Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Milpharm Limited, Ares, Odyssey Business Park, West End Road, South Ruislip, HA4 6QD, United Kingdom
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 end-diastolic 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.
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.
The elimination half-life of isosorbide mononitrate is about 5 hours. The plasma protein binding is less than 5%. The volume of distribution for isosorbide mononitrate is about 0.6 l/kg and the total clearance around 115 ml/minute. 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.
Impaired liver or kidney function has no major influence on the pharmacokinetic properties.
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 steady state. 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 tablets are divisible.
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).
Monomil XL/Carmil XL Tablets are effective as monotherapy as well as in combination with chronic β-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.
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.
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