Gengraf

GENGRAF- cyclosporine capsule
AbbVie Inc.

WARNING

Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Gengraf ® Capsules (cyclosporine capsules, 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 ® Capsules (cyclosporine capsules, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune ® Soft Gelatin Capsules (cyclosporine capsules, USP). 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 P soriasis P atients (S ee also BOXED WARNING 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® Capsules (cyclosporine capsules, 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® Capsules (cyclosporine capsules, USP [MODIFIED ]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment.

Cyclosporine, the active principle in Gengraf® Capsules, 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 ® Capsules (cyclosporine capsules, USP [MODIFIED ]) are available in 25 mg and 100 mg strengths.

Each 25 mg capsule contains

cyclosporine, 25 mg, alcohol, USP, absolute, 12.8% v/v (10.1% wt/vol.).

Each 100 mg capsule contains

cyclosporine, 100 mg, alcohol, USP, absolute, 12.8% v/v (10.1% wt/vol.).

Inactive Ingredients

FD&C Blue No. 2, gelatin NF, polyethylene glycol USP, polyoxyl 35 castor oil NF, polysorbate 80 NF, propylene glycol USP, sorbitan monooleate NF, titanium dioxide.

The chemical structure for cyclosporine USP is:

The chemical structure for cyclosporine USP is
(click image for full-size original)

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 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.

The Gengraf® Capsules (cyclosporine capsules, USP [MODIFIED ]) and Gengraf® Oral Solution (cyclosporine oral solution, USP [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 (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 (MODIFIED) and 19% to 26% for Sandimmune®. In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for cyclosporine (MODIFIED) and 16% to 38% for Sandimmune®.

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