Sandimmune (Cyclosporine) - Description and Clinical Pharmacology

T2005-44

Sandimmune ^®   Soft Gelatin Capsules

(cyclosporine capsules, USP)

Sandimmune ^®   Oral Solution

(cyclosporine oral solution, USP)

Sandimmune ^®   Injection

(cyclosporine injection, USP)

FOR INFUSION ONLY

Rx only

Prescribing Information

DESCRIPTION

Cyclosporine, the active principle in Sandimmune^® (cyclosporine) 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).

Sandimmune ^® Soft Gelatin Capsules   (cyclosporine capsules, USP) are available in 25 mg and 100 mg strengths.

Each 25 mg capsule contains:

cyclosporine, USP……………………………………………………………………...25 mg

alcohol, USP dehydrated…………………………………………...max 12.7% by volume

Each 100 mg capsule contains:

cyclosporine, USP……………………………………………………..……………...100 mg

alcohol, USP dehydrated…………………………………………...max 12.7% by volume

Inactive Ingredients: corn oil, gelatin, glycerol, Labrafil M 2125 CS (polyoxyethylated glycolysed glycerides), red iron oxide (25 mg and 100 mg capsule only), sorbitol, titanium dioxide, and other ingredients.

Sandimmune ^® Oral Solution   (cyclosporine oral solution, USP) is available in 50 mL bottles.

Each mL contains:

cyclosporine, USP……………………………………………………………………...100 mg

alcohol, Ph. Helv. …………………………………………………………..12.5% by volume

dissolved in an olive oil, Ph. Helv./Labrafil M 1944 CS (polyoxyethylated oleic glycerides) vehicle which must be further diluted with milk, chocolate milk, or orange juice before oral administration.

Sandimmune ^® Injection   (cyclosporine injection, USP) is available in a 5 mL sterile ampul for I.V. administration.

Each mL contains:

cyclosporine, USP……………………………………………………………………...50 mg

*Cremophor^® EL(polyoxyethylated castor oil) …………………………………….650 mg

alcohol, Ph. Helv..………………………………………………………..32.9% by volume

nitrogen…………………………………………………………………….........................qs

which must be diluted further with 0.9% Sodium Chloride Injection or 5% Dextrose Injection before use.

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

CLINICAL PHARMACOLOGY

Sandimmune^® (cyclosporine) is a potent immunosuppressive agent which in animals prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine, and lung. Sandimmune^® (cyclosporine) has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated 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.

      Successful kidney, liver, and heart allogeneic transplants have been performed in man using Sandimmune^® (cyclosporine).

      The exact mechanism of action of Sandimmune^® (cyclosporine) is not known. Experimental evidence suggests that the effectiveness of cyclosporine is due to specific and reversible inhibition of immunocompetent lymphocytes in the G₀- or 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. Sandimmune^® (cyclosporine) also inhibits lymphokine production and release including interleukin-2 or T-cell growth factor (TCGF).

      No functional effects on phagocytic (changes in enzyme secretions not altered, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) or tumor cells (growth rate, metastasis) can be detected in animals. Sandimmune^® (cyclosporine) does not cause bone marrow suppression in animal models or man.

      The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Peak concentrations (C_max) in blood and plasma are achieved at about 3.5 hours. C_max and area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood, the relationship is curvilinear (parabolic) between 0 and 1400 mg. As determined by a specific assay, C_max is approximately 1.0 ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood (for low to high doses). Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients. The bioavailability of Sandimmune^® Soft Gelatin Capsules (cyclosporine capsules, USP) is equivalent to Sandimmune^® Oral Solution, (cyclosporine oral solution, USP).

      Cyclosporine is distributed largely outside the blood volume. 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 uptake by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins.

      The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 hours (range: 10-27 hours). Elimination is primarily biliary with only 6% of the dose excreted in the urine.

      Cyclosporine is extensively metabolized but there is no major metabolic pathway. Only 0.1% of the dose is excreted in the urine as unchanged drug. Of 15 metabolites characterized in human urine, 9 have been assigned structures. The major pathways consist of hydroxylation of the Cγ-carbon of 2 of the leucine residues, Cη-carbon hydroxylation, and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl- N,4-dimethyl-L-2-amino-6-octenoic acid and N -demethylation of N -methyl leucine residues. Hydrolysis of the cyclic peptide chain or conjugation of the aforementioned metabolites do not appear to be important biotransformation pathways.