WARNING

Only physicians experienced in the management of systemic immunosuppressive therapy for the indicated disease should prescribe Gengraf (cyclosporine oral solution, USP [MODIFIED]). At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Gengraf. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Gengraf, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Gengraf may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients.

Gengraf (cyclosporine oral solution, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune®* (cyclosporine oral solution, USP [Non-Modified]). Gengraf and Sandimmune* are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Gengraf than with Sandimmune*. If a patient who is receiving exceptionally high doses of Sandimmune* is converted to Gengraf, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Gengraf to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed.

For Psoriasis Patients (see also Boxed WARNINGS above)
Psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking Gengraf (cyclosporine oral solution, USP [MODIFIED]).

Cyclosporine, the active ingredient in Gengraf, in recommended dosages, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.

DESCRIPTION

Gengraf (cyclosporine oral solution, USP [MODIFIED]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment.

Cyclosporine, the active principle in Gengraf Oral Solution, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Aphanocladium album.

Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic-(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N- methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α-amino-butyryl-N-methylglycyl-N -methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).

Gengraf Oral Solution (cyclosporine oral solution, USP [MODIFIED]) is available in 50 mL bottles. Each mL contains: cyclosporine 100 mg/mL.

Inactive Ingredients

Polyoxyl 40 hydrogenated castor oil NF, propylene glycol USP, sorbitan monooleate NF.

The chemical structure for cyclosporine USP is:

Chemical structure for cyclosporine USP.

CLINICAL PHARMACOLOGY

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 vs. 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.

The Gengraf Capsules (cyclosporine capsules, USP [MODIFIED]) and Gengraf Oral Solution (cyclosporine oral solution, USP [MODIFIED]) are bioequivalent. Gengraf Oral Solution diluted with orange juice or with apple juice is bioequivalent to Gengraf Oral Solution diluted with water. The effect of milk on the bioavailability of cyclosporine when administered as Gengraf Oral Solution has not been eva luated.

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 (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%-21% for cyclosporine (MODIFIED) and 19%-26% for Sandimmune®. In the same studies, intrasubject variability of trough concentrations (% CV) was 17%-30% for cyclosporine (MODIFIED) and 16%-38% for Sandimmune®.

Absorption

Cyclosporine (MODIFIED) has increased bioavailability compared to Sandimmune®. The absolute bioavailability of cyclosporine administered as Sandimmune (cyclosporine) 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 (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 (MODIFIED) compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered cyclosporine (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 [MODIFIED] relative to Sandimmune®) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on cyclosporine (MODIFIED) relative to Sandimmune®, the pre-dose trough concentrations (dose-normalized) are similar for the two formulations.

Following oral administration of cyclosporine (MODIFIED), the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine (MODIFIED) decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine (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 (MODIFIED) was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine (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%).

Pharmacokinetic Parameters (mean±SD)
1 Total daily dose was divided into two doses administered every 12 hours. 2 AUC was measured over one dosing interval. 3 Trough concentration was measured just prior to the morning cyclosporine (MODIFIED) dose, approximately 12 hours after the previous dose. 4 Assay: TDx specific monoclonal fluorescence polarization immunoassay. 5 Assay: Cyclo-trac specific monoclonal radioimmunoassay. 6 Assay: INCSTAR specific monoclonal radioimmunoassay.
Patient Population	Dose/day1 (mg/d)	Dose/ weight (mg/kg/d)	AUC2 (ng·hr/mL)	Cmax (ng/mL)	Trough3 (ng/mL)	CL/F (mL/min)	CL/F (mL/min/kg)
De novo renal transplant4 Week 4 (N = 37)	597 ± 174	7.95 ± 2.81	8772 ± 2089	1802 ± 428	361 ± 129	593 ± 204	7.8 ± 2.9
Stable renal transplant4 (N = 55)	344 ± 122	4.10 ± 1.58	6035 ± 2194	1333 ± 469	251 ± 116	492 ± 140	5.9 ± 2.1
De novo liver transplant5 Week 4 (N = 18)	458 ± 190	6.89 ± 3.68	7187 ± 2816	1555 ± 740	268 ± 101	577 ± 309	8.6 ± 5.7
De novo rheumatoid arthritis6 (N = 23)	182 ± 55.6	2.37 ± 0.36	2641 ± 877	728 ± 263	96.4 ± 37.7	613 ± 196	8.3 ± 2.8
De novo psoriasis6 Week 4 (N = 18)	189 ± 69.8	2.48 ± 0.65	2324 ± 1048	655 ± 186	74.9 ± 46.7	723 ± 186	10.2 ± 3.9

Distribution

Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3-5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-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 III-A 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 [MODIFIED] and Sandimmune® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered cyclosporine (MODIFIED), 3 administered Sandimmune®), the percentage of dose present as M1, M9, and M4N metabolites is similar when either cyclosporine (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 alter 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.

Special Populations

Pediatric Population

Pharmacokinetic data from pediatric patients administered cyclosporine (MODIFIED) or Sandimmune® are very limited. In 15 renal transplant patients aged 3-16 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 2-16, 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 (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 (MODIFIED) was 43% (range 30% to 68%) and for Sandimmune® in the same individuals absolute bioavailability was 28% (range 17% to 42%).