CycloSPORINE, Modfied 25 mg Capsule, Liquid Filled

WARNINGS ( See also BOXED WARNING ) All Patients Cyclosporine, the active ingredient of cyclosporine capsules (modified), can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine. Renal dysfunction including structural kidney damage is a potential consequence of cyclosporine capsules (modified) and therefore renal function must be monitored during therapy.

Care should be taken in using cyclosporine with nephrotoxic drugs (see PRECAUTIONS ) . Patients receiving cyclosporine capsules (modified) require frequent monitoring of serum creatinine (see Special Monitoring under DOSAGE AND ADMINISTRATION ) . Elderly patients should be monitored with particular care, since decreases in renal function also occur with age.

If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can be associated with the occurrence of structural kidney damage and persistent renal dysfunction. An increase in serum creatinine and BUN may occur during cyclosporine capsules (modified) therapy and reflect a reduction in the glomerular filtration rate. Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated.

The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation. Because cyclosporine capsules (modified) is not bioequivalent to Sandimmune ® , conversion from cyclosporine capsules (modified) to Sandimmune ® using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations.

Conversion from cyclosporine capsules (modified) to Sandimmune ® should be made with increased monitoring to avoid the potential of underdosing. Kidney, Liver, and Heart Transplant Nephrotoxicity Cyclosporine, the active ingredient of cyclosporine capsules (modified), can cause nephrotoxicity and hepatotoxicity when used in high doses. 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. Based on the historical Sandimmune ® experience with oral solution, nephrotoxicity associated with cyclosporine had 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 renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35 to 45 mg/dL and 2 to 2.5 mg/dL, respectively.

These elevations were often responsive to cyclosporine 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 renal rejection episodes, care must be taken to differentiate between them.

This form of nephrotoxicity is usually responsive to cyclosporine 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 with 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 Anti-donor immune response Prolonged kidney preservation Retransplant patient Prolonged anastomosis time Concomitant nephrotoxic drugs Clinical Often > 6 weeks postop b Often < 4 weeks postop b 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 tro…

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 (modified) were comparable with those observed in 208 transplanted patients who received Sandimmune ® 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 ® , 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 ® ) Sandimmune ® 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 Among 705 kidney transplant patients treated with cyclosporine oral solution (Sandimmune ® ) in clinical trials, the reason for treatment discontinuation was renal toxicity in 5.4%, infection in 0.9%, lack of efficacy in 1.4%, acute tubular necrosis in 1%, lymphoproliferative disorders in 0.3%, hypertension in 0.3%, and other reasons in 0.7% of the patients.

The following reactions occurred in 2% or less of cyclosporine-treated patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, migraine (cyclosporine capsules (modified)), 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.

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine -containing regimens, are at increased risk of infections (viral, bacterial,…

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 Antineoplastic s Antifungals Anti- Inflammatory Drugs Gastrointestinal Agents Immunosuppressives Other Drugs ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole 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 with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed.

If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment 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 (modified) dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (s ee 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/ colchicine 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 Coadministration 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 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 cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was…