Cyclosporine

CYCLOSPORINE- cyclosporine capsule, liquid filled
Mayne Pharma Inc.

Revised: March 2021

Rx only

Prescribing Information

DESCRIPTION

Cyclosporine capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] are oral formulations of cyclosporine that immediately forms a microemulsion in an aqueous environment.

Cyclosporine, the active principle in cyclosporine capsules [MODIFIED] and cyclosporine oral solution, USP [MODIFIED], is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.

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).

Each soft gelatin cyclosporine capsule, USP  [Modified] for oral administration contains 25 mg or 100 mg of cyclosporine, USP. In addition, each capsule contains the following inactive ingredients: Caprylic/capric triglyceride, dl-alpha-tocopherol, gelatin, glycerin, glyceryl caprylate, PEG-8 caprylic/capric glycerides, PEG-35 castor oil, red iron oxide, shellac, sorbitol special 76% and titanium dioxide USP.

Cyclosporine oral solution, USP [MODIFIED] contains 100 mg/mL of cyclosporine, USP. Inactive ingredients: Caprylic/capric triglyceride, dl-alpha-tocopherol, glyceryl caprylate, PEG-8 caprylic/capric glycerides, PEG-35 castor oil.

The chemical structure of cyclosporine, USP (also known as cyclosporin A) is:

Chemical Structure

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.

Cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED] are bioequivalent. Cyclosporine oral solution [MODIFIED] diluted with orange juice or apple juice is bioequivalent to cyclosporine oral solution [MODIFIED] diluted with water. The effect of milk on the bioavailability of cyclosporine when administered as cyclosporine oral solution [MODIFIED] has not been evaluated.

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®1 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 [MODIFIED] and 19% to 26% for Sandimmune®1. In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for cyclosporine [MODIFIED] and 16% to 38% for Sandimmune®1.

Absorption

Cyclosporine [MODIFIED] has increased bioavailability compared to Sandimmune®1 (cyclosporine). The absolute bioavailability of cyclosporine administered as Sandimmune®1 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 (C_max ) was approximately 40% to 106% greater following administration of cyclosporine [MODIFIED] compared to following administration of Sandimmune®1. The dose normalized AUC in de novo liver transplant patients administered cyclosporine [MODIFIED] 28 days after transplantation was 50% greater and C_max was 90% greater than in those patients administered Sandimmune®1. AUC and C_max are also increased (cyclosporine [MODIFIED] relative to Sandimmune®1) in heart transplant patients, but data are very limited. Although the AUC and C_max values are higher on cyclosporine [MODIFIED] relative to Sandimmune®1, 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 (T_max ) ranged from 1.5 to 2 hours. The administration of food with cyclosporine [MODIFIED] decreases the cyclosporine AUC and C_max . A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine [MODIFIED] administration decreased the AUC by 13% and C_max 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)

Patient Population	Dose/day *(mg/d)	Dose/Weight(mg/kg/d)	AUC †(ng∙mL)	Cmax (ng/mL)	Trough ‡(ng/mL)	CL/F(mL/min)	CL/F(mL/min/kg)
* Total daily dose was divided into two doses administered every 12 hours † AUC was measured over one dosing interval ‡ Trough concentration was measured just prior to the morning cyclosporine [Modified] dose, approximately 12 hours after the previous dose § Assay: TDx specific monoclonal fluorescence polarization immunoassay ¶ # Assay: Cyclo-trac specific monoclonal radioimmunoassay Þ Assay: INCSTAR specific monoclonal radioimmunoassay
De novo renal transplant §Week 4 (N=37)	597± 174	7.95±2.81	8772±2089	1802±428	361±129	593±204	7.8±2.9
Stable renal transplant §¶ (N=55)	344±122	4.10±1.58	6035±2194	1333±469	251±116	492±140	5.9±2.1
De novo liver transplant # 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 arthritis Þ(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 psoriasis Þ 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