CYCLOSPORINE MODIFIED

Cyclosporine capsules, USP MODIFIED are an oral formulation of cyclosporine, USP that immediately forms an emulsion 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 Tolypocladium inflatum . 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-amino-butyryl- N -methylglycyl- N -methyl-L-leucyl-L-valyl- N -methyl-L-leucyl) and has the following structural formula: Each soft gelatin capsule for oral administration contains either 25 mg, 50 mg or 100 mg of cyclosporine, USP MODIFIED and 15.8% v/v (12.4% wt./vol) dehydrated alcohol and has the following inactive ingredients: DL-alpha-tocopherol, gelatin, glycine, glycerol 99%, glyceryl monolinoleate, polyoxyl 40 hydrogenated castor oil, propylene glycol, sorbitol solution and titanium dioxide. In addition, the 25 mg and 50 mg contain ferric oxide (yellow) and the 100 mg contains ferric oxide (brown). structural formula

Kidney, Liver, and Heart Transplantation 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. Rheumatoid Arthritis 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. Psoriasis Cyclosporine capsules, USP MODIFIED are indicated for the treatment of adult, nonimmunocompromised patients with severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have failed to respond to at least one systemic therapy (e.g., PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated. While rebound rarely occurs, most patients will experience relapse with cyclosporine capsules, USP MODIFIED as with other therapies upon cessation of treatment.

Cyclosporine capsules, USP MODIFIED, soft gelatin capsules, has increased bioavailability in comparison to Sandimmune (cyclosporine capsules, USP). Cyclosporine capsules, USP MODIFIED and Sandimmune (cyclosporine capsules, USP) are not bioequivalent and cannot be used interchangeably without physician supervision. The daily dose of cyclosporine capsules, USP MODIFIED should always be given in two divided doses (BID). It is recommended that cyclosporine capsules, USP MODIFIED be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided. Specific Populations 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 ). Hepatic Impairment The clearance of cyclosporine may be significantly reduced in severe liver disease patients (see CLINICAL PHARMACOLOGY ). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (see WARNINGS and PRECAUTIONS ). Newly Transplanted Patients 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. Conversion from Sandimmune (cyclosporine capsules, USP) to cyclosporine capsules, USP MODIFIED in Transplant Patients 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. Transplant Patients with Poor Absorption of Sandimmune (cyclosporine capsules, USP) 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. Rheumatoid Arthritis 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. Psoriasis 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. 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.

General Cyclosporine capsules, USP MODIFIED are contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation. Rheumatoid Arthritis Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine capsules, USP MODIFIED. Psoriasis 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.

Kidney, Liver, and Heart Transplantation The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. Hypertension Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients. Glomerular Capillary Thrombosis Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to graft failure. The pathologic changes resembled those seen in the hemolytic-uremic syndrome and included thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been observed when other immunosuppressives have been employed post-transplantation. Hypomagnesemia Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine toxicity. Clinical Studies In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with cyclosporine capsules, USP MODIFIED were comparable with those observed in 208 transplanted patients who received Sandimmune (cyclosporine capsules, USP) 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 (cyclosporine capsules, USP), the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants. Randomized Kidney Patients Cyclosporine Patients (Sandimmune (cyclosporine capsules, USP)) Body System Adverse Reactions Sandimmune (cyclosporine capsules, USP) (N = 227)% Azathioprine (N = 228)% Kidney (N = 705)% Heart (N = 112)% Liver (N = 75)% Genitourinary Renal Dysfunction 32 6 25 38 37 Cardiovascular Hypertension 26 18 13 53 27 Cramps 4 < 1 2 < 1 0 Skin Hirsutism 21 < 1 21 28 45 Acne 6 8 2 2 1 Central Nervous System Tremor 12 0 21 31 55 Convulsions 3 1 1 4 5 Headache 2 < 1 2 15 4 Gastrointestinal Gum Hyperplasia 4 0 9 5 16 Diarrhea 3 < 1 3 4 8 Nausea/ Vomiting 2 < 1 4 10 4 Hepatotoxicity < 1 < 1 4 7 4 Abdominal Discomfort < 1 0 < 1 7 0 Autonomic Nervous System Paresthesia 3 0 1 2 1 Flushing < 1 0 4 0 4 Hematopoietic Leukopenia 2 19 < 1 6 0 Lymphoma < 1 0 1 6 1 Respiratory Sinusitis < 1 0 4 3 7 Miscellaneous Gynecomastia < 1 0 < 1 4 3 Among 705 kidney transplant patients treated with cyclosporine oral solution (Sandimmune) in clinical trials, the reason for treatment discontinuation was renal toxicity in 5.4%, infection in 0.9%, lack of efficacy in 1.4%, acute tubular necrosis in 1.0%, 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, USP 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 capsules, USP) Complication Cyclosporine Treatment (N=227) % of Complications Azathioprine with Steroids * (N=228) % of Complications Septicemia 5.3 4.8 Abscesses 4.4 5.3 Systemic Fungal Infection 2.2 3.9 Local Fungal Infection 7.5 9.6 Cytomegalovirus 4.8 12.3 Other Viral Infections 15.9 18.4 Urinary Tract Infections 21.1 20.2 Wound and Skin Infections 7.0 10.1 Pneumonia 6.2 9.2 * Some patients also received ALG. Postmarketing Experience, Kidney, Liver and Heart Transplantation Hepatotoxicity 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 Infections ). 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 Arthritis 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: Cyclosporine capsules, USP MODIFIED/Sandimmune (cyclosporine capsules, USP) Rheumatoid Arthritis Percentage of Patients with Adverse Events ≥ 3% in any Cyclosporine Treated Group Studies 651 + 652 + 2008 Study 302 Study 654 Study 654 Study 302 Studies 651 + 652 + 2008 Body System Preferred Term Sandimmune † (cyclosporine capsules, USP) (N = 269) Sandimmune (cyclosporine capsules, USP) (N = 155) Methotrexate & Sandimmune (cyclosporine capsules, USP) (N = 74) Methotrexate & Placebo (N = 73) Cyclosporine capsules, USP 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 Disorders 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 Disorders 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 5% 5% 5% 4% 4% 1% Gastrointestinal 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% Musculoskeletal 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 only. * 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, 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 Psoriasis 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. Adverse Events Occurring in 3% or More of Psoriasis Patients in Controlled Clinical Trials Body System * Preferred Term Cyclosporine capsules, USP MODIFIED (N = 182) Sandimmune (cyclosporine capsules, USP) (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 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. Postmarketing Experience, Psoriasis 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.