Advagraf Drug 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 substances known to inhibit or induce CYP3A4 may affect the metabolism of tacrolimus and thereby increase or decrease tacrolimus blood levels.
Significant tacrolimus dose reductions and prolongation of dosing interval may be required in order to maintain similar tacrolimus exposure when co-administered with strong CYP3A4 inhibitors, particularly telaprevir. Rapid increase in tacrolimus level may occur when co-administered with CYP3A4 inhibitors. Cases have been reported in which a sharp rise in tacrolimus levels occurred very rapidly, as early as within 1-3 days after co-administration with a strong CYP3A4 inhibitor, clarithromycin, despite immediate reduction of tacrolimus dose. Therefore early, within the first few days of co-administration, and frequent continued monitoring of tacrolimus blood levels, as well as monitoring for renal function, for QT prolongation with ECG, and for other side effects is strongly recommended (see Dosage & Administration and Precautions).
CYP3A4 inhibitors potentially leading to increased tacrolimus blood levels: Clinically the following substances have been shown to increase tacrolimus blood levels: Strong interactions have been observed with antifungal agents such as ketoconazole, fluconazole, itraconazole and voriconazole, the macrolide antibiotic erythromycin, HIV protease inhibitors (for example but not limited to ritonavir, nelfinavir, saquinavir), HCV protease inhibitors (for example but not limited to telaprevir, boceprevir), or letermovir. Concomitant use of these substances may require decreased tacrolimus doses in nearly all patients. Pharmacokinetics studies have indicated that the increase in blood levels 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.
Weaker interactions have been observed with clotrimazole, clarithromycin, josamycin, nifedipine, nicardipine, diltiazem, amiodarone, verapamil, danazol, ethinylestradiol, omeprazole, nefazodone and herbal remedies containing extracts of Schisandra sphenanthera.
In vitro the following substances have been shown to be potential inhibitors of tacrolimus metabolism: bromocriptine, cortisone, dapsone, ergotamine, gestodene, lidocaine, mephenytoin, miconazole, midazolam, nilvadipine, norethindrone, quinidine, tamoxifen, (triacetyl) oleandomycin.
Grapefruit juice has been reported to increase the blood level of tacrolimus and should therefore be avoided.
Lansoprazole and ciclosporin may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby increase tacrolimus whole blood concentrations.
Other interactions potentially leading to increased tacrolimus blood levels: Tacrolimus is extensively bound to plasma proteins. Possible interactions with other active substances known to have high affinity for plasma proteins should be considered (e.g., NSAIDs, oral anticoagulants, or oral antidiabetics).
Other potential interactions that may increase systemic exposure of tacrolimus include prokinetic agents (such as metoclopramide and cisapride), cimetidine and magnesium-aluminum-hydroxide.
Cannabidiol has been shown to increase the blood levels of tacrolimus. Mechanism of interaction has not been confirmed. When cannabidiol and Advagraf are co-administered, monitor tacrolimus blood levels and side effects closely, and adjust tacrolimus dose if needed.
CYP3A4 inducers potentially leading to decreased tacrolimus blood levels: Clinically the following substances have been shown to decrease tacrolimus blood levels: Strong interactions have been observed with rifampicin, phenytoin, St. John's wort (Hypericum perforatum) which may require increased tacrolimus doses in almost all patients. Clinically significant interactions have also been observed with phenobarbital. Maintenance doses of corticosteroids have been shown to reduce tacrolimus blood levels.
High dose prednisolone or methylprednisolone administered for the treatment of acute rejection have the potential to increase or decrease tacrolimus blood levels.
Carbamazepine, metamizole and isoniazid have the potential to decrease tacrolimus concentrations.
Caspofungin has been shown to decrease the blood levels of tacrolimus; the mechanism of interaction is not confirmed.
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 Dosage & Administration and Precautions).
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.
Combination therapy with mycophenolic acid (MPA) products: Caution should be exercised when switching combination therapy from ciclosporin to tacrolimus and vice versa. Exposure to MPA is higher with tacrolimus co-administration than with ciclosporin coadministration because ciclosporin interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Therapeutic drug monitoring of MPA is recommended.
Other interactions leading to clinically detrimental effects: Concurrent use of tacrolimus with medicinal products known to have nephrotoxic or neurotoxic effects may increase these effects (e.g., aminoglycosides, gyrase inhibitors, vancomycin, cotrimoxazole, NSAIDs, ganciclovir or aciclovir).
Enhanced nephrotoxicity has been observed following the administration of amphotericin B and ibuprofen in conjunction with tacrolimus.
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 Precautions).
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 Precautions).
Impact of direct-acting antiviral (DAA) therapy: The pharmacokinetics of tacrolimus 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 tacrolimus is warranted to ensure continued efficacy and safety.