Cyclosporine

INDICATIONS AND USAGE Kidney, Liver, and Heart Transplantation Cyclosporine capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] are indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] have been used in combination with azathioprine and corticosteroids. Rheumatoid Arthritis Cyclosporine capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] are indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Cyclosporine capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone. Psoriasis Cyclosporine capsules, USP [MODIFIED] and cyclosporine oral solution, USP [MODIFIED] are indicated for the treatment of adult, nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated. While rebound rarely occurs, most patients will experience relapse with cyclosporine, USP [MODIFIED] as with other therapies upon cessation of treatment.

DOSAGE AND ADMINISTRATION Cyclosporine Capsules [Modified] (Soft Gelatin) and CYCLOSPORINE ORAL SOLUTION [MODIFIED] Cyclosporine capsules [MODIFIED] and cyclosporine oral solution [MODIFIED] have increased bioavailability in comparison to Sandimmune® (cyclosporine capsules and cyclosporine oral solution). Cyclosporine [MODIFIED] and Sandimmune® are not bioequivalent and cannot be used interchangeably without physician supervision. The daily dose of cyclosporine [MODIFIED] should always be given in two divided doses (b.i.d.). It is recommended that cyclosporine [MODIFIED] be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided. Specific Populations Renal Impairment in Kidney, Liver and Heart Transplantation Cyclosporine undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments ( See CLINICAL PHARMACOLOGY ). However, due to its nephrotoxic potential ( See WARNINGS ), careful monitoring of renal function is recommended; cyclosporine dosage should be reduced if indicated. ( See WARNINGS and PRECAUTIONS ) Renal Impairment in Rheumatoid Arthritis and Psoriasis Patients with impaired renal function should not receive cyclosporine. ( see CONTRAINDICATIONS , WARNINGS and PRECAUTIONS ) Hepatic Impairment The clearance of cyclosporine may be significantly reduced in severe liver disease patients ( See CLINICAL PHARMACOLOGY ). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range. ( See WARNINGS and PRECAUTIONS ) Newly Transplanted Patients The initial oral dose of cyclosporine [MODIFIED] can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of cyclosporine [MODIFIED] varies depending on the transplanted organ and the other immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients, the initial oral dose of cyclosporine [MODIFIED] is the same as the initial oral dose of Sandimmune®. Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune® in U.S. transplant centers. The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4 mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The cyclosporine [MODIFIED] dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration. ( See Blood Concentration Monitoring in Transplant Patients , below ) If cyclosporine trough blood concentrations are used, the target range is the same for cyclosporine [MODIFIED] as for Sandimmune®. Using the same trough concentration target range for cyclosporine [MODIFIED] as for Sandimmune® results in greater cyclosporine exposure when cyclosporine [MODIFIED] is administered. ( See Pharmacokinetics, Absorption ) Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower cyclosporine [MODIFIED] doses may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the patient's weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical situation. Conversion from …

CONTRAINDICATIONS General Cyclosporine capsules, USP MODIFIED are contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation. Rheumatoid Arthritis Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine capsules, USP MODIFIED. Psoriasis Psoriasis patients who are treated with cyclosporine capsules, USP MODIFIED should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine capsules, USP MODIFIED.

ADVERSE REACTIONS Kidney, Liver, and Heart Transplantation The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. Hypertension Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients. Glomerular Capillary Thrombosis Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resembled those seen in the hemolytic-uremic syndrome and included thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed post-transplantation. Hypomagnesemia Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity. Clinical Studies In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with cyclosporine capsules, USP MODIFIED were comparable with those observed in 208 transplanted patients who received Sandimmune (cyclosporine capsules, USP) in these same studies when the dosage of the two drugs was adjusted to achieve the same cyclosporine blood trough concentrations. Based on the historical experience with Sandimmune (cyclosporine capsules, USP), the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants. Randomized Kidney Patients Cyclosporine Patients (Sandimmune (cyclosporine capsules, USP)) Body System Adverse Reactions Sandimmune (cyclosporine capsules, USP) (N = 227)% Azathioprine (N = 228)% Kidney (N = 705)% Heart (N = 112)% Liver (N = 75)% Genitourinary Renal Dysfunction 32 6 25 38 37 Cardiovascular Hypertension 26 18 13 53 27 Cramps 4 750 mg/dL) occur in about 15% of psoriasis patients; elevations of cholesterol (> 300 mg/dL) are observed in less than 3% of psoriasis patients. Generally these laboratory abnormalities are reversible upon dose reduction or discontinuation of cyclosporine. Postmarketing Experience, Psoriasis Cases of transformation to erythrodermic psoriasis or generalized pustular psoriasis upon either withdrawal or reduction of cyclosporine in patients with chronic plaque psoriasis have been reported. To report SUSPECTED ADVERSE EVENTS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

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. Specific Populations Renal Impairment 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 capsules (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 capsules (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 capsules (modified) was 43% (range 30% to 68%) and for Sandimmune ® in the same individuals absolute bioavailability was 28% (range 17% to 42%). Pediatric Pharmacokinetic Parameters (mean ± SD) Dose/day Dose/weight AUC 1 C max CL/F CL/F Patient Population (mg/d) (mg/kg/d) (ng·hr/mL) (ng/mL) (mL/min) (mL/min/kg) Stable liver transplant 2 Age 2 to 8, Dosed TID (N = 9) 101 ± 25 5.95 ± 1.32 2163 ± 801 629 ± 219 285 ± 94 16.6 ± 4.3 Age 8 to 15, Dosed BID (N = 8) 188 ± 55 4.96 ± 2.09 4272 ± 1462 975 ± 281 378 ± 80 10.2 ± 4.0 Stable liver transplant 3 Age 3, Dosed BID (N = 1) 120 8.33 5832 1050 171 11.9 Age 8 to 15, Dosed BID (N = 5) 158 ± 55 5.51 ± 1.91 4452 ± 2475 1013 ± 635 328 ± 121 11.0 ± 1.9 Stable renal transplant 3 Age 7 to 15, Dosed BID (N = 5) 328 ± 83 7.37 ± 4.11 6922 ± 1988 1827 ± 487 418 ± 143 8.7 ± 2.9 1 AUC was measured over one dosing interval. 2 Assay: Cyclo-trac specific monoclonal radioimmunoassay. 3 Assay: TDx specific monoclonal fluorescence polarization immunoassay.

Drug Interactions A. Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of NSAIDs with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function (see WARNINGS, Nephrotoxicity ). Drugs That May Potentiate Renal Dysfunction Antibiotics Antineoplastics Antifungals Anti-inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs ciprofloxacin melphalan amphotericin B azapropazon cimetidine tacrolimus fibric acid derivatives gentamicin ketoconazole colchicine ranitidine (e.g., bezafibrate, fenofibrate) tobramycin diclofen …

Specific Populations Renal Impairment 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 capsules, USP MODIFIED or Sandimmune (cyclosporine capsules, USP) are very limited. In 15 renal transplant patients aged 3 to 16 years, cyclosporine whole blood clearance after IV administration of Sandimmune (cyclosporine capsules, USP) 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 capsules, USP MODIFIED also demonstrate an increased bioavailability as compared to Sandimmune (cyclosporine capsules, USP). In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of cyclosporine capsules, USP MODIFIED was 43% (range 30% to 68%) and for Sandimmune (cyclosporine capsules, USP) in the same individuals absolute bioavailability was 28% (range 17% to 42%). Pediatric Pharmacokinetic Parameters (mean ± SD) Patient Population Dose/day (mg/d) Dose/weight (mg/kg/d) AUC 1 (ng•hr/mL) C max (ng/mL) CL/F (mL/min) CL/F (mL/min/kg) Stable liver transplant 2 Age 2 to 8, Dosed TID (N = 9) 101 ± 25 5.95 ± 1.32 2163 ± 801 629 ± 219 285 ± 94 16.6 ± 4.3 Age 8 to 15, Dosed BID (N = 8) 188 ± 55 4.96 ± 2.09 4272 ± 1462 975 ± 281 378 ± 80 10.2 ± 4.0 Stable liver transplant 3 Age 3, Dosed BID (N = 1) 120 8.33 5832 1050 171 11.9 Age 8 to 15, Dosed BID (N = 5) 158 ± 55 5.51 ± 1.91 4452 ± 2475 1013 ± 635 328 ± 121 11.0 ± 1.9 Stable renal transplant 3 Age 7 to 15, Dosed BID (N = 5) 328 ± 83 7.37 ± 4.11 6922 ± 1988 1827 ± 487 418 ± 143 8.7 ± 2.9 1 AUC was measured over one dosing interval. 2 Assay: Cyclo-trac specific monoclonal radioimmunoassay. 3 Assay: TDx specific monoclonal fluorescence polarization immunoassay. Geriatric Population 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.

DESCRIPTION Cyclosporine capsules, USP (modified) is an oral formulation of cyclosporine that immediately forms a microemulsion in an aqueous environment. Cyclosporine, USP the active principle in cyclosporine capsules, 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, USP 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). Cyclosporine capsules, USP (modified) (Soft Gelatin Capsules) are available in 25 mg, 50 mg and 100 mg strengths. Each 25 mg capsule contains: Cyclosporine, USP..........................................................................................25 mg Dehydrated alcohol................................................. (9.5% w/v or 12.0% v/v) Each 50 mg capsule contains: Cyclosporine, USP..........................................................................................50 mg Dehydrated alcohol................................................... (9.5% w/v or 12.0% v/v) Each 100 mg capsule contains: Cyclosporine, USP.......................................................................................100 mg Dehydrated alcohol.................................................. (9.5% w/v or 12.0% v/v) Inactive Ingredients: gelatin, glycerin, propylene glycol, titanium dioxide, ferric oxide black [25 mg and 100 mg], glyceryl monolinoleate, polyoxyl 40 hydrogenated castor oil, all-rac-alpha tocopherol [vitamin E synthetic], Ink contains- ammonium hydroxide 28%, iron oxide red, polyethylene glycol, polyvinyl acetate phthalate, propylene glycol. The chemical structure of cyclosporine (also known as cyclosporin A) is: Chemical structure

OVERDOSAGE There is a minimal experience with cyclosporine overdosage. Forced emesis and gastric lavage can be of value up to 2 hours after administration of cyclosporine capsules, USP MODIFIED. Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. Oral doses of cyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Cyclosporine is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral dosage at which half of experimental animals are estimated to die is 31 times, 39 times, and > 54 times the human maintenance dose for transplant patients (6 mg/kg; corrections based on body surface area) in mice, rats, and rabbits.

HOW SUPPLIED Cyclosporine capsules, USP MODIFIED are available as follows: 25 mg: yellow soft gelatin (oval 5) capsules, filled with yellowish to yellow-brown oily liquid, printed “Ivax hourglass logo” and “25 mg”, containing 25 mg cyclosporine, USP MODIFIED and 15.8% v/v (12.4% wt./vol) dehydrated alcohol USP, packaged in unit-dose cartons of 30 capsules (NDC 0093-9018-65). 50 mg: ochre-yellow soft gelatin (oblong 11) capsules, filled with yellowish to yellow-brown oily liquid, printed “Ivax hourglass logo” and “50 mg”, containing 50 mg cyclosporine, USP MODIFIED and 15.8% v/v (12.4% wt./vol) dehydrated alcohol USP, packaged in unit-dose cartons of 30 capsules (NDC 0093-9019-65). 100 mg: brown soft gelatin (oblong 20) capsules, filled with yellowish to yellow-brown oily liquid, printed “Ivax hourglass logo” and “100 mg”, containing 100 mg cyclosporine, USP MODIFIED and 15.8% v/v (12.4% wt./vol) dehydrated alcohol USP, packaged in unit-dose cartons of 30 capsules (NDC 0093-9020-65). Store and Dispense PHARMACIST: Dispense in original unit-dose container. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Keep this and all medications out of the reach of children. Brands listed are the trademarks of their respective owners. Manufactured In Czech Republic By: Teva Czech Industries s.r.o. Opava-Komarov, Czech Republic Manufactured For: Teva Pharmaceuticals Parsippany, NJ 07054 Rev. M 4/2024