PURI-NETHOL Tablet Ref.[49828] Active ingredients: Mercaptopurine

Absorption

The bioavailability of oral mercaptopurine monohydrate shows considerable inter-individual variability. When administered at a dosage of 75 mg/m² to seven paediatric patients, the bioavailability averaged 16 % of the administered dose, with a range of 5 to 37%. The variable bioavailability probably results from the metabolism of a significant portion of mercaptopurine monohydrate during first-pass hepatic metabolism.

After oral administration of mercaptopurine monohydrate 75 mg/m² to 14 children with acute lymphoblastic leukaemia, the mean C_max was 0.89 μM, with a range of 0.29‑1.82 μM and T_max was 2.2 hours with a range of 0.5-4 hours.

The mean relative bioavailability of mercaptopurine monohydrate was approximately 26 % lower following administration with food and milk compared to an overnight fast. Mercaptopurine monohydrate is not stable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see Section 4.2 Posology and method of administration).

Distribution

Concentrations of mercaptopurine monohydrate in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration (CSF: plasma ratios of 0.05 to 0.27). Concentrations in the CSF are higher after intrathecal administration.

Biotransformation

Mercaptopurine monohydrate is extensively metabolized by many multi-step pathways to active and inactive metabolites. Because of the complex metabolism, inhibition of one enzyme does not explain all cases of lack of efficacy and/or pronounced myelosuppression. The predominant enzymes responsible for the metabolism of mercaptopurine monohydrate or its downstream metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate dehydrogenase (IMPDH) and hypoxanthine guanine phosphribosyltransferase (HPRT). Additional enzymes involved in the formation of active and inactive metabolites are: guanosine monophosphate synthetase (GMPS, which form TGNs) and inosine triphosphate pyrophosphatase (ITPase). There are also multiple inactive metabolites formed via other pathways.

There is evidence that polymorphisms in the genes encoding the different enzyme systems involved with metabolism of mercaptopurine monohydrate may predict adverse drug reactions to mercaptopurine monohydrate therapy. For example, individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations (see Section 4.4).

Elimination

In a study with 22 adult patients the mean mercaptopurine monohydrate clearance and half-life after IV infusion was 864 mL/min/m² and 0.9 hours respectively. The mean renal clearance reported in 16 of these patients was 191 mL/min/m². Only about 20% of the dose was excreted in the urine as intact medicinal product after IV administration. In a study with 7 children patients the mean mercaptopurine monohydrate clearance and half-life after IV infusion was 719 ( +/- 610) ml/min/m² and 0.9 ( +/- 0.3) hours respectively.

Special patient populations

Older population

No specific studies have been carried out in the elderly (see Section 4.2 Posology and method of administration).

Renal impairment

Studies with a pro-drug of mercaptopurine monohydrate have shown no difference in mercaptopurine monohydrate pharmacokinetics in uremic patients compared to renal transplant patients. Since little is known about the active metabolites of mercaptopurine monohydrate in renal impairment (see Section 4.2 Posology and method of administration). Mercaptopurine monohydrate and/or its metabolites are eliminated by haemodialysis, with approximately 45% of radioactive metabolites eliminated during dialysis of 8 hours.

Hepatic impairment

A study with a pro-drug of mercaptopurine monohydrate was performed in three groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that mercaptopurine monohydrate exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and 6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease (see Section 4.2 Posology and method of administration).

Carcinogenesis, mutagenesis

Mercaptopurine monohydrate, in common with other antimetabolites is potentially mutagenic in man and chromosome damage has been reported in mice and rats, and man. In view of its action on cellular deoxyribonucleic acid (DNA) mercaptopurine monohydrate is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis with this treatment.

Teratogenicity

Mercaptopurine monohydrate causes embryolethality and severe teratogenic effects in mice, rats, hamsters and rabbits at doses that are non-toxic to the mother. In all species, the degree of embryotoxicity and type of malformations is dependent on the dose and the stage of gestation at the time of administration.