COVERSYL ARGININE PLUS Film-coated tablet Ref.[116777] Active ingredients:

Linked to Coversyl Arginine Plus 5mg/1.25mg

The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.

Linked to perindopril

Absorption and bioavailability

After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to 1 hour.

As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.

Distribution

The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent.

Biotransformation

Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.

Elimination

Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 4 days.

Linearity/non-linearity

It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.

Special populations

Elderly

Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.

Renal impairment

Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).

In case of dialysis

Dialysis clearance of perindoprilat is equal to 70 ml/min.

Cirrhosis

Perindopril kinetics are modified in patients with cirrhosis: hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore no dosage adjustment is required (see sections 4.2 and 4.4).

Linked to indapamide

Absorption

Indapamide is rapidly and completely absorbed from the digestive tract.

The peak plasma level is reached in humans approximately one hour after oral administration of the product.

Distribution

Plasma protein binding is 79%.

Biotransformation and Elimination

The elimination half-life is between 14 and 24 hours (average 18 hours). Repeated administration does not produce accumulation. Elimination is mainly in the urine (70% of the dose) and faeces (22%) in the form of inactive metabolites.

Special populations

Renal impairment

The pharmacokinetics are unchanged in patients with renal insufficiency.

Coversyl Arginine Plus 5mg/1.25mg has slightly increased toxicity than that of its components. Renal manifestations do not seem to be potentiated in the rat. However, the combination produces gastro-intestinal toxicity in the dog and the toxic effects on the mother seem to be increased in the rat (compared to perindopril).

Nonetheless, these adverse effects are shown at dose levels corresponding to a very marked safety margin by comparison to the therapeutic doses used.

Preclinical studies performed separately with perindopril and indapamide did not show genotoxic or carcinogenic potential. Reproduction toxicology studies showed no embryotoxicity or teratogenicity and fertility was not impaired.