NDC 60505-4631 Cyclosporine, Modfied

Cyclosporine

NDC Product Code 60505-4631

NDC CODE: 60505-4631

Proprietary Name: Cyclosporine, Modfied What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Cyclosporine What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Cyclosporine is used to prevent organ rejection in people who have received a liver, kidney, or heart transplant. It is usually taken along with other medications to allow your new organ to function normally. Cyclosporine belongs to a class of drugs known as immunosuppressants. It works by weakening the immune system to help your body accept the new organ as if it were your own.

Product Characteristics

Color(s):
GRAY (C48324 - OPAQUE GREY)
WHITE (C48325 - OPAQUE OFF-WHITE)
Shape: CAPSULE (C48336)
Size(s):
11 MM
18 MM
Imprint(s):
C25
C50
Score: 1

NDC Code Structure

  • 60505 - Apotex Corp.

NDC 60505-4631-3

Package Description: 30 BLISTER PACK in 1 CARTON > 5 CAPSULE, LIQUID FILLED in 1 BLISTER PACK

NDC Product Information

Cyclosporine, Modfied with NDC 60505-4631 is a a human prescription drug product labeled by Apotex Corp.. The generic name of Cyclosporine, Modfied is cyclosporine. The product's dosage form is capsule, liquid filled and is administered via oral form.

Labeler Name: Apotex Corp.

Dosage Form: Capsule, Liquid Filled - A solid dosage form in which the drug is enclosed within a soluble, gelatin shell which is plasticized by the addition of a polyol, such as sorbitol or glycerin, and is therefore of a somewhat thicker consistency than that of a hard shell capsule; typically, the active ingredients are dissolved or suspended in a liquid vehicle.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Cyclosporine, Modfied Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • CYCLOSPORINE 50 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • BENZYL ALCOHOL (UNII: LKG8494WBH)
  • GELATIN HYDROLYSATE (PORCINE SKIN, MW 3000) (UNII: 0K9R94573C)
  • PROPYLENE GLYCOL MONOLAURATE (UNII: 668Z5835Z3)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYOXYL 35 CASTOR OIL (UNII: 6D4M1DAL6O)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • SHELLAC (UNII: 46N107B71O)
  • AMMONIA (UNII: 5138Q19F1X)
  • BENZYL ALCOHOL (UNII: LKG8494WBH)
  • GELATIN HYDROLYSATE (PORCINE SKIN, MW 3000) (UNII: 0K9R94573C)
  • PROPYLENE GLYCOL MONOLAURATE (UNII: 668Z5835Z3)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • POLYOXYL 35 CASTOR OIL (UNII: 6D4M1DAL6O)
  • GLYCERIN (UNII: PDC6A3C0OX)
  • POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • SHELLAC (UNII: 46N107B71O)
  • AMMONIA (UNII: 5138Q19F1X)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Calcineurin Inhibitor Immunosuppressant - [EPC] (Established Pharmacologic Class)
  • Calcineurin Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 3A4 Inhibitors - [MoA] (Mechanism of Action)
  • P-Glycoprotein Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Apotex Corp.
Labeler Code: 60505
FDA Application Number: ANDA210721 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 11-05-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Cyclosporine, Modfied Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

For Psoriasis Patients (See Also Boxed Warning Above)

Psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking cyclosporine capsules (modified). Cyclosporine, the active ingredient in cyclosporine capsules (modified), in recommended dosages, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of cyclosporine therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of cyclosporine, and therefore, renal function must be monitored during therapy.

Description

Cyclosporine capsule, USP (modified) is an oral formulation of cyclosporine that immediately forms a microemulsion in an aqueous environment.   Cyclosporine, USP, the active principle in cyclosporine capsules, USP (modified), is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.   Chemically, cyclosporine, USP is designated as [R-[R*,R*-(E )]]-cyclic-(L-alanyl-D-alanyl-N-methyl-L-leucyl­ N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α -aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).   Cyclosporine capsules, USP (modified) (Soft Gelatin Capsules) are available in 25 mg, 50 mg and 100 mg strengths. Each 25 mg capsule contains:cyclosporine, USP…………………………………………………………………...25 mgbenzyl alcohol..................................................................... 7.79% v/v (8.13% wt/vol.)Each 50 mg capsule contains:  cyclosporine, USP…………………………………………………………………...50 mgbenzyl alcohol......................................................................7.79% v/v (8.13% wt/vol.)Each 100 mg capsule contains:cyclosporine, USP…………………………………………………..……………...100 mgbenzyl alcohol....................................................................... 7.79% v/v (8.13% wt/vol.)Inactive Ingredients: Polyethylene glycol 400, polyoxyl 35 castor oil, and propylene glycol monolaurate. The capsule shell contains the following inactive ingredients: gelatin, glycerine, iron oxide black (25 mg and 100 mg capsules only) and titanium dioxide. The capsule imprinting ink contains ammonium hydroxide, propylene glycol, iron oxide red and shellac.The chemical structure of cyclosporine is:

Clinical Pharmacology

Cyclosporine  is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund’s adjuvant arthritis, and graft versus host disease in many animal species for a variety of organs.The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T- helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release including interleukin-2.No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.PharmacokineticsThe 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.   Cyclosporine capsules [MODIFIED] and cyclosporine oral solution [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 capsule (modified) or Sandimmune® 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 capsule (modified) and 19% to 26% for Sandimmune®. In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for cyclosporine capsule (modified) and 16% to 38% for Sandimmune®.   AbsorptionCyclosporine capsule (modified) has increased bioavailability compared to Sandimmune®. The absolute bioavailability of cyclosporine administered as Sandimmune® 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 capsule (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 (Cmax) was approximately 40% to 106% greater following administration of cyclosporine capsule (modified) compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered cyclosporine capsule (modified) 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune®. AUC and Cmax are also increased (cyclosporine capsule (modified) relative to Sandimmune®) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on cyclosporine capsule (modified) relative to Sandimmune®, the predose trough concentrations (dose-normalized) are similar for the two formulations.   Following oral administration of cyclosporine capsule (modified), the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine capsule (modified) decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine capsule (modified) administration decreased the AUC by 13% and Cmax 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 capsule (modified) was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine capsule (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%).Pharmacokinetic Parameters (mean±SD)   Dose/day1Dose/weightAUC2C maxTrough3CL/FCL/FPatient Population(mgd)(mg/kg/d)(ng·hr/mL)(ng/mL)(ng/mL)(mL/min)(mL/min/kg) De novo renal               transplant4 597±174 7.95±2.81 8772±2089 1802±428 361±129 593±204 7.8±2.9 Week 4 (N=37)               Stable renal               transplant4 344±122 4.10±1.58 6035±2194 1333±469 251±116 492±140 5.9±2.1 (N=55)               De novo liver transplant5 Week 4 (N=18)   458±190   6.89±3.68   7187±2816   1555±740   268±101   577±309   8.6±5.7 De novo rheumatoid               arthritis6 182±55.6 2.37±0.36 2641±877 728±263 96.4±37.7 613±196 8.3±2.8 (N=23)               De novo psoriasis6     189±69.8     2.48±0.65     2324±1048     655±186     74.9±46.7     723±186     10.2±3.9 Week 4 (N=18)               1Total daily dose was divided into two doses administered every 12 hours 2AUC was measured over one dosing interval 3Trough concentration was measured just prior to the morning cyclosporine capsule (modified) dose, approximately 12 hours after the previous dose 4Assay: TDx specific monoclonal fluorescence polarization immunoassay 5Assay: Cyclo-trac specific monoclonal radioimmunoassay 6Assay: INCSTAR specific monoclonal radioimmunoassayDistributionCyclosporine 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)MetabolismCyclosporine 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®, 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 capsule (modified) and Sandimmune® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered cyclosporine capsule (modified), 3 administered Sandimmune®), the percentage of dose present as M1, M9, and M4N metabolites is similar when either cyclosporine capsule (modified) or Sandimmune® is administered.ExcretionOnly 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.Drug Interactions(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.Specific Populations Renal ImpairmentIn 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.Hepatic ImpairmentCyclosporine 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.Pediatric PopulationPharmacokinetic data from pediatric patients administered cyclosporine capsule (modified) or Sandimmune® are very limited. In 15 renal transplant patients aged 3 to 16 years, cyclosporine whole blood clearance after IV administration of Sandimmune® 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 capsule (modified) also demonstrates an increased bioavailability as compared to Sandimmune®. In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of cyclosporine capsule (modified) was 43% (range 30% to 68%) and for Sandimmune® in the same individuals absolute bioavailability was 28% (range 17% to 42%).Pediatric Pharmacokinetic Parameters (mean±SD)Patient PopulationDose/day (mg/d) Dose/weight (mg/kg/d)AUC1 (ng·hr/mL)C max (ng/mL)CL/F (mL/min)CL/F (mL/min/kg) Stable liver transplant2                                        Age 2 to 8, Dosed TID (N=9) 101±255.95±1.322163±801 629±219 285±94 16.6±4.3Age 8 to 15, Dosed BID (N=8)188±554.96±2.09 4272±1462 975±281378±8010.2±4Stable liver transplant3Age 3, Dosed BID (N=1)1208.335832105017111.9Age 8 to 15, Dosed BID (N=5)   158±55   5.51±1.91   4452±2475   1013±635   328±121   11.0±1.9 Stable renal transplant3             Age 7 to 15, Dosed BID (N=5) 328±83 7.37±4.11 6922±1988 1827±487 418±143 8.7±2.9 1AUC was measured over one dosing interval 2Assay: Cyclo-trac specific monoclonal radioimmunoassay 3Assay: TDx specific monoclonal fluorescence polarization immunoassayGeriatric Population 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.

Clinical Trials

Rheumatoid ArthritisThe effectiveness of Sandimmune® and cyclosporine capsules (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: 1.3–4.1). 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 capsule (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 capsule (modified) and 3.27 mg/kg/day (range: 0.73 to 5.68) for cyclosporine. See Graph below.

Indications And Usage

Kidney, Liver, and Heart TransplantationCyclosporine capsules (modified) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine capsules (modified) has been used in combination with azathioprine and corticosteroids.Rheumatoid ArthritisCyclosporine capsules (modified) is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Cyclosporine capsules (modified) can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.PsoriasisCyclosporine capsules (modified) is 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 (modified) as with other therapies upon cessation of treatment.

Contraindications

GeneralCyclosporine capsules (modified) is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.Rheumatoid ArthritisRheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine capsules (modified).PsoriasisPsoriasis patients who are treated with cyclosporine capsules (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 (modified).

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 TransplantNephrotoxicity 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 2.0 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. RejectionParameterNephrotoxicityRejectionHistoryDonor > 50 years old or hypotensiveAnti-donor immune responseProlonged kidney preservationRetransplant patientProlonged anastomosis timeConcomitant nephrotoxic drugsClinicalOften > 6 weeks postopbOften < 4 weeks postopbProlonged initial nonfunction Fever > 37.5°C(acute tubular necrosis) Weight gain > 0.5 kgGraft swelling and tendernessDecrease in daily urine volume > 500 mL (or 50%)LaboratoryCyA serum trough level > 200 ng/mLCyA serum trough level < 150 ng/mLGradual rise in Cr (< 0.15 mg/dL/day)aRapid rise in Cr (> 0.3 mg/dL/day)aCr plateau < 25% above baselineCr > 25% above baselineBUN/Cr ≥ 20BUN/Cr < 20BiopsyArteriolopathy (medial hypertrophya, Endovasculitisc (proliferationa, hyalinosis, nodular deposits, intimal intimal arteritisb, necrosis, sclerosis)thickening, endothelial vacuolization,progressive scarring)Tubular atrophy, isometric vacuolization, Tubulitis with RBCb and WBCb casts, isolated calcificationssome irregular vacuolizationMinimal edemaInterstitial edemac and hemorrhagebMild focal infiltratescDiffuse moderate to severe mononuclear infiltratesdDiffuse interstitial fibrosis,Glomerulitis (mononuclear cells)coften striped formAspiration CytologyCyA deposits in tubular and Inflammatory infiltrate with mononuclear phagocytes,endothelial cellsmacrophages, lymphoblastoid cells, andFine isometric vacuolization of tubular activated T-cellscells These strongly express HLA-DR antigensUrine CytologyTubular cells with vacuolization and Degenerative tubular cells, plasma cells, and granularizationlymphocyturia > 20% of sedimentManometryIntracapsular pressure < 40 mm HgbIntracapsular pressure > 40 mm HgbUltrasonographyUnchanged graft cross sectional areaIncrease in graft cross sectional areaAP diameter ≥ Transverse diameterMagnetic Resonance Normal appearanceLoss of distinct corticomedullary junction, swellingImageryimage intensity of parachyma approaching that of psoas, loss of hilar fatRadionuclide ScanNormal or generally decreased perfusionPatchy arterial flowDecrease in tubular function Decrease in perfusion > decrease in tubular function(131 I-hippuran) > decrease in perfusion Increased uptake of Indium 111 labeled platelets or (99m Tc DTPA)Tc-99m in colloidTherapyResponds to decreased  Responds to increased steroids orcyclosporine antilymphocyte globulinap < 0.05, bp < 0.01, cp < 0.001, dp < 0.0001A form of a cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys. From 5% to 15% of transplant recipients who have received cyclosporine will fail to show a reduction in rising serum creatinine despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies from these patients will demonstrate one or several of the following alterations: tubular vacuolization, tubular microcalcifications, peritubular capillary congestion, arteriolopathy, and a striped form of interstitial fibrosis with tubular atrophy. Though none of these morphologic changes is entirely specific, a diagnosis of cyclosporine-associated structural nephrotoxicity requires evidence of these findings.When considering the development of cyclosporine-associated nephropathy, it is noteworthy that several authors have reported an association between the appearance of interstitial fibrosis and higher cumulative doses or persistently high circulating trough concentrations of cyclosporine. This is particularly true during the first 6 post-transplant months when the dosage tends to be highest and when, in kidney recipients, the organ appears to be most vulnerable to the toxic effects of cyclosporine. Among other contributing factors to the development of interstitial fibrosis in these patients are prolonged perfusion time, warm ischemia time, as well as episodes of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its correlation to renal function have not yet been determined. Reversibility of arteriolopathy has been reported after stopping cyclosporine or lowering the dosage.Impaired renal function at any time requires close monitoring, and frequent dosage adjustment may be indicated.In the event of severe and unremitting rejection, when rescue therapy with pulse steroids and monoclonal antibodies fail to reverse the rejection episode, it may be preferable to switch to alternative immunosuppressive therapy rather than increase the cyclosporine capsules (modified) dose to excessive blood concentrations.Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering cyclosporine capsules (modified) with other drugs that may impair renal function. (See PRECAUTIONS, Drug Interactions)Thrombotic MicroangiopathyOccasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of cyclosporine and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans. (See ADVERSE REACTIONS)HyperkalemiaSignificant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.HepatotoxicityCases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine. Most reports included patients with significant co- morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported. (See ADVERSE REACTIONS, Postmarketing Experience, Kidney, Liver and Heart Transplantation)Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used. The chemistry elevations usually decreased with a reduction in dosage.MalignanciesAs in patients receiving other immunosuppressants, those patients receiving cyclosporine are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. Patients taking cyclosporine should be warned to avoid excess ultraviolet light exposure. The increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents. Because of the danger of oversuppression of the immune system resulting in increased risk of infection or malignancy, a treatment regimen containing multiple immunosuppressants should be used with caution. Some malignancies may be fatal. Transplant patients receiving cyclosporine are at increased risk for serious infection with fatal outcome.

Serious Infections

Patients receiving immunosuppressants, including cyclosporine capsules (modified), are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. (See BOXED WARNING, and ADVERSE REACTIONS)Polyoma Virus InfectionsPatients receiving immunosuppressants, including cyclosporine capsules (modified), are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), and polyoma virus-associated nephropathy (PVAN), especially due to BK virus infection, which have been observed in patients receiving cyclosporine. PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss, (See ADVERSE REACTIONS, Postmarketing Experience, Kidney, Liver and Heart Transplantation). Patient monitoring may help detect patients at risk for PVAN.   Cases of PML have been reported in patients treated with cyclosporine capsules (modified). PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.   Consideration should be given to reducing the total immunosuppression in transplant patients who develop PML or PVAN. However, reduced immunosuppression may place the graft at risk.NeurotoxicityThere have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high dose methylprednisolone.   Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), has been described both in post-marketing reports and in the literature. Manifestations include impaired consciousness, convulsions, visual disturbances (including blindness), loss of motor function, movement disorders and psychiatric disturbances. In many cases, changes in the white matter have been detected using imaging techniques and pathologic specimens. Predisposing factors such as hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine blood concentrations, and graft-versus­- host disease have been noted in many but not all of the reported cases. The changes in most cases have been reversible upon discontinuation of cyclosporine, and in some cases improvement was noted after reduction of dose. It appears that patients receiving liver transplant are more susceptible to encephalopathy than those receiving kidney transplant. Another rare manifestation of cyclosporine-­ induced neurotoxicity, occurring in transplant patients more frequently than in other indications, is optic disc edema including papilloedema, with possible visual impairment, secondary to benign intracranial hypertension.   Care should be taken in using cyclosporine with nephrotoxic drugs. (See PRECAUTIONS)Rheumatoid ArthritisCyclosporine 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 (modified) treatment for the development of malignancies. Moreover, use of cyclosporine capsules (modified) therapy with other immunosuppressive agents may induce an excessive immunosuppression which is known to increase the risk of malignancy.Psoriasis(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 (modified) should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in cyclosporine capsules (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 (modified).   Renal dysfunction is a potential consequence of cyclosporine capsules (modified) therefore renal function must be monitored during therapy.   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 cause structural kidney damage and persistent renal dysfunction.   An increase in serum creatinine and BUN may occur during cyclosporine capsules (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 (modified) only after complete resolution of suspicious lesions, and only if there are no other treatment options. (See Special Monitoring for Psoriasis Patients)

Hypertension

Cyclosporine is the active ingredient of cyclosporine capsules (modified). Hypertension is a common side effect of cyclosporine therapy which may persist. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION for monitoring recommendations) Mild or moderate hypertension is encountered more frequently than severe hypertension and the incidence decreases over time. In recipients of kidney, liver, and heart allografts treated with cyclosporine, antihypertensive therapy may be required. (See Special Monitoring of Rheumatoid Arthritis and Psoriasis Patients) However, since cyclosporine may cause hyperkalemia, potassium-sparing diuretics should not be used. While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, they can interfere with cyclosporine metabolism. (See Drug Interactions)

Vaccination

During treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.

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.

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

AntibioticsAntineoplastics   Antifungals           Anti- Inflammatory DrugsGastrointestinal  Agents Immunosuppressives     Other Drugsciprofloxacin gentamicintobramycin vancomycin trimethoprim with sulfamethoxazolemelphalan amphotericin Bketoconazoleazapropazoncolchicinediclofenacnaproxen sulindac cimetidine ranitidine tacrolimus fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

1. Drugs That Increase Cyclosporine Concentrations

Calcium Channel BlockersAntifungalsAntibioticsGlucocorticoidsOther Drugs                   diltiazemfluconazoleazithromycinmethylprednisolone    allopurinol                            nicardipineitraconazoleclarithromycinamiodaroneverapamilketoconazoleerythromycinbromocriptinevoriconazolequinupristin/colchicinedalfopristindanazolimatinibmetoclopramidenefazodoneoral contraceptivesHIV Protease inhibitorsThe 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 juiceGrapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided.

2. Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations

AntibioticsAnticonvulsantsOther Drugs/DietarySupplementsnafcillincarbamazepinebosentan St. John’s WortrifampinoxcarbazepineoctreotidephenobarbitalorlistatphenytoinsulfinpyrazoneterbinafineticlopidineBosentan Coadministration of bosentan (250 to 1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a Cmin of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, Cmax, and trough concentration of approximately 50%, 30%, and 60%, respectively, compared to when cyclosporine was given alone (See also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents). Coadministration of cyclosporine with bosentan should be avoided. BoceprevirCoadministration 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 Cmax of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.  Telaprevir Coadministration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and Cmax of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone. St. John’s WortThere have been reports of a serious drug interaction between cyclosporine and the herbal dietary supplement St. John’s Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.RifabutinRifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome P-450 system. The interaction between rifabutin and cyclosporine has not been studied. Care should be exercised when these two drugs are administered concomitantly.

B.  Effect Of Cyclosporine On The Pharmacokinetics And/Or Safety Of Other Drugs Or Agents

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.

Digoxin

Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored.

Colchicine

There are reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. Concomitant administration of cyclosporine and colchicine results in significant increases in colchicine plasma concentrations. If colchicine is used concurrently with cyclosporine, a reduction in the dosage of colchicine is recommended.

Hmg-Coa Reductase Inhibitors (Statins)

Literature and postmarketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of cyclosporine with lovastatin, simvastatin, atorvastatin, pravastatin, and, rarely fluvastatin. When concurrently administered with cyclosporine, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis.

Repaglinide

Cyclosporine may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycemia. In 12 healthy male subjects who received two doses of 100 mg cyclosporine capsule orally 12 hours apart with a single dose of 0.25 mg repaglinide tablet (one-half of a 0.5 mg tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide mean Cmax and AUC were increased 1.8 fold (range: 0.6 to -3.7 fold) and 2.4 fold (range 1.2 to 5.3 fold), respectively. Close monitoring of blood glucose level is advisable for a patient taking cyclosporine and repaglinide concomitantly.

Ambrisentan

Coadministration of ambrisentan (5 mg daily) and cyclosporine (100 to 150 mg twice daily initially, then dosing to achieve Cmin 150 to 200 ng/mL) for 8 days in healthy subjects resulted in mean increases in ambrisentan AUC and Cmax of approximately 2 fold and 1.5 fold, respectively, compared to ambrisentan alone. When coadministering ambrisentan with cyclosporine, the ambrisentan dose should not be titrated to the recommended maximum daily dose.

Anthracycline Antibiotics

High doses of cyclosporine (e.g., at starting intravenous dose of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) in cancer patients.

Aliskiren

Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single doses of cyclosporine (200 mg) and reduced dose aliskiren (75 mg), the mean Cmax of aliskiren was increased by approximately 2.5-fold (90% CI: 1.96 to 3.17) and the mean AUC by approximately 4.3 fold (90% CI: 3.52  to 5.21), compared to when these subjects received aliskiren alone. The concomitant administration of aliskiren with cyclosporine prolonged the median aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the Tmax (0.5 hours versus 1.5 to 2 hours). The mean AUC and Cmax of cyclosporine were comparable to reported literature values. Coadministration of cyclosporine and aliskiren in these subjects also resulted in an increase in the number and/or intensity of adverse events, mainly headache, hot flush, nausea, vomiting, and somnolence. The coadministration of cyclosporine with aliskiren is not recommended.

Bosentan

In healthy subjects, coadministration of bosentan and cyclosporine resulted in time-dependent mean increases in dose-normalized bosentan trough concentrations (i.e., approximately 21-fold on day 1 and 2- fold on day 8 (steady state)) compared to when bosentan was given alone as a single dose on day 1. (See also Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety)Coadministration of cyclosporine with bosentan should be avoided.

Dabigatran

The effect of cyclosporine on dabigatran concentrations had not been formally studied. Concomitant administration of dabigatran and cyclosporine may result in increased plasma dabigatran concentrations due to the P-gp inhibitory activity of cyclosporine. Coadministration of cyclosporine with dabigatran should be avoided.

Potassium-Sparing Diuretics

Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur. Caution is also required when cyclosporine is coadministered with potassium sparing drugs (e.g., angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists), potassium-containing drugs as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable.

Nonsteroidal Anti-Inflammatory Drug (Nsaid) Interactions

Clinical status and serum creatinine should be closely monitored when cyclosporine is used with NSAIDs in rheumatoid arthritis patients. (See WARNINGS)Pharmacodynamic interactions have been reported to occur between cyclosporine and both naproxen and sulindac, in that concomitant use is associated with additive decreases in renal function, as determined by 99mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does not affect blood concentrations of cyclosporine, it has been associated with approximate doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range.

Methotrexate Interaction

Preliminary data indicate that when methotrexate and cyclosporine were coadministered to rheumatoid arthritis patients (N=20), methotrexate concentrations (AUCs) were increased approximately 30% and the concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased by approximately 80%. The clinical significance of this interaction is not known. Cyclosporine concentrations do not appear to have been altered (N=6).

Sirolimus

Elevations in serum creatinine were observed in studies using sirolimus in combination with full-dose cyclosporine. This effect is often reversible with cyclosporine dose reduction. Simultaneous coadministration of cyclosporine significantly increases blood levels of sirolimus. To minimize increases in sirolimus concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration.

Nifedipine

Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine.

Methylprednisolone

Convulsions when high dose methylprednisolone is given concurrently with cyclosporine have been reported.

Other Immunosuppressive Drugs And Agents

Psoriasis patients receiving other immunosuppressive agents or radiation therapy (including PUVA and UVB) should not receive concurrent cyclosporine because of the possibility of excessive immunosuppression.

C.  Effect Of Cyclosporine On The Efficacy Of Live Vaccines

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 Apotex Corp. at 1-800-706-5575.

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

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 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. Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical maintenance dose (6 mg/kg). 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 was not mutagenic in appropriate test systems. 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 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. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown.No impairment in fertility was demonstrated in studies 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.

Pregnancy Category C

Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally.) Only at dose levels toxic to dams, were adverse effects seen in reproduction studies in rats. Cyclosporine has been shown to be embryo- and fetotoxic in rats and rabbits following oral administration at maternally toxic doses. Fetal toxicity was noted in rats at 0.8 and rabbits at 5.4 times the transplant doses in humans of 6.0 mg/kg, where dose corrections are based on body surface area. Cyclosporine was embryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardation.There are no adequate and well-controlled studies in pregnant women therefore, cyclosporine capsules (modified) should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.In pregnant transplant recipients who are being treated with immunosuppressants the risk of premature birth is increased. The following data represent the reported outcomes of 116 pregnancies in women receiving cyclosporine during pregnancy, 90% of whom were transplant patients, and most of whom received cyclosporine throughout the entire gestational period. The only consistent patterns of abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for gestational age. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) were complicated by disorders; including, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility, and fetoplacental dysfunction. Pre-term delivery occurred in 47%. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were small for gestational age. Neonatal complications occurred in 27%. Therefore, the risks and benefits of using cyclosporine capsules (modified) during pregnancy should be carefully weighed.A limited number of observations in children exposed to cyclosporine in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.Because of the possible disruption of maternal-fetal interaction, the risk/benefit ratio of using cyclosporine capsules (modified) in psoriasis patients during pregnancy should carefully be weighed with serious consideration for discontinuation of cyclosporine capsules (modified).

Nursing Mothers

Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from cyclosporine capsules (modified), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

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 (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.

Adverse Reactions

Kidney, Liver, and Heart TransplantationThe 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 StudiesIn 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 PatientsCyclosporine Patients(Sandimmune®)Sandimmune®AzathioprineKidneyHeartLiverBody System/(N=227)(N=228)(N=705)(N=112)(N=75)      Adverse Reactions%%%%%Genitourinary      Renal Dysfunction326253837Cardiovascular      Hypertension2618135327      Cramps4< 12< 10Skin      Hirsutism21< 1212845      Acne68221Central Nervous System      Tremor120213155      Convulsions31145      Headache2< 12154Gastrointestinal      Gum Hyperplasia409516      Diarrhea3< 1348      Nausea/Vomiting2< 14104      Hepatotoxicity< 1< 1474      Abdominal Discomfort< 10< 170Autonomic Nervous System      Paresthesia30121      Flushing< 10404Hematopoietic      Leukopenia219< 160      Lymphoma< 10161Respiratory      Sinusitis< 10437Miscellaneous      Gynecomastia< 10< 143Among 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 1.0%, 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, fungal, parasitic). Both generalized and localized infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. (See WARNINGS)Infectious Complications in Historical Randomized Studies in Renal Transplant Patients Using Sandimmune® Cyclosporine Treatment             Azathioprine with Steroids*(N=227)(N=228)Complication% of Complications% of ComplicationsSepticemia5.34.8Abscesses4.45.3Systemic Fungal Infection2.23.9Local Fungal Infection7.59.6Cytomegalovirus4.812.3Other Viral Infections15.918.4Urinary Tract Infections21.120.2Wound and Skin Infections7.010.1Pneumonia6.29.2*Some patients also received ALG.Postmarketing Experience, Kidney, Liver and Heart TransplantationHepatotoxicity Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported. (See WARNINGS, Hepatotoxicity)Increased Risk of Infections Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported. (See WARNINGS, Polyoma Virus Infection)Headache, including Migraine Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.Pain of lower extremities Isolated cases of pain of lower extremities have been reported in association with cyclosporine. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.Rheumatoid ArthritisThe 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:     Cyclosporine capsules (modified)/Sandimmune® Rheumatoid Arthritis  Percentage of Patients with Adverse Events ≥3% in any Cyclosporine Treated Group   Studies 651+652+2008Study 302 Study654Study654Study302 Studies651+652+2008Body SystemPreferred TermSandimmune®†(N=269)Sandimmune®(N=155)Methotrexate &Sandimmune®(N=74)Methotrexate &Placebo (N=73)cyclosporine capsules, (modified) (N=143)Placebo(N=201) Autonomic Nervous System Disorders    Flushing 2% 2% 3% 0% 5% 2% Body As A Whole–General Disorders   Accidental Trauma   0% 1% 10%  4%   4%  0%   Edema NOS* 5% 14% 12% 4% 10% <1%   Fatigue 6% 3% 8% 12% 3% 7%   Fever 2% 3% 0% 0% 2% 4%   Influenza-like symptoms <1% 6% 1% 0% 3% 2%   Pain 6% 9% 10% 15% 13% 4%   Rigors 1% 1% 4% 0% 3% 1% Cardiovascular Disorder   Arrhythmia 2% 5% 5% 6% 2% 1%   Chest Pain 4% 5% 1% 1% 6% 1%   Hypertension 8% 26% 16% 12% 25% 2% Central and Peripheral Nervous System Disorders   Dizziness 8% 6% 7% 3% 8% 3%   Headache 17% 23% 22% 11% 25% 9%   Migraine 2% 3% 0% 0% 3% 1%   Paresthesia 8% 7% 8% 4% 11% 1%   Tremor 8% 7% 7% 3% 13% 4% Gastrointestinal System Disorder   Abdominal Pain 15% 15% 15% 7% 15% 10%   Anorexia 3% 3% 1% 0% 3% 3%   Diarrhea 12% 12% 18% 15% 13% 8%   Dyspepsia 12% 12% 10% 8% 8% 4%   Flatulence Gastrointestinal 5% 5% 5% 4% 4% 1%   Disorder NOS* 0% 2% 1% 4% 4% 0%   Gingivitis 4% 3% 0% 0% 0% 1%   Gum Hyperplasia 2% 4% 1% 3% 4% 1%   Nausea 23% 14% 24% 15% 18% 14%   Rectal               Hemorrhage 0% 3% 0% 0% 1% 1%   Stomatitis 7% 5% 16% 12% 6% 8%   Vomiting 9% 8% 14% 7% 6% 5% Hearing and Vestibular Disorders   Ear Disorder  NOS* 0% 5% 0% 0% 1% 0% Metabolic and Nutritional Disorders   Hypomagnesemia 0% 4% 0% 0% 6% 0% Musculosketal System Disorders   Arthropathy 0% 5% 0% 1% 4% 0%   Leg Cramps / Involuntary               Muscle Contractions 2% 11% 11% 3% 12% 1% Psychiatric Disorders   Depression 3% 6% 3% 1% 1% 2%   Insomnia 4% 1% 1% 0% 3% 2% Renal                 Creatinine elevations ≥30% 43% 39% 55% 19% 48% 13%   Creatinine elevations ≥50% 24% 18% 26% 8% 18% 3% Reproductive Disorders, Female   Leukorrhea 1% 0% 4% 0% 1% 0%   Menstrual Disorder 3% 2% 1% 0% 1% 1% Respiratory System Disorders   Bronchitis 1% 3% 1% 0% 1% 3%   Coughing 5% 3% 5% 7% 4% 4%   Dyspnea 5% 1% 3% 3% 1% 2%   Infection NOS* 9% 5% 0% 7% 3% 10%   Pharyngitis 3% 5% 5% 6% 4% 4%   Pneumonia 1% 0% 4% 0% 1% 1%   Rhinitis 0% 3% 11% 10% 1% 0%   Sinusitis 4% 4% 8% 4% 3% 3%   Upper Respiratory Tract 0% 14% 23% 15% 13% 0% Skin and Appendages Disorders   Alopecia 3% 0% 1% 1% 4% 4%   Bullous Eruption 1% 0% 4% 1% 1% 1%   Hypertrichosis 19% 17% 12% 0% 15% 3%   Rash 7% 12% 10% 7% 8% 10%   Skin Ulceration 1% 1% 3% 4% 0% 2% Urinary System Disorders   Dysuria 0% 0% 11% 3% 1% 2%   Micturition               Frequency 2% 4% 3% 1% 2% 2%   NPN, Increased 0% 19% 12% 0% 18% 0%   Urinary Tract Infection 0% 3% 5% 4% 3% 0% Vascular (Extracardiac) Disorders   Purpura 3% 4% 1% 1% 2% 0% †Includes patients in 2.5 mg/kg/day dose group. *NOS=Not Otherwise Specified. 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, lymphadenopathyLiver 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 SpecifiedPsoriasisThe 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.Adverse Events Occurring in 3% or More of Psoriasis Patients in Controlled Clinical TrialsBody System*Preferred TermCyclosporine capsules (modified) (N=182)Sandimmune® (N=185) Infection or Potential Infection   24.7% 24.3%   Influenza-Like Symptoms 9.9% 8.1%   Upper Respiratory Tract Infections 7.7% 11.3% Cardiovascular System   28.0% 25.4%   Hypertension** 27.5% 25.4% Urinary System   24.2% 16.2%   Increased Creatinine 19.8% 15.7% Central and Peripheral Nervous System   26.4% 20.5%   Headache 15.9% 14.0%   Paresthesia 7.1% 4.8% Musculoskeletal System   13.2% 8.7%   Arthralgia 6.0% 1.1% Body As a Whole–General   29.1% 22.2%   Pain 4.4% 3.2% Metabolic and Nutritional   9.3% 9.7% Reproductive, Female   8.5% (4 of 47 females) 11.5% (6 of 52 females) Resistance Mechanism   18.7% 21.1% Skin and Appendages   17.6% 15.1%   Hypertrichosis 6.6% 5.4% Respiratory System   5.0% 6.5%   Bronchospasm, Coughing, Dyspnea, Rhinitis 5.0% 4.9% Psychiatric   5.0% 3.8% Gastrointestinal System   19.8% 28.7%   Abdominal Pain 2.7% 6.0%   Diarrhea 5.0% 5.9%   Dyspepsia 2.2% 3.2%   Gum Hyperplasia 3.8% 6.0%   Nausea 5.5% 5.9% White cell and RES   4.4% 2.7% *Total percentage of events within the system **Newly occurring hypertension=SBP ≥160 mm Hg and/or DBP ≥90 mm Hg 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 visionMild 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.Postmarketing Experience, PsoriasisCases 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.

Overdosage

There is a minimal experience with cyclosporine overdosage. Forced emesis and gastric lavage can be of value up to 2 hours after administration of cyclosporine capsules (modified). Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. Oral doses of cyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Cyclosporine is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral dosage at which half of experimental animals are estimated to die is 31 times, 39 times, and >54 times the human maintenance dose for transplant patients (6mg/kg; corrections based on body surface area) in mice, rats, and rabbits.

Blood Concentration Monitoring In Transplant Patients

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.

How Supplied

Cyclosporine capsules, USP (modified) (Soft Gelatin Capsules)25 mg An oval, opaque grey coloured softgel capsule filled with liquid, printed with "C25" in red ink across one side. Packages of 30 unit-dose blisters (NDC 60505-4630-3). 50 mg An oblong, opaque off-white coloured soft gel capsule filled with liquid, printed with "C50" in red ink across one side. Packages of 30 unit-dose blisters (NDC 60505-4631-3).100 mg An oblong opaque grey coloured softgel capsule filled with liquid, printed with "C100" in red ink across one side. Packages of 30 unit-dose blisters (NDC 60505-4632-3).Store and Dispense Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in original unit-dose container.Cyclosporine Capsules, USP (MODIFIED) (Soft Gelatin Capsules) All registered trademarks in this document are the property of their respective owners. Manufactured byManufactured forCatalent Ontario LimitedApotex Corp.Windsor, OntorioWeston, FloridaCanada N9C 3R5USA 33326Revised: July 2018Revision: 3

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