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


Drug/Substance Class or Name Drug interaction effect                  Recommendations concerning co-administration
Moderate or weak CYP3A4            May increase tacrolimus whole      Monitor tacrolimus whole blood inhibitors:                        blood trough concentrations and    trough concentrations antifungal agents (e.g.            increase the risk of serious       frequently, starting within the fluconazole, isavuconazole,        adverse reactions (e.g.            first few days of co- clotrimazole, miconazole), the     neurotoxicity, QT prolongation)    administration. Reduce macrolide antibiotics (e.g.        [see section 4.4]. A rapid         tacrolimus dose if needed [see azithromycin, calcium channel      increase in tacrolimus level may   section 4.2].
blockers (e.g. nifedipine,         occur.                             Monitor renal function, ECG for nicardipine, diltiazem,                                               QT prolongation, and other side verapamil), amiodarone,                                               effects closely.
danazol, ethinylestradiol,
lansoprazole, omeprazole, the
HCV antivirals elbasvir/grazoprevir and glecaprevir/pibrentasvir, the
CMV antiviral letermovir, and the tyrosine kinase inhibitors nilotinib, crizotinib, imatinib,
and (Chinese) herbal remedies containing extracts of
Schisandra sphenanthera
In vitro the following             May increase tacrolimus whole      Monitor tacrolimus whole blood substances have been shown to      blood trough concentrations and    trough concentrations and be potential inhibitors of         increase the risk of serious       reduce tacrolimus dose if needed tacrolimus metabolism:             adverse reactions (e.g.            [see section 4.2].
bromocriptine, cortisone,          neurotoxicity, QT prolongation)    Monitor renal function, ECG for dapsone, ergotamine,               [see section 4.4].                 QT prolongation, and other side gestodene, lidocaine,                                                 effects closely.
mephenytoin, midazolam,
nilvadipine, norethisterone,
quinidine, tamoxifen
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     avoided. If unavoidable, patients enzalutamide, mitotane, or         [see section 4.4]. Maximal         may require an increase in St. John’s wort (Hypericum         effect on tacrolimus blood         tacrolimus dose. Changes in perforatum)                        concentrations may be achieved     tacrolimus dose should be 1-2 weeks after                    individualized and adjusted as co-administration. The effect      needed based on tacrolimus may remain 1-2 weeks after         trough concentrations, which completion of the treatment.       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.


Drug/Substance Class or Name Drug interaction effect                   Recommendations concerning co-administration
Moderate CYP3A4 inducers:          May decrease tacrolimus whole       Monitor tacrolimus whole blood metamizole, phenobarbital,         blood trough concentrations and     trough concentrations and isoniazid, rifabutin, efavirenz,   increase the risk of rejection      increase tacrolimus dose if etravirine, nevirapine; weak       [see section 4.4].                  needed [see section 4.2].
CYP3A4 inducers:                                                       Monitor graft function closely.
flucloxacillin
Caspofungin                        May decrease tacrolimus whole       Monitor tacrolimus whole blood blood trough concentrations and     trough concentrations and increase the risk of rejection.     increase tacrolimus dose if
Mechanism of interaction has        needed [see section 4.2].
not been confirmed                  Monitor graft function closely.
Cannabidiol (P-gp inhibitor)       There have been reports of          Tacrolimus and cannabidiol increased tacrolimus blood          should be co-administered with levels during concomitant use of    caution, closely monitoring for tacrolimus with cannabidiol.        side effects. Monitor tacrolimus
This may be due to inhibition of    whole blood trough intestinal P-glycoprotein,          concentrations and adjust the leading to increased                tacrolimus dose if needed [see bioavailability of tacrolimus.      sections 4.2 and 4.4].
Products known to have high        Tacrolimus is extensively bound     Monitor tacrolimus whole blood affinity for plasma proteins,      to plasma proteins. Possible        trough concentrations and adjust e.g. NSAIDs, oral                  interactions with other active      tacrolimus dose if needed [see anticoagulants, oral               substances known to have high       section 4.2].
antidiabetics                      affinity for plasma proteins should be considered.
Prokinetic agents:                 May increase tacrolimus whole       Monitor tacrolimus whole blood metoclopramide, cimetidine         blood trough concentrations and     trough concentrations and and magnesium-aluminium-           increase the risk of serious        reduce tacrolimus dose if needed hydroxide                          adverse reactions (e.g.             [see section 4.2].
neurotoxicity, QT 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 blood corticosteroids                    blood trough concentrations and     trough concentrations and increase the risk of rejection      increase tacrolimus dose if
[see section 4.4].                  needed [see section 4.2].
Monitor graft function closely.
High dose prednisolone or          May have impact on tacrolimus       Monitor tacrolimus whole blood methylprednisolone                 blood levels (increase or           trough concentrations and adjust decrease) when administered for     tacrolimus dose if needed.
the treatment of acute rejection.


Drug/Substance Class or Name Drug interaction effect                  Recommendations concerning co-administration
Direct-acting antiviral (DAA)      May have impact on the             Monitor tacrolimus whole blood therapy                            pharmacokinetics of tacrolimus     trough concentrations and adjust by changes in liver function       tacrolimus dose if needed to during DAA therapy, related to     ensure continued efficacy and clearance of HCV virus. A          safety.
decrease in 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. Available data suggests 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 phenazone.
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).