This information is intended for use by health professionals

1. Name of the medicinal product

Isosorbide mononitrate 40mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 40 mg of isosorbide mononitrate.

Excipient with known effect: 10 mg of lactose monohydrate/tablet

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

Isosorbide mononitrate 40mg tablets:

White to off white, round, flat, bevelled edge uncoated tablets, debossed with 'AT' 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

Posology

Adults

The usual dose of Isosorbide mononitrate is 1 tablet of Isosorbide mononitrate 40 mg taken asymmetrically (to allow a nitrate low period) 2 to 3 times daily.

The dosage may be increased to 120mg per day.

Dosage regime should be designed according to the clinical response of the patient.

The lowest effective dose should be used.

In patients taking isosorbide mononitrate twice daily, the second dose should be taken 8 hours after the 1st dosage. If the dose is one three times daily, take one every 6 hours. This provides a nitrate-free period of 6 – 8 hours.

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 duration of application is decided by the treating physician.

Treatment with isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually (see section 4.4).

Elderly

There is no evidence to suggest that an adjustment of the dosage is necessary in elderly.

Pediatric population

There is as yet no data on the safety and efficacy of isosorbide mononitrate in children.

For oral administration.

Method of administration

The tablet should be swallowed whole, taken after meals. It should be unchewed with little fluid.

4.3 Contraindications

Hypersensitivity to the the isosorbide mononitrate or to any of the excipients listed in section 6.1.

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), constrictive pericarditis, 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 severe anaemia, severe hypotension, closed angle glaucoma or severe 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

Isosorbide mononitrate may give rise to postural hypotension and syncope in some patients. Severe postural hypotension with light-headedness and dizziness is frequently observed after the consumption of alcohol.

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 low filling pressures e.g. in acute myocardial infraction, impaired left ventricular function (left ventricular failure), or orthostatic dysfunction. Reducing systolic blood-pressure below 90mmHg must be avoided.

It should also be used with caution in patients 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, or pre-existing hyperdynamic (abnormally increased blood circulatory volume) conditions.

Symptoms of circulatory collapse may arise after first dose, particularly in patients with labile circulation.

Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and increased angina.

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)

Isosorbide mononitrate tablets contain lactose and therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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. The onset of action of isosorbide mononitrate is not sufficiently rapid to be useful to treat an acute anginal attack.

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.

Treatment with Isosorbide mononitrate, as with any other nitrate, should not be stopped suddenly. Both the dosage and frequency should be tapered gradually. (See section 4.2)

In patients with decreased gastrointestinal transit time, a decrease in release of the active ingredient may occur.

Patients who undergo a maintenance treatment with isosorbide mononitrate should be informed that they must not use phosphodiesterase inhibitor-containing products (e.g. sildenafil, tadalafil, vardenafil).

Isosorbide mononitrate therapy should not be interrupted to take phosphodiesterase inhibitor-containing products (e.g. sildenafil, tadalafil, vardenafil), because the risk of inducing an attack of angina pectoris could increase by doing so (see section 4.3 & 4.5).

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 (e.g. sildenafil, tadalafil, vardenafil)(section 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 occur 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.

Sapropterine (Tetrahydrobiopterine, BH4) is a cofactor for nitric oxide synthetase. Caution is recommended during concomitant use of sapropterine-containing medicine with all agents that cause vasodilation by affecting nitric oxide (NO) metabolism or action, including classical NO donors (e.g. glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (5-ISMN) and others).

There are no data available on the interaction with food.

4.6 Fertility, 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 is data that nitrates are excreted in breast milk and may cause methemoglobinemia in infants. 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.

Therefore isosorbide monohydrate should only be used in pregnancy and during lactation if, in the opinion of the physician, the possible benefits of treatment outweigh the hazards.

4.7 Effects on ability to drive and use machines

Isosorbide mononitrate may occasionally trigger a drop in blood pressure, which can cause dizziness. Dizziness, tiredness or blurred vision might occur at the start of treatment or increasing doses. If affected do not drive or operate machinery. This effect may be increased by alcohol.

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.

The frequencies of adverse events are ranked according to the following:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000),

Not known (cannot be estimated from the available data)

System Organ Class

Frequency

Adverse event

Nervous System Disorders

Very common

Headache

Common

Dizziness, (including dizziness postural), Somnolence

Rare

Syncope

General disorders and administration site conditions

Common

Asthenia

Vascular Disorders

Common

Orthostatic Hypotension, Hypotension

Uncommon

Circulatory collapse with worsening of symptoms of angina pectoris (sometimes accompanied by bradyarrhythmia and syncope);

Transient hypoxemia with myocardial hypoxia in patients with coronary artery disease.

Cardiac disorders:

Common

Tachycardia

Uncommon

Angina pectoris aggravated

Not known

Paroxysmal bradycardia

Gastrointestinal disorders

Uncommon

Nausea, vomiting, diarrhoea

Very rare

Dyspepsia (heartburn)*

Skin and subcutaneous tissue disorders

Uncommon

Allergic skin reactions (e.g. rash, pruritus), flushing

Not known

Exfoliative dermatitis, flushing, allergic skin reactions**

* 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.

Severe hypotensive responses have been reported for organic nitrates and include nausea, vomiting, restlessness, pallor and excessive perspiration.

During treatment with isosorbide mononitrate, a temporary hypoxemia may occur due to a relative redistribution of the blood flow in hypoventilated alveolar areas. Particularly in patients with coronary artery disease this may lead to a myocardial hypoxia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Animal experience:

In rats and mice, significant lethality at oral doses of 1965mg/kg and 2581mg/kg, respectively, was observed.

Human experience:

Signs and symptoms:

- Headache

- Hypotension (fall in blood pressure ≤ 90 mmHg

- Paleness

- Nausea

- Vomiting

- Sweating

- Weak pulse

- Tachycardia

- Light-headedness of standing

- Weakness

- Dizziness

- Anxiety

- hot and red skin

- blurred vision

- syncope

- Diarrhoea.

An increase in intracranial pressure with confusion and neurological deficit occurs uncommonly. In very high doses the intracranial pressure may be increased. This may lead to cerebral symtoms. Methaemoglobinaemia (cyanosis, hypoxaemia, agitation, respiratory depression, convulsions, cardiac arrhythmias, circulatory insufficiency, increased intracranial pressure) occurs rarely.

Methaemoglobinaemia has been reported in patients receiving other organic nitrates. During isosorbide mononitrate biotransformation nitrite ions are released, which may induce methaemoglobinaemia and cyanosis with subsequent tachypnoea, anxiety, loss of consciousness and cardiac arrest. It cannot be excluded that an overdose of isosorbide mononitrate may cause this adverse reaction.

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.

- Expand plasma volume (I.V. fluids)

- Specific treatment for shock (admit patient to intensive care unit).

Special procedure:

• Raising the blood pressure if the blood pressure is very low.

• Treatment of methaemoglobinaemia

- Reduction therapy of choice with vitamin C, methylene-blue or toluidine-blue

- Administer oxygen (if necessary)

- Initiate artificial ventilation

- Hemodialysis (if necessary)

• Resuscitation measures

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

Isosorbide mononitrate is an organic nitrate which in common with other cardioactive nitrates is a vasodilator. It produces decreased left and right ventricular end-diastolic pressures to a greater extent than the decrease in systemic arterial pressure, thereby reducing afterload and especially the preload of the heart.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.

Isosorbide mononitrate influences the oxygen supply to ischaemic myocardium by causing the redistribution of blood flow along collateral channels and from epicardial to endocardial regions by selective dilation of large epicardial vessels.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.

Mechanism of action:

Like all organic nitrates, isosorbide mononitrate acts as a donor of nitric oxide (NO). NO causes a relaxation of vascular smooth muscle via the stimulation of guanylyl cyclase and the subsequent increase of intracellular cyclic guanosine monophosphate (cGMP) concentration. A cGMP-dependent protein kinase is thus stimulated, with resultant alteration of the phosphorylation of various proteins in the smooth muscle cell. This eventually leads to the dephosphorylation of the light chain of myosin and the lowering of smooth muscle tone.

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

Acute toxicity:

Studies on acute toxicity in mice and rats with different routes of administration indicate a low acute toxicity (LD50 oral approximately 2,000 - 2,500 mg/kg b.w.).

Chronic toxicity:

Long term toxicity has been tested in rats for 78 weeks and in dogs for 52 weeks. First toxic reactions occurred in dosages of 90 mg/kg (dog) and 405 mg/kg (rat), respectively. Thus taking into account the recommended dosage of 20 to 30 mg/d in humans, the therapeutic index can be stated as high.

Reproduction studies:

These studies included a fertility and breeding study over two generations in rats; teratology studies in rats and rabbits; and a rat peri-postnatal study. The dosage levels used were generally high and produced maternal toxic effects at the highest dose. No teratogenic effects of isosorbide mononitrate were observed.

Mutagenicity:

Isosorbide mononitrate was tested in different studies both in vitro and in vivo (Ames test,Human peripheral lymphocytes, Bone marrow of rats and hamsters, V 79 test, SCE test) on possible mutagenic effects. As all tests were negative the mutagenic risk in humans is considered low.

Carcinogenicity:

Neither the long term toxicity studies in rats and dogs nor a special carcinogenicity study, performed in rats over 125 weeks (males) and 138 weeks (females), indicated neoplastic properties of isosorbide mononitrate. Therefore, it can be concluded that the carcinogenic risk in humans is low.

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, 28, 30, 40, 50, 56, 60, 80, 84, 90, 100, 200 or 500 Tablets in a carton.

Pack sizes: 20, 28, 30, 40, 50, 56, 60, 80, 84, 90, 100, 200 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 20075/0313

9. Date of first authorisation/renewal of the authorisation

16/03/2011

10. Date of revision of the text

25/07/2014