ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Kidney, Liver, and Heart Transplantation. The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.HypertensionHypertension, which is usually mild to moderate, may occur in approximately 50% of patients following renal transplantation and in most cardiac transplant patients.Glomerular Capillary ThrombosisGlomerular 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.HypomagnesemiaHypomagnesemia 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 Neoral 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)SandimmuneAzathioprineKidneyHeartLiverBody SystemAdverse Reactions(N 227)%(N 228)%(N 705)%(N 112)%(N 75)%GenitourinaryRenal Dysfunction326253837CardiovascularHypertension2618135327Cramps4< 12< 10SkinHirsutism21< 1212845Acne68221Central Nervous System Tremor120213155Convulsions31145Headache2< 12154GastrointestinalGum Hyperplasia409516Diarrhea3< 1348Nausea/Vomiting2< 14104Hepatotoxicity< 1< 1474Abdominal Discomfort< 10< 170Autonomic Nervous SystemParesthesia30121Flushing< 10404HematopoieticLeukopenia219< 160 Lymphoma< 10161RespiratorySinusitis< 10437MiscellaneousGynecomastia< 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 (Neoral), 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).Some patients also received ALG.Infectious Complications in Historical Randomized Studies in Renal Transplant Patients Using SandimmuneCyclosporine TreatmentAzathioprine 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. Postmarketing Experience, Kidney, Liver and Heart Transplantation. HepatotoxicityCases 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 InfectionsCases 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 MigraineCases 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 extremitiesIsolated 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:+ Includes patients in 2.5 mg/kg/day dose group only. NOS Not Otherwise Specified.Neoral/Sandimmune Rheumatoid ArthritisPercentage of Patients with Adverse Events >= 3% in any Cyclosporine Treated GroupStudiesStudyStudyStudyStudyStudies651 652 2008302654654302651 652 2008BodyPreferredSandimmune+Sandimmune Methotrexate SandimmuneMethotrexate PlaceboNeoralPlaceboSystemTerm(N 269)(N 155)(N 74)(N 73)(N 143)(N 201)Autonomic Nervous System DisordersFlushing 2%2%3%0%5%2%Body As Whole-General DisordersAccidental Trauma0%1%10%4%4%0%Edema NOS5%14%12%4%10%< 1%Fatigue6%3%8%12%3%7%Fever2%3%0%0%2%4%Influenza-like symptoms< 1%6%1%0%3%2%Pain6%9%10%15%13%4%Rigors1%1%4%0%3%1%Cardiovascular DisordersArrhythmia2%5%5%6%2%1%Chest Pain4%5%1%1%6%1%Hypertension8%26%16%12%25%2%Central and Peripheral Nervous System DisordersDizziness8%6%7%3%8%3%Headache17%23%22%11%25%9%Migraine2%3%0%0%3%1%Paresthesia8%7%8%4%11%1%Tremor8%7%7%3%13%4%Gastrointestinal System DisordersAbdominal Pain15%15%15%7%15%10%Anorexia3%3%1%0%3%3%Diarrhea12%12%18%15%13%8%Dyspepsia12%12%10%8%8%4%Flatulence5%5%5%4%4%1%Gastrointestinal Disorder NOS0%2%1%4%4%0%Gingivitis4%3%0%0%0%1%Gum Hyperplasia2%4%1%3%4%1%Nausea23%14%24%15%18%14%Rectal Hemorrhage0%3%0%0%1%1%Stomatitis7%5%16%12%6%8%Vomiting9%8%14%7%6%5%Hearing and Vestibular DisordersEar Disorder NOS0%5%0%0%1%0%Metabolic and Nutritional DisordersHypomagnesemia0%4%0%0%6%0%Musculoskeletal System DisordersArthropathy0%5%0%1%4%0%Leg Cramps Involuntary Muscle Contractions2%11%11%3%12%1%Psychiatric DisordersDepression3%6%3%1%1%2%Insomnia4%1%1%0%3%2%RenalCreatinine elevations >= 30%43%39%55%19%48%13%Creatinine elevations >= 50%24%18%26%8%18%3%Reproductive Disorders, FemaleLeukorrhea1%0%4%0%1%0%Menstrual Disorder3%2%1%0%1%1%Respiratory System DisordersBronchitis1%3%1%0%1%3%Coughing5%3%5%7%4%4%Dyspnea5%1%3%3%1%2%Infection NOS9%5%0%7%3%10%Pharyngitis3%5%5%6%4%4%Pneumonia1%0%4%0%1%1%Rhinitis0%3%11%10%1%0%Sinusitis4%4%8%4%3%3%Upper Respiratory Tract0%14%23%15%13%0%Skin and Appendages DisordersAlopecia3%0%1%1%4%4%Bullous Eruption1%0%4%1%1%1%Hypertrichosis19%17%12%0%15%3%Rash7%12%10%7%8%10%Skin Ulceration1%1%3%4%0%2%Urinary System DisordersDysuria0%0%11%3%1%2%Micturition Frequency2%4%3%1%2%2%NPN, Increased0%19%12%0%18%0%Urinary Tract Infection0%3%5%4%3%0%Vascular (Extracardiac) DisordersPurpura3%4%1%1%2%0%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 sweatingBody as Whole: allergy, asthenia, hot flushes, malaise, overdose, procedure NOS, tumor NOS, weight decrease, weight increaseCardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemiaCentral and Peripheral Nervous System: hypoesthesia, neuropathy, vertigoEndocrine: goiterGastrointestinal: constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorderInfection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infectionHematologic: anemia, epistaxis, leukopenia, lymphadenopathyLiver and Biliary System: bilirubinemiaMetabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemiaMusculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorderNeoplasms: breast fibroadenosis, carcinomaPsychiatric: anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolenceReproductive (Female): breast pain, uterine hemorrhageRespiratory System: abnormal chest sounds, bronchospasmSkin and Appendages: abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticariaSpecial Senses: abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorderUrinary System: abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinenceNOS 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. 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.Total percentage of events within the system.Newly occurring hypertension SBP >= 160 mm Hg and/or DBP >= 90 mm Hg.Adverse Events Occurring in 3% or More of Psoriasis Patients in Controlled Clinical TrialsBody SystemPreferred TermNeoral (N 182)Sandimmune (N 185)Infection or Potential Infection24.7%24.3%Influenza-Like Symptoms9.9%8.1%Upper Respiratory Tract Infections7.7%11.3%Cardiovascular System28.0%25.4%Hypertension27.5%25.4%Urinary System24.2%16.2%Increased Creatinine19.8%15.7%Central and Peripheral Nervous System26.4%20.5%Headache15.9%14.0%Paresthesia7.1%4.8%Musculoskeletal System13.2%8.7%Arthralgia6.0%1.1%Body As Whole-General29.1%22.2%Pain4.4%3.2%Metabolic and Nutritional9.3%9.7%Reproductive, Female8.5% (4 of 47 females)11.5% (6 of 52 females)Resistance Mechanism18.7%21.1%Skin and Appendages17.6%15.1%Hypertrichosis6.6%5.4%Respiratory System5.0%6.5%Bronchospasm, Coughing, Dyspnea, Rhinitis5.0%4.9%Psychiatric5.0%3.8%Gastrointestinal System19.8%28.7%Abdominal Pain2.7%6.0%Diarrhea5.0%5.9%Dyspepsia2.2%3.2%Gum Hyperplasia3.8%6.0%Nausea5.5%5.9%White cell and RES4.4%2.7%The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:Body as Whole: fever, flushes, hot flushes Cardiovascular: chest painCentral and Peripheral Nervous System: appetite increased, insomnia, dizziness, nervousness, vertigoGastrointestinal: abdominal distention, constipation, gingival bleedingLiver and Biliary System: hyperbilirubinemiaNeoplasms: skin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]Reticuloendothelial: platelet, bleeding, and clotting disorders, red blood cell disorderRespiratory: infection, viral and other infectionSkin and Appendages: acne, folliculitis, keratosis, pruritus, rash, dry skinUrinary 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. minor and dose related hyperbilirubinemia has been observed in the absence of hepatocellular damage. Cyclosporine therapy may be associated with 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.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Cyclosporine is 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 greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freunds adjuvant arthritis, and graft versus host disease in many animal species for 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.. Pharmacokinetics. The immunosuppressive activity of cyclosporine is primarily due to parent drug. Following oral administration, absorption of cyclosporine is incomplete. The extent of absorption of cyclosporine is dependent on the individual patient, the patient population, and the formulation. Elimination of cyclosporine is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of cyclosporine from blood is generally biphasic, with terminal half-life of approximately 8.4 hours (range to 18 hours). Following intravenous administration, the blood clearance of cyclosporine (assay: HPLC) is approximately to mL/min/kg in adult recipients of renal or liver allografts. Blood cyclosporine clearance appears to be slightly slower in cardiac transplant patients.The Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED are bioequivalent. Neoral Oral Solution diluted with orange juice or apple juice is bioequivalent to Neoral Oral Solution diluted with water. The effect of milk on the bioavailability of cyclosporine when administered as Neoral Oral Solution has not been evaluated.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 Neoral 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 Neoral and 19% to 26% for Sandimmune. In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for Neoral and 16% to 38% for Sandimmune.. Absorption. Neoral 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 Neoral 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 Neoral compared to following administration of Sandimmune. The dose normalized AUC in de novo liver transplant patients administered Neoral 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune. AUC and Cmax are also increased (Neoral relative to Sandimmune) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on Neoral relative to Sandimmune, the predose trough concentrations (dose-normalized) are similar for the two formulations.Following oral administration of Neoral, the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5 to 2.0 hours. The administration of food with Neoral decreases the cyclosporine AUC and Cmax. high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Neoral administration decreased the AUC by 13% and Cmax by 33%. The effects of low fat meal (667 kcal, 15 grams fat) were similar.The effect of T-tube diversion of bile on the absorption of cyclosporine from Neoral was investigated in eleven de novo liver transplant patients. When the patients were administered Neoral 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%).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 Neoral 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 radioimmunoassay.Pharmacokinetic Parameters (mean +- SD)Dose/day1Dose/weightAUC2CmaxTrough3CL/FCL/FPatient Population(mg/d)(mg/kg/d)(ng.hr/mL)(ng/mL)(ng/mL)(mL/min)(mL/min/kg)De novo renal transplant4 597 +- 1747.95 +- 2.818772 +- 20891802 +- 428361 +- 129593 +- 2047.8 +- 2.9Week (N 37)Stable renal transplant4 344 +- 1224.10 +- 1.586035 +- 21941333 +- 469251 +- 116492 +- 1405.9 +- 2.1(N=55)De novo liver transplant5 458 +- 1906.89 +- 3.687187 +- 28161555 +- 740268 +- 101577 +- 3098.6 +- 5.7Week (N 18)De novo rheumatoid arthritis6 182 +- 55.62.37 +- 0.362641 +- 877728 +- 26396.4 +- 37.7613 +- 1968.3 +- 2.8(N 23)De novo psoriasis6 189 +- 69.82.48 +- 0.652324 +- 1048655 +- 18674.9 +- 46.7723 +- 18610.2 +- 3.9Week (N 18). Distribution. Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as to 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).. Metabolism. Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the coadministration of 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 Neoral and Sandimmune in crossover study), and bile concentration data from de novo liver transplant patients (4 administered Neoral, administered Sandimmune), the percentage of dose present as M1, M9, and M4N metabolites is similar when either Neoral or Sandimmune is administered.. Excretion. Only 0.1% of 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 PopulationsRenal ImpairmentIn study performed in subjects with end-stage renal disease (creatinine clearance 5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over hours administered at the end of hemodialysis session resulted in 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 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 Population. Pharmacokinetic data from pediatric patients administered Neoral or Sandimmune are very limited. In 15 renal transplant patients aged 3-16 years, cyclosporine whole blood clearance after IV administration of Sandimmune was 10.6 +- 3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In study of renal transplant patients aged to 16, the cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 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, Neoral also demonstrates an increased bioavailability as compared to Sandimmune. In liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of Neoral was 43% (range 30% to 68%) and for Sandimmune in the same individuals absolute bioavailability was 28% (range 17% to 42%).1AUC was measured over one dosing interval.2Assay: Cyclo-trac specific monoclonal radioimmunoassay.3Assay: TDx specific monoclonal fluorescence polarization immunoassay.Pediatric Pharmacokinetic Parameters (mean +- SD)Dose/dayDose/weightAUC1CmaxCL/FCL/FPatient Population(mg/d)(mg/kg/d)(ng.hr/mL)(ng/mL)(mL/min)(mL/min/kg)Stable liver transplant2 Age 2-8, Dosed TID (N 9)101 +- 255.95 +- 1.322163 +- 801629 +- 219285 +- 9416.6 +- 4.3Age 8-15, Dosed BID (N 8)188 +- 554.96 +- 2.094272 +- 1462975 +- 281378 +- 8010.2 +- 4.0Stable liver transplant3 Age 3, Dosed BID (N 1)1208.335832105017111.9Age 8-15, Dosed BID (N 5)158 +- 555.51 +- 1.914452 +- 24751013 +- 635328 +- 12111.0 +- 1.9Stable renal transplant3 Age 7-15, Dosed BID (N 5)328 +- 837.37 +- 4.116922 +- 19881827 +- 487418 +- 1438.7 +- 2.9. Geriatric 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 STUDIES SECTION.

CLINICAL TRIALS. 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 of treatment groups (1) Neoral(R) and (2) cyclosporine, both of which were started at 2.5 mg/kg/day and increased after weeks for inefficacy in increments of 0.5 mg/kg/day to maximum of 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: 0.72-5.17) for Neoral(R) and 3.27 mg/kg/day (range: 0.73 5.68) for cyclosporine.. Rheumatoid Arthritis. The effectiveness of Sandimmune and Neoral in the treatment of severe rheumatoid arthritis was evaluated in clinical studies involving 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 responder being defined as patient having completed the trial with 20% improvement in the tender and the swollen joint count and 20% improvement in of of investigator global, patient global, disability, and erythrocyte sedimentation rates (ESR) for the Studies 651 and 652 and of 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 3:3:2 randomization to one of the following three groups: (1) cyclosporine dosed at 2.5 to 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 3:3:2 randomization to of treatment arms: (1) 1.5 to mg/kg/day of cyclosporine, (2) 2.5 to mg/kg/day of cyclosporine, and (3) placebo. Treatment duration was 16 weeks. The mean cyclosporine dose for group 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 of treatment groups (1) cyclosporine 2.5 to mg/kg/day with adjustments after the first month to achieve 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 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 and if there was no evidence of toxicity and further increases of 0.5 mg/kg/day at weeks and 16 if < 30% decrease in active joint count occurred without any significant toxicity; dose decreases could be made at any time for toxicity or (2) placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the last visit was 2.8 mg/kg/day (range: 1.3 to 4.1). See Graph below.Study 302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive or intolerant to at least one prior major RA drug. Patients were randomized to of treatment groups (1) Neoral and (2) cyclosporine, both of which were started at 2.5 mg/kg/day and increased after weeks for inefficacy in increments of 0.5 mg/kg/day to maximum of 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 Neoral and 3.27 mg/kg/day (range: 0.73 to 5.68) for cyclosporine. See Graph below.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIEDNeoral has increased bioavailability in comparison to Sandimmune. Neoral and Sandimmune are not bioequivalent and cannot be used interchangeably without physician supervision.The daily dose of Neoral should always be given in two divided doses (BID). It is recommended that Neoral be administered on 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 PopulationsRenal Impairment in Kidney, Liver, and Heart TransplantationCyclosporine 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 PsoriasisPatients with impaired renal function should not receive cyclosporine (see CONTRAINDICATIONS, WARNINGS and PRECAUTIONS).Hepatic ImpairmentThe 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 Neoral can be given to 12 hours prior to transplantation or be given postoperatively. The initial dose of Neoral 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 Neoral is the same as the initial oral dose of Sandimmune. Suggested initial doses are available from the results of 1994 survey of the use of Sandimmune in US transplant centers. The mean +- SD initial doses were +- mg/kg/day for renal transplant patients (75 centers), +- mg/kg/day for liver transplant patients (30 centers), and +- mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses. The Neoral dose is subsequently adjusted to achieve 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 Neoral as for Sandimmune. Using the same trough concentration target range for Neoral as for Sandimmune results in greater cyclosporine exposure when Neoral is administered (see Pharmacokinetics, Absorption). Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Neoral 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. representative dosage schedule based on the patients weight started with 2.0 mg/kg/day for the first days tapered to 1.0 mg/kg/day by week, 0.6 mg/kg/day by weeks, 0.3 mg/kg/day by month, and 0.15 mg/kg/day by months and thereafter as 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 to Neoral in Transplant Patients. In transplanted patients who are considered for conversion to Neoral from Sandimmune, Neoral should be started with the same daily dose as was previously used with Sandimmune (1:1 dose conversion). The Neoral dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Neoral as for Sandimmune results in greater cyclosporine exposure when Neoral is administered (see Pharmacokinetics, Absorption). Patients with suspected poor absorption of Sandimmune require different dosing strategies (see Transplant Patients with Poor Absorption of Sandimmune, 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 to days after conversion to Neoral. 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 Neoral must be adjusted accordingly.. Transplant Patients with Poor Absorption of Sandimmune. Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune may have poor or inconsistent absorption of cyclosporine from Sandimmune. After conversion to Neoral, patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Neoral, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Neoral at doses greater than 10 mg/kg/day. The dose of Neoral 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 week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.. Rheumatoid Arthritis. The initial dose of Neoral is 2.5 mg/kg/day, taken twice daily as divided (BID) oral dose. Salicylates, NSAIDs, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS, Drug Interactions). Onset of action generally occurs between and 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 weeks and again after 12 weeks to maximum of mg/kg/day. If no benefit is seen by 16 weeks of therapy, Neoral 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 patients 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, Neoral should be discontinued. The same initial dose and dosage range should be used if Neoral is combined with the recommended dose of methotrexate. Most patients can be treated with Neoral doses of 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 weeks after stopping cyclosporine.. Psoriasis. The initial dose of Neoral should be 2.5 mg/kg/day. Neoral should be taken twice daily, as divided (1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least weeks, barring adverse events. If significant clinical improvement has not occurred in patients by that time, the patients 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 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 patients 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, Neoral should be discontinued (see Special Monitoring of Psoriasis Patients).Patients generally show some improvement in the clinical manifestations of psoriasis in weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of dose-titration clinical trial with Neoral indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after weeks and in 79% of the patients after 16 weeks. Treatment should be discontinued if satisfactory response cannot be achieved after weeks at mg/kg/day or the patients maximum tolerated dose. Once patient is adequately controlled and appears stable the dose of Neoral 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 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 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 cases of pustular and cases of erythrodermic psoriasis. Long term experience with Neoral 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.. Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED-Recommendations for Administration. To make Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED more palatable, it should be diluted with orange or apple juice that is at room temperature. Patients should avoid switching diluents frequently. Grapefruit juice affects metabolism of cyclosporine and should be avoided. The combination of Neoral solution with milk can be unpalatable. The effect of milk on the bioavailability of cyclosporine when administered as Neoral Oral Solution has not been evaluated.Take the prescribed amount of Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED from the container using the dosing syringe supplied, after removal of the protective cover, and transfer the solution to glass of orange or apple juice. Stir well and drink at once. Do not allow diluted oral solution to stand before drinking. Use glass container (not plastic). Rinse the glass with more diluent to ensure that the total dose is consumed. After use, dry the outside of the dosing syringe with clean towel and replace the protective cover. Do not rinse the dosing syringe with water or other cleaning agents. If the syringe requires cleaning, it must be completely dry before resuming use.. 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 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. 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 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 broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not replacement for renal function monitoring or tissue biopsies.

GENERAL PRECAUTIONS SECTION.

General. HypertensionCyclosporine is the active ingredient of Neoral. Hypertension is 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).VaccinationDuring treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.Special Monitoring of Rheumatoid Arthritis PatientsBefore initiating treatment, careful physical examination, including blood pressure measurements (on at least two occasions) and two creatinine levels to estimate baseline should be performed. Blood pressure and serum creatinine should be evaluated every weeks during the initial months and then monthly if the patient is stable. It is advisable to monitor serum creatinine and blood pressure always after an increase of the dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and after initiation of new NSAID therapy during Neoral treatment. If coadministered with methotrexate, CBC and liver function tests are recommended to be monitored monthly (see also PRECAUTIONS, General, Hypertension).In patients who are receiving cyclosporine, the dose of Neoral should be decreased by 25% to 50% if hypertension occurs. If hypertension persists, the dose of Neoral should be further reduced or blood pressure should be controlled with antihypertensive agents. In most cases, blood pressure has returned to baseline when cyclosporine was discontinued.In placebo-controlled trials of rheumatoid arthritis patients, systolic hypertension (defined as an occurrence of two systolic blood pressure readings 140 mmHg) and diastolic hypertension (defined as two diastolic blood pressure readings 90 mmHg) occurred in 33% and 19% of patients treated with cyclosporine, respectively. The corresponding placebo rates were 22% and 8%.Special Monitoring for Psoriasis PatientsBefore initiating treatment, careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since Neoral is an immunosuppressive agent, patients should be evaluated for the presence of occult infection on their first physical examination and for the presence of tumors initially, and throughout treatment with Neoral. Skin lesions not typical for psoriasis should be biopsied before starting Neoral. Patients with malignant or premalignant changes of the skin should be treated with Neoral only after appropriate treatment of such lesions and if no other treatment option exists.Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium, potassium, uric acid, and lipids.The risk of cyclosporine nephropathy is reduced when the starting dose is low (2.5 mg/kg/day), the maximum dose does not exceed 4.0 mg/kg/day, serum creatinine is monitored regularly while cyclosporine is administered, and the dose of Neoral is decreased when the rise in creatinine is greater than or equal to 25% above the patients pretreatment level. The increase in creatinine is generally reversible upon timely decrease of the dose of Neoral or its discontinuation.Serum creatinine and BUN should be evaluated every weeks during the initial months of therapy and then monthly if the patient is stable. If the serum creatinine is greater than or equal to 25% above the patients pretreatment level, serum creatinine should be repeated within two weeks. If the change in serum creatinine remains greater than or equal to 25% above baseline, Neoral should be reduced by 25% to 50%. If at any time the serum creatinine increases by greater than or equal to 50% above pretreatment level, Neoral should be reduced by 25% to 50%. Neoral should be discontinued if reversibility (within 25% of baseline) of serum creatinine is not achievable after two dosage modifications. It is advisable to monitor serum creatinine after an increase of the dose of nonsteroidal anti-inflammatory drug and after initiation of new nonsteroidal anti-inflammatory therapy during Neoral treatment.Blood pressure should be evaluated every weeks during the initial months of therapy and then monthly if the patient is stable, or more frequently when dosage adjustments are made. Patients without history of previous hypertension before initiation of treatment with Neoral, should have the drug reduced by 25% to 50% if found to have sustained hypertension. If the patient continues to be hypertensive despite multiple reductions of Neoral, then Neoral should be discontinued. For patients with treated hypertension, before the initiation of Neoral therapy, their medication should be adjusted to control hypertension while on Neoral. Neoral should be discontinued if change in hypertension management is not effective or tolerable.CBC, uric acid, potassium, lipids, and magnesium should also be monitored every weeks for the first months of therapy, and then monthly if the patient is stable or more frequently when dosage adjustments are made. Neoral dosage should be reduced by 25% to 50% for any abnormality of clinical concern.In controlled trials of cyclosporine in psoriasis patients, cyclosporine blood concentrations did not correlate well with either improvement or with side effects such as renal dysfunction.Information for Patients: Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for change in dosage.Patients should be informed of the necessity of repeated laboratory tests while they are receiving cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.Patients should be advised that during treatment with cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.Patients should be given careful dosage instructions. Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED should be diluted, preferably with orange or apple juice that is at room temperature. The combination of Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED with milk can be unpalatable.Patients should be advised to take Neoral on 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.

PRECAUTIONS SECTION.

PRECAUTIONS. General. HypertensionCyclosporine is the active ingredient of Neoral. Hypertension is 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).VaccinationDuring treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.Special Monitoring of Rheumatoid Arthritis PatientsBefore initiating treatment, careful physical examination, including blood pressure measurements (on at least two occasions) and two creatinine levels to estimate baseline should be performed. Blood pressure and serum creatinine should be evaluated every weeks during the initial months and then monthly if the patient is stable. It is advisable to monitor serum creatinine and blood pressure always after an increase of the dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and after initiation of new NSAID therapy during Neoral treatment. If coadministered with methotrexate, CBC and liver function tests are recommended to be monitored monthly (see also PRECAUTIONS, General, Hypertension).In patients who are receiving cyclosporine, the dose of Neoral should be decreased by 25% to 50% if hypertension occurs. If hypertension persists, the dose of Neoral should be further reduced or blood pressure should be controlled with antihypertensive agents. In most cases, blood pressure has returned to baseline when cyclosporine was discontinued.In placebo-controlled trials of rheumatoid arthritis patients, systolic hypertension (defined as an occurrence of two systolic blood pressure readings 140 mmHg) and diastolic hypertension (defined as two diastolic blood pressure readings 90 mmHg) occurred in 33% and 19% of patients treated with cyclosporine, respectively. The corresponding placebo rates were 22% and 8%.Special Monitoring for Psoriasis PatientsBefore initiating treatment, careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since Neoral is an immunosuppressive agent, patients should be evaluated for the presence of occult infection on their first physical examination and for the presence of tumors initially, and throughout treatment with Neoral. Skin lesions not typical for psoriasis should be biopsied before starting Neoral. Patients with malignant or premalignant changes of the skin should be treated with Neoral only after appropriate treatment of such lesions and if no other treatment option exists.Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium, potassium, uric acid, and lipids.The risk of cyclosporine nephropathy is reduced when the starting dose is low (2.5 mg/kg/day), the maximum dose does not exceed 4.0 mg/kg/day, serum creatinine is monitored regularly while cyclosporine is administered, and the dose of Neoral is decreased when the rise in creatinine is greater than or equal to 25% above the patients pretreatment level. The increase in creatinine is generally reversible upon timely decrease of the dose of Neoral or its discontinuation.Serum creatinine and BUN should be evaluated every weeks during the initial months of therapy and then monthly if the patient is stable. If the serum creatinine is greater than or equal to 25% above the patients pretreatment level, serum creatinine should be repeated within two weeks. If the change in serum creatinine remains greater than or equal to 25% above baseline, Neoral should be reduced by 25% to 50%. If at any time the serum creatinine increases by greater than or equal to 50% above pretreatment level, Neoral should be reduced by 25% to 50%. Neoral should be discontinued if reversibility (within 25% of baseline) of serum creatinine is not achievable after two dosage modifications. It is advisable to monitor serum creatinine after an increase of the dose of nonsteroidal anti-inflammatory drug and after initiation of new nonsteroidal anti-inflammatory therapy during Neoral treatment.Blood pressure should be evaluated every weeks during the initial months of therapy and then monthly if the patient is stable, or more frequently when dosage adjustments are made. Patients without history of previous hypertension before initiation of treatment with Neoral, should have the drug reduced by 25% to 50% if found to have sustained hypertension. If the patient continues to be hypertensive despite multiple reductions of Neoral, then Neoral should be discontinued. For patients with treated hypertension, before the initiation of Neoral therapy, their medication should be adjusted to control hypertension while on Neoral. Neoral should be discontinued if change in hypertension management is not effective or tolerable.CBC, uric acid, potassium, lipids, and magnesium should also be monitored every weeks for the first months of therapy, and then monthly if the patient is stable or more frequently when dosage adjustments are made. Neoral dosage should be reduced by 25% to 50% for any abnormality of clinical concern.In controlled trials of cyclosporine in psoriasis patients, cyclosporine blood concentrations did not correlate well with either improvement or with side effects such as renal dysfunction.Information for Patients: Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for change in dosage.Patients should be informed of the necessity of repeated laboratory tests while they are receiving cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.Patients should be advised that during treatment with cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.Patients should be given careful dosage instructions. Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED should be diluted, preferably with orange or apple juice that is at room temperature. The combination of Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED with milk can be unpalatable.Patients should be advised to take Neoral on 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.

WARNINGS SECTION.

WARNINGS. (See also BOXED WARNING). All Patients. Cyclosporine, the active ingredient of Neoral, can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of cyclosporine. Renal dysfunction including structural kidney damage is potential consequence of Neoral and therefore renal function must be monitored during therapy. Care should be taken in using cyclosporine with nephrotoxic drugs (see PRECAUTIONS).Patients receiving Neoral 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 Neoral therapy and reflect 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 Neoral is not bioequivalent to Sandimmune, conversion from Neoral to Sandimmune using 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from Neoral to Sandimmune should be made with increased monitoring to avoid the potential of underdosing.. Kidney, Liver, and Heart Transplant. NephrotoxicityCyclosporine, the active ingredient of Neoral, 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 to months after renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at 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 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, 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.ap 0.05, bp 0.01, cp 0.001, dp 0.0001Nephrotoxicity vs. RejectionParameterNephrotoxicityRejectionHistoryDonor 50 years old or hypotensiveProlonged kidney preservationProlonged anastomosis timeConcomitant nephrotoxic drugs Anti-donor immune responseRetransplant patientClinicalOften 6 weeks postopb Prolonged initial nonfunction (acute tubular necrosis)Often 4 weeks postopb Fever 37.5CWeight gain 0.5 kgGraft swelling and tendernessDecrease in daily urine volume 500 mL (or 50%) LaboratoryCyA serum trough level 200 ng/mLGradual rise in Cr (< 0.15 mg/dL/day)a Cr plateau 25% above baselineBUN/Cr >= 20 CyA serum trough level 150 ng/mLRapid rise in Cr (> 0.3 mg/dL/day)a Cr 25% above baselineBUN/Cr 20BiopsyArteriolopathy (medial hypertrophy a, hyalinosis,nodular deposits, intimal thickening, endothelialvacuolization, progressive scarring)Tubular atrophy, isometric vacuolization, isolated calcificationsMinimal edemaMild focal infiltratesc Diffuse interstitial fibrosis, often striped formEndovasculitisc (proliferationa, intimal arteritisb,necrosis, sclerosis) Tubulitis with RBCb and WBCb casts, some irregular vacuolizationInterstitial edemac and hemorrhageb Diffuse moderate to severe mononuclear infiltratesd Glomerulitis (mononuclear cells)c Aspiration CytologyCyA deposits in tubular and endothelial cellsFine isometric vacuolization of tubular cells Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cellsThese strongly express HLA-DR antigens Urine CytologyTubular cells with vacuolization and granularizationDegenerative tubular cells, plasma cells, and lymphocyturia 20% of sediment Manometry UltrasonographyIntracapsular pressure 40 mm Hgb Unchanged graft cross sectional areaIntracapsular pressure 40 mm Hgb Increase in graft cross sectional area AP diameter >= Transverse diameter Magnetic Resonance ImageryNormal appearanceLoss of distinct corticomedullary junction, swelling image intensity of parachyma approaching that of psoas, loss of hilar fat Radionuclide ScanNormal or generally decreased perfusionDecrease in tubular function(131 I-hippuran) decrease in perfusion (99m Tc DTPA)Patchy arterial flowDecrease in perfusion decrease in tubular functionIncreased uptake of Indium 111 labeled platelets or Tc-99m in colloid TherapyResponds to decreased cyclosporineResponds to increased steroids or antilymphocyte globulinA form of 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 reduction in rising serum creatinine despite 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 striped form of interstitial fibrosis with tubular atrophy. Though none of these morphologic changes is entirely specific, 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 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 Neoral dose to excessive blood concentrations.Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering Neoral with other drugs that may impair renal function (see PRECAUTIONS, Drug Interactions).Thrombotic MicroangiopathyOccasionally patients have developed 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 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, 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 InfectionsPatients receiving immunosuppressants, including Neoral, 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 Neoral, 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 Neoral. 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 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 Arthritis. Cyclosporine nephropathy was detected in renal biopsies of out of 60 (10%) rheumatoid arthritis patients after the average treatment duration of 19 months. Only one patient, out of these patients, was treated with dose <= mg/kg/day. Serum creatinine improved in all but one patient after discontinuation of cyclosporine. The maximal creatinine increase appears to be factor in predicting cyclosporine nephropathy.There is 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 survey of approximately 2,300 patients treated with cyclosporine for rheumatoid arthritis, and another case of lymphoma was reported in clinical trial. Although other tumors (12 skin cancers, 24 solid tumors of diverse types, and multiple myeloma) were also reported in this survey, epidemiologic analyses did not support relationship to cyclosporine other than for malignant lymphomas.Patients should be thoroughly evaluated before and during Neoral treatment for the development of malignancies. Moreover, use of Neoral 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 potent immunosuppressive agent with number of potentially serious side effects, the risks and benefits of using Neoral should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in Neoral, 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 Neoral.Renal dysfunction is potential consequence of Neoral therefore renal function must be monitored during therapy.Patients receiving Neoral 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 Neoral therapy and reflects reduction in the glomerular filtration rate.Kidney biopsies from 86 psoriasis patients treated for 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 mean of additional years, the number with cyclosporine induced nephropathy rose to 26/86 (30%). The majority of patients (19/26) were on dose of >= 5.0 mg/kg/day (the highest recommended dose is mg/kg/day). The patients were also on cyclosporine for greater than 15 months (18/26) and/or had clinically significant increase in serum creatinine for greater than month (21/26). Creatinine levels returned to normal range in 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 patients in cyclosporine postmarketing experience. Skin malignancies were reported in 16 (1.1%) of these patients; all but of them had previously received PUVA therapy. Methotrexate was received by patients. UVB and coal tar had been used by and patients, respectively. Seven patients had either history of previous skin cancer or potentially predisposing lesion was present prior to cyclosporine exposure. Of the 16 patients with skin cancer, 11 patients had 18 squamous cell carcinomas and patients had 10 basal cell carcinomas.There were two lymphoproliferative malignancies; one case of non-Hodgkins 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: 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 Neoral only after complete resolution of suspicious lesions, and only if there are no other treatment options (see Special Monitoring for Psoriasis Patients).Special ExcipientsAlcohol (ethanol)The alcohol content (see DESCRIPTION) of Neoral should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g., pregnant or breastfeeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients, or pediatric patients. For an adult weighing 70 kg, the maximum daily oral dose would deliver about gram of alcohol which is approximately 6% of the amount of alcohol contained in standard drink.