CyclosporineRx

Trade Names: Sandimmune, Neoral (microemulsion)

Synonyms: Cyclosporin A, CyA, CSA (abbreviations not recommended)

Drug Class: Immunosuppressant, DMARD

Preparations
Soft gelatin capsules: 25, 50, 100 mg
Oral liquid: 100 mg/mL
Injection: 50 mg/mL

Dose: Starting dose in autoimmune disease is 2.5 mg/kg/day orally in divided doses. Calculate dose according to approximate ideal body weight in obese patients. After 8–12 weeks, the dose may be increased monthly by 0.5 mg/kg/day to maximum of 4 mg/kg/day. The risk of renal disease increases with doses >4 mg/kg/day and duration of therapy. The dosing of the two preparations available (Neoral and Sandimmune) is similar but they are not equivalent. If switching from Sandimmune to Neoral, lower doses of Neoral may be required because it has better bioavailability.

Indications: RA refractory to standard DMARD treatment; also approved for use in psoriasis; anecdotal reports of efficacy in psoriatic arthritis, SLE, myositis, Behçet’s syndrome, and pyoderma gangrenosum

Mechanism of Action: Inhibits production of IL-2; immunomodulator

Contraindications: Hypersensitivity to cyclosporine; immunodeficiency; renal impairment

Precautions: Avoid if past or present malignancy, uncontrolled hypertension, or renal or hepatic dysfunction. Avoid live virus vaccines.

Monitoring: Monitor blood pressure and creatinine every 2 weeks for first 2–3 months and then monthly if stable. If creatinine rises by >25% above baseline values, reduce dose of cyclosporine by 25-50% and check again. Continue dose reduction until the creatinine concentration is back within 25% of baseline. If creatinine  dose not  return to within 25% of baseline within 2 dose modifications, discontinue cyclosporine.  Elevations of creatinine level (>25% of baseline), even if within the normal range, require action. Monitor potassium and uric acid levels, and hepatic enzymes every 1–3 months.

Pregnancy Risk: C

Adverse Effects
Common: Hypertension, increased creatinine, hirsutism, nausea, cramps, tremor, gingival hypertrophy, hyperkalemia, hypomagnesemia, renal impairment, hyperuricemia
Less common: Seizures, headache, muscle cramps, allergy, myositis, pancreatitis, infection, lymphoma

Drug Interactions
Increased concentrations of cyclosporine: CYP3A inhibitors such as grapefruit juice, clarithromycin, erythromycin,    ketoconazole, fluconazole, itraconazole, diltiazem, verapamil, nicardipine, protease inhibitors, and others

Decreased cyclosporine concentrations: rifampicin, phenytoin, phenobarbital, carbamazepine, isoniazid

Colchicine: Cyclosporine and colchicine increase each other’s concentrations

K+-sparing diuretics: Hyperkalemia

Statins: Increased risk of myopathy, rhabdomyolysis, acute renal failure

Nephrotoxic drugs: Increased nephrotoxicity

Patient Instructions: Avoid sunlight (skin cancer). Regular blood monitoring is required.

Comments: Neoral is a newer microemulsion formulation of cyclosporine that gives a more favorable pharmacokinetic profile with higher peak levels and less inter- and intraindividual variability in levels. Efficacy and toxicity of Neoral and Sandimmune are similar. Cyclosporine as a single agent in RA is no more effective than other available drugs. The combination of MTX and cyclosporine is more effective than MTX alone but side effects with long term use have meant that cyclosporine is very seldom used to treat RA. The use of NSAIDs is permitted in patients with RA taking cyclosporine, and in many studies they have been used together. However, NSAIDs should be stopped if renal function declines while taking cyclosporine. Monitoring blood levels of cyclosporine is a poor predictor of efficacy and toxicity in autoimmune disease and is seldom indicated (e.g., assessing compliance, absorption, drug interaction).

Clinical Pharmacology: Cyclosporine is variably and erratically absorbed. The Neoral formulation has more predictable bioavailability. Hepatic metabolism is by CYP3A enzymes, which is the source of the multiple drug interactions with cyclosporine. Renal excretion of metabolites.

Cost: $$$$

BIBLIOGRAPHY

American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002;46:328-46. PMID: 11840435.