Interactions : אינטראקציות

4.5    Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on dabrafenib
Dabrafenib is a substrate for the metabolising enzymes CYP2C8 and CYP3A4, while the active metabolites hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates.
Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are therefore likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents should be considered during administration with dabrafenib when possible. Use caution if strong inhibitors (e.g. ketoconazole, gemfibrozil, nefazodone, clarithromycin, ritonavir, saquinavir, telithromycin, itraconazole, voriconazole, posaconazole, atazanavir) are co-administered with dabrafenib. Avoid co-administration of dabrafenib with potent inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum)) of CYP2C8 or CYP3A4.

Administration of ketoconazole (a CYP3A4 inhibitor) 400 mg once daily, with dabrafenib 75 mg twice daily, resulted in a 71% increase in dabrafenib AUC and a 33% increase in dabrafenib Cmax relative to administration of dabrafenib 75 mg twice daily alone. Co- administration resulted in increases in hydroxy- and desmethyl-dabrafenib AUC (increases of 82% and 68%, respectively). A decrease of 16% in AUC was noted for carboxy-dabrafenib.

Administration of gemfibrozil (a CYP2C8 inhibitor) 600 mg twice daily, with dabrafenib 75 mg twice daily, resulted in a 47% increase in dabrafenib AUC but did not alter dabrafenib Cmax relative to administration of dabrafenib 75 mg twice daily alone. Gemfibrozil had no clinically relevant effect on the systemic exposure to dabrafenib metabolites (≤13%).

Administration of rifampin (a CYP3A4/CYP2C8 inducer) 600 mg once daily with dabrafenib 150 mg twice daily resulted in a decrease in repeat dose dabrafenib Cmax (27%) and AUC (34%). No relevant change in AUC was noted for hydroxy-dabrafenib. There was an increase in AUC of 73% for carboxy-dabrafenib and a decrease in AUC of 30% for desmethyl-dabrafenib.

Co-administration of repeat doses of dabrafenib 150 mg twice daily and the pH-elevating agent rabeprazole 40 mg once daily resulted in a 3% increase in AUC and a 12% decrease in dabrafenib Cmax. These changes in dabrafenib AUC and Cmax are considered not clinically meaningful. Medicinal products that alter the pH of the upper gastrointestinal (GI) tract (e.g.
proton pump inhibitors, H2-receptor antagonists, antacids) are not expected to reduce the bioavailability of dabrafenib.

Effect of dabrafenib on other medicinal products

Dabrafenib is an enzyme inducer and increases the synthesis of drug-metabolising enzymes including CYP3A4, CYP2Cs and CYP2B6 and may increase the synthesis of transporters.

This results in reduced plasma levels of medicinal products metabolised by these enzymes, and may affect some transported medicinal products. The reduction in plasma concentrations can lead to lost or reduced clinical effect of these medicinal products. There is also a risk of increased formation of active metabolites of these medicinal products. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGTs (glucuronide conjugating enzymes). The transport protein Pgp may also be induced as well as other transporters, e.g. MRP-2. Induction of OATP1B1/1B3 and BCRP is not likely based on the observations from a clinical study with rosuvastatin.

In vitro, dabrafenib produced dose-dependent increases in CYP2B6 and CYP3A4. In a clinical drug interaction study, Cmax and AUC of oral midazolam (a CYP3A4 substrate) decreased by 47% and 65%, respectively with co-administration of repeat-dose dabrafenib.

Administration of dabrafenib 150 mg twice daily and warfarin resulted in a decrease in AUC of S- and R- warfarin of 37% and 33% respectively, compared to administration of warfarin alone. Cmax of S- and R-warfarin increased 18% and 19%.

Interactions with many medicinal products eliminated through metabolism or active transport is expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.

The number of affected medicinal products is expected to be large; although the magnitude of the interaction will vary. Groups of medicinal products that can be affected include, but are not limited to:
•      Analgesics (e.g. fentanyl, methadone)
•      Antibiotics (e.g. clarithromycin, doxycycline)
•      Anticancer agents (e.g. cabazitaxel)
•      Anticoagulants (e.g. acenocoumarol, warfarin, see section 4.4)
•      Antiepileptic (e.g. carbamazepine, phenytoin, primidone, valproic acid)
•      Antipsychotics (e.g. haloperidol)
•      Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil)
•      Cardiac glycosides (e.g. digoxin, see section 4.4)
•      Corticosteroids (e.g. dexamethasone, methylprednisolone)
•      HIV antivirals (e.g. amprenavir, atazanavir, darunavir, delavirdine, efavirenz, fosamprenavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir)
•      Hormonal contraceptives (see section 4.6)
•      Hypnotics (e.g. diazepam, midazolam, zolpidem)
•      Immunosuppressants (e.g. cyclosporin, tacrolimus, sirolimus)
•      Statins metabolised by CYP3A4 (e.g. atorvastatin, simvastatin) 
Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib. Upon discontinuation of dabrafenib offset of induction is gradual, concentrations of sensitive CYP3A4, CYP2B6, CYP2C8, CYP2C9 and CYP2C19, UDP glucuronosyl transferase (UGT) and transporter substrates (e.g. Pgp or MRP-2) may increase and patients should be monitored for toxicity and dose of these agents may need to be adjusted.

In vitro, dabrafenib is a mechanism based inhibitor of CYP3A4. Therefore, transient inhibition of CYP3A4 may be observed during the first few days of treatment.


Effects of dabrafenib on substance transport systems
Dabrafenib is an in vitro inhibitor of human organic anion transporting polypeptide (OATP) 1B1 (OATP1B1), OATP1B3 and BCRP. Following co-administration of a single dose of rosuvastatin (OATP1B1, OATP1B3 and BCRP substrate) with repeat-dose dabrafenib 150 mg twice daily in 16 patients, Cmax of rosuvastatin increased 2.6-fold whereas the AUC was only minimally changed (7% increase). The increased Cmax of rosuvastatin is unlikely to have clinical relevance

Combination with trametinib

Co-administration of repeat dosing of trametinib 2 mg once daily and dabrafenib 150 mg twice daily resulted in no clinically meaningful changes in trametinib or dabrafenib Cmax and AUC with increases of 16 and 23%, respectively, in dabrafenib Cmax and AUC. A small decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was estimated when trametinib is administered in combination with dabrafenib, a CYP3A4 inducer, using a population pharmacokinetic analysis.

When dabrafenib is used in combination with trametinib refer to the guidance for medicinal product interactions found in sections 4.4 and 4.5 of dabrafenib and trametinib Prescribing Information.

Effect of food on dabrafenib

Patients should take dabrafenib as monotherapy or in combination with trametinib at least one hour prior to or two hours after a meal due to the effect of food on dabrafenib absorption (see section 5.2).

Paediatric population

Interaction studies have only been performed in adults.