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Drug Reference

cyclosporine

calcineurin inhibitor· Brands: Neoral, Sandimmune, Gengraf, RestasisIVPOTOP

Mechanism of action
Cyclosporine is a calcineurin inhibitor. It binds to cyclophilin to form a complex that inhibits calcineurin phosphatase. This prevents dephosphorylation of nuclear factor of activated T cells (NFAT), blocking its translocation to the nucleus and reducing transcription of interleukin-2 and other cytokines. Consequently, T cell activation and proliferation are suppressed, providing immunosuppression.
Pharmacokinetics
Cyclosporine is administered orally or intravenously. Oral bioavailability varies by formulation, approximately 30% for the original emulsion but higher with the microemulsion form. It is extensively metabolised by CYP3A4 in the liver and intestinal wall, with an elimination half-life of about 19 hours. Excretion is primarily in the bile, with a small proportion in urine. Because of a narrow therapeutic index, monitoring of blood concentrations is essential for dose adjustment.
Indications & dosing

Prophylaxis of organ rejection in kidney transplant

Individualised based on trough levels

  • adult · PO: 5–10 mg/kg/day twice daily · Individualised based on trough levels

Prophylaxis of organ rejection in liver transplant

Individualised based on trough levels

  • adult · PO: 5–10 mg/kg/day twice daily · Individualised based on trough levels

Prophylaxis of organ rejection in heart transplant

Individualised based on trough levels

  • adult · PO: 5–10 mg/kg/day twice daily · Individualised based on trough levels

Severe chronic plaque psoriasis

For severe disease unresponsive to other therapy

  • adult · PO: 2.5–5 mg/kg/day once daily · For severe disease unresponsive to other therapy

Rheumatoid arthritis

For severe active disease when conventional treatment fails

  • adult · PO: 2.5–4 mg/kg/day once daily · For severe active disease when conventional treatment fails

Steroid-dependent nephrotic syndrome

Licensed in some regions, off-label in others

  • adult · PO: 5 mg/kg/day once daily · Licensed in some regions, off-label in others
Contraindications & precautions
  • Hypersensitivity to cyclosporine or any of its excipients · Severe allergic reactions can occur; avoid in those with a history of such reactions.
  • Uncontrolled hypertension · Cyclosporine can cause or worsen hypertension; control blood pressure before starting therapy.
  • Uncontrolled malignancy or premalignant conditions · Immunosuppression may increase the risk of cancer progression.
  • Severe renal impairment (in non-transplant indications) · Use with caution; in transplant recipients, renal impairment is not an absolute contraindication but requires careful monitoring and dose adjustment.
  • Severe hepatic impairment · Cyclosporine is metabolised in the liver; may require dose reduction and close monitoring.
  • Monitor renal function (serum creatinine, estimated GFR) regularly, especially during dose titration or when adding interacting drugs.
  • Monitor blood pressure, liver function, serum lipids, and electrolytes (potassium, magnesium) as cyclosporine can cause elevations or depletions.
  • Use therapeutic drug monitoring to guide dosing, as cyclosporine has a narrow therapeutic index and wide interpatient variability.
  • Avoid grapefruit juice and products containing it, as it inhibits CYP3A4 and increases cyclosporine levels.
  • Avoid live vaccines during therapy, as immunosuppression may reduce efficacy and increase risk of infection.
  • Use effective contraception in women of childbearing potential, as cyclosporine may cause harm to the fetus, though benefits may outweigh risks in some cases.
Adverse effects
  • Nephrotoxicityserious
  • Hypertension
  • Tremor
  • Gingival hyperplasia
  • Hirsutism
  • Hyperkalaemiaserious
  • Hepatotoxicityserious
  • Increased risk of infectionserious
  • Malignancy (e.g., lymphoma, skin cancer)serious
  • Neurotoxicity (e.g., seizures, confusion, posterior reversible encephalopathy syndrome)serious
Interactions
  • diltiazemmajorConsider avoiding the combination if possible. If co-prescribed, monitor cyclosporine trough levels frequently (e.g., every 1-2 weeks initially) and adjust the cyclosporine dose to maintain therapeutic concentrations. Monitor renal function and blood pressure. Reduce cyclosporine dose by 30-50% when starting diltiazem, and re-monitor after discontinuation of diltiazem.
  • ibuprofenmajorAvoid concomitant use if possible. If necessary, use the lowest effective dose of ibuprofen for the shortest duration. Monitor serum creatinine, blood urea nitrogen, and cyclosporine trough levels frequently (e.g., every 2-4 weeks) during therapy and for several weeks after discontinuation. Ensure adequate hydration and consider alternative analgesics such as paracetamol for pain relief.
  • fluconazolemajorIf co-administration is necessary, monitor cyclosporine trough concentrations before starting fluconazole and then at frequent intervals (e.g., twice weekly) during therapy and after discontinuation of fluconazole. Adjust the cyclosporine dose according to the measured levels and clinical response. Monitor renal function and serum creatinine. Consider an alternative antifungal with less CYP3A4 inhibition, such as an echinocandin, but fluconazole may be used with careful monitoring and dose adjustment.
  • rifampicinmajorAvoid co-prescription where possible. If concurrent use is necessary, increase the cyclosporine dose and monitor whole-blood trough levels frequently, adjusting the dose as needed. After stopping rifampicin, reduce the cyclosporine dose and monitor closely to avoid toxicity.
  • erythromycinmajorAvoid concomitant use if possible. If co-prescription is necessary, consider a non-interacting macrolide (e.g., azithromycin). When erythromycin is required, closely monitor cyclosporine trough levels, renal function, and blood pressure. Expect to reduce the cyclosporine dose, often by 25-50%, and adjust based on levels. Monitor levels frequently during therapy and for several days after stopping erythromycin.
  • clarithromycinmajorAvoid concomitant use of clarithromycin and cyclosporine if possible. If co-administration is considered necessary, reduce the cyclosporine dose empirically by approximately 50% and closely monitor cyclosporine trough levels, renal function, and blood pressure. Measure cyclosporine concentrations before starting clarithromycin, then twice weekly during co-administration, and after discontinuing clarithromycin. Adjust the cyclosporine dose to maintain therapeutic levels. Consider alternative macrolides with less CYP3A4 inhibitory activity, such as azithromycin, if appropriate.
  • amlodipinemajorMonitor cyclosporine trough levels closely, especially after initiating, discontinuing, or changing the dose of amlodipine. Adjust the cyclosporine dose as necessary to maintain therapeutic levels. Monitor renal function, blood pressure, and signs of toxicity. Advise patients to report symptoms such as headache, tremor, or significant hypotension. Consider alternative antihypertensive agents if the interaction cannot be managed.
  • simvastatincontraindicatedCo-prescription is contraindicated. Do not use simvastatin with cyclosporine. If a statin is needed, consider an alternative with lower interaction risk, such as pravastatin, under specialist advice.
  • atorvastatinmajorAvoid co-prescription where possible. If concurrent use is unavoidable, use the lowest recommended atorvastatin dose (e.g., 10 mg daily) and monitor for muscle symptoms and creatine kinase levels. Advise the patient to report unexplained muscle pain or weakness.
  • rosuvastatinmajorAvoid concomitant use where possible. If co-administration is essential, use the lowest effective rosuvastatin dose (not exceeding 5 mg daily) and monitor the patient for muscle symptoms and for creatine kinase elevations at baseline and periodically thereafter. Reassess renal function and consider an alternative statin with less interaction potential.
Renal & hepatic adjustment
  • Hepatic impairment (mild): No dose adjustment required, but monitor liver function and cyclosporine levels.
  • Hepatic impairment (moderate): Use with caution, consider dose reduction, and monitor levels frequently.
  • Hepatic impairment (severe): Reduce initial dose by 25-50%, monitor levels closely, and consider alternative if possible.
Monitoring, pregnancy & toxicity
  • Cyclosporine trough concentration · Just before next dose
  • Serum creatinine and estimated GFR · Regularly, initially twice weekly
  • Blood pressure · At each visit
  • Liver function tests (ALT, AST, bilirubin) · Monthly
  • Serum potassium · Monthly
  • Serum magnesium · Monthly
  • Pregnancy: Use only when potential benefit outweighs risk; specialist supervision recommended.
  • Toxicity: Nephrotoxicity: rise in serum creatinine, reduced urine output, and hypertension. · Reduce dose or discontinue; monitor levels, ensure adequate hydration, and adjust other nephrotoxic agents.
  • Toxicity: Hypertension: commonly occurs, may be severe. · Treat with antihypertensives; consider dose reduction or switching to alternative immunosuppressant.
  • Toxicity: Neurotoxicity: tremor, headache, confusion, paresthesia, seizures. · Reduce dose; discontinue if severe symptoms occur; monitor serum levels.
  • Toxicity: Hyperkalemia: may be due to decreased renal potassium excretion. · Monitor potassium; treat with potassium binders or diuretics; adjust cyclosporine dose.
Clinical notes
Cyclosporine is used for prevention of organ transplant rejection and for severe psoriasis, rheumatoid arthritis, and nephrotic syndrome. It can cause nephrotoxicity, hypertension, tremor, and gingival hyperplasia. Drug interactions are significant: CYP3A4 inhibitors increase levels, while inducers decrease them. Grapefruit juice raises levels. Blood pressure, renal function, and serum levels should be monitored. Immunosuppression increases susceptibility to infections and malignancies. Live vaccines should be avoided. Use in pregnancy only if benefit outweighs risk.

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BNF; local formulary