Cyclosporine

Cyclosporine (ciclosporin) is a calcineurin inhibitor used in organ transplantation, severe psoriasis, rheumatoid arthritis, atopic dermatitis, uveitis, nephrotic syndrome and aplastic anaemia. It has a narrow therapeutic window, wide pharmacokinetic variability and many interactions, so dosing is directed by trough levels, blood pressure and creatinine.

Class. Calcineurin inhibitor immunosuppressant.

Mechanism. It binds cyclophilin, and the complex inhibits calcineurin, blocking nuclear factor of activated T cells and interleukin 2 transcription, so T cell activation is suppressed.

Pharmacokinetics. Absorption is variable (bioavailability 20 to 50 percent), and differs between formulations; microemulsion formulations are not interchangeable with older oil-based ones. Metabolised by CYP3A4 and a P-glycoprotein substrate. Half-life 8 to 19 hours. Biliary excretion predominates, so renal dose adjustment is not needed for clearance but nephrotoxicity limits use.

Solid organ transplantation (adult).

• Oral: 10 to 15 mg/kg/day in 2 divided doses starting 4 to 12 hours before surgery in some centres, then maintenance 2 to 6 mg/kg/day in 2 divided doses, adjusted to trough level.

• Intravenous: 3 to 5 mg/kg/day by continuous infusion (about one third of the oral dose).

• Typical trough target: 100 to 200 ng/mL in early kidney transplantation and 50 to 150 ng/mL later, varying by organ and co-immunosuppression.

Rheumatoid arthritis (specialist).

• Start 2.5 mg/kg/day in 2 divided doses.

• Titration: after 8 weeks increase by 0.5 to 0.75 mg/kg/day, then again after 4 weeks if needed.

• Maximum dose: 4 mg/kg/day. Stop if no benefit by 6 months at the maximum dose.

• Loading dose: none.

Severe psoriasis. Start 2.5 mg/kg/day in 2 divided doses; after 4 weeks increase by 0.5 mg/kg/day to a maximum of 5 mg/kg/day. Duration normally limited to 1 year of continuous use (up to 2 years in some regions).

Severe atopic dermatitis. 2.5 to 5 mg/kg/day for short courses of up to 8 to 12 weeks, specialist initiated.

Steroid-dependent nephrotic syndrome and aplastic anaemia (specialist). Dose to trough: nephrotic syndrome 3 to 5 mg/kg/day, aplastic anaemia 5 mg/kg/day.

Dose reduction for renal toxicity. In non-transplant use, if creatinine rises by more than 30 percent from baseline on two readings 2 weeks apart, reduce the dose by 25 to 50 percent; if it does not recover within 1 month, stop.

Contraindications. Uncontrolled hypertension, impaired renal function (non-transplant indications), uncontrolled infection, malignancy (except non-melanoma skin), hypersensitivity to polyoxyethylated castor oil in the intravenous form, and concurrent PUVA, tar or other topical immunosuppressives in psoriasis.

Boxed-warning-level risks. Nephrotoxicity, hypertension, skin cancer and lymphoma, serious infection, and risk of overimmunosuppression; treatment only under specialist supervision.

Adverse effects. Common: tremor, hirsutism, gingival hyperplasia, hypertension, raised creatinine, hyperkalaemia, hypomagnesaemia, hyperlipidaemia, headache. Serious: chronic nephrotoxicity and interstitial fibrosis, thrombotic microangiopathy, posterior reversible encephalopathy syndrome, seizures, hyperuricaemia and gout, hepatotoxicity.

Major interactions.

• Raised cyclosporine level: diltiazem, verapamil, erythromycin, clarithromycin, azole antifungals, grapefruit, ritonavir, amiodarone.

• Lowered level: rifampicin, carbamazepine, phenytoin, phenobarbital, St John's wort.

• Additive nephrotoxicity: NSAIDs, aminoglycosides, amphotericin, tacrolimus.

• Hyperkalaemia: potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers.

• Myopathy: statins (avoid simvastatin; limit atorvastatin and rosuvastatin), colchicine.

• Sirolimus and everolimus: give 4 hours after cyclosporine.

Common prescribing errors. Switching formulations without level checks; adding a CYP3A4 inhibitor or inducer without dose change; prescribing with NSAIDs; omitting blood pressure and creatinine checks.

Special groups.

• Pregnancy: used in transplant recipients and severe autoimmune disease when benefit outweighs risk; monitor blood pressure, levels and foetal growth.

• Breastfeeding: avoid in most regions; some specialists permit with infant monitoring.

• Children: weight-based; higher doses in mg/kg are often needed.

• Older adults: lower starting doses and closer renal and blood pressure monitoring.

• Kidney impairment: no clearance adjustment, but avoid in non-transplant use if eGFR is reduced.

• Liver impairment: reduce the dose and monitor levels.

• Region: drug availability and level monitoring may be limited; fixed formulation and avoidance of unsupervised interacting drugs matter most.

Formulations. Capsules (25, 50 and 100 mg), oral solution, and intravenous concentrate (dilute in 0.9 percent sodium chloride or 5 percent glucose and infuse over 2 to 6 hours or continuously). Take at the same times each day, consistently with or without food. Do not take with grapefruit.

Baseline. Blood pressure (two readings), creatinine and eGFR (two readings), potassium, magnesium, liver enzymes, lipids, uric acid, and skin and infection screen.

Monitoring. Whole blood trough levels (12 hour) in transplantation: frequently in the first weeks then monthly to 3 monthly. In rheumatological use: blood pressure and creatinine every 2 weeks for 3 months, then monthly. Potassium, magnesium and lipids at least 3 monthly.

Stop or reduce thresholds. Creatinine rise of more than 30 percent from baseline on repeat testing; sustained hypertension not controlled by treatment (reduce dose or stop); new neurological signs or microangiopathy (stop and investigate).

Overdose. No specific antidote. Supportive care, activated charcoal if early; dialysis is not effective.

Referral and escalation. Always specialist initiated. Refer urgently for acute kidney injury, seizure, haemolytic anaemia with thrombocytopenia, or levels outside target.