Sandimmun/Sandimmun Neoral Drug Interactions

Of the many drugs reported to interact with ciclosporin, those for which the interactions are adequately substantiated and considered to have clinical implications are listed as follows.
Interactions resulting in concomitant use not being recommended: During treatment with ciclosporin, vaccination may be less effective, the use of live-attenuated vaccines should be avoided (see Precautions).
Interactions to be considered: Caution is required for concomitant use of potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium containing drugs since they may lead to significant increases in serum potassium (see Precautions).
Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased threefold and the AUC of ciclosporin was increased 21%. Therefore caution is recommended when co-administering ciclosporin together with lercanidipine (see Precautions).
Care should be taken when using ciclosporin together with methotrexate in rheumatoid arthritis patients due to the risk of nephrotoxic synergy (see Precautions).
Interactions increasing or decreasing ciclosporin levels to be considered: Various agents are known to either increase or decrease plasma or whole blood ciclosporin levels usually by inhibition or induction of enzymes involved in the metabolism of ciclosporin, in particular CYP3A4. Ciclosporin is a substrate of P-gp, hence inhibitors or inducers of P-gp may alter the concentrations of ciclosporin.
If the concomitant use of drugs known to interact with ciclosporin cannot be avoided, the following basic recommendations should be observed: In transplant patients: frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment are required, particularly during the introduction or withdrawal of the co-administered drug.
In non-transplant patients: the value of ciclosporin blood level monitoring is questionable, as in these patients the relationship between blood level and clinical effects is less well established. If drugs known to increase ciclosporin levels are given concomitantly, frequent assessment of renal function and careful monitoring for ciclosporin-related side effects may be more appropriate than blood level measurement.
Interactions decreasing ciclosporin levels: Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine i.v., rifampicin, octreotide, probucol, orlistat, Hypericum perforatum (St. John's wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Interactions increasing ciclosporin levels: Macrolide antibiotics (e.g. erythromycin, azithromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high dose); allopurinol; amiodarone; cholic acid and derivatives; protease inhibitors; imatinib; colchicine; nefazodone.
Other relevant interactions: Drug-food/drink interactions: The concomitant intake of grapefruit juice has been reported to increase the bioavailability of ciclosporin (see Dosage & Administration).
Interactions resulting in a potential increased nephrotoxicity: During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered drug should be reduced or alternative treatment considered.
Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy such as: aminoglycosides (incl. gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); non-steroidal anti-inflammatory drugs (incl. diclofenac, naproxen, sulindac); melphalan, histamine H₂-receptor-antagonists (e.g. cimetidine, ranitidine); methotrexate (see previously mentioned Interactions resulting in concomitant use not being recommended).
Concomitant use with tacrolimus should be avoided due to increased potential for nephrotoxicity.
The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its high first-pass effect. If non-steroidal anti-inflammatory drugs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected. Non-steroidal anti-inflammatory drugs known to undergo strong first-pass metabolism (e.g. diclofenac) should be given at doses lower than those that would be used in patients not receiving ciclosporin.
In graft recipients there have been isolated reports of considerable but reversible impairment of kidney function (with corresponding increase in serum creatinine) following concomitant administration of fibric acid derivatives (e.g. bezafibrate, fenofibrate). Kidney function must therefore be closely monitored in these patients. In the event of significant impairment of kidney function the co-medication should be withdrawn.
Interaction resulting in an increased rate of gingival hyperplasia: The concurrent administration of nifedipine with ciclosporin may result in an increased rate of gingival hyperplasia compared with that observed when ciclosporin is given alone. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of ciclosporin (see Adverse Reactions).
Interactions resulting in an increase of other drug levels: Ciclosporin is also an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter.
Ciclosporin may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), etoposide, aliskiren, bosentan or dabigatran.
Severe digitalis toxicity has been seen within days of starting ciclosporin in several patients taking digoxin. There are also reports on the potential of ciclosporin to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine is used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage or its withdrawal.
Literature and postmarketing cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported with concomitant administration of ciclosporin with lovastatin, simvastatin, atorvastatin, pravastatin, and, rarely, fluvastatin. When concurrently administered with ciclosporin, the dosage of these statins should be reduced according to label recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury, including renal failure, secondary to rhabdomyolysis.
If digoxin, colchicine or HMG-CoA reductase inhibitors (statins) are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the drugs, followed by reduction of its dosage or its withdrawal.
Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus and sirolimus.
Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycemia.
Co-administration of bosentan and ciclosporin in healthy volunteers resulted in an approximately 2-fold increase in bosentan exposure and a 35% decrease in ciclosporin exposure (see previously mentioned Interactions decreasing ciclosporin levels and Precautions).
Following concomitant administration of ciclosporin and aliskiren, the Cmax of aliskiren was increased by approximately 2.5 fold and the AUC by approximately 5 fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered (see Precautions).
Concomitant administration of dabigatran and ciclosporin leads to increased plasma level of dabigatran due to the P-gp inhibitory activity of ciclosporin (see Precautions). Dabigatran has a narrow therapeutic index and an increase in plasma level may be associated with an increased risk of bleeding.
Multiple dose administration of ambrisentan and ciclosporin in healthy volunteers resulted in an approximately 2-fold increase in ambrisentan exposure while the ciclosporin exposure was marginally increased (approximately 10%).
A significant increased exposure in anthracycline antibiotics (e.g doxorubicine, mitoxanthrone, daunorubicine) was observed in oncology patients with the intravenous co-administration of anthracycline antibiotics and very high doses of ciclosporin.
Interactions resulting in decrease of other drug levels: Concomitant administration of ciclosporin and mycophenolate sodium or mycophenolate mofetil in transplant patients may decrease the mean exposure of mycophenolic acid by 20-50% when compared with other immunosuppressants. This information should be taken into consideration especially in case of interruption or discontinuation of ciclosporin therapy.
The coadministration of a single dose of ciclosporin (200 mg or 600 mg) with a single dose of eltrombopag (50 mg) decreased plasma eltrombopag AUCinf by 18% to 24% and Cmax by 25% to 39%.
Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient's platelet count. Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased based on these platelet counts.