Cyclosporine 25 mg Capsule, Gelatin Coated — NDC 68084-879-25 (Billing 68084-0879-25)

WARNINGS Kidney, Liver, and Heart Transplant Cyclosporine capsules, (NON-MODIFIED), when used in high doses, can cause hepatotoxicity and nephrotoxicity (see Boxed Warning . ) Nephrotoxicity It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated. Nephrotoxicity has been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation.

Mild nephrotoxicity was generally noted 2 to 3 months after transplant and consisted of an arrest in the fall of the preoperative elevations of BUN and creatinine at a range of 35 to 45 mg/dl and 2.0 to 2.5 mg/dl, respectively. These elevations were often responsive to dosage reduction. More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine.

Since these events are similar to rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to cyclosporine capsules dosage reduction. Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated to one or the other.

It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection. Nephrotoxicity vs. Rejection Parameter Nephrotoxicity Rejection History Donor > 50 years old or hypotensive Antidonor immune response Prolonged kidney preservation Prolonged anastomosis time Retransplant patient Concomitant nephrotoxic drugs Clinical Often > 6 weeks postop p < 0.05, Often < 4 weeks postop p < 0.01, Prolonged initial nonfunction Fever > 37.5°C (acute tubular necrosis) Weight gain > 0.5 kg Graft swelling and tenderness Decrease in daily urine volume > 500 mL (or 50%) Laboratory CyA serum trough level > 200 ng/mL CyA serum trough level < 150 ng/mL Gradual rise in Cr (< 0.15 mg/dL/day) Rapid rise in Cr (> 0.3 mg/dL/day) Cr plateau < 25% above baseline Cr > 25% above baseline BUN/Cr ≥ 20 BUN/Cr < 20 Biopsy Arteriolopathy (medial hypertrophy , Endovasculitis p < 0.001, (proliferation , hyalinosis, nodular deposits, intimal intimal arteritis , necrosis, sclerosis) thickening, endothelial vacuolization, progressive scarring) Tubular atrophy, isometric vacuolization, Tubulitis with RBC and WBC casts, isolated calcifications some irregular vacuolization Minimal edema Interstitial edema and hemorrhage Mild focal infiltrates Diffuse moderate to severe mononuclear infiltrates p < 0.0001 Diffuse interstitial fibrosis, often striped form Glomerulitis (mononuclear cells) Aspiration Cytology CyA deposits in tubular and endothelial cells Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cells Fine isometric vacuolization of tubular cells These strongly express HLA-DR antigens Urine Cytology Tubular cells with vacuolization and Degenerative tubular cells, plasma cells, and granularization lymphocyturia > 20% of sediment Manometry Intracapsular pressure < 40 mm Hg Intracapsular pressure > 40 mm Hg Ultrasonography Unchanged graft cross-sectional area Increase in graft cross-sectional area AP diameter ≥ Transverse diameter Magnetic Resonance Imagery Normal appearance Loss of distinct corticomedullary junction, swelling, image intensity of parachyma approaching that of psoas, loss of hilar fat Radionuclide Scan Normal or generally decreased perfusion Patchy arterial flow Decrease in tubular function Decrease in perfusion > decrease in tubular function ( 131 I-hippuran) > decrease in perfusion Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid ( 99m Tc DTPA) Therapy Responds to decreased cyclosporine capsules Responds to increased steroids or antilymphocyte… [Excerpted — this section continues on DailyMed.]

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. 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 capsules 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 capsules Patients Cyclosporine capsules Azathioprine (N=227) (N=228) (N=705) Reason for Discontinuation % % % Renal Toxicity 5.7 0

5.4Infection 0 0.4

0.9Lack of Efficacy 2.6 0.9

1.4Acute Tubular Necrosis 2.6 0

1.0Lymphoma/Lymphoproliferative Disease 0.4 0

0.3 Hypertension 0 0

0.3Hematological Abnormalities 0 0.4 0 Other 0 0

0.7Cyclosporine capsules 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 Some patients also received ALG.

(N=227) (N=228) Complication % of Complica… [Excerpted — this section continues on DailyMed.]

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 Immuno-suppressives Other Drugs ciprofloxacin melphalan amphotericin B azapropazone cimetidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) gentamicin ketoconazole colchicine ranitidine tobramycin diclofenac trimethoprim with sulfamethoxazole naproxen sulindac vancomycin 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 voriconazole quinupristin/ dalfopristin colchicine 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/ Dietary Supplements nafcillin carbamazepine bosentan St. John’s Wort rifampin oxcarbazepine octreotide phenobarbital orlistat phenytoin sulfinpyrazone terbinafine ticlopidine Bosentan Co-administration 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 ).

Coadministration of cyclosporine with bosentan should be avoided. Boceprevir Coadministration 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 cyclospori… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS General Patients with malabsorption may have difficulty in achieving therapeutic concentrations with cyclosporine capsules. Hypertension Hypertension is a common side effect of cyclosporine capsules therapy (see ADVERSE REACTIONS ). Mild or moderate hypertension is more frequently encountered than severe hypertension and the incidence decreases over time.

Antihypertensive therapy may be required. Control of blood pressure can be accomplished with any of the common antihypertensive agents. However, since cyclosporine may cause hyperkalemia, potassium-sparing diuretics should not be used.

While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, care should be taken since interference with cyclosporine metabolism may require a dosage adjustment (see Drug Interactions ). Vaccination During treatment with cyclosporine capsules, (NON-MODIFIED), vaccination may be less effective and the use of live attenuated vaccines should be avoided. Information for Patients Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.

Patients should be informed of the necessity of repeated laboratory tests while they are receiving the drug. They should be given careful dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Cyclosporine may impact the ability to drive and use machines.

Patients should be advised to exercise care when driving or using machines if they experience neurological disturbances including confusion, somnolence, or dizziness and discuss with their healthcare provider (see WARNINGS and ADVERSE REACTIONS ). Laboratory Tests Renal and liver functions should be assessed repeatedly by measurement of BUN, serum creatinine, serum bilirubin, and liver enzymes. 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 Immuno-suppressives Other Drugs ciprofloxacin melphalan amphotericin B azapropazone cimetidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) gentamicin ketoconazole colchicine ranitidine tobramycin diclofenac trimethoprim with sulfamethoxazole naproxen sulindac vancomycin 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 Concentrati… [Excerpted — this section continues on DailyMed.]