Get your patient on Cyclosporine modified - Cyclosporine capsule, Liquid Filled (Cyclosporine)

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.

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.

In a study performed in 4 subjects with end-stage renal disease (creatinine clearance < 5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate.

Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients.

Pharmacokinetic data from pediatric patients administered cyclosporine capsules, USP MODIFIED or Sandimmune (cyclosporine capsules, USP) are very limited. In 15 renal transplant patients aged 3 to 16 years, cyclosporine whole blood clearance after IV administration of Sandimmune (cyclosporine capsules, USP) was 10.6 ± 3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2 to 16, the cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 9 liver transplant patients aged 0.6 to 5.6 years, clearance was 9.3 ± 5.4 mL/min/kg (assay: HPLC).

In the pediatric population, cyclosporine capsules, USP MODIFIED also demonstrate an increased bioavailability as compared to Sandimmune (cyclosporine capsules, USP). In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of cyclosporine capsules, USP MODIFIED was 43% (range 30% to 68%) and for Sandimmune (cyclosporine capsules, USP) in the same individuals absolute bioavailability was 28% (range 17% to 42%).

Comparison of single dose data from both normal elderly volunteers (N = 18, mean age 69 years) and elderly rheumatoid arthritis patients (N = 16, mean age 68 years) to single dose data in young adult volunteers (N = 16, mean age 26 years) showed no significant difference in the pharmacokinetic parameters.

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.

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

Neoplasm s

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

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.

The effectiveness of Sandimmune (cyclosporine capsules, USP) and cyclosporine capsules, USP MODIFIED in the treatment of severe rheumatoid arthritis was evaluated in 5 clinical studies involving a total of 728 cyclosporine treated patients and 273 placebo treated patients.

A summary of the results is presented for the “responder” rates per treatment group, with a responder being defined as a patient having completed the trial with a 20% improvement in the tender and the swollen joint count and a 20% improvement in 2 of 4 of investigator global, patient global, disability, and erythrocyte sedimentation rates (ESR) for the Studies 651 and 652 and 3 of 5 of investigator global, patient global, disability, visual analog pain, and ESR for Studies 2008, 654 and 302.

Study 651 enrolled 264 patients with active rheumatoid arthritis with at least 20 involved joints, who had failed at least one major RA drug, using a 3:3:2 randomization to one of the following three groups: (1) cyclosporine dosed at 2.5 to 5 mg/kg/day, (2) methotrexate at 7.5 to 15 mg/week, or (3) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 3.1 mg/kg/day. See graph below.

Study 652 enrolled 250 patients with active RA with > 6 active painful or tender joints who had failed at least one major RA drug. Patients were randomized using a 3:3:2 randomization to 1 of 3 treatment arms: (1) 1.5 to 5 mg/kg/day of cyclosporine, (2) 2.5 to 5 mg/kg/day of cyclosporine, and (3) placebo. Treatment duration was 16 weeks. The mean cyclosporine dose for group 2 at the last visit was 2.92 mg/kg/day. See graph below.

Study 2008 enrolled 144 patients with active RA and > 6 active joints who had unsuccessful treatment courses of aspirin and gold or Penicillamine. Patients were randomized to 1 of 2 treatment groups (1) cyclosporine 2.5 to 5 mg/kg/day with adjustments after the first month to achieve a target trough level and (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 3.63 mg/kg/day. See graph below.

Study 654 enrolled 148 patients who remained with active joint counts of 6 or more despite treatment with maximally tolerated methotrexate doses for at least three months. Patients continued to take their current dose of methotrexate and were randomized to receive, in addition, one of the following medications: (1) cyclosporine 2.5 mg/kg/day with dose increases of 0.5 mg/kg/day at weeks 2 and 4 if there was no evidence of toxicity and further increases of 0.5 mg/kg/day at weeks 8 and 16 if a < 30% decrease in active joint count occurred without any significant toxicity; dose decreases could be made at any time for toxicity or (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 2.8 mg/kg/day (range: 1.3 to 4.1). See graph below.

Study 302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive or intolerant to at least one prior major RA drug. Patients were randomized to 1 of 2 treatment groups (1) cyclosporine capsules, USP MODIFIED and (2) cyclosporine, both of which were started at 2.5 mg/kg/day and increased after 4 weeks for inefficacy in increments of 0.5 mg/kg/day to a maximum of 5 mg/kg/day and decreased at any time for toxicity. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 2.91 mg/kg/day (range: 0.72 to 5.17) for cyclosporine capsules, USP MODIFIED and 3.27 mg/kg/day (range: 0.73 to 5.68) for cyclosporine. See graph below.