea, heartburn.
Tiredness, sleep disturbances (6%) and gastrointestinal disturbances (6%) have been reported during clinical trials with isosorbide mononitrate tablets, but at a frequency no greater than for placebo.
Sulfhydryl Containing Compounds: The metabolism of organic nitrates to nitric oxide is dependent on the presence of sulfhydryl groups in the muscle. The combination of oral N-acetylcysteine and a single dose of sustained release isosorbide mononitrate 60mg significantly prolonged the total exercise time in patients with angina pectoris and angiographically proven significant coronary artery disease, when compared with isosorbide mononitrate alone. Concomitant administration of other exogenous sources of sulfhydryl groups such as methionine and captopril may produce a similar interaction.
Phenylalkylamine Calcium Antagonists: The addition of a calcium channel blocker of the verapamil type, such as gallopamil 75mg, has been shown to further improve left ventricular functional parameters when given in combination with isosorbide mononitrate in a sustained release formulation.
Propranolol: The addition of isosorbide mononitrate to propranolol treatment in patients with cirrhosis and portal hypertension caused a marked fall in portal pressure, a reduction in hepatic blood flow, cardiac output and mean arterial blood pressure, but no additional change in azygos blood flow. The additional effect of isosorbide mononitrate was especially evident in patients whose portal pressure was not reduced by propranolol.
Calcium Antagonists (general): Marked symptomatic orthostatic hypotension has been reported when calcium antagonists and organic nitrates were used in combination. Dose adjustments of either class of agent may be necessary.
Concomitant use of IMTRATE and sildenafil (Viagra) enhances the hypotensive effect. Therefore, the concomitant administration of IMTRATE and Viagra is contraindicated.
Symptoms: The most common symptom of overdose is a pulsing headache. More serious symptoms are excitation, flushing, cold sweats, nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure.
Treatment: Induce emesis if possible, then administer activated charcoal. In patients with severe hypotension, place patient in supine position with the legs raised. If necessary, further symptomatic treatment should be given, including intravenous fluid administration. Gastroscopy should be performed even if spontaneous vomiting has occurred. This should apply even if 24 hours has elapsed since ingestion. In large overdoses with sustained release preparations, aggressive measures are indicated including removal of the contents of the stomach & small intestine under endoscopy, intestinal lavage, use of repeated doses of activated charcoal, cathartics & high enemas.
Store below 25°C. Protect from light and moisture.
Keep out of reach of children.
Pharmacy Medicine.
IMTRATE 60mg tablets: Blister packs of 30 Tablets.
Chemical name: 1,4:6-dianhydro-D-glucitol 5-nitrate. Empirical formula: C6H9NO6.
MW: 191.14.
CAS no. 16051-77-7
Other ingredients of the tablet are: Hydroxypropylmethylcellulose, Carnauba wax,
Purified stearic acid, Lactose, Magnesium stearate, Talc, Titanium dioxide,
Purified siliceous earth, Polyethilene glycol 4000 and Iron oxide.
Douglas Pharmaceuticals Ltd
PO Box 45-027
AUCKLAND 8
Ph: (09) 835-0660
Fax: (09) 835-0665
3 March 1999