NEORAL Oral solution Ref.[6694] Active ingredients: Ciclosporin

Absorption

Following oral administration of Neoral peak blood concentrations of ciclosporin are reached within 1-2 hours. The absolute oral bioavailability of ciclosporin following administration of Neoral is 20 to 50%. About 13 and 33% decrease in AUC and C_max was observed when Neoral was administered with a high-fat meal. The relationship between administered dose and exposure (AUC) of ciclosporin is linear within the therapeutic dose range. The intersubject and intrasubject variability for AUC and C_max is approximately 10-20%. Neoral Oral Solution and Soft Gelatin Capsules are bioequivalent.

Neoral administration results in a 59% higher C_max and approximately 29% higher bioavailability than Sandimmun. The available data indicate that following a 1:1 switch from Sandimmun Soft Gelatin Capsules to Neoral Soft Gelatin Capsules trough concentrations in whole blood are comparable and remain in the desired therapeutic range. Neoral administration improves dose linearity in ciclosporin exposure (AUCB). It provides a more consistent absorption profile with less influence from concomitant food intake or from diurnal rhythm than Sandimmun.

Distribution

Ciclosporin is distributed largely outside the blood volume, with an average apparent distribution volume of 3.5 l/kg. In the blood, 33 to 47% is present in plasma, 4 to 9% in lymphocytes, 5 to 12% in granulocytes, and 41 to 58% in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.

Biotransformation

Ciclosporin is extensively metabolised to approximately 15 metabolites. Metabolism mainly takes place in the liver via cytochrome P450 3A4 (CYP3A4), and the main pathways of metabolism consist of mono- and dihydroxylation and N-demethylation at various positions of the molecule. All metabolites identified so far contain the intact peptide structure of the parent compound; some possess weak immunosuppressive activity (up to one-tenth that of the unchanged drug).

Elimination

The excretion is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1% is excreted in the urine as unchanged parent compound.

There is a high variability in the data reported on the terminal half-life of ciclosporin depending on the assay applied and on the target population. The terminal half-life ranged from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease (see sections 4.2 and 4.4). The elimination half-life in kidney-transplanted patients was approximately 11 hours, with a range between 4 and 25 hours.

Special populations

Patients with renal impairment

In a study performed in patients with terminal renal failure, the systemic clearance was approximately two thirds of the mean systemic clearance in patients with normally functioning kidneys. Less than 1% of the administered dose is removed by dialysis.

Patients with hepatic impairment

An approximate 2- to 3-fold increase in ciclosporin exposure may be observed in patients with hepatic impairment. In a study performed in severe liver disease patients with biopsy-proven cirrhosis, the terminal half-life was 20.4 hours (range between 10.8 to 48.0 hours) compared to 7.4 to 11.0 hours in healthy subjects.

Paediatric population

Pharmacokinetic data from paediatric patients given Neoral or Sandimmun are very limited. In 15 renal transplant patients aged 3-16 years, ciclosporin whole blood clearance after intravenous administration of Sandimmun was 10.6±3.7 ml/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2-16 years, the ciclosporin clearance ranged from 9.8 to15.5 ml/min/kg. In 9 liver transplant patients aged 0.65-6 years, clearance was 9.3±5.4 ml/min/kg (assay: HPLC). In comparison to adult transplant populations, the differences in bioavailability between Neoral and Sandimmun in paediatrics are comparable to those observed in adults.

Ciclosporin gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg/day and rabbits up to 30 mg/kg/day orally). At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day orally), ciclosporin was embryo- and foetotoxic as indicated by increased prenatal and postnatal mortality, and reduced foetal weight together with related skeletal retardations.

In two published research studies, rabbits exposed to ciclosporin in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension, and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of ciclosporin intravenously (twice the recommended human intravenous dose) had foetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown. No impairment in fertility was demonstrated in studies in male and female rats.

Ciclosporin was tested in a number of in vitro and in vivo tests for genotoxicity with no evidence for a clincally relevant mutagenic potential.

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate at the low dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.