Cyclosporine

INDICATIONS AND USAGE Cyclosporine capsules, (NON-MODIFIED) are indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. It is always to be used with adrenal corticosteroids. The drug may also be used in the treatment of chronic rejection in patients previously treated with other immunosuppressive agents.

DOSAGE AND ADMINISTRATION Recommended Dosage for Cyclosporine capsules, (NON-MODIFIED) Cyclosporine capsules, (NON-MODIFIED) 25 mg and 100 mg and Neoral (cyclosporine capsules), MODIFIED 25 mg and 100 mg are not mutually substitutable on a mg-to-mg basis due to differences in pharmacokinetic profiles. If it is appropriate to switch from Neoral capsules, MODIFIED, to cyclosporine capsules, (NON-MODIFIED), increase the frequency of cyclosporine monitoring (the cyclosporine dosage may need to be increased to reach the desired cyclosporine exposure and reduce the risk of insufficient efficacy). If it is appropriate to switch from cyclosporine capsules, (NON-MODIFIED) to Neoral capsules, increase the frequency of cyclosporine monitoring (the cyclosporine dosage may need to be decreased to reach the desired cyclosporine exposure and reduce the risk of cyclosporine-related adverse reactions). The initial oral dose of cyclosporine capsules, (NON-MODIFIED) should be given 4 to 12 hours prior to transplantation as a single dose of 15 mg/kg. Although a daily single dose of 14 to 18 mg/kg was used in most clinical trials, few centers continue to use the highest dose, most favoring the lower end of the scale. There is a trend towards use of even lower initial doses for renal transplantation in the ranges of 10 to 14 mg/kg/day. The initial single daily dose is continued postoperatively for 1 to 2 weeks and then tapered by 5% per week to a maintenance dose of 5 to 10 mg/kg/day. Some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate. See Blood Concentration Monitoring , below. Recommended Dosage of the Cyclosporine Capsules in Patients with Renal Impairment 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 ) . Recommended Dosage of the Cyclosporine Capsules in Patients with 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 ) . R ecommended Dosage of the Cyclosporine Capsules in Pediatric Patients In pediatric usage, the same dose and dosing regimen may be used as in adults although in several studies, children have required and tolerated higher doses than those used in adults. Adjunct therapy with adrenal corticosteroids is recommended. Different tapering dosage schedules of prednisone appear to achieve similar results. A 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. Another center started with an initial dose of 200 mg tapered by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further reduction to 10 mg/day was made. Adjustments in dosage of prednisone must be made according to the clinical situation. Cyclosporine capsules should be administered on a consistent schedule with regard to time of day and relation to meals. Blood Cyclosporine Concentration Monitoring Several study centers have found blood concentration monitoring of cyclosporine useful in patient management. While no fixed relationships have yet been established, in one series of 375 consecutive cadaveric renal transplant recipients, dosage was adjusted to achieve specific whole blood 24-hour trough concentrations of 100 to 200 …

CONTRAINDICATIONS Cyclosporine capsules are contraindicated in patients with a hypersensitivity reaction to cyclosporine or to any of the ingredients of the formulation.

ADVERSE REACTIONS The principal adverse reactions of cyclosporine capsules 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 resemble those seen in the hemolytic-uremic syndrome and include 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. Adverse Reactions in Clinical Studies The following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants: Randomized Kidney Patients All Cyclosporine-Treated Patients Cyclosporine capsules Azathioprine Kidney Heart Liver Body System/ (N=227) (N=228) (N=705) (N=112) (N=75) Adverse Reactions % % % % % Genitourinary Renal Dysfunction 32 6 25 38 37 Cardiovascular Hypertension 26 18 13 53 27 Cramps 4 < 1 2 < 1 0 Skin Hirsutism 21 < 1 21 28 45 Acne 6 8 2 2 1 Central Nervous System Tremor 12 0 21 31 55 Convulsions 3 1 1 4 5 Headache 2 < 1 2 15 4 Gastrointestinal Gum Hyperplasia 4 0 9 5 16 Diarrhea 3 < 1 3 4 8 Nausea/Vomiting 2 < 1 4 10 4 Hepatotoxicity < 1 < 1 4 7 4 Abdominal Discomfort < 1 0 < 1 7 0 Autonomic Nervous System Paresthesia 3 0 1 2 1 Flushing < 1 0 4 0 4 Hematopoietic Leukopenia 2 19 < 1 6 0 Lymphoma < 1 0 1 6 1 Respiratory Sinusitis < 1 0 4 3 7 Miscellaneous Gynecomastia < 1 0 < 1 4 3 The following reactions occurred in 2% or less of patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus. The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss. Renal Transplant Patients in Whom Therapy Was Discontinued Randomized Patients All Cyclosporine -Treated Patients Cyclosporine capsules Azathioprine (N=227) (N=228) (N=705) Reason for Discontinuation % % % Renal Toxicity 5.7 0 5.4 Infection 0 0.4 0.9 Lack of Efficacy 2.6 0.9 1.4 Acute Tubular Necrosis 2.6 0 1.0 Lymphoma/Lymphoproliferative Disease 0.4 0 0.3 Hypertension 0 0 0.3 Hematological Abnormalities 0 0.4 0 Other 0 0 0.7 Cyclosporine capsule was discontinued on a temporary basis and then restarted in 18 additional patients. Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine-containing regimens, are at increased risk of infections (viral, bacterial, fungal, and parasitic). Both generalized and localized infections can occur. Preexisting infections may also be aggravated. Fatal outcomes have been reported (see WARNINGS ) . Infectious Complications in the Randomized Renal Transplant Patients Cyclosporine Capsules Treatment Standard Treatment (N=227) (N=228) Complication % of Complications % of Co …

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 nonsteroidal anti-inflammatory drugs (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 Antineoplastic Antifungals Anti- Inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs ciprofloxacin gentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin melphalan amphotericin B ketoconazole azapropazon colchicine diclofenac naproxen sulindac cimetidine ranitidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate During the concomitant use of a drug that may exhibit additive or synergistic renal impairment potential with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, reduction in the dosage of cyclosporine and/or coadministered drug or an alternative treatment should be considered. Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase or decrease plasma or whole blood concentrations of cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption, such as orlistat, should be avoided. Appropriate cyclosporine capsules dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (see DOSAGE AND ADMINISTRATION , Blood Concentration Monitoring ) . 1. Drugs That Increase Cyclosporine Concentrations Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs diltiazem fluconazole azithromycin methylprednisolone allopurinol nicardipine itraconazole clarithromycin amiodarone verapamil ketoconazole erythromycin bromocriptine quinupristin/ colchicine voriconazole dalfopristin danazol imatinib metoclopramide nefazodone oral contraceptives HIV Protease inhibitors The HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and thus could potentially increase the concentrations of cyclosporine, however, no formal studies of the interaction are available. Care should be exercised when these drugs are administered concomitantly. Grapefruit Juice Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided. 2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations Antibiotics Anticonvulsants Other Drugs/DietarySupplements nafcillin carbamazepine bosentan St. John’s Wort rifampin oxcarbazepine octreotide phenobarbital orlistat phenytoin sulfinpyrazone terbinafine ticlopidine Bosentan Concomitant use of bosentan (250 to 1,000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a C min of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, C max , and trough concentration of approximately 50%, 30% and 60%, respectively, compared to when cyclosporine was given alone (see also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents) . Concomitant use of cyclosporine with bosentan should be avoided. Boceprevir Concomitant use of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and C max of cyclosporine …

DESCRIPTION Cyclosporine, USP, the active principle in cyclosporine capsules, USP (NON-MODIFIED) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Tolypocladium inflatum Gams. 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). The chemical structure of cyclosporine (also known as cyclosporin A) is: C 62 H 111 N 11 O 12 Mol. wt. 1202.61 Cyclosporine capsules, USP (NON-MODIFIED) are available in 25 mg and 100 mg strengths. Each 25 mg capsule contains: Cyclosporine, USP.................................................................................25 mg Each 100 mg capsule contains: Cyclosporine, USP................................................................................100 mg Each capsule contains the following inactive ingredients: methanol, sodium lauryl sulfate and talc. The 25 mg and the 100 mg capsule shell contains gelatin, red iron oxide and titanium dioxide. The 25 mg and 100 mg capsule black imprinting ink contains the following inactive ingredients: n-butyl alcohol, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #40 aluminum lake, pharmaceutical glaze, propylene glycol, SDA-3A alcohol and synthetic black iron oxide. structure

OVERDOSAGE There is a minimal experience with cyclosporine overdosage. Because of the slow absorption of cyclosporine, forced emesis and gastric lavage would be of value up to 2 hours after administration. 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 associated with vomiting, drowsiness, headache, tachycardia, and in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of cyclosporine intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. The oral LD 50 is 2,329 mg/kg in mice, 1,480 mg/kg in rats, and > 1,000 mg/kg in rabbits. The intravenous LD 50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits. General supportive measures and symptomatic treatment should be followed in all cases of cyclosporine overdosage. Cyclosporine is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. If a cyclosporine overdose occurs, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

HOW SUPPLIED Cyclosporine capsules, USP (NON-MODIFIED ) 25 mg Pale reddish brown opaque body, pale reddish brown opaque cap, hard gelatin capsule, imprinted " APO" over "133" and "25" in black ink; supplied in bottles of 30 (NDC 60505-0133-0), in bottles of 500 (NDC 60505-0133-2), and in bottles of 1,000 (NDC 60505-0133-1). 100 mg Reddish brown opaque body, reddish brown opaque cap, hard gelatin capsule, imprinted "APO" over "134" and "100" in black ink; supplied in bottles of 30 (NDC 60505-0134-0), in bottles of 500 (NDC 60505-0134-2), and in bottles of 1,000 (NDC 60505-0134-1). Store and Dispense Store at 20°C to 25°C (66°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP]. APOTEX INC. CYCLOSPORINE CAPSULES, USP 25 mg and 100 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 33326 Revised: April 2026 Rev. 12 *Neoral ® (cyclosporine capsules, USP) MODIFIED manufactured by Novartis.