Neoral Drug Information

Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED Neoral 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 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 Neoral can be given 4 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 a 1994 survey of the use of Sandimmune 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 Neoral 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 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. 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 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 4 to 7 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 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 Neoral 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, 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 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, 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 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 Neoral should be 2.5 mg/kg/day. Neoral 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, Neoral should be discontinued (see Special Monitoring of 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 Neoral 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 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 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 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 lifelong 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 a glass of orange or apple juice. Stir well and drink at once.

Do not allow diluted oral solution to stand before drinking. Use a 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 a 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 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 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.

Wound and Skin Infections 7.0 10.1 Pneumonia 6.2 9.2 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 Infection). Headache, Including Migraine Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks. Pain of lower extremities Isolated cases of pain of lower extremities have been reported in association with cyclosporine.

Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature. Rheumatoid 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 Arthritis Percentage of Patients with Adverse Events ≥ 3% in any Cyclosporine Treated Group Studies Study Study Study Study Studies 651 + 652 + 2008 302 654 654 302 651 + 652 + 2008 Body Preferred Sandimmune† Sandimmune Methotrexate & Sandimmune Methotrexate & Placebo Neoral Placebo System Term (N = 269) (N = 155) (N = 74) (N = 73) (N = 143) (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% In addition, the following adverse events have been reported in 1% to < 3% of the rheumatoid arthritis patients in the cyclosporine treatment group in controlled clinical trials. Autonomic Nervous System: dry mouth, increased sweating Body as a Whole: allergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor NOS*, weight decrease, weight increase Cardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia Central and Peripheral Nervous System: hypoesthesia, neuropathy, vertigo Endocrine: goiter Gastrointestinal: constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder Infection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection Hematologic: anemia, epistaxis, leukopenia, lymphadenopathy Liver and Biliary System: bilirubinemia Metabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia Musculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder Neoplasms: breast fibroadenosis, carcinoma Psychiatric: anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence Reproductive (Female): breast pain, uterine hemorrhage Respiratory System: abnormal chest sounds, bronchospasm Skin and Appendages: abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria Special Senses: abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder Urinary System: abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence *NOS = Not Otherwise Specified.

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. *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 Trials Body System* Preferred Term Neoral (N = 182) Sandimmune (N = 185) Infection or Potential Infection 24.7% 24.3% Influenza-Like Symptoms 9.9% 8.1% Upper Respiratory Tract Infections 7.7% 11.3% Cardiovascular System 28.0% 25.4% Hypertension** 27.5% 25.4% Urinary System 24.2% 16.2% Increased Creatinine 19.8% 15.7% Central and Peripheral Nervous System 26.4% 20.5% Headache 15.9% 14.0% Paresthesia 7.1% 4.8% Musculoskeletal System 13.2% 8.7% Arthralgia 6.0% 1.1% Body As a Whole–General 29.1% 22.2% Pain 4.4% 3.2% Metabolic and Nutritional 9.3% 9.7% Reproductive, Female 8.5% (4 of 47 females) 11.5% (6 of 52 females) Resistance Mechanism 18.7% 21.1% Skin and Appendages 17.6% 15.1% Hypertrichosis 6.6% 5.4% Respiratory System 5.0% 6.5% Bronchospasm, Coughing, Dyspnea, Rhinitis 5.0% 4.9% Psychiatric 5.0% 3.8% Gastrointestinal System 19.8% 28.7% Abdominal Pain 2.7% 6.0% Diarrhea 5.0% 5.9% Dyspepsia 2.2% 3.2% Gum Hyperplasia 3.8% 6.0% Nausea 5.5% 5.9% White cell and RES 4.4% 2.7% 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 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.

Drug Interactions When diclofenac or methotrexate was coadministered with cyclosporine in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased (see PRECAUTIONS, Drug Interactions). No clinically significant pharmacokinetic interactions occurred between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin. Specific Populations Renal Impairment In a study performed in 4 subjects with end-stage renal disease (creatinine clearance < 5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function.

In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate. Hepatic Impairment Cyclosporine is extensively metabolized by the liver.

Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients.

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to cyclosporine, including Neoral, during pregnancy. Encourage women who are taking Neoral during pregnancy to enroll in the Transplant Pregnancy Registry International (TPRI) by calling 1-877-955-8677 or visiting https://www.transplantpregnancyregistry.org. Risk Summary Available data from published literature, including the Transplant Pregnancy Registry International, observational cohort studies, case-controlled studies, meta-analysis, case series, and case reports, over decades of use with cyclosporine in pregnancy have not identified a drug associated risk of major birth defects, or miscarriage.

Adverse maternal or fetal outcomes including hypertension, preeclampsia, preterm birth, and low birth weight are increased in patients treated with cyclosporine. However, patients receiving cyclosporine during pregnancy have underlying medical conditions and may be treated with concomitant medications that limit the interpretability of these findings (see Data). Embryo-fetal developmental (EFD) studies in rats and rabbits with cyclosporine have shown embryo-fetal toxicity at dose levels below the MRHD based on BSA. The alcohol content of Neoral should be taken into account when given to pregnant women (see WARNINGS, Special Excipients). The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Available data from the National Transplantation Pregnancy Registry (NTPR) including 622 pregnancies in renal, liver, and heart transplant recipients exposed to cyclosporine during pregnancy found that the overall rate of major birth defects, live birth rates, and miscarriage rates were comparable to the general population. Maternal and fetal adverse outcomes, including the rate of hypertension, preeclampsia, premature births, and low birth weight infants appear to be increased in transplant recipients treated with cyclosporine compared to the general population.

However, these patients have underlying medical conditions that confound the above findings. Animal Data Animal studies have shown reproductive toxicity in rats and rabbits. Three EFD studies (two oral and one intravenous) are available in rats.

In two EFD studies, pregnant rats were orally administered with cyclosporine either at doses of 10, 17, 30, 100 and 300 mg/kg/day or 4, 10 and 25 mg/kg/day from gestation day (GD) 6 to 15 or from GD 7 to 17, respectively. Maternal toxicity characterized by mortality, clinical signs of toxicity and impaired body weight gain were observed at 30 mg/kg/day and above. Cyclosporine was embryo- and fetotoxic as indicated by increased embryonic mortality and reduced fetal weight together with skeletal retardations in rats at 25 mg/kg/day and above.

In addition, ventricular septal defect was observed at 25 mg/kg/day in fetuses. In the first study, the oral no observed effect level (NOEL) for both dams and fetuses was 17 mg/kg/day (0.2 times the MRHD based on BSA). In the other oral study, the NOEL for dams and fetuses were 10 and 4 mg/kg/day (0.13 and 0.05 times the MRHD based on BSA), respectively. In the IV EFD study, rats were administered with 3, 6 and 12 mg/kg/day of cyclosporine from GD 7 to 17. An increase in post implantation loss was observed at 12 mg/kg/day; ventricular septal defect was observed at ≥ 6 mg/kg/day in fetuses.

The IV NOEL for dams and fetus were 6 and 3 mg/kg/day (0.08 and 0.04 times the MRHD, respectively, based on BSA), respectively, after IV administration. In rabbits, cyclosporine was orally administered at dose levels of 10, 30, 100 or 300 mg/kg/day from GD 6 to 18. At 100 mg/kg/day and above, reduction in body weight gain of dams and at 300 mg/kg/day abortions were observed. Maternal toxicity, embryo-fetotoxicity as indicated by increased pre- and postnatal mortality, reduced fetal weight together with skeletal retardations were observed at 100 mg/kg/day and above.

The NOEL for dams and fetuses was 30 mg/kg/day (1 times the MRHD based on BSA). In two published research studies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. These findings have not been demonstrated in other species and their relevance for humans is unknown. In a peri- and postnatal development study in rats, pregnant rats were orally administered with cyclosporine (5, 15 or 45 mg/kg/day) from GD 15 until end of lactation.

At 45 mg/kg/day (0.5 times the MRHD based on BSA), increased pre and postnatal mortality of offspring and reduced body weight gain of surviving pups were observed. Cyclosporine up to 15 mg/kg/day (0.2 times the MRHD based on BSA) had no effect on pregnancy, pre and postnatal development of offspring.

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

General Neoral is 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 Neoral. Psoriasis Psoriasis patients who are treated with Neoral 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 Neoral.

There is a minimal experience with cyclosporine overdosage. Forced emesis and gastric lavage can be of value up to 2 hours after administration of Neoral. Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal.

Oral doses of cyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. General supportive measures and symptomatic treatment should be followed in all cases of overdosage.

Cyclosporine is not dialyzable to any great extent, nor is it cleared well by charcoal hemoperfusion. The oral dosage at which half of experimental animals are estimated to die is 31 times, 39 times, and > 54 times the human maintenance dose for transplant patients (6mg/kg; corrections based on body surface area) in mice, rats, and rabbits.