Inactive Ingredients: Polyethylene glycol 400, polyoxyl 35 castor oil, and propylene glycol monolaurate. The capsule shell contains the following inactive ingredients: gelatin, glycerine, iron oxide black (25 mg and 100 mg capsules only) and titanium dioxide. The capsule imprinting ink contains hypromellose, iron oxide black, and propylene glycol.
Cyclosporine is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft versus host disease in many animal species for a variety of organs.
The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T- helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release, including interleukin-2.
No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.
Pharmacokinetics
The immunosuppressive activity of cyclosporine is primarily due to parent drug. Following oral administration, absorption of cyclosporine is incomplete. The extent of absorption of cyclosporine is dependent on the individual patient, the patient population, and the formulation. Elimination of cyclosporine is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of cyclosporine from blood is generally biphasic, with a terminal half-life of approximately 8.4 hours (range 5 to 18 hours). Following intravenous administration, the blood clearance of cyclosporine (assay: HPLC) is approximately 5 to 7 mL/min/kg in adult recipients of renal or liver allografts. Blood cyclosporine clearance appears to be slightly slower in cardiac transplant patients.
Cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED] are bioequivalent.
The relationship between administered dose and exposure (area under the concentration versus time curve, AUC) is linear within the therapeutic dose range. The intersubject variability (total, %CV) of cyclosporine exposure (AUC) when cyclosporine capsule (modified) or Sandimmune® is administered ranges from approximately 20% to 50% in renal transplant patients. This intersubject variability contributes to the need for individualization of the dosing regimen for optimal therapy (see DOSAGE AND ADMINISTRATION). Intrasubject variability of AUC in renal transplant recipients (%CV) was 9% to 21% for cyclosporine capsule (modified) and 19% to 26% for Sandimmune®. In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for cyclosporine capsule (modified) and 16% to 38% for Sandimmune®.
Absorption
Cyclosporine capsule (modified) has increased bioavailability compared to Sandimmune®. The absolute bioavailability of cyclosporine administered as Sandimmune® is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. The absolute bioavailability of cyclosporine administered as cyclosporine capsule (modified) has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC was approximately 20% to 50% greater and the peak blood cyclosporine concentration (Cmax) was approximately 40% to 106% greater following administration of cyclosporine capsule (modified) compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered cyclosporine capsule (modified) 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune®. AUC and Cmax are also increased (cyclosporine capsule (modified) relative to Sandimmune®) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on cyclosporine capsule (modified) relative to Sandimmune®, the predose trough concentrations (dose-normalized) are similar for the two formulations.
Following oral administration of cyclosporine capsule (modified), the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5 to 2 hours. The administration of food with cyclosporine capsule (modified) decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine capsule (modified) administration decreased the AUC by 13% and Cmax by 33%. The effects of a low-fat meal (667 kcal, 15 grams fat) were similar.
The effect of T-tube diversion of bile on the absorption of cyclosporine from cyclosporine capsule (modified) was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine capsule (modified) with and without T- tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9±41% (range 55% to 68%).
1Total daily dose was divided into two doses administered every 12 hours.
2AUC was measured over one dosing interval.
3Trough concentration was measured just prior to the morning cyclosporine capsule (modified) dose, approximately 12 hours after the previous dose.
4Assay: TDx specific monoclonal fluorescence polarization immunoassay.
5Assay: Cyclo-trac specific monoclonal radioimmunoassay.
6Assay: INCSTAR specific monoclonal radioimmunoassay.
Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 58% in erythrocytes. At high concentrations, the binding capacity of leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk (see PRECAUTIONS, Nursing Mothers).
Metabolism
Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the coadministration of a variety of agents (see PRECAUTIONS, Drug Interactions). At least 25 metabolites have been identified from human bile, feces, blood, and urine. The biological activity of the metabolites and their contributions to toxicity are considerably less than those of the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. At steady state following the oral administration of Sandimmune®, the mean AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5% of the AUC for blood cyclosporine concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered cyclosporine capsule (modified) and Sandimmune® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered cyclosporine capsule (modified), 3 administered Sandimmune®), the percentage of dose present as M1, M9, and M4N metabolites is similar when either cyclosporine capsule (modified) or Sandimmune® is administered.
Excretion
Only 0.1% of a cyclosporine dose is excreted unchanged in the urine. Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Neither dialysis nor renal failure alters cyclosporine clearance significantly.
Drug Interactions
(See PRECAUTIONS, Drug Interactions) When diclofenac or methotrexate was coadministered with cyclosporine in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased (see PRECAUTIONS, Drug Interactions). No clinically significant pharmacokinetic interactions occurred between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin.
In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate.
Hepatic Impairment
Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients.
Pediatric Population
Pharmacokinetic data from pediatric patients administered cyclosporine capsule (modified) or Sandimmune® are very limited. In 15 renal transplant patients aged 3 to 16 years, cyclosporine whole blood clearance after IV administration of Sandimmune® was 10.6±3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2 to 16, the cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 9 liver transplant patients aged 0.6 to 5.6 years, clearance was 9.3±5.4 mL/min/kg (assay: HPLC).
In the pediatric population, cyclosporine capsule (modified) also demonstrates an increased bioavailability as compared to Sandimmune®. In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of cyclosporine capsule (modified) was 43% (range 30% to 68%) and for Sandimmune® in the same individuals absolute bioavailability was 28% (range 17% to 42%).
1AUC was measured over one dosing interval
2Assay: Cyclo-trac specific monoclonal radioimmunoassay
3Assay: TDx specific monoclonal fluorescence polarization immunoassay
Comparison of single dose data from both normal elderly volunteers (N=18, mean age 69 years) and elderly rheumatoid arthritis patients (N=16, mean age 68 years) to single dose data in young adult volunteers (N=16, mean age 26 years) showed no significant difference in the pharmacokinetic parameters.