cycloSPORINE Capsules, USP MODIFIED (Soft Gelatin Capsules)

Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe 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 cyclosporine capsules, USP MODIFIED. 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.

Cyclosporine capsules, USP MODIFIED, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients cyclosporine capsules, USP MODIFIED 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.

Cyclosporine capsules, USP MODIFIED have increased bioavailability in comparison to Sandimmune^® (cyclosporine capsules, USP). Cyclosporine capsules, USP MODIFIED and Sandimmune (cyclosporine capsules, USP) are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with cyclosporine capsules, USP MODIFIED than with Sandimmune (cyclosporine capsules, USP). If a patient who is receiving exceptionally high doses of Sandimmune (cyclosporine capsules, USP) is converted to cyclosporine capsules, USP MODIFIED, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking cyclosporine capsules, USP MODIFIED 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 (see DOSAGE AND ADMINISTRATION).

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 cyclosporine capsules, USP MODIFIED and 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 capsules, USP MODIFIED or Sandimmune (cyclosporine capsules, USP) 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 capsules, USP MODIFIED and 19% to 26% for Sandimmune (cyclosporine capsules, USP). In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for cyclosporine capsules, USP MODIFIED and 16% to 38% for Sandimmune (cyclosporine capsules, USP).

Cyclosporine capsules, USP MODIFIED have increased bioavailability compared to Sandimmune (cyclosporine capsules, USP). The absolute bioavailability of cyclosporine administered as Sandimmune (cyclosporine capsules, USP) is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. The absolute bioavailability of cyclosporine administered as cyclosporine capsules, USP MODIFIED has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC was approximately 20% to 50% greater and the peak blood cyclosporine concentration (C_max) was approximately 40% to 106% greater following administration of cyclosporine capsules, USP MODIFIED compared to following administration of Sandimmune (cyclosporine capsules, USP). The dose normalized AUC in de novo liver transplant patients administered cyclosporine capsules, USP MODIFIED 28 days after transplantation was 50% greater and C_max was 90% greater than in those patients administered Sandimmune (cyclosporine capsules, USP). AUC and C_max are also increased (cyclosporine capsules, USP MODIFIED relative to Sandimmune (cyclosporine capsules, USP)) in heart transplant patients, but data are very limited. Although the AUC and C_max values are higher on cyclosporine capsules, USP MODIFIED relative to Sandimmune (cyclosporine capsules, USP), the predose trough concentrations (dose-normalized) are similar for the two formulations.

Following oral administration of cyclosporine capsules, USP MODIFIED, the time to peak blood cyclosporine concentrations (T_max) ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine capsules, USP MODIFIED decreases the cyclosporine AUC and C_max. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine capsules, USP MODIFIED administration decreased the AUC by 13% and C_max by 33%. The effects of a low-fat meal (667 kcal, 15 grams fat) were similar.

The effect of T-tube diversion of bile on the absorption of cyclosporine from cyclosporine capsules, USP MODIFIED was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine capsules, USP MODIFIED with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9 ± 41% (range 55% to 68%).

Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 58% in erythrocytes. At high concentrations, the binding capacity of leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk (see PRECAUTIONS, Nursing Mothers).

Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the coadministration of a variety of agents (see PRECAUTIONS, Drug Interactions). At least 25 metabolites have been identified from human bile, feces, blood, and urine. The biological activity of the metabolites and their contributions to toxicity are considerably less than those of the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. At steady state following the oral administration of Sandimmune (cyclosporine capsules, USP), the mean AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5% of the AUC for blood cyclosporine concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered cyclosporine capsules, USP MODIFIED and Sandimmune (cyclosporine capsules, USP) in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered cyclosporine capsules, USP MODIFIED, 3 administered Sandimmune (cyclosporine capsules, USP)), the percentage of dose present as M1, M9, and M4N metabolites is similar when either cyclosporine capsules, USP MODIFIED or Sandimmune (cyclosporine capsules, USP) is administered.

Only 0.1% of a cyclosporine dose is excreted unchanged in the urine. Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Neither dialysis nor renal failure alters cyclosporine clearance significantly.

(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.

Cyclosporine capsules, USP MODIFIED are indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine capsules, USP MODIFIED have been used in combination with azathioprine and corticosteroids.

Cyclosporine capsules, 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 can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.

Cyclosporine capsules, 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 capsules, USP MODIFIED as with other therapies upon cessation of treatment.

Cyclosporine capsules, USP MODIFIED are contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine capsules, USP MODIFIED.

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.

Cyclosporine, the active ingredient of cyclosporine capsules, USP 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, USP 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, USP 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, USP 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, USP MODIFIED are not bioequivalent to Sandimmune (cyclosporine capsules, USP), conversion from cyclosporine capsules, USP MODIFIED to Sandimmune (cyclosporine capsules, USP) using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from cyclosporine capsules, USP MODIFIED to Sandimmune (cyclosporine capsules, USP) should be made with increased monitoring to avoid the potential of underdosing.

Cyclosporine nephropathy was detected in renal biopsies of 6 out of 60 (10%) rheumatoid arthritis patients after the average treatment duration of 19 months. Only one patient, out of these 6 patients, was treated with a dose ≤ 4 mg/kg/day. Serum creatinine improved in all but one patient after discontinuation of cyclosporine. The “maximal creatinine increase” appears to be a factor in predicting cyclosporine nephropathy.

There is a potential, as with other immunosuppressive agents, for an increase in the occurrence of malignant lymphomas with cyclosporine. It is not clear whether the risk with cyclosporine is greater than that in rheumatoid arthritis patients or in rheumatoid arthritis patients on cytotoxic treatment for this indication. Five cases of lymphoma were detected: four in a survey of approximately 2,300 patients treated with cyclosporine for rheumatoid arthritis, and another case of lymphoma was reported in a clinical trial. Although other tumors (12 skin cancers, 24 solid tumors of diverse types, and 1 multiple myeloma) were also reported in this survey, epidemiologic analyses did not support a relationship to cyclosporine other than for malignant lymphomas.

Patients should be thoroughly evaluated before and during cyclosporine capsules, USP MODIFIED treatment for the development of malignancies. Moreover, use of cyclosporine capsules, USP MODIFIED therapy with other immunosuppressive agents may induce an excessive immunosuppression which is known to increase the risk of malignancy.

(See also BOXED WARNING for Psoriasis)

Since cyclosporine is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using cyclosporine capsules, USP MODIFIED should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in cyclosporine capsules, USP MODIFIED, can cause nephrotoxicity and hypertension (see PRECAUTIONS) and the risk increases with increasing dose and duration of therapy. Patients who may be at increased risk, such as those with abnormal renal function, uncontrolled hypertension or malignancies, should not receive cyclosporine capsules, USP MODIFIED.

Renal dysfunction is a potential consequence of cyclosporine capsules, USP MODIFIED therefore renal function must be monitored during therapy.

Patients receiving cyclosporine capsules, USP 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 cause structural kidney damage and persistent renal dysfunction.

An increase in serum creatinine and BUN may occur during cyclosporine capsules, USP MODIFIED therapy and reflects a reduction in the glomerular filtration rate.

Kidney biopsies from 86 psoriasis patients treated for a mean duration of 23 months with 1.2 to 7.6 mg/kg/day of cyclosporine showed evidence of cyclosporine nephropathy in 18/86 (21%) of the patients. The pathology consisted of renal tubular atrophy and interstitial fibrosis. On repeat biopsy of 13 of these patients maintained on various dosages of cyclosporine for a mean of 2 additional years, the number with cyclosporine induced nephropathy rose to 26/86 (30%). The majority of patients (19/26) were on a dose of ≥ 5.0 mg/kg/day (the highest recommended dose is 4 mg/kg/day). The patients were also on cyclosporine for greater than 15 months (18/26) and/or had a clinically significant increase in serum creatinine for greater than 1 month (21/26). Creatinine levels returned to normal range in 7 of 11 patients in whom cyclosporine therapy was discontinued.

There is an increased risk for the development of skin and lymphoproliferative malignancies in cyclosporine-treated psoriasis patients. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive agents.

Tumors were reported in 32 (2.2%) of 1439 psoriasis patients treated with cyclosporine worldwide from clinical trials. Additional tumors have been reported in 7 patients in cyclosporine postmarketing experience. Skin malignancies were reported in 16 (1.1%) of these patients; all but 2 of them had previously received PUVA therapy. Methotrexate was received by 7 patients. UVB and coal tar had been used by 2 and 3 patients, respectively. Seven patients had either a history of previous skin cancer or a potentially predisposing lesion was present prior to cyclosporine exposure. Of the 16 patients with skin cancer, 11 patients had 18 squamous cell carcinomas and 7 patients had 10 basal cell carcinomas.

There were two lymphoproliferative malignancies; one case of non-Hodgkin’s lymphoma which required chemotherapy, and one case of mycosis fungoides which regressed spontaneously upon discontinuation of cyclosporine. There were four cases of benign lymphocytic infiltration: 3 regressed spontaneously upon discontinuation of cyclosporine, while the fourth regressed despite continuation of the drug. The remainder of the malignancies, 13 cases (0.9%), involved various organs.

Patients should not be treated concurrently with cyclosporine and PUVA or UVB, other radiation therapy, or other immunosuppressive agents, because of the possibility of excessive immunosuppression and the subsequent risk of malignancies (see CONTRAINDICATIONS). Patients should also be warned to protect themselves appropriately when in the sun, and to avoid excessive sun exposure. Patients should be thoroughly evaluated before and during treatment for the presence of malignancies remembering that malignant lesions may be hidden by psoriatic plaques. Skin lesions not typical of psoriasis should be biopsied before starting treatment. Patients should be treated with cyclosporine capsules, USP MODIFIED only after complete resolution of suspicious lesions, and only if there are no other treatment options (see Special Monitoring for Psoriasis 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 cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.

Patients should be advised that during treatment with cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Patients should be given careful dosage instructions.

Patients should be advised to take cyclosporine capsules, USP MODIFIED 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.

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

In all patients treated with cyclosporine, renal and liver functions should be assessed repeatedly by measurement of serum creatinine, BUN, serum bilirubin, and liver enzymes. Serum lipids, magnesium, and potassium should also be monitored. Cyclosporine blood concentrations should be routinely monitored in transplant patients (see DOSAGE AND ADMINISTRATION, Blood Concentration Monitoring in Transplant Patients), and periodically monitored in rheumatoid arthritis patients.

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).

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, USP MODIFIED dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly (see Blood Concentration Monitoring).

Cyclosporine is an inhibitor of CYP3A4 and of multiple drug efflux transporters (e.g., P-glycoprotein) and may increase plasma concentrations of comedications that are substrates of CYP3A4, P-glycoprotein or organic anion transporter proteins.

Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), and, aliskiren, bosentan, dabigatran, repaglinide, NSAIDs, sirolimus, etoposide, and other drugs.

See the full prescribing information of the other drug for further information and specific recommendations. The decision on coadministration of cyclosporine with other drugs or agents should be made by the healthcare provider following the careful assessment of benefits and risks.

During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be avoided.

For additional information on Cyclosporine Drug Interactions please contact Teva at 1-888-838-2872.

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose  (0.03 times the maximum recommended human dose (MRHD) based on body surface area (BSA) males significantly exceeded the control value. In the 24-month rat study, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level (0.006 times the MRHD based on BSA). The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. Published reports indicate that co-treatment of hairless mice with UV irradiation and cyclosporine or other immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone.

Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE), at high concentrations in this system.

In a fertility study in rats, increased perinatal mortality and impaired postnatal development of F1 pups were observed at 15 mg/kg/day (0.2 times the MRHD based on BSA). No adverse effects on fertility and reproduction were observed up to 5 mg/kg/day (0.06 times the MRHD based on BSA) in male and female rats.

Widely distributed papillomatosis of the skin was observed after chronic treatment of dogs with cyclosporine at 9 times the human initial psoriasis treatment dose of 2.5 mg/kg, where doses are expressed on a body surface area basis. This papillomatosis showed a spontaneous regression upon discontinuation of cyclosporine.

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants and patients with rheumatoid arthritis and psoriasis. The most common forms of neoplasms are non-Hodgkin’s lymphoma and carcinomas of the skin. The risk of malignancies in cyclosporine recipients is higher than in the normal, healthy population but similar to that in patients receiving other immunosuppressive therapies. Reduction or discontinuance of immunosuppression may cause the lesions to regress.

In psoriasis patients on cyclosporine, development of malignancies, especially those of the skin has been reported (see WARNINGS). Skin lesions not typical for psoriasis should be biopsied before starting cyclosporine treatment. Patients with malignant or premalignant changes of the skin should be treated with cyclosporine only after appropriate treatment of such lesions and if no other treatment option exists.

Risk Summary

Available data from published literature, including the Transplant Pregnancy Registry International, observational cohort studies, case-controlled studies, meta-analysis, case series, and case reports, over decades of use with cyclosporine in pregnancy have not identified a drug associated risk of major birth defects, or miscarriage. Adverse maternal or fetal outcomes including hypertension, preeclampsia, preterm birth, and low birth weight are increased in patients treated with cyclosporine. However, patients receiving cyclosporine during pregnancy have underlying medical conditions and may be treated with concomitant medications that limit the interpretability of these findings (see Data).

Embryo-fetal developmental (EFD) studies in rats and rabbits with cyclosporine have shown embryo-fetal toxicity at dose levels below the maximum recommended human dose (MRHD) based on body surface area (BSA).

The alcohol content of cyclosporine capsules, USP MODIFIED should be taken into account when given to pregnant women (see WARNINGS, Special Excipients).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Available data from the National Transplantation Pregnancy Registry (NTPR) including 622 pregnancies in renal, liver, and heart transplant recipients exposed to cyclosporine during pregnancy found that the overall rate of major birth defects, live birth rates, and miscarriage rates were comparable to the general population. Maternal and fetal adverse outcomes, including the rate of hypertension, preeclampsia, premature births, and low birth weight infants appear to be increased in transplant recipients treated with cyclosporine compared to the general population. However, these patients have underlying medical conditions that confound the above findings.

Animal Data

Animal studies have shown reproductive toxicity in rats and rabbits.

Three EFD studies (two oral and one intravenous) are available in rats. In two EFD studies, pregnant rats were orally administered with cyclosporine either at doses of 10, 17, 30, 100 and 300 mg/kg/day or 4, 10 and 25 mg/kg/day from gestation day (GD) 6 to 15 or from GD 7 to 17, respectively. Maternal toxicity characterized by mortality, clinical signs of toxicity and impaired body weight gain were observed at 30 mg/kg/day and above. Cyclosporine was embryo- and fetotoxic as indicated by increased embryonic mortality and reduced fetal weight together with skeletal retardations in rats at 25 mg/kg/day and above. In addition, ventricular septal defect was observed at 25 mg/kg/day in fetuses. In the first study, the oral no observed effect level (NOEL) for both dams and fetuses was 17 mg/kg/day (0.2 times the MRHD based on BSA). In the other oral study, the NOEL for dams and fetuses were 10 and 4 mg/kg/day (0.13 and 0.05 times the MRHD based on BSA), respectively. In the IV EFD study, rats were administered with 3, 6 and 12 mg/kg/day of cyclosporine from GD 7 to 17. An increase in post implantation loss was observed at 12 mg/kg/day; ventricular septal defect was observed at ≥ 6 mg/kg/day in fetuses. The IV NOEL for dams and fetus were 6 and 3 mg/kg/day (0.08 and 0.04 times the MRHD, respectively, based on BSA), respectively, after IV administration.

In rabbits, cyclosporine was orally administered at dose levels of 10, 30, 100 or 300 mg/kg/day from GD 6 to 18. At 100 mg/kg/day and above, reduction in body weight gain of dams and at 300 mg/kg/day abortions were observed. Maternal toxicity, embryo-fetotoxicity as indicated by increased pre- and postnatal mortality, reduced fetal weight together with skeletal retardations were observed at 100 mg/kg/day and above. The NOEL for dams and fetuses was 30 mg/kg/day (1 times the MRHD based on BSA).

In two published research studies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. These findings have not been demonstrated in other species and their relevance for humans is unknown.

In a peri- and postnatal development study in rats, pregnant rats were orally administered with cyclosporine (5, 15 or 45 mg/kg/day) from GD 15 until end of lactation. At 45 mg/kg/day (0.5 times the MRHD based on BSA), increased pre and postnatal mortality of offspring and reduced body weight gain of surviving pups were observed. Cyclosporine up to 15 mg/kg/day (0.2 times the MRHD based on BSA) had no effect on pregnancy, pre and postnatal development of offspring.

Risk Summary

Cyclosporine and its metabolites are present in human milk following oral and intravenous administration. Adverse effects on the breastfed infant have not been reported. There are no data on the effects of the drug on milk production. The alcohol content of cyclosporine capsules, USP MODIFIED should be taken into account when given to lactating women (see WARNINGS, Special Excipients). Lactating women are encouraged to avoid additional alcohol intake during treatment. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for cyclosporine capsules, USP MODIFIED and any potential adverse effects on the breastfed infant from cyclosporine capsules, USP MODIFIED or from the underlying maternal condition.

Although no adequate and well-controlled studies have been completed in pediatric patients, transplant recipients as young as one year of age have received cyclosporine capsules, USP MODIFIED with no unusual adverse effects. The safety and efficacy of cyclosporine capsules, USP MODIFIED treatment in pediatric patients with juvenile rheumatoid arthritis or psoriasis below the age of 18 have not been established.

In rheumatoid arthritis clinical trials with cyclosporine, 17.5% of patients were age 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥ 50% above the baseline after 3 to 4 months of therapy.

Clinical studies of cyclosporine capsules, USP MODIFIED in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.

The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction (see WARNINGS), hypertension (see PRECAUTIONS), headache, gastrointestinal disturbances, and hirsutism/hypertrichosis.

In rheumatoid arthritis patients treated in clinical trials within the recommended dose range, cyclosporine therapy was discontinued in 5.3% of the patients because of hypertension and in 7% of the patients because of increased creatinine. These changes are usually reversible with timely dose decrease or drug discontinuation. 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.

The following adverse events occurred in controlled clinical trials:

In addition, the following adverse events have been reported in 1% to < 3% of the rheumatoid arthritis patients in the cyclosporine treatment group in controlled clinical trials.

Autonomic Nervous System

Dry mouth, increased sweating

Body as a Whole

Allergy, asthenia, hot flushes, malaise, overdose, procedure NOS^*, tumor NOS^*, weight decrease, weight increase

Cardiovascular

Abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia

Central and Peripheral Nervous System

Hypoesthesia, neuropathy, vertigo

Endocrine

Goiter

Gastrointestinal

Constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder

Infection

Abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection

Hematologic

Anemia, epistaxis, leukopenia, lymphadenopathy

Liver and Biliary System

Bilirubinemia

Metabolic and Nutritional

Diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia

Musculoskeletal System

Arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder

Neoplasms

Breast fibroadenosis, carcinoma

Psychiatric

Anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence

Reproductive (Female)

Breast pain, uterine hemorrhage

Respiratory System

Abnormal chest sounds, bronchospasm

Skin and Appendages

Abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria

Special Senses

Abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder

Urinary System

Abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence

*NOS = Not Otherwise Specified

The principal adverse reactions associated with the use of cyclosporine in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.

In psoriasis patients treated in US controlled clinical studies within the recommended dose range, cyclosporine therapy was discontinued in 1.0% of the patients because of hypertension and in 5.4% of the patients because of increased creatinine. In the majority of cases, these changes were reversible after dose reduction or discontinuation of cyclosporine.

There has been one reported death associated with the use of cyclosporine in psoriasis. A 27-year-old male developed renal deterioration and was continued on cyclosporine. He had progressive renal failure leading to death.

Frequency and severity of serum creatinine increases with dose and duration of cyclosporine therapy. These elevations are likely to become more pronounced and may result in irreversible renal damage without dose reduction or discontinuation.

The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:

Body as a Whole

Fever, flushes, hot flushes

Cardiovascular

Chest pain

Central and Peripheral Nervous System

Appetite increased, insomnia, dizziness, nervousness, vertigo

Gastrointestinal

Abdominal distention, constipation, gingival bleeding

Liver and Biliary System

Hyperbilirubinemia

Neoplasms

Skin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]

Reticuloendothelial

Platelet, bleeding, and clotting disorders, red blood cell disorder

Respiratory

Infection, viral and other infection

Skin and Appendages

Acne, folliculitis, keratosis, pruritus, rash, dry skin

Urinary System

Micturition frequency

Vision

Abnormal vision

Mild hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases in uric acid may occur and attacks of gout have been rarely reported. A minor and dose related hyperbilirubinemia has been observed in the absence of hepatocellular damage. Cyclosporine therapy may be associated with a modest increase of serum triglycerides or cholesterol. Elevations of triglycerides (> 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.

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 www.fda.gov/medwatch for voluntary reporting of adverse reactions.

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).

The initial oral dose of cyclosporine capsules, USP MODIFIED can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of cyclosporine capsules, USP 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 capsules, USP MODIFIED is the same as the initial oral dose of Sandimmune (cyclosporine capsules, USP). Suggested initial doses are available from the results of a 1994 survey of the use of Sandimmune (cyclosporine capsules, USP) in US 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 capsules, USP 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 capsules, USP MODIFIED as for Sandimmune (cyclosporine capsules, USP). Using the same trough concentration target range for cyclosporine capsules, USP MODIFIED as for Sandimmune (cyclosporine capsules, USP) results in greater cyclosporine exposure when cyclosporine capsules, USP MODIFIED are administered (see Pharmacokinetics, Absorption). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower cyclosporine capsules, USP 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 2.0 mg/kg/day for the first 4 days tapered to 1.0 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.

In transplanted patients who are considered for conversion to cyclosporine capsules, USP MODIFIED from Sandimmune (cyclosporine capsules, USP), cyclosporine capsules, USP MODIFIED should be started with the same daily dose as was previously used with Sandimmune (cyclosporine capsules, USP) (1:1 dose conversion). The cyclosporine capsules, USP MODIFIED dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for cyclosporine capsules, USP MODIFIED as for Sandimmune (cyclosporine capsules, USP) results in greater cyclosporine exposure when cyclosporine capsules, USP MODIFIED are administered (see Pharmacokinetics, Absorption). Patients with suspected poor absorption of Sandimmune (cyclosporine capsules, USP) require different dosing strategies (see Transplant Patients with Poor Absorption of Sandimmune (cyclosporine capsules, USP), below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to cyclosporine capsules, USP MODIFIED. In addition, clinical safety parameters, such as serum creatinine and blood pressure, should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of cyclosporine capsules, USP MODIFIED must be adjusted accordingly.

Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune (cyclosporine capsules, USP) may have poor or inconsistent absorption of cyclosporine from Sandimmune (cyclosporine capsules, USP). After conversion to cyclosporine capsules, USP MODIFIED, patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to cyclosporine capsules, USP MODIFIED, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to cyclosporine capsules, USP MODIFIED at doses greater than 10 mg/kg/day. The dose of cyclosporine capsules, USP MODIFIED should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

The initial dose of cyclosporine capsules, USP MODIFIED is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, NSAIDs, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS, Drug Interactions). Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, cyclosporine capsules, USP MODIFIED therapy should be discontinued.

Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient’s pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS).

If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, cyclosporine capsules, USP MODIFIED should be discontinued. The same initial dose and dosage range should be used if cyclosporine capsules, USP MODIFIED are combined with the recommended dose of methotrexate. Most patients can be treated with cyclosporine capsules, USP MODIFIED doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week (see CLINICAL PHARMACOLOGY, Clinical Trials).

There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine.

The initial dose of cyclosporine capsules, USP MODIFIED should be 2.5 mg/kg/day. Cyclosporine capsules, USP MODIFIED should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patient’s dosage should be increased at 2-week intervals. Based on patient response, dose increases of approximately 0.5 mg/kg/day should be made to a maximum of 4.0 mg/kg/day.

Dose decreases by 25% to 50% should be made at any time to control adverse events, e.g., hypertension, elevations in serum creatinine (≥ 25% above the patient’s pretreatment level), or clinically significant laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, cyclosporine capsules, USP MODIFIED should be discontinued (see Special Monitoring for Psoriasis Patients).

Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with cyclosporine capsules, USP MODIFIED indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient’s maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of cyclosporine capsules, USP MODIFIED should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long term experience with cyclosporine capsules, USP MODIFIED in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long term management of patients with this life long disease.

Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed. Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994; 31: 420-446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.