RIMACTANE Capsule Ref.[49654] Active ingredients: Rifampicin

Absorption

Rifampicin is rapidly and completely absorbed. Following a single dose taken on an empty stomach (600 mg) the peak serum concentrations (approx. 10 g/ml) are observed after about 2 hours. Ingestion with food may adversely affect the absorption of rifampicin.

Distribution

The apparent distribution volume is 1.6 L/kg in adults and 1.1 L/kg in children. Binding to serum proteins amounts to 84%-91%.

Rifampicin penetrates rapidly into various body fluids and tissues, including bone tissue. Rifampicin crosses the blood/brain barrier in the case of inflamed meninges only, but concentrations in the cerebrospinal fluid may remain above the MIC for Mycobacterium tuberculosis for up to two months with continuous therapy of 600 mg/day orally.

Rifampicin crosses the human placenta and is secreted in human breast milk. However, it is estimated that a breast-fed infant would receive no more than 1% of the usual therapeutic dose.

Biotransformation

Rifampicin is metabolised in the liver, the principal metabolite being 25-O-deacetylrifampicin, which is microbiologically active and, like rifampicin, subject to enterohepatic circulation. Rifampicin induces its own metabolism.

Elimination

The plasma elimination half-life of rifampicin increases with increasing doses and amounts to 2.5h, 3-4h and about 5h after single doses of 300 mg, 600 mg and 900 mg respectively. After a few days of repeated daily administration, the bioavailability of rifampicin diminishes, and the half-life value following repeated doses of 600 mg falls to 1-2 hours.

Owing to its enzyme-inducing effect in the liver, rifampicin accelerates its own metabolism, with the result that its systemic clearance, which amounts to approx. 6 L/h after the first dose, rises to approx. 9 L/h after repeated dosing.

Although the bulk of the drug is eliminated in the bile, 80% of the quantity excreted being accounted for by the deacetylrifampicin metabolite, rifampicin also appears in the urine. In a dosage range of 150-900 mg, 4-18% of a dose is excreted dose-dependently in the urine in unchanged form.

Characteristics in patients

In elderly patients, renal clearance is reduced, but, owing to the large scale on which the drug is eliminated via the liver, the plasma concentrations are similar to those in young patients.

With impaired renal function, the elimination half-life becomes prolonged only at doses exceeding 600 mg daily. Provided that hepatic excretory function is normal, the dosage in patients with impaired renal function does not need to be reduced below 600 mg daily. Rifampicin is eliminated by peritoneal or haemodialysis. Dosage adjustment is not necessary during dialysis. Because rifampicin is dialysable it is recommended that the drug should not be administered until after the period of dialysis is complete.

In patients with severe hepatic dysfunction the dosage may have to be adjusted as plasma concentrations are raised and half-life prolonged.

There is limited evidence as to the carcinogenic potential of rifampicin in animals. In female mice of a strain known to be susceptible to hepatomas, a significant increase in such tumours was observed after 1 year of treatment with rifampicin in quantities equivalent to 2-10 times the maximum clinical doses.

In mice of another strain treated for 1 year, and in rats treated for 2 years, no significant increase was noted in the incidence of any type of tumour. Studies with various mammalian models, as well as with bacteria, yielded no evidence that rifampicin has a mutagenic effect.

In daily doses of 150-250 mg/kg, rifampicin proved teratogenic in mice and rats, insofar as an increased occurrence of spina bifida and cleft palate was observed. In rabbits it had no teratogenic effect. In all three animal species, unspecific embryotoxic effects occurred after doses >150 mg/kg.