Sandimmun Neoral Drug Interactions

Food: The concomitant intake of grapefruit juice has been reported to increase the bioavailability of ciclosporin.
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.
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 cytochrome P-450 enzymes.
Drugs that Decrease Ciclosporin Levels: Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine IV; rifampicin; octreotide; probucol; orlistat; Hypericum perforatum (St. John's wort); ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Drugs that Increase Ciclosporin Levels: Macrolide antibiotics (eg, 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.
Other Relevant Drug Interactions: Care should be taken when using ciclosporin together with other drugs that exhibit nephrotoxic synergy eg, aminoglycosides (including gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); NSAIDs (including diclofenac, naproxen, sulindac); melpahalan, histamine H₂-receptor antagonists (eg, cimetidine, ranitidine), methotrexate (see Precautions).
Concomitant use with tacrolimus should be avoided due to increased potential for nephrotoxicity.
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.
Following concomitant administration of ciclosporin and lercanidipine, the AUC of lercanidipine was increased 3-fold and the AUC of ciclosporin was increased 21%. Therefore, caution is recommended when co-administering ciclosporin together with lercanidipine (see Precautions).
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 NSAIDs with a low first-pass effect (eg, acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.
Ciclosporin may reduce the clearance of digoxin, colchicine, prednisolone and HMG-CoA reductase inhibitors (statins).
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 eg, myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine are 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.
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.
Caution is required for concomitant use of potassium-sparing drugs (eg, 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).
Recommendations: If the concomitant use of drugs known to interact with ciclosporin cannot be avoided, the following basic recommendations should be observed: 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.
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 (eg, 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.
Drugs Known to Reduce or Increase the Bioavailability of Ciclosporin: 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.
The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of ciclosporin.
Nonsteroidal anti-inflammatory drugs known to undergo strong first-pass metabolism (eg, diclofenac) should be given at doses lower than those that would be used in patients not receiving ciclosporin.
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 dosage or by withdrawal.