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 juice.
blood trough concentrations and 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 ciclosporin blood trough concentrations. In      and tacrolimus should be avoided addition, synergistic/additive       [see section 4.4].
nephrotoxic effects can occur.
Products known to have                  May enhance nephrotoxic or           Concurrent use of tacrolimus with nephrotoxic or neurotoxic effects:      neurotoxic effects of tacrolimus.    drugs known to have nephrotoxic aminoglycosides, gyrase                                                      effects should be avoided. When inhibitors, vancomycin,                                                      co-administration cannot be sulfamethoxazole + trimethoprim,                                             avoided, monitor renal function and NSAIDs, ganciclovir, acyclovir,                                              other side effects and adjust amphotericin B, ibuprofen,                                                   tacrolimus dose if needed.
cidofovir, foscarnet
Strong CYP3A4 inhibitors:               May increase tacrolimus whole        It is recommended that concomitant antifungal agents (e.g.,                blood trough concentrations and      use should be avoided. If co- ketoconazole, itraconazole,             increase the risk of serious         administration of a strong CYP3A4 posaconazole, voriconazole), the        adverse reactions (e.g.,             inhibitor is unavoidable, consider macrolide antibiotics (e.g.,            nephrotoxicity, neurotoxicity, QT    omitting the dose of tacrolimus the telithromycin, troleandomycin,          prolongation) which requires         day the strong CYP3A4 inhibitor is clarithromycin, josamycin), HIV         close monitoring [see                initiated. Reinitiate tacrolimus the protease inhibitors (e.g., ritonavir,   section 4.4].                        next day at a reduced dose based on nelfinavir, saquinavir), HCV            Rapid and sharp increases in         tacrolimus blood concentrations.
protease inhibitors (e.g.,              tacrolimus levels, may occur, as     Changes in both tacrolimus dose telaprevir, boceprevir, and the         early as within 1-3 days after co-   and/or dosing frequency should be combination of ombitasvir and           administration, despite immediate    individualized and adjusted as paritaprevir with ritonavir, when       reduction of tacrolimus dose.        needed based on tacrolimus trough used with and without dasabuvir),       Overall tacrolimus exposure may      concentrations, which should be nefazodone, the pharmacokinetic         increase >5 fold. When ritonavir     assessed at initiation, monitored enhancer cobicistat, and the            combinations are co-administered,    frequently throughout (starting kinase inhibitors idelalisib,           tacrolimus exposure may increase     within the first few days) and re- ceritinib.                              >50 fold.                            evaluated on and after completion Strong interactions have also been      Nearly all patients may require a    of the CYP3A4 inhibitor. Upon observed with the macrolide             reduction in tacrolimus dose and     completion, appropriate dose and antibiotic erythromycin                 temporary interruption of            dosing frequency of tacrolimus tacrolimus may also be necessary.    should be guided by tacrolimus
The effect on tacrolimus blood       blood concentrations. Monitor renal concentrations may remain for        function, ECG for QT prolongation, several days after co-               and other side effects closely.
administration is completed.


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 frequently, antifungal agents (e.g.,              increase the risk of serious          starting within the first few days of fluconazole, isavuconazole,           adverse reactions (e.g.,              co-administration. Reduce clotrimazole, miconazole), the        neurotoxicity, QT prolongation)       tacrolimus dose if needed [see macrolide antibiotics (e.g.,          [see section 4.4]. A rapid increase   section 4.2]. Monitor renal azithromycin), calcium channel        in tacrolimus level may occur.        function, ECG for QT prolongation, blockers (e.g., nifedipine,                                                 and other side effects closely.
nicardipine, diltiazem,
verapamil), amiodarone, 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 substances     May increase tacrolimus whole         Monitor tacrolimus whole blood have been shown to be potential       blood trough concentrations and       trough concentrations and reduce inhibitors of tacrolimus              increase the risk of serious          tacrolimus dose if needed [see metabolism: bromocriptine,            adverse reactions (e.g.,              section 4.2].
cortisone, dapsone, ergotamine,       neurotoxicity, QT prolongation)       Monitor renal function, ECG for gestodene, lidocaine,                 [see section 4.4].                    QT prolongation, and other side mephenytoin, midazolam,                                                     effects closely.
nilvadipine, norethisterone,
quinidine, tamoxifen
Strong CYP3A4 inducers:               May decrease tacrolimus whole         It is recommended that concomitant rifampicin, phenytoin,                blood trough concentrations and       use should be avoided. If carbamazepine, apalutamide,           increase the risk of rejection [see   unavoidable, patients may require enzalutamide, mitotane, or            section 4.4].                         an increase in tacrolimus dose.
St. John’s wort (Hypericum            Maximal effect on tacrolimus          Changes in tacrolimus dose should perforatum)                           blood concentrations may be           be individualized and adjusted as achieved 1-2 weeks after              needed based on tacrolimus trough co-administration. The effect may     concentrations, which should be remain 1-2 weeks after                assessed at initiation, monitored completion of the treatment.          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 blood metamizole, phenobarbital,            blood trough concentrations and       trough concentrations and increase isoniazid, rifabutin, efavirenz,      increase the risk of rejection [see   tacrolimus dose if needed [see etravirine, nevirapine; weak          section 4.4].                         section 4.2].
CYP3A4 inducers: flucloxacillin                                             Monitor graft function closely.
Caspofungin                           May decrease tacrolimus whole         Monitor tacrolimus whole blood blood trough concentrations and       trough concentrations and increase increase the risk of rejection.       tacrolimus dose if needed [see
Mechanism of interaction has not      section 4.2]. Monitor graft function been confirmed.                       closely.


Drug/Substance Class or Name          Drug interaction effect               Recommendations concerning co- administration
Cannabidiol (P-gp inhibitor)          There have been reports of            Tacrolimus and cannabidiol should increased tacrolimus blood levels     be co-administered with caution, during concomitant use of             closely monitoring for side effects.
tacrolimus with cannabidiol. This     Monitor tacrolimus whole blood may be due to inhibition of           trough concentrations and adjust intestinal P-glycoprotein, leading    the tacrolimus dose if needed [see to increased bioavailability of       sections 4.2 and 4.4].
tacrolimus.
Products known to have high           Tacrolimus is extensively bound       Monitor tacrolimus whole blood affinity for plasma proteins, e.g.:   to plasma proteins. Possible          trough concentrations and adjust NSAIDs, oral anticoagulants, oral     interactions with other active        tacrolimus dose if needed [see antidiabetics                         substances known to have high         section 4.2].
affinity for plasma proteins should be considered.
Prokinetic agents:                    May increase tacrolimus whole         Monitor tacrolimus whole blood metoclopramide, cimetidine and        blood trough concentrations and       trough concentrations and reduce magnesium-aluminium-hydroxide         increase the risk of serious          tacrolimus dose if needed [see adverse reactions (e.g.,              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 increase the risk of rejection [see   tacrolimus dose if needed [see section 4.4].                         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.
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 ensure during DAA therapy, related to        continued efficacy and safety.
clearance of hepatitis virus. A 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).