Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

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 below.

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 also an inhibitor of CYP3A4, the multidrug efflux transporter P-gp and organic anion transporter proteins (OATP) and may increase plasma levels of co-medications that are substrates of this enzyme and/or transporters.

Medicinal products known to reduce or increase the bioavailability of ciclosporin: In transplant patients frequent measurement of ciclosporin levels and, if necessary, ciclosporin dosage adjustment is required, particularly during the introduction or withdrawal of the co-administered medication. In non- transplant patients the relationship between blood level and clinical effects is less well established. If medicinal products 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.

Drugs that decrease ciclosporin levels
All inducers of CYP3A4 and/or P-gp are expected to decrease ciclosporin levels. Examples of drugs that decrease ciclosporin levels are:
Barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, intravenous sulfadimidine, probucol, orlistat, hypericum perforatum (St. John’s wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Products containing Hypericum perforatum (St John´s Wort) must not be used concomitantly with Sandimmun Neoral due to the risk of decreased blood levels of ciclosporin and thereby reduced effect (see section 4.3).

Rifampicin induces ciclosporin intestinal and liver metabolism. Ciclosporin doses may need to be increased 3- to 5-fold during co-administration.

Octreotide decreases oral absorption of ciclosporin and a 50% increase in the ciclosporin dose or a switch to intravenous administration could be necessary.


Drugs that increase ciclosporin levels
All inhibitors of CYP3A4 and/or P-gp may lead to increased levels of ciclosporin . Examples are: Nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high dose), allopurinol, cholic acid and derivatives, protease inhibitors, imatinib, colchicine, nefazodone.

Macrolide antibiotics: Erythromycin can increase ciclosporin exposure 4- to 7-fold, sometimes resulting in nephrotoxicity. Clarithromycin has been reported to double the exposure of ciclosporin.
Azitromycin increases ciclosporin levels by around 20%.

Azole antimycotics : Ketoconazole, fluconazole, itraconazole and voriconazole could more than double ciclosporin exposure.

Verapamil increases ciclosporin blood concentrations 2- to 3-fold.

Co-administration with telaprevir resulted in approximately 4.64-fold increase in ciclosporin dose normalised exposure (AUC).

Amiodarone substantially increases the plasma ciclosporin concentration concurrently with an increase in serum creatinine. This interaction can occur for a long time after withdrawal of amiodarone, due to its very long half-life (about 50 days).

Danazol has been reported to increase ciclosporin blood concentrations by approximately 50%.

Diltiazem (at doses of 90 mg/day) can increase ciclosporin plasma concentrations by up to 50%.
Imatinib could increase ciclosporin exposure and Cmax by around 20%.

Cannabidiol (P-gp inhibitor): There have been reports of increased blood levels of another calcineurin inhibitor during concomitant use with cannabidiol. This interaction may occur due to inhibition of intestinal P-gp efflux, leading to increased bioavailability of the calcineurin inhibitor. Ciclosporin and cannabidiol should therefore be co-administered with caution, closely monitoring for side effects. In transplant recipients, monitor ciclosporin whole blood trough concentrations and adjust the ciclosporin dose if needed. In non-transplant patients, monitoring of ciclosporin blood levels, with dose adjustment if needed, should be considered (see sections 4.2 and 4.4).

Food interactions
The concomitant intake of grapefruit and grapefruit juice has been reported to increase the bioavailability of ciclosporin.

Combinations with increased risk for nephrotoxicity
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as: aminoglycosides (including gentamycin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); fibric acid derivatives (e.g., bezafibrate, fenofibrate); NSAIDs (including diclofenac, naproxen, sulindac); melphalan, histamine H2-receptor antagonists (e.g., cimetidine, ranitidine); methotrexate (see section 4.4).

During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced, or alternative treatment considered.

Concomitant use of ciclosporin and tacrolimus should be avoided due to the risk for nephrotoxicity and pharmacokinetic interaction via CYP3A4 and/or P-gp (see section 4.4).



Impact of DAA therapy
The pharmacokinetics of ciclosporin may be impacted by changes in liver function during DAA therapy, related to clearance of HCV virus. A close monitoring and potential dose adjustment of ciclosporin is warranted to ensure continued efficacy.

Effects of ciclosporin on other drugs
Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-gp and organic anion transporter proteins (OATP). Co-administration of drugs that are substrates of CYP3A4, P-gp and OATP with ciclosporin may increase plasma levels of co-medications that are substrates of this enzyme and/or transporter.

Some examples are listed below:
Ciclosporin may reduce the clearance of digoxin, colchicine, HMG-CoA reductase inhibitors (statins) and etoposide. If any of these drugs are used concurrently with ciclosporin, close clinical observation is required in order to enable early detection of toxic manifestations of the medicinal products, followed by reduction of its dosage or its withdrawal. When concurrently administered with ciclosporin, the dosage of the statins should be reduced, and concomitant use of certain statins should be avoided according to their label recommendations. Exposure changes of commonly used statins with ciclosporin are summarised in Table 1. 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.

Table 1        Summary of exposure changes of commonly used statins with ciclosporin 
Statin              Doses available       Fold change in exposure with ciclosporin
Atorvastatin        10-80 mg              8-10
Simvastatin         10-80 mg              6-8
Fluvastatin         20-80 mg              2-4
Lovastatin          20-40 mg              5-8
Pravastatin         20-80 mg              5-10
Rosuvastatin        5-40 mg               5-10
Pitavastatin        1-4 mg                4-6

Caution is recommended when co-administering ciclosporin with lercanidipine (see section 4.4).
Following concomitant administration of ciclosporin and aliskiren, a P-gp substrate, the Cmax of aliskiren was increased approximately 2.5-fold and the AUC approximately 5-fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered. Co-administration of ciclosporin and aliskiren is not recommended (see section 4.3).

Concomitant administration of dabigatran etexilate is not recommended due to the P-gp inhibitory activity of ciclosporin (see section 4.3).

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 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 (e.g., acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.


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 with concomitant use of potassium-sparing medicinal products (e.g., potassium- sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products since they may lead to significant increases in serum potassium (see section 4.4).

Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.

Co-administration of bosentan and ciclosporin in healthy volunteers increases the bosentan exposure several-fold and there was a 35% decrease in ciclosporin exposure. Co-administration of ciclosporin with bosentan is not recommended (see above subsection “Drugs that decrease ciclosporin levels” and section 4.3).

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 significantly increased exposure to 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.

During treatment with ciclosporin, vaccination may be less effective and the use of live attenuated vaccines should be avoided.

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.

Paediatric population
Interaction studies have only been performed in adults.