RISOPET Film coated tablet Ref.[115165] Active ingredients: Ethambutol Isoniazid Pyrazinamide Rifampicin

Rifampicin

Absorption

Rifampicin is well absorbed when taken on an empty stomach. The rate and extent of absorption is decreased when taken with food. Maximum plasma concentrations are reached about 2 hours after administration.

Distribution

Rifampicin is rapidly distributed throughout the body. The concentration in cerebrospinal fluid is, however, generally low, except in meningitis. The volume of distribution is about 55 L. The protein binding is high (80%).

Biotransformation

Rifampicin is deacetylated to the active metabolite desacetylrifampicin. Rifampicin and desacetylrifampicin are excreted in the bile and rifampicin undergoes enterohepatic recycling.

Elimination

The elimination half-life initially is 3 to 5 hours, decreasing to 2 to 3 hours on repeated administration. The rate of elimination is increased during the first 6 to 10 days of therapy, due to auto-induction of hepatic microsomal oxidative enzymes. After high doses excretion may be slower because of saturation of the biliary excretion.

Isoniazid

Absorption

Isoniazid is absorbed following oral administration. The rate and extent of absorption is decreased when taken with food. Maximum plasma concentrations are reached 1 to 2 hours after a dose.

Distribution

Isoniazid is widely distributed to most body fluids and tissues. The volume of distribution is about 43 L. Protein binding is very low, approximately 0 to 10%.

Biotransformation

Isoniazid is acetylated by N-acetyltransferase to N-acetylisoniazid. It is then bio-transformed to isonicotinic acid and monoacetylhydrazine. Monoacetylhydrazine is associated with hepatotoxicity via formation of a reactive intermediate metabolite. The rate of acetylation is genetically determined; slow acetylators are characterised by a relative lack of hepatic N-acetyltransferase.

Elimination

The half-life is generally between 1 and 4 hours, but can vary between 0,5 to 6 hours, depending of the rate of acetylation.

Approximately 75-95% of the dose is excreted by the kidneys within 24 hours, primarily as the inactive metabolites N-acetylisoniazid and isonicotinic acid.

Pyrazinamide

Absorption

Pyrazinamide is well absorbed from the gastrointestinal tract. The absorption is not affected by concomitant food intake. Maximum plasma concentrations are reached after 1 to 2 hours in adults and about 3 hours in children.

Distribution

Pyrazinamide is rapidly distributed throughout the body.

Biotransformation

Pyrazinamide is hydrolysed by a microsomal deaminase to pyrazinoic acid, an active metabolite, and then hydroxylated by xanthine oxidase to 5-hydroxypyrazinoic acid.

Elimination

Pyrazinamide is renally excreted, mainly as metabolites.

Only 3% of the dose is excreted unchanged in urine. The half-life is about 10 hours.

Ethambutol

Absorption

Ethambutol is absorbed following oral administration. The bioavailability is approximately 80%. The absorption is not affected by concomitant food intake. Maximum plasma concentrations are reached 2 to 4 hours after a dose.

Distribution

Ethambutol is widely distributed to most tissues. It is not distributed to cerebrospinal fluid. However, in patients with tuberculous meningitis the concentration in cerebrospinal fluid may reach therapeutic levels. Concentrations in erythrocytes are 2 to 3 times higher than in serum. Protein binding is low (10 to 40%). The volume of distribution is about 20 L.

Biotransformation

Ethambutol is metabolised in the liver, up to 15% to inactive metabolites. The half-life of ethambutol is 3 to 4 hours, but increases up to 8 hours in patients with impaired renal function.

Elimination

Up to 80% excreted renally within 24 hours (at least 50% unchanged and up to 15% as inactive metabolites). About 20% is excreted unchanged in the faeces.

Pharmacokinetics in special patient groups

Rifampicin

With impaired renal function, the elimination half-life becomes prolonged at doses exceeding 600 mg daily (10 mg/kg). Rifampicin is not removed from the blood by haemodialysis.

In patients with impaired liver function, the plasma concentrations are raised and the elimination half-life prolonged. For treatment of patients with impaired liver function (see section 4.4).

Isoniazid

In slow acetylators with severely impaired renal function, accumulation of isoniazid may occur. In such cases, the serum concentration of isoniazid should be closely monitored and, if necessary, the dosage reduced. In the presence of impaired liver function, the elimination half-life of isoniazid is prolonged.

For use in patients with impaired liver function (see section 4.4).

Pyrazinamide

Patients with hepatic cirrhotic insufficiency exhibit a marked reduction of the pyrazinamide clearance and an increase in half-life. The area under the curve of pyrazinoic acid (the main metabolite) is increased three-fold (see section 4.4).

There is no information regarding the pharmacokinetics of pyrazinamide in renal impairment. Pyrazinamide is removed from blood by haemodialysis.

Ethambutol

The elimination half-life of ethambutol is increased in patients with impaired renal function, which may require an adjustment of dosage. Ethambutol is not removed from the blood by haemodialysis.