What is the usage and dosage of Cyclosporin (Cyclosporine) in treating autoimmune diseases and preventing organ rejection?

Cyclosporine: Usage and Dosage in Autoimmune Diseases and Organ Transplantation

FDA-Approved Indications

Cyclosporine is FDA-approved for prophylaxis of organ rejection in kidney, liver, and heart transplantation (always used with corticosteroids), treatment of severe active rheumatoid arthritis refractory to methotrexate, and treatment of severe recalcitrant plaque psoriasis in adults who have failed at least one systemic therapy. 1, 2

Organ Transplantation

• Primary indication: Prevention of organ rejection in kidney, liver, and heart allogeneic transplants 1, 2
• Must be combined with adrenal corticosteroids 2
• Can also treat chronic rejection in patients previously on other immunosuppressants 2
• Target trough levels: 250-400 ng/mL (or C2 levels of 600-1,500 ng/mL) 3

Rheumatoid Arthritis

• Reserved for severe active disease inadequately responsive to methotrexate 1
• Can be combined with methotrexate in patients who don't respond to methotrexate alone 1

Psoriasis

• For adult, nonimmunocompromised patients with severe, extensive/disabling, recalcitrant plaque psoriasis 1
• Must have failed at least one systemic therapy (PUVA, retinoids, or methotrexate) or have contraindications to other systemic therapies 1

Dosing Regimens by Indication

Psoriasis Dosing

Start at 2.5-3.0 mg/kg/day divided twice daily for approximately 4 weeks, then gradually increase if needed to a maximum of 5 mg/kg/day for 12-16 weeks. 3

• Lower dose (2.5 mg/kg/day): Achieves PASI 75 in 28-85% of patients 3
• Higher dose (5 mg/kg/day): Achieves PASI 75 in 50-97% of patients 3
• Moderate dose (3 mg/kg/day): 50-70% achieve PASI 75,30-50% achieve PASI 90 3
• Microemulsion formulation demonstrates more rapid onset and greater initial efficacy than conventional formulation 3
• Treatment duration: 12-16 weeks for short courses 3
• Most patients relapse approximately 3 months after discontinuation unless other treatments are substituted 3

Atopic Dermatitis Dosing

Dose range: 3-6 mg/kg/day (standardly 150-300 mg/day in adults), divided twice daily, taken at the same time each day. 3

• Higher initial doses result in more rapid disease control and improved quality of life measures (pruritus, sleep disturbance) 3
• Most patients note significant decrease in disease activity within 2-6 weeks 3
• Once clearance or near-clearance is achieved and maintained, taper or discontinue 3
• Maintain remission with emollients, topical agents, and/or phototherapy 3
• Long-term effectiveness cannot be determined from current literature; data on relapse after discontinuation is limited 3

Dermatology General Principles

Cyclosporine is reserved for severe disease and is generally regarded as a second-line agent, especially when treatment is likely to be prolonged beyond 2-3 months, due to its narrow therapeutic index. 3

Autoimmune Hepatitis (Off-Label)

• Dose: 2-5 mg/kg daily (Neoral formulation) 3
• Target trough levels: 100-300 ng/mL 3
• Effective in 93% of patients as front-line or salvage therapy 3
• Reserved for corticosteroid-refractory disease 3

Chronic Urticaria (Off-Label)

For antihistamine-refractory chronic urticaria, use cyclosporine 4 mg/kg daily for up to 2 months, or up to 5 mg/kg body weight if omalizumab fails. 4, 5

• Effective in two-thirds of severe autoimmune urticaria cases unresponsive to antihistamines 5
• Only consider after failure of standard and high-dose antihistamines (up to 4x standard dose) and omalizumab 4

Critical Safety Considerations

Most Important Hazards

The most important hazards are nephrotoxicity and hypertension, requiring careful monitoring to balance benefit against toxicity. 3

Comprehensive Toxicity Profile

• Nephrotoxicity: Most common adverse event 3
• Neurotoxicity: Ranges from mild tremor/paresthesias to frank delirium and seizures 3
• Cardiovascular: Hypertension 3
• Metabolic: Hyperglycemia, hyperlipidemia 3
• Dermatologic: Hirsutism, gingival hypertrophy 3
• Hematologic: Hemolytic-uremic syndrome 3
• Infectious: Increased bacterial, fungal, and viral infections when combined with other immunosuppressants 3
• Malignancy: Higher risk of skin malignancies and lymphoproliferative disorders 3

Mandatory Monitoring

Monitor CBC, renal function (creatinine), glucose, lipid profile, potassium, magnesium levels, and blood pressure closely after initiating cyclosporine. 3

• Blood concentration monitoring: Essential due to erratic absorption and narrow therapeutic index 2
• Cyclosporine levels should be monitored regularly with dose adjustments to avoid toxicity from high concentrations and organ rejection from low absorption 2
• Consider C2 monitoring (level 2 hours post-dose) as it may be associated with improved renal function 3

Critical Drug Interactions

Cyclosporine is metabolized through hepatic cytochrome P450 (CYP3A4); any medication or hepatic dysfunction affecting this system will cause variable cyclosporine trough levels. 3

• Cyclosporine inhibits CYP3A4 and may reduce clearance of digoxin, colchicine, and HMG-CoA reductase inhibitors 3
• Cyclosporine may increase bosentan concentration when used together 3
• Review medication lists before initiating therapy and periodically thereafter 3

Pregnancy and Special Populations

Cyclosporine is FDA Pregnancy Category C; it crosses the placenta but has not been shown to be teratogenic in animal studies. 3

• Case series of pregnant liver transplant recipients showed no increased risk of maternal complications, congenital malformation, or impaired child development 3
• Manufacturer does not recommend use in pregnant women unless maternal benefit justifies potential risk 3

Formulation Considerations

Cyclosporine capsules (NON-MODIFIED) and Neoral (cyclosporine MODIFIED/microemulsion) are NOT bioequivalent and cannot be used interchangeably without physician supervision. 2

• The microemulsion formulation (MODIFIED) has decreased bioavailability compared to NON-MODIFIED 2
• Microemulsion formulation shows more rapid onset and greater initial efficacy in atopic dermatitis 3
• Both formulations available as oral capsules and solution 3

Infection Prophylaxis

Prophylaxis against Pneumocystis jiroveci should be implemented with cyclosporine use. 3

Prescriber Requirements

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe cyclosporine (NON-MODIFIED). 2

• Patients must be managed in facilities equipped with adequate laboratory and supportive medical resources 2
• The physician responsible for maintenance therapy must have complete information for patient follow-up 2