Revolade Drug Interactions

Effects of Revolade on other medicinal products: HMG CoA reductase inhibitors: Administration of Revolade 75 mg once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate rosuvastatin to 39 healthy adult subjects increased plasma rosuvastatin C_max 103% (90% confidence interval [CI]: 82%, 126%) and AUC_0-∞ 55% (90% CI: 42%, 69%). Interactions are also expected with other HMG-CoA reductase inhibitors, including atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When co-administered with Revolade, a reduced dose of statins should be considered and careful monitoring for statin adverse reactions should be undertaken (see Pharmacology: Pharmacokinetics under Actions).
OATP1B1 and BCRP substrates: Concomitant administration of Revolade and OATP1B1 (e.g. methotrexate) and BCRP (e.g. topotecan and methotrexate) substrates should be undertaken with caution (see Pharmacology: Pharmacokinetics under Actions).
Cytochrome P450 substrates: In studies utilising human liver microsomes, Revolade (up to 100 μM) showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 2E1, 3A4/5, and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9 as measured using paclitaxel and diclofenac as the probe substrates. Administration of Revolade 75 mg once daily for 7 days to 24 healthy male subjects did not inhibit or induce the metabolism of probe substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in humans. No clinically significant interactions are expected when Revolade and CYP450 substrates are co-administered (see Pharmacology: Pharmacokinetics under Actions).
HCV protease inhibitors: Dose adjustment is not required when Revolade is co-administered with either telaprevir or boceprevir. Co-administration of a single dose of Revolade 200 mg with telaprevir 750 mg every 8 hours did not alter plasma telaprevir exposure.
Co-administration of a single dose of Revolade 200 mg with boceprevir 800 mg every 8 hours did not alter plasma boceprevir AUC_(0-τ), but increased C_max by 20%, and decreased C_min by 32%. The clinical relevance of the decrease in C_min has not been established, increased clinical and laboratory monitoring for HCV suppression is recommended.
Effects of other medicinal products on Revolade: Ciclosporin: A decrease in Revolade exposure was observed with co-administration of 200 mg and 600 mg ciclosporin (a BCRP inhibitor). The co-administration of 200 mg ciclosporin decreased the C_max and the AUC_0-∞ of Revolade by 25% and 18%, respectively. The co-administration of 600 mg ciclosporin decreased the C_max and the AUC_0-∞ of Revolade by 39% and 24%, respectively. Revolade 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 Revolade is co-administered with ciclosporin. Revolade dose may need to be increased based on these platelet counts.
Polyvalent cations (chelation): Revolade chelates with polyvalent cations such as iron, calcium, magnesium, aluminium, selenium and zinc. Administration of a single dose of Revolade 75 mg with a polyvalent cation-containing antacid (1524 mg aluminium hydroxide and 1425 mg magnesium carbonate) decreased plasma Revolade 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 or mineral supplements containing polyvalent cations to avoid significant reduction in Revolade absorption due to chelation (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Lopinavir/ritonavir: Co-administration of Revolade with lopinavir/ritonavir may cause a decrease in the concentration of Revolade. A study in 40 healthy volunteers showed that the co-administration of a single 100 mg dose of Revolade with repeat dose lopinavir/ritonavir 400/100 mg twice daily resulted in a reduction in Revolade plasma AUC_0-∞ by 17% (90% CI: 6.6%, 26.6%). Therefore, caution should be used when co-administration of Revolade with lopinavir/ritonavir takes place. Platelet count should be closely monitored in order to ensure appropriate medical management of the dose of Revolade when lopinavir/ritonavir therapy is initiated or discontinued.
CYP1A2 and CYP2C8 inhibitors and inducers: Revolade is metabolised through multiple pathways including CYP1A2, CYP2C8, UGT1A1, and UGT1A3 (see Pharmacology: Pharmacokinetics under Actions). Medicinal products that inhibit or induce a single enzyme are unlikely to significantly affect plasma Revolade concentrations, whereas medicinal products that inhibit or induce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease (e.g. rifampicin) Revolade concentrations.
HCV protease inhibitors: Results of a drug-drug pharmacokinetic (PK) interaction study show that co-administration of repeat doses of boceprevir 800 mg every 8 hours or telaprevir 750 mg every 8 hours with a single dose of Revolade 200 mg did not alter plasma Revolade exposure to a clinically significant extent.
Medicinal products for treatment of ITP: Medicinal products used in the treatment of ITP in combination with Revolade in clinical studies included corticosteroids, danazol, and/or azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. Platelet counts should be monitored when combining Revolade with other medicinal products for the treatment of ITP in order to avoid platelet counts outside of the recommended range (see Dosage & Administration).
Food interaction: The administration of Revolade tablet with a high-calcium meal (e.g. a meal that included dairy products) significantly reduced plasma Revolade AUC_0-∞ and C_max. In contrast, the administration of Revolade 2 hours before or 4 hours after a high-calcium meal or with low-calcium food [<50 mg calcium] did not alter plasma Revolade exposure to a clinically significant extent (see Dosage & Administration).
Administration of a single 50 mg dose of Revolade in tablet form with a standard high-calorie, high-fat breakfast that included dairy products reduced plasma Revolade mean AUC_0-∞ by 59% and mean C_max by 65%.
Food low in calcium (<50 mg calcium), including fruit, lean ham, beef and unfortified (no added calcium, magnesium or iron) fruit juice, unfortified soya milk and unfortified grain, did not significantly impact plasma Revolade exposure, regardless of calorie and fat content (see Dosage & Administration and Interactions).