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ATC code: L04AD01.
Pharmacology: Mechanism of action/Pharmacodynamics: Ciclosporin is a cyclic polypeptide consisting of eleven amino acids. It is a highly effective immunosuppressive agent that has been shown in animal studies to prolong skin, heart, kidney, pancreas, bone marrow, small intestine and lung allograft survival. Studies show that ciclosporin inhibits both the development of cell-mediated reactions - including allograft immunity, delayed cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, graft-versus-host disease (GVHD) and T-cell-dependent antibody production - and the production and release of lymphokines, including interleukin-2 (T-cell growth factor, TCGF).
There is evidence that ciclosporin blocks the resting lymphocytes in the G0 or early G1 phase of the cell cycle and inhibits lymphokine release by activated T cells in response to antigen contact.
All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not depress haemopoiesis or affect phagocyte function. Transplant patients treated with ciclosporin are thus less prone to infection than those receiving other immunosuppressive therapy.
Sandimmun/Sandimmun Neoral has been used successfully in the prevention and management of graft rejection and GVHD in humans undergoing organ and bone marrow transplantation.
Ciclosporin has been used successfully both in hepatitis C-positive and hepatitis C-negative transplant recipients.
Beneficial effects have also been seen in a number of conditions known or assumed to be of autoimmune origin.
Sandimmun Neoral: Sandimmun Neoral is a microemulsion preconcentrate; the actual microemulsion, which is formed as soon as the solution comes into contact with water (in the form of a drink or gastric fluid), reduces variability in pharmacokinetic parameters and achieves dose linearity in ciclosporin exposure.
Pharmacokinetics: Sandimmun Neoral: Sandimmun Neoral displays linearity between dose and ciclosporin exposure (AUC) over the whole clinical dose range, a low level of dependence on the bile and a constant absorption profile and is only negligibly affected by concomitant food intake or diurnal rhythm. As a result of these properties, intraindividual pharmacokinetic variability is low (between 10% and 22% in renal transplant patients), correlation between trough blood levels and total ciclosporin exposure (AUC) is high and ingestion can take place independently of food intake.
Results from various studies have shown that monitoring of the AUC for ciclosporin during the first 4 hours following administration of the dose (AUC0-4) allows more accurate prediction of Sandimmun Neoral exposure than does the monitoring of this parameter at the time of administration of the dose (C0 monitoring).
The results of other studies show that in transplant patients, one-time monitoring 2 hours after dose administration (C2 monitoring) correlates well with AUC0-4.
Sandimmun Neoral soft gelatin capsules and Sandimmun Neoral oral solution are bioequivalent.
Absorption: Ciclosporin is rapidly absorbed (tmax = 1-2 hours) following administration of Sandimmun Neoral to organ transplant patients. Absolute bioavailability is 30-60%. In stable renal transplant recipients, mean Cmax and AUC at steady state (dosage standardised to 100 mg/day) are 793 ng/ml and 2,741 hours x ng/ml, respectively.
Sandimmun/Sandimmun Neoral: Distribution: Ciclosporin is distributed largely in the extravascular space, with a mean apparent distribution volume of 3.5 litres/kg. In the blood, distribution depends on the active substance concentration: 33 to 47% is found in plasma, 4 to 9% in lymphocytes, 5 to 12% in granulocytes and 41 to 58% in erythrocytes. At high concentrations leukocyte and erythrocyte uptake is saturated. In plasma, approx. 90% of ciclosporin is bound to proteins, mostly lipoproteins.
Metabolism: Ciclosporin is extensively metabolised, the main site of metabolism being the cytochrome P450 (CYP450 3A4)-dependent monooxygenase system. Over 15 metabolites are known thus far. Metabolites primarily arise from monohydroxylation, dihydroxylation and N-demethylation at various molecular sites. Medicines that affect the cytochrome P450 (CYP450 3A4)-dependent enzyme system have been found to increase or reduce ciclosporin levels (see Interactions). All metabolites identified so far contain the intact peptide structure of the unchanged drug. Some possess a slight immunosuppressive action (up to 10% of that of ciclosporin).
Elimination: Figures for the terminal elimination half-life of ciclosporin vary considerably, depending on the method of determination used and the subjects involved. They range from 6.3 hours in healthy volunteers to 7 to 16 hours in renal transplant patients and 20.4 hours in patients with severe liver disease. Elimination is primarily biliary. Only 6% of an oral dose is excreted in the urine and less than 1% as unchanged drug.
Pharmacokinetics in special populations: Elderly patients: No data are available on the absorption of Sandimmun Neoral in elderly patients. However, distribution of ciclosporin is no different in elderly patients than in middle-aged patients.
Children: On average, elimination of ciclosporin is somewhat more rapid in children than in adults. Higher dosages (relative to body weight) may therefore be necessary to obtain the same blood levels.
Renal impairment: Renal impairment has no clinically-relevant effect on pharmacokinetics, as ciclosporin is eliminated primarily via the bile.
Hepatic impairment: Hepatic impairment slows down elimination of ciclosporin. Close monitoring of serum creatinine and blood ciclosporin levels, with corresponding dosage adjustment, is therefore necessary in patients with severe hepatic dysfunction.
Sandimmun Neoral: Nephrotic syndrome: Oral administration to patients with nephrotic syndrome does not result in pharmacokinetic data deviating from the reference values. Dose adjustment is thus not necessary.
Toxicology: Preclinical data: Ciclosporin showed no mutagenic or teratogenic effects in the standard test systems with oral administration (oral daily doses of up to 17 mg/kg in rats and up to 30 mg/kg in rabbits). However, it was embryotoxic and fetotoxic at maternally toxic doses (100 mg/kg/day in rabbits and 30 mg/kg/day in rats), as indicated by increased prenatal and postnatal mortality and reduced birth weight together with delayed growth.
In two published studies, exposure to ciclosporin in utero (10 mg/kg/day) was associated with reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency in rabbits up to 35 weeks of age.
Pregnant rats given i.v. ciclosporin doses of 12 mg/kg/day (twice the recommended human i.v. dosage) had fetuses with an increased incidence of ventricular septal defects.
These findings have not been demonstrated in other species and their relevance to humans is unclear.
Carcinogenicity studies were carried out in male and female rats and mice. In a 78-week study in mice given doses of 1, 4 and 16 mg/kg per day, there was evidence of a statistically-significant trend towards the formation of lymphocytic lymphomas in females and the incidence of hepatocellular carcinomas in males given doses in the middle dosage range significantly exceeded the control value.
In a 24-month study in rats given doses of 0.5, 2 and 8 mg/kg per day, the incidence of pancreatic islet cell adenomas significantly exceeded that of controls given low dosages. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose-related.
Doses of up to 5 mg/kg/day did not impair fertility in either male or female rats.
An increased incidence of malignancy is a recognised complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin (see Precautions for information regarding the risk of developing lymphomas and other malignancies). The risk of malignancies during ciclosporin treatment is higher than in the normal, healthy population, but similar to that in patients receiving other immunosuppressive therapies. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.
