Food interactions: Concomitant intake of grapefruit juice increases the bioavailability of ciclosporin.
Drug interactions: Interactions with many different drugs have been reported with ciclosporin. Listed as follows are those which are well documented and considered to be clinically relevant.
Medicines that inhibit or induce the hepatic enzymes involved in the metabolism and excretion of ciclosporin, particularly CYP3A4, affect the plasma or whole blood levels of ciclosporin accordingly. Ciclosporin is also an inhibitor of CYP3A4 and a potent inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp). It may increase plasma levels of co-medications that are substrates of CYP3A4 or P-gp.
Sandimmun Neoral: A comprehensive document entitled "Sandimmun Neoral Drug Interactions", which lists all known drug interactions, including those based on isolated observations or contradictory reports, is available on request.
Medicines that reduce ciclosporin levels: Barbiturates, carbamazepine, oxcarbazepine, phenytoin, nafcillin, sulfadimidine i.v., rifampicin, octreotide, probucol, orlistat, Hypericum (St. John's wort) preparations, ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Sandimmun Neoral: trimethoprim i.v.
Medicines that increase ciclosporin levels: Macrolide antibiotics (erythromycin, azithromycin and clarithromycin), ketoconazole, fluconazole and itraconazole, voriconazole, diltiazem, nicardipine, verapamil, metoclopramide, oral contraceptives, danazol, methylprednisolone (high doses), allopurinol, amiodarone, cholic acid and derivatives, protease inhibitors, imatinib, colchicine, nefazodone.
Sandimmun Neoral: Chloroquine.
Other relevant drug interactions: Caution is required when using ciclosporin with other medicines that cause nephrotoxicity: aminoglycosides (including gentamicin and tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole), NSAIDs (including diclofenac, indometacin, naproxen and sulindac), melphalan, histamine H2-receptor antagonists (e.g. cimetidine, ranitidine), methotrexate, tacrolimus.
Co-administration of nifedipine with ciclosporin may lead to an increased incidence of gingival hyperplasia, as compared with administration of ciclosporin alone.
Following co-administration of ciclosporin and lercanidipine, the AUC of lercanidipine increased three-fold and the AUC of ciclosporin increased by 21%. Preference should be given to an antihypertensive agent that has no pharmacokinetic interactions with ciclosporin.
The co-administration of diclofenac and ciclosporin results in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase is most probably caused by a reduction in the high first-pass effect of diclofenac. Co-administration of ciclosporin with NSAIDs having a low first-pass effect (e.g. acetylsalicylic acid) is not normally associated with an increase in their bioavailability.
Ciclosporin may also reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), etoposide, aliskiren, bosentan or dabigatran.
Severe digitalis intoxication has been observed within days of starting ciclosporin therapy in a number of patients on digoxin. There have also been reports on the potential of ciclosporin to potentiate toxic effects of colchicine such as myopathy and neuropathy, particularly in patients with renal dysfunction. If digoxin or colchicine are used concomitantly with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine and to reduce the dose or withdraw the medicine, if appropriate.
A significant increase in exposure to anthracycline antibiotics (e.g doxorubicine, mitoxanthrone, daunorubicine) was observed in oncology patients with the intravenous co-administration of anthracycline antibiotics with ciclosporin.
Cases of myotoxicity, including muscle pain and weakness, myositis and rhabdomyolysis, have been described in the literature and in post-marketing studies in patients taking ciclosporin concomitantly with lovastatin, simvastatin, atorvastatin, pravastatin and, in rare cases, fluvastatin. When used concomitantly with ciclosporin, the dose of these statins should be reduced in accordance with the instructions given in the relevant prescribing information. Statin therapy must be temporarily withdrawn or discontinued in patients with symptoms of myopathy or in patients with risk factors predisposing to severe renal impairment, including renal failure secondary to rhabdomyolysis.
Elevations in serum creatinine were observed in combination with everolimus or sirolimus. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor effect on the pharmacokinetics of ciclosporin. In contrast, blood levels of everolimus and sirolimus were significantly increased.
Caution is called for when co-administering ciclosporin with potassium-sparing drugs (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or medicines containing potassium, as this may result in a significant increase in serum potassium.
Ciclosporin may raise plasma levels of repaglinide, thereby increasing the risk of hypoglycaemia.
Pharmacokinetic interaction studies in healthy volunteers showed that bosentan can decrease ciclosporin levels by around 35%, while bosentan exposure increases by around 2-fold.
Co-administration of ciclosporin and aliskiren increases the Cmax concentration of aliskiren 2.5-fold and AUC 5-fold. By contrast, the pharmacokinetic profile of ciclosporin was not significantly altered.
Co-administration of dabigatran and ciclosporin results in an increase in the plasma concentration of dabigatran due to the P-gp inhibitory effect (see Precautions). Dabigatran has a narrow therapeutic index and an increase in plasma concentrations is accompanied by an increased risk of bleeding.
Co-administration of ambrisentan and ciclosporin resulted in a 2-fold increase in ambrisentan exposure and a 10% increase in ciclosporin exposure.
Recommendations: If co-administration of medicines reported to interact with ciclosporin cannot be avoided, the following basic recommendations should be followed: Renal function (in particular serum creatinine levels) should be closely monitored in patients concomitantly using a medicine that may cause synergistic nephrotoxicity. In the event of significant renal impairment, the dosage of the co-administered medicine should be reduced or alternative treatment considered.
In transplant/graft recipients there have been isolated reports of considerable, but reversible, renal dysfunction (with corresponding increases in serum creatinine) following co-administration of fibrates (e.g. bezafibrate, fenofibrate). Renal function must therefore be closely monitored in such patients. In the event of significant renal dysfunction, the co-medication should be withdrawn.
Medicines known to reduce or increase the bioavailability of ciclosporin: Frequent determinations of blood ciclosporin levels should be performed in transplant recipients, particularly at the start and end of treatment with the other medicine and ciclosporin dosage should be adjusted if necessary.
In the case of co-administration of medicines known to increase blood ciclosporin levels, frequent monitoring of renal function and close monitoring of adverse effects of ciclosporin may be more appropriate than blood level determinations.
Sandimmun Neoral: In non-transplantation indications the value of blood ciclosporin determinations is uncertain, as the relationship between blood levels and clinical effects has been less clearly established.
Nifedipine: Co-administration with nifedipine should be avoided in patients who have previously developed gingival hyperplasia during ciclosporin therapy.
NSAIDs: NSAIDs subject to a high first-pass effect (e.g. diclofenac) should be given at lower doses than those used in patients not receiving ciclosporin.
Digoxin, colchicine, HMG Co-A reductase inhibitors: If digoxin, colchicine, lovastatin or HMG-CoA reductase inhibitors (statins) are given concomitantly with ciclosporin, close clinical monitoring is necessary to allow early detection of toxic effects and subsequent dose reduction or withdrawal of the medicine.
Drug interactions are more likely to occur in elderly patients.