Ciclosporin

Immunosuppressants. Calcineurin inhibitors

ATC code: L04AD01 (Ciclosporin)

Brand names

Sandimmune, Neoral, Gengraf, Restasis

Mechanism of action

Binds the cytoplasmic protein cyclophilin in T lymphocytes. The cyclosporine-cyclophilin complex inhibits the phosphatase calcineurin, blocking dephosphorylation of the transcription factor NFAT and its nuclear translocation. The result is suppression of interleukin-2 and other cytokine synthesis, T-lymphocyte activation and proliferation. Effects on B cells and neutrophils are markedly weaker. Metabolized by CYP3A4 and subject to numerous drug interactions.

Indications

Maintenance immunosuppression after organ transplantation

First line

Cyclosporine is one of the cornerstone maintenance immunosuppressants after kidney, liver, heart, lung and bone marrow transplantation. Standard regimens combine it with an antimetabolite (mycophenolate mofetil, ) and a glucocorticoid. In recent years has gradually replaced cyclosporine in most protocols due to better graft survival, but cyclosporine remains an alternative when tacrolimus is not tolerated or specific adverse effects develop.

Drug–drug interactions

12 pairs found. Sorted from critical to minor.

Critical

Colchicine

Antigout agents

Mechanism

Cyclosporine inhibits both CYP3A4 and P-glycoprotein – the clearance routes of colchicine. Fatal myopathy, neuropathy, and pancytopenia have been reported in transplant patients on both drugs.

Symptoms

Profuse diarrhoea, vomiting, abdominal pain – first signs of toxicity. Pancytopenia (drop in leukocytes, erythrocytes, platelets), muscle weakness, peripheral neuropathy, hepatic and renal injury follow. Fatal cases have been reported.

Management

For patients with renal or hepatic impairment, the combination is not prescribed. With preserved function, colchicine 0.3 mg every other day. For acute gout in a transplant patient, an alternative is intra-articular or short-course systemic glucocorticoid.

Sources

FDA: Colcrys (colchicine) prescribing information (2012)

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Critical

Dronedarone

Class III antiarrhythmic

Mechanism

Cyclosporine is a strong CYP3A4 and P-glycoprotein inhibitor. Dronedarone levels rise several-fold, plus cyclosporine itself is proarrhythmic. Multaq Section 4.3 specifically lists cyclosporine.

Symptoms

QT prolongation on ECG. Clinically: dizziness, syncope, palpitations. Severe cases progress to polymorphic ventricular tachycardia (torsades de pointes) with risk of ventricular fibrillation and sudden cardiac death. Risk rises with hypokalaemia and hypomagnesaemia.

Management

The combination is not prescribed. For post-transplant atrial fibrillation, use amiodarone or rhythm control via catheter ablation. Alternative immunosuppression: tacrolimus, with attention to its own QT risk.

Sources

FDA: Multaq (dronedarone) prescribing information (2020)

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Critical

Rosuvastatin

HMG-CoA reductase inhibitors (statins)

Mechanism

Cyclosporine blocks the OATP1B1 transporter, the uptake route of rosuvastatin into hepatocytes. Rosuvastatin levels rise 7-fold. This is unique among statins: other cyclosporine–statin pairs go through CYP3A4, but rosuvastatin barely uses CYP3A4 – OATP1B1 drives the risk.

Symptoms

Pain and weakness in large muscle groups (thighs, shoulders, calves), dark urine, elevated creatine kinase. Severe cases progress to rhabdomyolysis with acute kidney injury. Symptoms appear within 1–2 weeks of co-prescription.

Management

The combination is not prescribed. For transplant patients needing a statin, use pravastatin up to 20 mg/day. Check creatine kinase at 4–6 weeks.

Sources

FDA: Crestor (rosuvastatin) prescribing information (2010)

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Critical

Simvastatin

HMG-CoA reductase inhibitors (statins)

Mechanism

Cyclosporine blocks two simvastatin clearance routes: the OATP1B1 transporter (uptake into hepatocytes) and CYP3A4. Active simvastatin levels rise 5- to 8-fold. The Zocor label specifically lists cyclosporine as an absolute contraindication.

Symptoms

Management

The combination is not prescribed. For transplant patients needing a statin, use pravastatin up to 20 mg/day or fluvastatin (minimal interaction with cyclosporine). Check creatine kinase every 4–6 weeks.

Sources

FDA: Zocor (simvastatin) prescribing information (2012)

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Major

Atorvastatin

HMG-CoA reductase inhibitors (statins)

Mechanism

Cyclosporine blocks the OATP1B1 transporter and CYP3A4 – two atorvastatin clearance routes. Atorvastatin plasma levels rise 8- to 15-fold, with high myopathy and rhabdomyolysis risk, particularly in transplant patients.

Symptoms

Management

For transplant patients needing a statin, use pravastatin up to 20 mg/day or fluvastatin (minimal cyclosporine interaction). Use atorvastatin only when no alternative exists, capped at 10 mg/day, with creatine kinase every 4 weeks.

Sources

FDA: Lipitor (atorvastatin) prescribing information (2017)

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Major

Carbamazepine

Antiepileptics. Carboxamide derivatives

Mechanism

Carbamazepine induces CYP3A4 – the main cyclosporine metabolic route. Cyclosporine plasma levels drop sharply; immunosuppression weakens, raising transplant rejection risk.

Symptoms

Rejection symptoms depend on the organ: fever, graft tenderness, rising creatinine (kidney); jaundice and rising liver enzymes (liver); dyspnoea (heart, lungs). Symptoms appear 1–3 weeks after starting carbamazepine.

Management

Avoid the combination. Alternative anticonvulsants in transplant patients: levetiracetam, lamotrigine, or gabapentin (minimal CYP3A4 effect). If carbamazepine is unavoidable, measure cyclosporine levels 2–3 times weekly and increase the dose.

Sources

FDA: Tegretol (carbamazepine) prescribing information (2009)

Major

Clarithromycin

Macrolide antibiotic

Mechanism

Cyclosporine (an immunosuppressant used after solid-organ transplantation and in severe autoimmune disease) is cleared through hepatic CYP3A4 and actively transported by P-glycoprotein. Clarithromycin inhibits both the enzyme and the transporter. Cyclosporine plasma levels rise 2- to 4-fold. The narrow therapeutic window (minimal margin between therapeutic and toxic dose) makes any concentration rise clinically dangerous.

Symptoms

Acute nephrotoxicity: rising creatinine and falling glomerular filtration rate. Hypertension, headache, tremor. In transplant patients, accelerated graft function decline. Symptoms appear within a few days of concurrent dosing.

Management

Avoid the combination. Replace clarithromycin with azithromycin – minimal CYP3A4 and P-glycoprotein interaction with comparable activity. If clarithromycin is essential, reduce the cyclosporine dose by 30–50% immediately, measure cyclosporine trough or C2 levels (per the transplant centre protocol) every 2–3 days, and monitor creatinine.

Sources

FDA: Sandimmune (cyclosporine) prescribing information (2021)

Major

diltiazem

Calcium channel blocker, non-DHP (benzothiazepine derivative)

Mechanism

Diltiazem blocks CYP3A4 and P-glycoprotein – cyclosporine clearance routes. Cyclosporine plasma levels rise by 50–100%. The combination is sometimes used intentionally in transplant patients to reduce cyclosporine dose (sparing effect), but requires monitoring.

Symptoms

Acute nephrotoxicity: rising creatinine, hypertension, tremor, headache. In transplant patients: accelerated graft function decline.

Management

For intentional sparing, reduce cyclosporine by 25–50% when starting diltiazem; check trough (C0) at days 3 and 7. For incidental combination: monitor cyclosporine and creatinine.

Sources

FDA: Sandimmune section 7 (2015)

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Major

Ketoconazole

Systemic antimycotics. Imidazole derivatives

Mechanism

Ketoconazole is a potent CYP3A4 and P-glycoprotein inhibitor – two main cyclosporine clearance routes. Cyclosporine plasma levels rise 2- to 3-fold; nephrotoxicity and neurotoxicity risk.

Symptoms

Acute nephrotoxicity: rising creatinine, hypertension, tremor, headache. In transplant patients: accelerated graft function decline.

Management

If unavoidable, reduce cyclosporine by 50–66% and check trough (C0) daily. Alternative antifungals: terbinafine for dermatophytosis or echinocandins for systemic mycoses.

Sources

FDA: Sandimmune (cyclosporine) prescribing information (2015)

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Major

Rifampicin

Antituberculous antibiotic

Mechanism

Rifampicin strongly induces CYP3A4 and P-glycoprotein. Cyclosporine plasma levels fall by 50–70%; immunosuppression is lost, raising transplant rejection risk.

Symptoms

Rejection symptoms depend on the organ: fever, graft tenderness, rising creatinine (kidney), jaundice (liver), dyspnoea (heart, lungs). Symptoms appear 1–3 weeks after starting rifampicin.

Management

Avoid the combination. Alternative anti-TB drug: rifabutin (weaker CYP3A4 induction) with cyclosporine dose titration. If rifampicin is unavoidable, raise cyclosporine 2- to 3-fold with trough (C0) twice weekly.

Sources

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Moderate

Digoxin

Cardiac glycosides (digitalis)

Mechanism

Ciclosporin inhibits P-glycoprotein in gut and renal tubules, reducing digoxin clearance. Digoxin AUC rises by 50–100%; toxicity risk is substantial.

Symptoms

Nausea, vomiting, loss of appetite, confusion, yellow-green halos around lights, arrhythmia (bigeminy, AV block). Symptoms appear earlier in older patients and chronic kidney disease.

Management

On ciclosporin start, reduce digoxin dose by 25–50% and check levels at 5–7 days. Target: 0.5–0.8 ng/mL. In parallel, monitor potassium and creatinine (ciclosporin is nephrotoxic and raises hyperkalaemia risk).

Sources

FDA: Sandimmune (cyclosporine) prescribing information (2015)

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Moderate

Paracetamol

Anilides. Analgesics and antipyretics

Mechanism

Paracetamol does not interact significantly with ciclosporin in short courses. On long-term high-dose use (over 3 g/day for more than 7 days), mild hepatocyte suppression may slightly amplify ciclosporin hepatotoxicity.

Symptoms

Fatigue, nausea, jaundice, elevated liver enzymes. Symptoms with long-term therapy are rare.

Management

Paracetamol remains the analgesic and antipyretic of choice in transplant patients. For chronic need, cap at 2 g/day. Check ALT, AST, GGT monthly. If enzymes rise 2–3-fold above the upper limit, stop paracetamol temporarily.

Sources

FDA: Sandimmune (cyclosporine) prescribing information (2015)

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Frequently asked

What is Ciclosporin used for?

Ciclosporin is evaluated for the following indications with varying evidence strength: Severe plaque psoriasis (evidence tier A), Maintenance immunosuppression after organ transplantation (evidence tier A), Severe atopic dermatitis (evidence tier A). See the full indication matrix with dosing and citations above on this page.

What are the side effects of Ciclosporin?

Common side effects of Ciclosporin (≥ 1 in 100): Arterial hypertension, Decreased eGFR, raised creatinine, Hypertrichosis, Gingival hyperplasia, Tremor, Paresthesias. See the Safety section for uncommon and serious reactions.

Is Ciclosporin safe during pregnancy?

FDA category C. FDA category C. In transplant patients, pregnancy on cyclosporine is feasible – data on thousands of live births are available. Risks: prematurity, low birth weight, hypertension. In pregnant patients with other indications, use is strictly individualized by a team including a transplantation specialist or rheumatologist.

Is Ciclosporin compatible with breastfeeding?

Transfers into breast milk. LactMed notes conflicting data: milk levels are low, but a few reports document measurable infant levels. The decision to breastfeed is individualized with the pediatrician and transplantation team.

Who should not take Ciclosporin?

Ciclosporin is contraindicated in: Hypersensitivity to cyclosporine; Uncontrolled arterial hypertension; Active untreated infections; Malignancy (except post-transplant use); Severe renal impairment outside transplantation. Full list in the Safety section.

Does Ciclosporin carry an FDA boxed warning?

FDA boxed warning: cyclosporine therapy is delivered only by physicians experienced in immunosuppression and transplantation. The drug increases risk of severe infections and lymphoproliferative disorders. Oral Sandimmune and microemulsion (Neoral, Gengraf) are not bioequivalent and not interchangeable without dose recalculation and concentration monitoring.

cyclosporine can be stopped on adverse effects

in transplant patients, abrupt withdrawal causes acute rejection. Only gradual tapering by the transplantation team.

cyclosporine works the same at any dose

individual bioavailability varies, and therapeutic drug monitoring with C0 or C2 dose adjustment is required.

cyclosporine can be taken for years for psoriasis

course is limited to 1–2 years due to cumulative nephrotoxicity and lymphoma risk.

Mechanism of action

Indications

Practical notes

Timing and administration

Monitoring

Special situations

Drug interactions

Common myths

Drug–nutrient interactions

Grapefruit juice

Magnesium

Potassium

Grapefruit

Drug–drug interactions

Check interaction with another drug

Official sources

Safety

Contraindications

Serious adverse effects

Common adverse effects

Uncommon adverse effects

PregnancyFDA C

Frequently asked