Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Metabolic interactions
Systemically available tacrolimus is metabolised by hepatic CYP3A4. There is also evidence of gastrointestinal metabolism by CYP3A4 in the intestinal wall. Concomitant use of medicinal products or herbal remedies known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels. Similarly, discontinuation of such products or herbal remedies may affect the rate of metabolism of tacrolimus and thereby the blood levels of tacrolimus.

Pharmacokinetics studies have indicated that the increase in tacrolimus blood levels when co- administered with inhibitors of CYP3A4 is mainly a result of increase in oral bioavailability of tacrolimus owing to the inhibition of gastrointestinal metabolism. Effect on hepatic clearance is less pronounced.

It is recommended strongly to closely monitor tacrolimus blood levels under supervision of a transplant specialist, as well as, monitor for graft function, QT prolongation (with ECG), renal function and other side effects including neurotoxicity, whenever substances which have the potential to alter CYP3A4 metabolism are used concomitantly, and to adjust or interrupt the tacrolimus dose if appropriate in order to maintain similar tacrolimus exposure (see sections 4.2 and 4.4). Similarly, patients should be closely monitored when using tacrolimus concomitantly with multiple substances that affect CYP3A4 as the effects on tacrolimus exposure may be enhanced or counteracted.


Medicinal products which have effects on tacrolimus are listed in the table below. The examples of drug- drug interactions are not intended to be inclusive or comprehensive and therefore, the label of each drug that is co-administered with tacrolimus should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to co- administration.

Medicinal products which have effects on tacrolimus
Drug/Substance Class or        Drug interaction effect                  Recommendations concerning Name                                                                    co-administration Grapefruit or grapefruit juice   May increase tacrolimus whole          Avoid grapefruit or grapefruit blood trough concentrations and        juice.
increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see section 4.4].
Ciclosporin                      May increase tacrolimus whole          The simultaneous use of blood trough concentrations. In        ciclosporin and tacrolimus addition, synergistic/additive         should be avoided [see nephrotoxic effects can occur.         section 4.4].
Products known to have           May enhance nephrotoxic or             Concurrent use of tacrolimus nephrotoxic or neurotoxic        neurotoxic effects of tacrolimus.      with drugs known to have effects:                                                                nephrotoxic effects should be aminoglycosides, gyrase                                                 avoided. When co- inhibitors, vancomycin,                                                 administration cannot be sulfamethoxazole +                                                      avoided, monitor renal trimethoprim, NSAIDs,                                                   function and other side effects ganciclovir, acyclovir,                                                 and adjust tacrolimus dose if amphotericin B, ibuprofen,                                              needed.
cidofovir, foscarnet


Drug/Substance Class or             Drug interaction effect                Recommendations concerning Name                                                                       co-administration Strong CYP3A4 inhibitors:           May increase tacrolimus whole          It is recommended that antifungal agents (e.g.,            blood trough concentrations and        concomitant use should be ketoconazole, itraconazole,         increase the risk of serious adverse   avoided. If co-administration posaconazole, voriconazole),        reactions (e.g., nephrotoxicity,       of a strong CYP3A4 inhibitor the macrolide antibiotics (e.g.,    neurotoxicity, QT prolongation)        is unavoidable, consider telithromycin,                      which requires close monitoring        omitting the dose of tacrolimus troleandomycin,                     [see section 4.4].                     the day the strong CYP3A4 clarithromycin, josamycin),         Rapid and sharp increases in           inhibitor is initiated. Reinitiate HIV protease inhibitors (e.g.,      tacrolimus levels may occur, as        tacrolimus the next day at a ritonavir, nelfinavir,              early as within 1-3 days after co-     reduced dose based on saquinavir), HCV protease           administration, despite immediate      tacrolimus blood inhibitors (e.g., telaprevir,       reduction of tacrolimus dose.          concentrations. Changes in boceprevir, and the                 Overall tacrolimus exposure may        both tacrolimus dose and/or combination of ombitasvir           increase >5 fold. When ritonavir       dosing frequency should be and paritaprevir with               combinations are co-administered,      individualized and adjusted as ritonavir, when used with and       tacrolimus exposure may increase       needed based on tacrolimus without dasabuvir),                 >50 fold. Nearly all patients may      trough concentrations, which nefazodone, the                     require a reduction in tacrolimus      should be assessed at initiation, pharmacokinetic enhancer            dose and temporary interruption of     monitored frequently cobicistat, and the kinase          tacrolimus may also be necessary.      throughout (starting within the inhibitors idelalisib, ceritinib.   The effect on tacrolimus blood         first few days) and re- concentrations may remain for          evaluated on and after
Strong interactions have also several days after co-administration   completion of the CYP3A4 been observed with the is completed.                          inhibitor. Upon completion,
macrolide antibiotic appropriate dose and dosing erythromycin frequency of tacrolimus should be guided by tacrolimus blood concentrations. Monitor renal function, ECG for QT prolongation, and other side effects closely.


Drug/Substance Class or            Drug interaction effect                Recommendations concerning Name                                                                      co-administration Moderate or weak CYP3A4            May increase tacrolimus whole          Monitor tacrolimus whole inhibitors:                        blood trough concentrations and        blood trough concentrations antifungal agents (e.g.,           increase the risk of serious adverse   frequently, starting within the fluconazole, isavuconazole,        reactions (e.g., neurotoxicity, QT     first few days of co- clotrimazole, miconazole), the     prolongation) [see section 4.4]. A     administration. Reduce macrolide antibiotics (e.g.,       rapid increase in tacrolimus level     tacrolimus dose if needed [see azithromycin), calcium             may occur.                             section 4.2]. Monitor renal channel blockers (e.g.,                                                   function, ECG for QT nifedipine, nicardipine,                                                  prolongation, and other side diltiazem, verapamil),                                                    effects closely.
amiodarone, danazol,
ethinylestradiol, lansoprazole,
omeprazole, the HCV antivirals elbasvir/grazoprevir and glecaprevir/pibrentasvir,
the CMV antiviral letermovir,
and the tyrosine kinase inhibitors nilotinib, crizotinib and imatinib and (Chinese) herbal remedies containing extracts of Schisandra sphenanthera
In vitro the following             May increase tacrolimus whole          Monitor tacrolimus whole substances have been shown         blood trough concentrations and        blood trough concentrations to be potential inhibitors of      increase the risk of serious adverse   and reduce tacrolimus dose if tacrolimus metabolism:             reactions (e.g., neurotoxicity, QT     needed [see section 4.2].
bromocriptine, cortisone,          prolongation) [see section 4.4].       Monitor renal function, ECG dapsone, ergotamine,                                                      for QT prolongation, and other gestodene, lidocaine,                                                     side effects closely.
mephenytoin, midazolam,
nilvadipine, norethisterone,
quinidine, tamoxifen


Drug/Substance Class or            Drug interaction effect                 Recommendations concerning Name                                                                       co-administration Strong CYP3A4 inducers:           May decrease tacrolimus whole           It is recommended that rifampicin, phenytoin,            blood trough concentrations and         concomitant use should be carbamazepine, apalutamide,       increase the risk of rejection [see     avoided. If unavoidable, enzalutamide, mitotane, or        section 4.4].                           patients may require an St. John’s wort (Hypericum        Maximal effect on tacrolimus blood      increase in tacrolimus dose.
perforatum)                       concentrations may be achieved          Changes in tacrolimus dose 1-2 weeks after co-administration.      should be individualized and
The effect may remain 1-2 weeks         adjusted as needed based on after completion of the treatment.      tacrolimus trough concentrations, which should be assessed at initiation,
monitored frequently throughout (starting within the first few days) and re- evaluated on and after completion of the CYP3A4 inducer. After use of the
CYP3A4 inducer has ended,
tacrolimus dose may need to be adjusted gradually. Monitor graft function closely.
Moderate CYP3A4 inducers:          May decrease tacrolimus whole           Monitor tacrolimus whole metamizole, phenobarbital,         blood trough concentrations and         blood trough concentrations isoniazid, rifabutin, efavirenz,   increase the risk of rejection [see     and increase tacrolimus dose if etravirine, nevirapine; weak       section 4.4].                           needed [see section 4.2].
CYP3A4 inducers:                                                           Monitor graft function closely.
flucloxacillin
Caspofungin                        May decrease tacrolimus whole           Monitor tacrolimus whole blood trough concentrations and         blood trough concentrations increase the risk of rejection.         and increase tacrolimus dose if Mechanism of interaction has not        needed [see section 4.2].
been confirmed.                         Monitor graft function closely.
Cannabidiol (P-gp inhibitor)       There have been reports of              Tacrolimus and cannabidiol increased tacrolimus blood levels       should be co-administered with during concomitant use of               caution, closely monitoring for tacrolimus with cannabidiol. This       side effects. Monitor may be due to inhibition of             tacrolimus whole blood trough intestinal P-glycoprotein, leading to   concentrations and adjust the increased bioavailability of            tacrolimus dose if needed [see tacrolimus.                             sections 4.2 and 4.4].
Products known to have high        Tacrolimus is extensively bound to      Monitor tacrolimus whole affinity for plasma proteins,      plasma proteins. Possible               blood trough concentrations e.g., NSAIDs, oral                 interactions with other active          and adjust tacrolimus dose if anticoagulants, oral               substances known to have high           needed [see section 4.2].
antidiabetics                      affinity for plasma proteins should be considered.


Drug/Substance Class or         Drug interaction effect                Recommendations concerning Name                                                                   co-administration Prokinetic agents:              May increase tacrolimus whole          Monitor tacrolimus whole metoclopramide, cimetidine      blood trough concentrations and        blood trough concentrations and magnesium-aluminium-        increase the risk of serious adverse   and reduce tacrolimus dose if hydroxide                       reactions (e.g., neurotoxicity, QT     needed [see section 4.2].
prolongation).                         Monitor closely for renal function, for QT prolongation with ECG, and for other side effects.
Maintenance doses of            May decrease tacrolimus whole          Monitor tacrolimus whole corticosteroids                 blood trough concentrations and        blood trough concentrations increase the risk of rejection [see    and increase tacrolimus dose if section 4.4].                          needed [see section 4.2].
Monitor graft function closely.
High dose prednisolone or       May have impact on tacrolimus          Monitor tacrolimus whole methylprednisolone              blood levels (increase or decrease)    blood trough concentrations when administered for the treatment    and adjust tacrolimus dose if of acute rejection.                    needed.

Direct-acting antiviral (DAA)   May have impact on the                 Monitor tacrolimus whole therapy                         pharmacokinetics of tacrolimus by      blood trough concentrations changes in liver function during       and adjust tacrolimus dose if
DAA therapy, related to clearance      needed to ensure continued of hepatitis virus. A decrease in      efficacy and safety.
tacrolimus blood levels may occur.
However, the CYP3A4 inhibiting potential of some DAAs may counteract that effect or lead to increased tacrolimus blood levels.

Concomitant administration of tacrolimus with a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus, everolimus) may increase the risk of thrombotic microangiopathy (including haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura) (see section 4.4).

As tacrolimus treatment may be associated with hyperkalaemia, or may increase pre-existing hyperkalaemia, high potassium intake, or potassium-sparing diuretics (e.g., amiloride, triamterene, or spironolactone) should be avoided (see section 4.4). Care should be taken when tacrolimus is co- administered with other agents that increase serum potassium, such as trimethoprim and cotrimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic like amiloride. Close monitoring of serum potassium is recommended.

Effect of tacrolimus on the metabolism of other medicinal products
Tacrolimus is a known CYP3A4 inhibitor; thus concomitant use of tacrolimus with medicinal products known to be metabolised by CYP3A4 may affect the metabolism of such medicinal products.
The half-life of ciclosporin is prolonged when tacrolimus is given concomitantly. In addition, synergistic/additive nephrotoxic effects can occur. For these reasons, the combined administration of ciclosporin and tacrolimus is not recommended and care should be taken when administering tacrolimus to patients who have previously received ciclosporin (see sections 4.2 and 4.4).
Tacrolimus has been shown to increase the blood level of phenytoin.
As tacrolimus may reduce the clearance of steroid-based contraceptives leading to increased hormone exposure, particular care should be exercised when deciding upon contraceptive measures.
Limited knowledge of interactions between tacrolimus and statins is available. Clinical data suggest that the pharmacokinetics of statins are largely unaltered by the co-administration of tacrolimus.
Animal data have shown that tacrolimus could potentially decrease the clearance and increase the half-life of pentobarbital and antipyrine.

Mycophenolic acid. Caution should be exercised when switching combination therapy from ciclosporin, which interferes with enterohepatic recirculation of mycophenolic acid, to tacrolimus, which is devoid of this effect, as this might result in changes of mycophenolic acid exposure. Drugs which interfere with mycophenolic acid's enterohepatic cycle have potential to reduce the plasma level and efficacy of mycophenolic acid. Therapeutic drug monitoring of mycophenolic acid may be appropriate when switching from ciclosporin to tacrolimus or vice versa.

Immunosuppressants may affect the response to vaccination and vaccination during treatment with tacrolimus may be less effective. The use of live attenuated vaccines should be avoided (see section 4.4).