Revolade Drug Interactions

In vitro evaluation of drug interaction potential: Based on a human study with radiolabelled eltrombopag, glucuronidation plays a minor role in the metabolism of eltrombopag. Human liver microsome studies identified UGT1A1 and UGT1A3 as the enzymes responsible for eltrombopag glucuronidation. In vitro studies demonstrate that eltrombopag is an inhibitor of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 (IC₅₀ values 3-33 μM; 1.3-14.6 μg/mL). Clinically significant drug interactions involving glucuronidation are not anticipated due to limited contribution of individual UGT enzymes in the glucuronidation of eltrombopag and potential co-medications.
Based on a human study with radiolabelled eltrombopag, approximately 21 % of an eltrombopag dose could undergo oxidative metabolism. Human liver microsome studies identified CYP1A2 and CYP2C8 as the enzymes responsible for eltrombopag oxidation. In vitro eltrombopag was an inhibitor of CYP2C8 and CYP2C9 (IC₅₀ 20-25 μM; 8.9-11 μg/mL), but eltrombopag did not inhibit or induce the metabolism of the CYP2C9 probe substrate flurbiprofen in a clinical drug interaction study when eltrombopag was administered as 75 mg once daily for 7 days to 24 healthy adult patients. In the same study, eltrombopag also did not inhibit or induce the metabolism of probe substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole) or CYP3A3 (midazolam). No clinically significant interactions are expected when eltrombopag and CYP450 substrates, inducers, or inhibitors are co-administered.
In vitro studies demonstrated that eltrombopag is not a substrate for the organic anion transporter polypeptide, OATP1B1, but is an inhibitor of this transporter with an IC₅₀ value of 2.7 μM (1.2 μg/mL). In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor with an IC₅₀ value of 2.7 μM (1.2 μg/mL).
Effects of other drugs on REVOLADE and effects of REVOLADE on other drugs: Rosuvastatin: Administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult patients increased plasma rosuvastatin C_max 103% (90 % CI: 82 %, 126 %) and AUC_0-∞ 55 % (90 % CI: 42 %, 69 %). When co-administered with eltrombopag, a reduced dose of rosuvastatin should be considered and careful monitoring should be undertaken. In clinical studies with eltrombopag, a dose reduction of rosuvastatin by 50 % was recommended for co-administration of rosuvastatin and eltrombopag. Concomitant administration of eltrombopag and other OATP1B1 and BCRP substrates should be undertaken with caution.
Lopinavir/ritonavir: Co-administration of eltrombopag with lopinavir/ritonavir (LPV/RTV) may cause a decrease in the concentration of eltrombopag. A study in 40 healthy volunteers, of which 23 (58 %) were women and 30 (75 %) were of White/Caucasian/European, 9 (23 %) of African American/African, and 1 (3 %) of Central/South Asian heritage, showed that the co-administration of a single dose of REVOLADE 100 mg with repeat dose LPV 400 mg/RTV 100 mg twice daily resulted in a reduction in eltrombopag plasma AUC_(0-∞) by 17 % (90 % CI: 6.6 %, 26.6 %). Therefore, caution should be used when co-administration of eltrombopag with LPV/RTV takes place. Platelet count should be closely monitored at least weekly for 2 to 3 weeks in order to ensure appropriate medical management of the dose of eltrombopag when LPV/RTV therapy is initiated or discontinued.
Polyvalent Cations (Chelation): Eltrombopag chelates with polyvalent cations such as aluminium, calcium, iron, magnesium, selenium and zinc. Administration of a single dose of eltrombopag 75 mg with a polyvalent cation-containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma eltrombopag AUC_0-∞ by 70 % (90 % CI: 64 %, 76 %) and C_max by 70 % (90 % CI: 62 %, 76 %). REVOLADE should be taken at least two hours before or four hours after any products such as antacids, dairy products and other products containing polyvalent cations to avoid significant reduction in eltrombopag absorption (see Dosage & Administration).
Calcium interaction: Administration of a single 50 mg-dose of REVOLADE tablet with a standard high-calorie, high-fat breakfast that included dairy products, reduced plasma eltrombopag AUC_0-∞ by 59 % and C_max by 65 % (see Pharmacology: Pharmacokinetics: Absorption under Actions, and Dosage & Administration).
Ciclosporin: In vitro studies also demonstrated that eltrombopag is a breast cancer resistance protein (BCRP) substrate and inhibitor. A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). Administration of a single dose of eltrombopag 50 mg with 200 mg ciclosporin (a BCRP inhibitor) decreased the C_max and the AUC_0-∞ of eltrombopag by 25 % (90 % CI: 15 %, 35 %) and 18 % (90 % CI: 8 %, 28 %), respectively. The co-administration of 600 mg ciclosporin decreased the C_max and the AUC_0-∞ of eltrombopag by 39 % (90 % CI: 30 %, 47 %) and 24% (90 % CI: 14 %, 32 %), respectively. This decrease in exposure is not considered clinically meaningful. Eltrombopag dose adjustment is permitted during the course of the treatment based on the patient's platelet count (see Dosage & Administration). Platelet count should be monitored at least weekly for 2 to 3 weeks when eltrombopag is co-administered with ciclosporin. Eltrombopag dose may need to be increased based on these platelet counts.