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CHEMYDUR 60XL

Active substance(s): ISOSORBIDE 5-MONONITRATE / ISOSORBIDE 5-MONONITRATE / ISOSORBIDE 5-MONONITRATE

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1.

NAME OF THE MEDICINAL PRODUCT
Chemydur 60XL
Mitrate 60XL

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 60 mg of isosorbide-5-mononitrate.
International non-proprietary name (INN): Isosorbide mononitrate.
Chemical name: 1,4 : 3,6 dianhydro-D-glucitol-5-nitrate.
Excipients with known effect:
Lactose
(38.167 mg/ tablet)
For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM
Tablets (modified release).
Oval, cream coloured tablets, half scored on both sides and marked with a crown and 60
on one side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications
Chemydur 60XL Tablets are indicated in adults for the prophylactic treatment of angina
pectoris

4.2

Posology and Method of Administration
Posology
Adults:
One tablet (60 mg) once daily given in the morning. The dose may be increased to two
tablets (120 mg), to be taken together.
The dose can be titrated to minimise the possibility of headache by initiating treatment
with half a tablet (30 mg) for the first two to four days.

The tablets should not be chewed or crushed and should be swallowed with half a glass of
fluid.
Paediatric population
The safety and efficacy of Chemydur 60XL Tablets in children have not been established.
Elderly:
There is no need for routine dose adjustment in the elderly, but care may be needed in
those patients with increased susceptibility to hypotension, and in those with marked
hepatic or renal insufficiency.
The lowest effective dose should be used.
There is a risk of tolerance developing to modified release preparations. In such patients
intermittent therapy may be more appropriate.
As with other drugs for the treatment of angina pectoris, abrupt discontinuation of
therapy may lead to exacerbation of symptoms. When discontinuing long-term treatment,
the dosage should be reduced gradually over several days, and the patient carefully
monitored (see section 4.4).
Method of administration
Oral.
4.3

Contraindications
Hypersensitivity to isosorbide mononitrate or to any of the excipients listed in section
6.1.
Acute myocardial infarction with low filling pressures, hypertrophic obstructive
cardiomyopathy, constrictive pericarditis, cardiac tamponade, aortic/mitral stenosis and
severe anaemia, hypovolaemia, conditions causing raised intracranial pressure (e.g.
cerebral haemorrhage, head trauma) and closed-angle glaucoma. Severe cerebrovascular
insufficiency or hypotension are contraindications to use.
Phosphodiesterase type-5 inhibitors (e.g. sildenafil) have been shown to potentiate the
hypotensive effects of nitrates, their co-administration with nitrates or nitric oxide donors
is therefore contraindicated.

4.4

Special warnings and precautions for use
The lowest effective dose should be used.

There is a risk of tolerance developing to modified release preparations. In such patients
intermittent therapy may be more appropriate.
Therapy should not be discontinued suddenly. Both dosage and frequency should be
tapered gradually (see section 4.2).
Symptoms of circulatory collapse may arise after the first dose, particularly in patients
with labile circulation.
Hypotension induced by nitrates may be accompanied by paradoxical bradycardia and
increased angina.
Severe postural hypotension with light-headedness and dizziness is frequently observed
after the consumption of alcohol.
Chemydur 60XL Tablets are not indicated for relief of acute anginal attacks: in the event
of an acute attack, glyceryl trinitrate should be used.
The administration of isosorbide mononitrate causes a decrease of) effective renal plasma
flow (eRPF) in cirrhotic patients and should be used with caution.
Caution should be used in patients who have a recent history of myocardial infarction and
in patients suffering from hypothyroidism, hypothermia, malnutrition, and severe liver or
renal disease. Oral nitrates should also be used with caution in patients with angina due to
other causes, or pre-existing hyperdynamic conditions.
Since oral nitrates can cause venous dilatation, they should not be used in patients with
increased intracranial pressure.
Chemydur 60XL Tablets contain lactose,
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
4.5

Interactions with other medicinal products and other forms of interaction
The hypotensive effect of nitrates will be increased if used together with
phosphodiesterase type-5 inhibitors (e.g. sildenafil). This might lead to life threatening
cardiovascular complications.
Any medication which may cause hypotension may have its hypotensive effects
potentiated by concurrent administration of Chemydur 60XL Tablets (e.g. alcohol,
antihypertensives, vasodilators, calcium channel blockers, and diuretics).
Reports suggest that concomitant administration of isosorbide mononitrate may increase
the blood level of dihydroergotamine and its hypertensive effect.

Alcohol can attenuate cerebral ischaemia associated with postural hypotension.
Isosorbide mononitrate can act as a physiological antagonist to noradrenaline,
acetylcholine and histamine.
4.6

Fertility, pregnancy and lactation
Pregnancy
The safety and efficacy of 1Chemydur 60XL Tablets/Mitrate 60XL Tablets during
pregnancy in humans has not been established. Animal studies have shown reproductive
toxicity (see section 5.3). Isosorbide mononitrate should only be used in pregnancy if, in
the opinion of the physician, the possible benefits of treatment outweigh the hazards.
Breast-feeding
The safety and efficacy of 2Chemydur 60XL Tablets/Mitrate 60XL Tablets during
lactation in humans has not been established. It is not known whether nitrates are
excreted in human milk and therefore caution should be exercised when administered to
nursing women. Isosorbide mononitrate should only be used 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
The patient should be warned not to drive or operate machinery if hypotension or
dizziness occurs.

4.8

Undesirable effects
Most of the adverse reactions are pharmacodynamically mediated and dose dependent.
Headache is very common (>10%). The incidence of headache usually disappears after 12 weeks of treatment. (see section 4.2)
Immune system disorders
Allergic dermatitis, exfoliative dermatitis.
Nervous system disorders
Headache, restlessness, somnolence, pituitary haemorrhage.
Cardiac disorders
Tachycardia, bradycardia - these symptoms generally disappear during long-term
treatment.
Vascular disorders

1
2

PL 06464/0506-0020; 11/12/2009
PL 06464/0506-0020; 11/12/2009

Flushing, dizziness, orthostatic hypotension - these symptoms generally disappear during
long-term treatment. Pallor. Circulatory collapse (sometimes accompanied by
bradyarrhythmia, bradycardia and syncope). Severe hypotension may lead to enhanced
angina pectoris symptoms.
Respiratory, thoracic and mediastinal disorders
Hypoxia.
Gastrointestinal disorders
Nausea, vomiting, diarrhoea
Skin and subcutaneous tissue disorders
Hyperhidrosis, pruritus.
Musculoskeletal and connective tissue disorders
Myalgia.
General disorders and administration site conditions
Asthenia.
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
the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard).
4.9

Overdose
Symptoms and signs
Pulsing headache. More serious symptoms are excitation, flushing, cold perspiration,
nausea, vomiting, vertigo, syncope, tachycardia and a fall in blood pressure. A rise in
intracranial pressure with confusion and neurological deficits can sometimes occur.
Methaemoglobinaemia (cyanosis, hypoxaemia, change in mental status, respiratory
depression, convulsions, cardiac arrhythmias, circulatory failure and raised intracranial
pressure) occurs rarely.
Management
Induction of emesis, activated charcoal.
In case of pronounced hypotension the patient should first be placed in the supine position
with legs raised. If necessary, fluids should be administrated intravenously.
Consider oral activated charcoal if ingestion of a potentially toxic amount has occurred
within 1 hour. Observe for at least 12 hours after the overdose. Monitor blood pressure and
pulse.

If methaemoglobinaemia occurs seek expert advice. Treat with supplemental oxygen and
methylene blue. In cases not responding to methylene blue or where methylene blue is
contraindicated consider exchange transfusion or red blood cell concentrates. In case of
cerebral convulsions, consider diazepam or clonazepam IV or, if therapy fails,
phenobarbital, phenytoin or propofol anaesthesia.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group:
ATC code:
C01DA14

organic nitrate

Mechanism of action
Organic nitrates (including glyceryl trinitrate, isosorbide dinitrate and isosorbide
mononitrate) are potent relaxers of smooth muscle. They have a powerful effect on
vascular smooth muscle with less effect on bronchiolar, gastrointestinal, ureteral and
uterine smooth muscle. Low concentrations dilate both arteries and veins.
Venous dilatation pools blood in the periphery leading to a decrease in venous return,
central blood volume, and ventricular filling volumes and pressures. Cardiac output may
remain unchanged or it may decline as a result of the decrease in venous return. Arterial
blood pressure usually declines secondary to a decrease in cardiac output or arteriolar
vasodilatation, or both. A modest reflex increase in heart rate results from the decrease in
arterial blood pressure. Nitrates can dilate epicardial coronary arteries including
atherosclerotic stenoses.

5.2

Pharmacodynamic effects
The cellular mechanism of nitrate-induced smooth muscle relaxation has become
apparent in recent years. Nitrates enter the smooth muscle cell and are cleaved to
inorganic nitrate and eventually to nitric oxide. This cleavage requires the presence of
sulphydryl groups, which apparently come from the amino acid cysteine. Nitric oxide
undergoes further reduction to nitrosothiol by further interaction with sulphydryl groups.
Nitrosothiol activates guanylate cyclase in the vascular smooth muscle cells, thereby
generating cyclic guanosine monophosphate (cGMP). It is this latter compound,
cGMP,that produces smooth muscle relaxation by accelerating the release of calcium
from these cells.
Pharmacokinetic properties
Absorption
Isosorbide mononitrate is readily absorbed from the gastro-intestinal tract. After oral
administration of extended release tablets, Isosorbide mononitrate is slowly and
completely absorbed as compared to Isosorbide dinitrate.

Distribution
Following oral administration of extended release tablet formulation of Isosorbide
mononitrate, peak plasma levels are reached in approximately 3 hours. Isosorbide
mononitrate are distributed throughout the whole body fluid. Unlike isosorbide dinitrate,
isosorbide mononitrate does not undergo first pass hepatic metabolism and bioavailability
is 77-80%.
Elimination
The pharmacokinetics are unaffected by the presence of heart failure, renal or hepatic
insufficiency. Isosorbide mononitrate is excreted mainly in the urine; compounds
recovered in urine after isosorbide mononitrate administration have included isosorbide,
sorbitol, and conjugates; only 2% of a dose is excreted as unchanged drug. About 96% of
an administered dose of isosorbide mononitrate is excreted in urine and about 1% in feces
within 5 days; most excretion (about 93%) occurs within 48 hours. An elimination halflife of about 4-5 hours has been reported.
5.3

Preclinical safety data
3

High concentrations of isosorbide mononitrate in rats is associated with prolonged
gestation and parturition, stillbirths and deaths.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Stearic acid, carnauba wax, hydroxypropylmethylcellulose, lactose, magnesium stearate,
talc, purified siliceous earth, polyethylene glycol 4000, titanium dioxide E171, yellow
iron oxide E172.

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

Special precautions for storage
Store in a dry place at or below 25oC. Protect from sunlight.

6.5

3

Nature and contents of container

PL 06464/0506-0020; 11/12/2009

The tablets are packed in aluminium foil/PVC blisters packed in boxes of 28, 30, 56, 60
and 100 oval, cream-coloured tablets, half-scored on both sides and marked with a crown
and 60 on one side.
Not all pack sizes may be marketed.
6.6

Special precautions for disposal and other handling
The tablets should be swallowed whole with half a glass of water. They must not be
chewed or crushed.

7

MARKETING AUTHORISATION HOLDER
Amdipharm UK Limited
Capital House, 85 King William Street,
London EC4N 7BL, UK

8.

MARKETING AUTHORISATION NUMBER
PL 20072/0220

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
Date of first authorisation:

10

12 March 1998

DATE OF REVISION OF THE TEXT
29/12/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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