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MONOMIL XL TABLETS
Active substance(s): ISOSORBIDE 5-MONONITRATE
NAME OF THE MEDICINAL PRODUCT
Monomil XL Tablets
Carmil XL Tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Isosorbide – 5 – mononitrate: 60mg/tablet. Also contains lactose.
For full list of excipients, see Section 6.1
Prolonged release tablets.
For the prophylaxis of angina pectoris.
Posology and Method of Administration
Adults: One tablet to be taken once daily in the morning. The dose may be
increased to 120mg (two tablets) daily, both to be taken once daily in the
morning. The dose can be titrated to minimise the possibility of headache, by
initiating the treatment with 30mg (half tablet) for the first 2 – 4 days.
Monomil XL/Carmil XL tablets must not be chewed or crushed. They should
be swallowed whole with a small amount of water.
Children: The safety and efficacy of Monomil XL/Carmil XL tablets in
children has not been established.
Elderly: No evidence of a need for routine dosage adjustment in the elderly
has been found, but special care may be needed in those with increased
susceptibility to hypotension or marked hepatic or renal insufficiency.
Severe cerebrovascular insufficiency or hypotension are relative
contraindications to the use of Monomil XL/Carmil XL tablets.
Monomil XL/Carmil XL tablets should not be given to patients with a known
sensitivity to nitrates (or any other ingredient in this product), very low blood
pressure, acute myocardial infarction with low filling pressure, acute
circulatory failure (shock, vascular collapse), hypertrophic cardiomyopathy
and constrictive pericarditis, aortic stenosis, cardiac tamponade, mitral
stenosis, severe anaemia and during the first three months of pregnancy.
Phosphodiesterase type-5 inhibitors (e.g. sildenafil, tadalafil and vardenafil)
have been shown to potentiate the hypotensive effects of nitrates, and their coadministration with nitrates or nitric oxide donors is therefore contraindicated
(see section 4.5)
Monomil XL/Carmil XL is contraindicated in diseases associated with a raised
intra-cranial pressure e.g. following a head trauma and including a cerebral
haemorrhage, and in patients with closed angle glaucoma.
Special Warnings and Precautions for use
Monomil XL/Carmil XL tablets are not indicated for the relief of acute angina
attacks; in the event of an acute attack, sublingual or buccal glyceryl trinitrate
tablets should be used.
Severe postural hypotension with light-headedness and dizziness is frequently
observed after the consumption of alcohol. Consumption of alcohol should be
avoided during the treatment with Carmil/Monomil XL tablets as the
vasodilator activity of isosorbide mononitrate may be enhanced.
Monomil XL/ Carmil XL tablets should be used with caution in patients who
have a recent history of myocardial infarction, or who are suffering from
hypothyroidism, hypothermia, malnutrition and severe liver or renal disease.
Monomil XL/Carmil XL tablets contain lactose and therefore should not be
used in patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption.
Interaction with other Medicinal Products and other forms of Interaction
Concomitant administration of Monomil XL/Carmil XL tablets and
Phosphodiesterase Type 5 Inhibitors can potentiate the vasodilatory effect of
Monomil XL/Carmil XL tablets with the potential result of serious side effects
such as syncope or myocardial infarction. Therefore, Monomil XL/Carmil XL
tablets and Phosphodiesterase Type 5 Inhibitors (e.g. sildenafil) must not be
Concurrent administration of drugs with blood pressure lowering properties,
e.g. beta-blockers, calcium channel blockers, vasodilators, alprostadil,
aldesleukin, angiotensin II receptor antagonists etc and/or alcohol may
potentiate the hypotensive effect of Monomil XL / Carmil XL. This may also
occur with neuroleptics and tricyclic antidepressants.
Fertility, pregnancy and lactation
The safety and efficacy of Monomil XL/Carmil XL tablets during pregnancy
or lactation has not been established.
Effects on Ability to Drive and Use Machines
Patients may develop dizziness when first using Monomil XL/Carmil XL
tablets. Patients should be advised to determine how they react to Monomil
XL/Carmil XL tablets before they drive or operate machinery.
The adverse reactions which follow have been reported in studies with
mononitrate. Most of the adverse reactions are
pharmacodynamically mediated and dose dependent.
Headache may occur when treatment is initiated, but usually disappears after
1-2 weeks of treatment. Hypotension, with symptoms such as dizziness and
nausea with syncope in isolated cases, has occasionally been reported. These
symptoms generally disappear during continued treatment.
The following definitions of frequencies are used: 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) and very rare (<1/10,000).
Nervous system disorders
Common: Headache, Dizziness
Not known: paradoxical bradycardia.
Common: Postural hypotension, Hypotension
Uncommon: Vomiting, Diarrhoea.
Skin and subcutaneous tissue disorders
Rare: Rash and pruritus
Musculoskeletal, connective tissue and bone disorders
Very rare: Myalgia
General disorders and administration site conditions
Not known: Fatigue
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
products 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
Symptoms: Pulsing headache. More serious symptoms are excitation, flushing,
cold perspiration, nausea, vomiting, vertigo, syncope, tachycardia and a fall in
Treatment: Induction of emesis, activated charcoal. In case of pronounced
hypotension the patient should first be placed in the supine position with the
legs raised. If necessary fluids should be administered intravenously.
Pharmacotherapeutic group: Vasodilators used in cardiovascular disease
(organic nitrates). ATC Code: C01DA14.
The principal pharmacological action of isosorbide mononitrate, an active
metabolite of isosorbide dinitrate, is relaxation of vascular smooth muscle,
producing vasodilation of both arteries and veins with the latter effect
predominating. The effect of the treatment is dependent on the dose. Low
plasma concentrations lead to venous dilatation, resulting in peripheral pooling
of blood, decreased venous return and reduction in left ventricular enddiastolic pressure (preload). High plasma concentrations also dilate the arteries
reducing systemic vascular resistance and arterial pressure leading to a
reduction in cardiac afterload. Isosorbide mononitrate may also have a direct
dilatory effect on the coronary arteries. By reducing the end diastolic pressure
and volume, the preparation lowers the intramural pressure, thereby leading to
an improvement in the subendocardial blood flow.
The net effect when administering isosorbide mononitrate is therefore a
reduced workload of the heart and an improved oxygen supply/demand
balance in the myocardium.
Monomil XL/Carmil XL tablets are effective as monotherapy as well as in
combination with beta -blocker therapy.
The clinical effects of nitrates may be attenuated during repeated
administration owing to high and/or even plasma levels. This can be avoided
by allowing low plasma levels for a certain period of the dosage interval.
Extended release tablets containing isosorbide mononitrate, when
administered once daily in the morning, produce a plasma profile of high
levels during the day and low levels during the night. With the 60mg or 120mg
once daily tablet, no development of tolerance with respect to antianginal
effect has been observed. Rebound phenomenon between doses as described
with intermittent nitrate patch therapy has not been seen with this formulation.
In placebo-controlled studies, once daily extended release tablets containing
isosorbide mononitrate have been shown to effectively control angina pectoris
both in terms of exercise capacity and symptoms, and also in reducing signs of
myocardial ischaemia. The duration of the effect is at least 12 hours; at this
point the plasma concentration is at the same level as at around 1 hour after
dose intake (around 1300 nmol/l).
Isosorbide mononitrate is completely absorbed and is not subject to first pass
metabolism by the liver. This reduces the intra- and inter-individual variations
in plasma levels and leads to predictable and reproducible clinical effects.
Monomil XL/Carmil XL Tablets are prolonged release formulations. The
active substance is released independently of pH, over a 10-hour period.
Compared to ordinary tablets the absorption phase is prolonged and the
duration of effect is extended.
The extent of bioavailability of isosorbide mononitrate in extended release
tablets is about 90% compared to immediate release tablets. Absorption is not
significantly affected by food intake and there is no accumulation during
Isosorbide mononitrate in extended release tablets exhibits dose proportional
kinetics up to 120mg. After repeated peroral administration with 60mg once
daily, maximal plasma concentration (around 3000 nmol/l) is achieved after
around 4 hours. The plasma concentration then gradually falls to under 500
nmol/l at the end of the dosage interval (24 hours after dose intake).
The plasma protein binding is less than 5%. The volume of distribution for
isosorbide mononitrate is about 0.6 l/kg and total clearance around 115
Elimination is primarily by denitration and conjugation in the liver. The
metabolites are excreted mainly via the kidneys. Only about 2% of the dose
given is excreted intact via the kidneys.
The elimination half-life of isosorbide mononitrate is around 5 hours.
Impaired liver or kidney function has no major influence on the
Preclinical safety data
Non clinical data reveal no special hazard for humans based on conventional
studies of safety pharmacology, repeated dose toxicity, genotoxicity,
carcinogenic potential, and toxicity to reproduction.
List of excipients
Lactose monohydrate, hypromellose, maize starch, glyceryl palmitostearate
and magnesium stearate.
Special precautions for storage
Do not store above 25°C. Store in original container.
Nature and contents of container
PVC/Aluminium blisters in a cardboard carton. Each strip of blister contains
14 tablets and there are two strips of blisters per carton.
Instructions for use/handling
MARKETING AUTHORISATION HOLDER
Ares, Odyssey Business Park
West End Road
South Ruislip, HA4 6QD
MARKETING AUTHORISATION NUMBER
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT
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