Ciclosporin

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

In Spain the colchicine SmPC contraindicates it during use of CYP3A4 or P-glycoprotein inhibitors and for 14 days afterwards, and cyclosporine blocks both routes. So a patient taking cyclosporine is not given colchicine. An acute gout flare after transplantation is treated with a glucocorticoid, intra-articular or as a short oral course. The FDA label contraindicates the pair in renal or hepatic impairment. With normal renal and hepatic function the FDA allows colchicine at a reduced dose, for example 0.3 mg once daily instead of 0.6 mg twice daily for flare prophylaxis.

Mechanism

Dabigatran etexilate is a substrate of the efflux transporter P-glycoprotein (P-gp). Ciclosporin inhibits this transporter, so dabigatran plasma concentrations rise (dabigatran and ciclosporin labels). There are no clinical studies of the pair (ciclosporin label, US Food and Drug Administration, FDA). Based on in vitro data, the dabigatran manufacturer expects an effect similar to that of ketoconazole. Ketoconazole 400 mg increased the dabigatran area under the concentration–time curve (AUC) 2.38-fold after a single dose and 2.53-fold after multiple once-daily doses (dabigatran label, European Medicines Agency, EMA). The kidneys clear dabigatran mainly unchanged, and ciclosporin often raises serum creatinine and urea (dabigatran and ciclosporin labels). According to the FDA dabigatran label, P-gp inhibition and impaired renal function are the major independent factors that increase dabigatran exposure. Together, they are expected to raise it more than either factor alone.

Symptoms

The main risk is bleeding from the nose, stomach and gut, rectum and haemorrhoids, and the urinary and genital tract, with blood in the urine. Bleeding into the skin and joints, bruising, coughing up blood and, less often, intracranial haemorrhage can also occur (dabigatran label). Bleeding can present as weakness, pallor, dizziness, headache, shortness of breath, or unexplained swelling or shock (dabigatran label). An unexplained fall in haemoglobin, haematocrit or blood pressure points to hidden bleeding (dabigatran label).

Management

The combination is contraindicated. The dabigatran label lists ciclosporin among its contraindications (European Medicines Agency, EMA). The ciclosporin label lists dabigatran among its contraindications (Spanish Agency of Medicines and Medical Devices, AEMPS). The ciclosporin label of the US Food and Drug Administration (FDA) says the combination should be avoided. The table of the European Heart Rhythm Association (EHRA 2021) marks the pair red, meaning contraindicated or not advisable because dabigatran levels rise. If a patient taking ciclosporin needs an oral anticoagulant, the same table marks apixaban and rivaroxaban with ciclosporin yellow with hatching (caution required, no clinical or pharmacokinetic data). For edoxaban, it gives a dose reduction to 30 mg once daily according to the edoxaban label (EHRA 2021). If the two drugs have already been taken together, watch closely for signs of bleeding or anaemia. Look for the bleeding site if haemoglobin, haematocrit or blood pressure falls without explanation (dabigatran label, EMA). The international normalised ratio (INR) is unreliable with dabigatran and should not be measured. Diluted thrombin time, ecarin clotting time and activated partial thromboplastin time can help detect excess dabigatran (dabigatran label, EMA). Check renal function often during ciclosporin treatment (ciclosporin label, AEMPS). Stop dabigatran if acute kidney failure develops (dabigatran label, EMA). In severe bleeding, stop dabigatran and find the cause. In adults, the specific reversal agent idarucizumab can be considered, and haemodialysis can remove dabigatran (dabigatran label, EMA).

Mechanism

Dronedarone is cleared mainly by CYP3A4. The FDA classes cyclosporine as a strong CYP3A inhibitor and names it in section 4 (Contraindications) of the dronedarone label. The labels give no figure for cyclosporine itself; ketoconazole raised dronedarone levels 17-fold. The effect also runs the other way: dronedarone may raise cyclosporine levels, so the EU SmPC of dronedarone asks for monitoring of the immunosuppressant.

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.

Mechanism

Cyclosporine inhibits OATP1B1 – pitavastatin rises 5-7 fold. FDA Livalo contraindication.

Symptoms

Myalgia, weakness, dark urine, rising CK within 5-10 days.

Management

Combination contraindicated.

Mechanism

Cyclosporine inhibits OATP1B1 – rosuvastatin hepatic uptake falls, plasma concentration rises 7-fold. FDA Crestor Section 7 contraindication.

Symptoms

Myalgia, weakness, dark urine, rising CK within 5-10 days.

Management

Combination contraindicated. Alternative – pravastatin 20 mg (minimal risk).

Mechanism

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

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 or fluvastatin (minimal interaction with cyclosporine). Check creatine kinase every 4–6 weeks.

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

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 1–4 weeks of co-administration.

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.

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.

Mechanism

Cyclosporine is cleared through CYP3A4, and clarithromycin inhibits this enzyme. Clarithromycin roughly doubles cyclosporine exposure (cyclosporine SmPC). Excess cyclosporine damages the kidneys and raises blood pressure (cyclosporine SmPC).

Symptoms

Rising creatinine and urea, high blood pressure, tremor, headache, high blood potassium.

Management

During the clarithromycin course, adjust the cyclosporine dose according to its blood concentration. The US Food and Drug Administration (FDA) lists clarithromycin among drugs that increase cyclosporine concentrations and states that dose adjustment to the desired concentration is essential when a drug significantly alters cyclosporine levels (cyclosporine FDA label). In transplant recipients, measure cyclosporine levels frequently, especially when clarithromycin is started and stopped, and adjust the dose as needed (cyclosporine SmPC). In patients without a transplant, check kidney function more often and watch for cyclosporine adverse effects (cyclosporine SmPC).

Mechanism

Ciclosporin inhibits P-glycoprotein and reduces digoxin clearance (ciclosporin SmPC). Digoxin is cleared by the kidneys, so ciclosporin nephrotoxicity can also keep it in the blood longer (both labels). The US Food and Drug Administration (FDA) ciclosporin label describes severe digitalis toxicity within days of starting ciclosporin. The size of the rise cannot be predicted: the FDA digoxin label calls it unclear.

Symptoms

Nausea, vomiting, loss of appetite, weakness, confusion. Visual changes: blurred vision, green-yellow colour changes, halos around lights. Rhythm disorders: ventricular premature beats, often as bigeminy, atrioventricular block, atrial tachycardia with block. Older age, low body weight, reduced kidney function and electrolyte disorders raise the risk of toxicity (digoxin label).

Management

The combination is acceptable only with close monitoring. The ciclosporin SmPC requires close clinical observation to detect digoxin toxicity early, followed by a lower digoxin dose or stopping digoxin. The US Food and Drug Administration (FDA) ciclosporin label says serum digoxin concentrations should be monitored. Measure the digoxin concentration before ciclosporin is started, keep monitoring and reduce the digoxin dose as needed (FDA digoxin label). Draw the sample just before the next digoxin dose or at least 6 hours after the last one (FDA digoxin label). Ciclosporin requires frequent checks of kidney function and raises the risk of hyperkalaemia, so check creatinine and potassium regularly (ciclosporin SmPC). The digoxin SmPC already asks for periodic electrolyte and creatinine checks.

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.

Mechanism

Cyclosporine inhibits OATP1B1. Fluvastatin rises 2-fold. FDA recommends dose cap.

Symptoms

Myalgia, weakness, dark urine, rising CK within 5–10 days.

Management

In patients taking cyclosporine, do not exceed fluvastatin capsules 20 mg twice daily (FDA label). The FDA advises avoiding fluvastatin 80 mg extended-release tablets with cyclosporine. The Spanish fluvastatin SmPC requires the lowest possible starting and maintenance dose with cyclosporine, and the cyclosporine SmPC requires statin dose reduction. If muscle pain, weakness or dark urine appear, check creatine kinase (CK). Stop fluvastatin if CK exceeds 5 times the upper limit of normal (fluvastatin SmPC).

Mechanism

St. John's wort is a potent inducer of the CYP3A4 enzyme (and of CYP2C9 and P-glycoprotein). After 1–2 weeks it speeds up the breakdown of Ciclosporin and lowers its blood level, weakening its effect.

Symptoms

Fall in ciclosporin blood levels, risk of acute transplant rejection (confirmed in case reports).

Management

Contraindicated in transplant patients. Monitor ciclosporin levels; if the herb was used, stop it and track drug concentration.

Mechanism

Strong CYP3A4 inhibitor. Cyclosporine rises 5+ fold.

Symptoms

Nephrotoxicity.

Management

Reduce cyclosporine by 75%.

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.

Mechanism

Strong CYP3A4 inhibitor. Cyclosporine rises 1.4-fold.

Symptoms

Nephrotoxicity.

Management

Reduce cyclosporine by 25%.

Mechanism

Rifampicin is a strong inducer of CYP3A4 and P-glycoprotein, the pathways that clear cyclosporine. In healthy volunteers cyclosporine oral bioavailability fell from 33% to 9% with rifampicin, and in kidney transplant recipients cyclosporine AUC fell by about 60%. Levels drop below the therapeutic range and the risk of graft rejection rises.

Symptoms

Rejection signs within 1–2 weeks.

Management

Increase cyclosporine 3–5 fold with level monitoring. Alternative – rifabutin (weaker).

Mechanism

Ritonavir strongly inhibits CYP3A4, which is why it is used as a pharmacokinetic booster in HIV regimens. Cyclosporine is cleared through CYP3A4 and P-glycoprotein, so its blood level rises on ritonavir. Both labels expect the rise: the ritonavir SmPC names cyclosporine, and the cyclosporine SmPC lists protease inhibitors among drugs that raise its levels. The size of the rise is not known in advance: the FDA cyclosporine label notes that no formal studies of this pair are available. Excess cyclosporine damages the kidneys and raises blood pressure.

Symptoms

Sharp creatinine rise, hypertension.

Management

The combination is possible only with cyclosporine level monitoring: the FDA ritonavir label recommends therapeutic concentration monitoring of the immunosuppressant, and the ritonavir SmPC asks for careful monitoring of effect and adverse reactions. Cyclosporine trough levels are measured before ritonavir starts, frequently in the first days and after any change of the antiretroviral regimen, and the cyclosporine dose follows the result. Creatinine, potassium and blood pressure are watched in parallel. When ritonavir stops, cyclosporine levels fall and the dose is reviewed again by level. The transplant team and the HIV specialist agree on the plan together.

Mechanism

Voriconazole inhibits CYP3A4. Cyclosporine rises 1.7-fold.

Symptoms

Nephrotoxicity.

Management

Halve cyclosporine dose.

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.