1. Name Of The Medicinal Product
Isosorbide mononitrate 20mg Tablets
2. Qualitative And Quantitative Composition
Each tablet contains 20 mg of isosorbide mononitrate.
Excipient: 5 mg of lactose monohydrate/tablet
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Tablet
Isosorbide mononitrate 20mg tablets:
White to off white, round, flat, bevelled edge uncoated tablets, debossed with 'AS' on one side and break line on the other side. The tablets can be divided in to equal halves.
4. Clinical Particulars
4.1 Therapeutic Indications
Prophylactic treatment of angina pectoris.
4.2 Posology And Method Of Administration
For oral administration.
Adults
The usual dose of Isosorbide mononitrate is 1 tablet of Isosorbide mononitrate 20 mg, 2 to 3 times daily. If result is not adequate, the dose may be increased to 1 tablet of Isosorbide mononitrate 40 mg, 2 to 3 times daily.
The maximum dose is 3 tablets isosorbide mononitrate 40 mg per day.
In order to prevent possible initial undesirable effect, it may be adequate to initiate treatment with possible lowest dose and slowly increase to the required dose.
To prevent tolerance, it is recommended that the dosage be kept as low as possible and that a sufficiently long nitrate-free interval is ensured to restore sensitivity (first dose in the morning and last dose late in the afternoon, e.g. at 8 am and 15 pm).
The tablet should be swallowed whole with sufficient liquid to take. (e.g. 1 glass of water)
The duration of application is decided by the treating physician.
As with other nitrates, treatment with isosorbide mononitrate must not be stopped suddenly. Both the dosage and frequency of intake should be tapered off slowly (see section 4.4).
Elderly
There are no indications that adjustment is necessary.
Children
There are as yet no data on the safety and efficacy of isosorbide mononitrate in children
4.3 Contraindications
Hypersensitivity to nitrates or to any of the excipients.
Isosorbide mononitrate should not be used in cases of acute myocardial infarction with low filling pressure, acute circulatory failure (shock, vascular collapse), or hypertrophic obstructive cardiomyopathy (HOCM), low cardiac filling pressures, aortic/mitral valve stenosis and diseases associated with a raised intra-cranial pressure e.g following a head trauma and including cerebral haemorrhage.
Isosorbide mononitrate should not be used in patients with marked anaemia, severe hypotension, closed angle glaucoma or hypovolaemia.
Phosphodiesterase type-5 inhibitors (eg sildenafil, tadalafil and vardenafil) have been shown to potentiate the hypotensive effects of nitrates, and their co-administration with nitrates or nitric oxide donors is therefore contraindicated (see section 4.5)
4.4 Special Warnings And Precautions For Use
In the event of an acute angina attack, a sublingual treatment such as a GTN spray or tablet should be used instead of Isosorbide mononitrate.
Vascular dilatation can precipitate venous pooling with decreased return to the heart, hypotension and reflex tachycardia. Therefore, oral nitrates should not be used by patients who are sensitive to the effects of hypotension, such as those with pre-existing hypotension, shock, vascular collapse or significant cerebrovascular disease, significant anaemia or hypothyroidism. Isosorbide mononitrate should be used with caution in patients who have a recent history of myocardial infarction, or who are suffering from hypothermia, malnutrition and severe liver or renal disease. For the same reason, oral nitrates should also be used with caution in patients with angina due to other causes angina or with pre-existing hyperdynamic conditions.
Since oral nitrates cause venous dilatation they should not be used in patients with increased intracranial pressure. (With high dose i.v. administration of Glyceroltrinitrate a further increase in pressure was observed)
Development of tolerance and cross tolerance to other nitrates was described. A continuous administration of high doses should be avoided. The lowest effective dose should be used.
Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.
Isosorbide mononitrate may give rise to postural hypotension and syncope in some patients. Severe postural hypotension with is frequently observed with concomitant consumption of alcohol.
Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.
Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
The antihypertensive effect of isosorbide mononitrate will increase when it is used concomitantly with phosphodiesterase type 5 inhibitors, which are used in erectile dysfunction. This can lead to life-threatening vascular complications. Patients treated with isosorbide mononitrate must not use phosphodiesterase type 5 inhibitors (see 4.3).
Concomitant use of drugs with an antihypertensive action, e.g. beta blockers, calcium antagonists, vasodilators (including neuroleptics and tricyclic antidepressants), alprostadil, aldesleukin, antihypertensives, diuretics, angiotensin II receptor antagonists etc and / or alcohol can potentiate the hypotensive effect of Isosorbide mononitrate. This can also occure with buse of neuroleptics and tricyclic antidepressant.
Reports suggest that concomitant use of Isosorbide mononitrate increases the blood levels of dihydroergotamine and that the hypertensive effect is potentiated.
There are no data available on the interaction with food.
4.6 Pregnancy And Lactation
Pregnancy
Data on the use of isosorbide mononitrate during pregnancy are insufficient to be able to assess the possible harmful effect. Limited data from animal studies indicate no adverse effects on the pregnancy or the unborn child. As precautionary measure, it is preferable to avoid the use of isosorbide mononitrate during pregnancy.
Breastfeeding
There are no data on passage of isosorbide mononitrate in human milk, but some excretion seems likely. The effects of this exposure on a nursing infant are unknown. As precautionary measure, breast-feeding should be discontinued during treatment with isosorbide mononitrate.
Fertility
Animal data do not suggest an effect of the treatment of isosorbide mononitrate on male and female fertility. Human data are lacking.
4.7 Effects On Ability To Drive And Use Machines
Isosorbide mononitrate may occasionally trigger a drop in blood pressure, which can cause dizziness. This is particularly true at the start of treatment or increasing doses.
4.8 Undesirable Effects
Most undesirable effects are pharmacologically mediated and are dose dependent. Headache occurs in approximately 25% of patients at the start of treatment and can be attributed to the vasodilatory effect of the preparation; The headache usually disappears within about one week. Hypotension (with dizziness and nausea) has been reported, but this disappears with continued treatment.
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* Most likely due to a nitrate induced sphincter relaxation
** Sometimes severe
The frequency of headache can be reduced by starting treatment with 30 mg during the first 2-4 days and gradually titrating the dose upwards as necessary. A drop in blood pressure can lead to reflex tachycardia, dizziness and fainting.
4.9 Overdose
Signs and symptoms:
Headache, hypotension, nausea, vomiting, sweating, tachycardia, dizziness, anxiety, hot and red skin, blurred vision and syncope. An increase in intracranial pressure with confusion and neurological deficit occurs uncommonly. Methaemoglobinaemia (cyanosis, hypoxaemia, agitation, respiratory depression, convulsions, cardiac arrhythmias, circulatory insufficiency, increased intracranial pressure) occurs rarely.
Treatment
The following treatments are intended only as guidelines and are at the discretion of the treating physician.
General procedure:
• Stop using isosorbide mononitrate.
• Consider absorption-reducing therapy (administration of activated charcoal) and in case of suspected severe intoxication consider flushing of the stomach (where practicable within one hour after ingestion).
• General procedure in case of incident of nitrate-related low blood pressure:
- Put the patient in horizontal position with the legs up and lower the head.
- Give oxygen.
- Maintain plasma volume.
In case of persistent hypotension
• Administration of norepinephrine HCl or dopamine.
Treatment for methemoglobinemia
• Administration of antidote:
- methylene blue: up to 50 ml of a 1% solution i.v.;
- vitamin C: 1 g p.o. or as sodium salt i.v;
- toluidine blue: initially 2 - 4 mg/kg body weight strictly i.v.; if necessary repeated several times with a time lag of one hour with 2 mg/kg body weight.
• If necessary, apply artificial respiration.
• In severe refractory methemoglobinemia (metHEB> 70%) consider hemodialysis, exchange transfusion.
In case of signals of a respiratory and circulatory arrest, start reanimation immediately.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: VASODILATORS USED IN CARDIAC DISEASES; Organic nitrates
ATC code: C01DA14
This preparation is a prolonged release form of Isosorbide mononitrate, an active metabolite of isosorbide dinitrate. Nitro-compounds cause a dose-dependent relaxation of smooth muscle. The therapeutic effect is dependent on dose and individual sensitivity.
Low doses cause dilatation of the veins and a decreased venous return to the heart (reduced preload). High doses also cause arterial dilatation and decreased vascular resistance (reduced afterload). Isosorbide mononitrate reduces the load on the heart by venous and arterial dilatation and can have a direct vasodilatory effect on the coronary arteries. By reducing end-diastolic pressure and volume, it lowers the pressure inside the ventricle and thus improves the subendocardial blood flow. The net effect of isosorbide mononitrate is a reduced load on the heart and better oxygen supply to the myocardium.
Isosorbide mononitrate is intended for use in the prophylactic treatment of angina pectoris.
Continuous treatment with nitro-preparations is associated with the development of tolerance. For this reason, the tablets should be taken once a day in order to obtain an interval with low nitrate concentration.
5.2 Pharmacokinetic Properties
Isosorbide mononitrate is rapidly absorbed and peak plasma levels are reached approximately 1 hour after oral dosing.
Following oral administration, bioavailability of Isosorbide mononitrate is 100%. It does not undergo a first-pass effect.
Isosorbide mononitrate is eliminated from plasma with a half-life of approximately 5.1 hours. It is metabolised to isosorbide-5-MN-glucuronide, which has a half-life of approximately 2.5 hours. It is also excreted unchanged in the urine.
After multiple oral doses, plasma levels are consistent with predictions based on the kinetic parameters of a single dose.
5.3 Preclinical Safety Data
Non clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose monohydrate
Microcrystalline cellulose (PH 102) (E460)
Sodium starch glycolate (type-A)
Colloidal anhydrous silica (E551)
Magnesium stearate (E470b)
6.2 Incompatibilities
Not applicable
6.3 Shelf Life
2 years.
6.4 Special Precautions For Storage
Store below 30°C.
Store in original container
6.5 Nature And Contents Of Container
Al/PVC and Al/PVC-PVDC blister with 20, 30, 40, 50, 80, 90, 100 or 500 Tablets in a carton.
Pack sizes: 20, 30, 40, 50, 80, 90, 100 or 500 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements
7. Marketing Authorisation Holder
Accord Healthcare Limited,
Sage House, 319, Pinner Road,
North Harrow, Middlesex,
HA1 4HF,
United Kingdom
8. Marketing Authorisation Number(S)
PL 20075/0312
9. Date Of First Authorisation/Renewal Of The Authorisation
16/03/2011
10. Date Of Revision Of The Text
16/03/2011
11 DOSIMETRY
IF APPLICABLE
12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS
IF APPLICABLE
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