Dolutegravir sodium

This product is a compound preparation, each tablet contains 300 mg of lamivudine and 50 mg of dolutegravir sodium (calculated as dolutegravir).

Drug interaction studies have not been conducted for this product. This product contains dolutegravir and lamivudine, therefore, any interactions found with these drugs when used alone are related to this product. There are no clinically significant drug interactions between dolutegravir and lamivudine. Effects of Other Drugs on the Pharmacokinetics of Dolutegravir and Lamivudine Dolutegravir is primarily metabolized and eliminated by uridine diphosphate glucuronosyltransferase (UGT) 1A1. Dolutegravir is also a substrate for UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP. Therefore, co-administration of this product with other drugs that inhibit UGTA1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may increase dolutegravir plasma concentrations. Drugs that induce these enzymes or transporters may decrease dolutegravir plasma concentrations and thus reduce dolutegravir efficacy. Certain antacids and supplements of metal cations may reduce dolutegravir absorption (see Table 2). Lamivudine is cleared by the kidneys. The kidneys actively secrete lamivudine into the urine, which is mediated by organic cation transporters (OCT2) and multidrug and toxic compound efflux transporters (MATE1 and MATE2-K). It has been shown that trimethoprim (an inhibitor of these transporters) can increase the plasma concentration of lamivudine, but its increase is not clinically significant (see Table 2). Dolutegravir is an inhibitor of OCT2 and MATE1, but according to a cross-study analysis, the concentration of lamivudine when administered with or without dolutegravir is similar, indicating that in vivo, dolutegravir does not affect the exposure level of lamivudine. Lamivudine is also a substrate for the liver uptake transporter OCT1. Since liver elimination plays a minor role in the clearance of lamivudine, drug interactions caused by inhibiting OCT1 are unlikely to have clinical significance. Although lamivudine is a substrate of BCRP and P-gp in vitro, inhibitors of these efflux transporters are unlikely to have a clinically relevant effect on lamivudine concentrations given its high absolute bioavailability (see [Pharmacokinetics]). Effects of Dolutegravir and Lamivudine on the Pharmacokinetics of Other Drugs Dolutegravir had no effect on midazolam (a CYP3A4 probe) in vitro. Based on in vitro and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of major enzymes or transporters (e.g., CYP3A4, CYP2C9, and P-gp) (see [Pharmacokinetics]). In vitro, dolutegravir inhibits the renal transporters OCT2 and MATE1. In vivo, a 10% to 14% decrease in creatinine clearance was observed in patients (the excretion ratio is dependent on the OCT2 and MATE-1 transporters). In vivo, dolutegravir may increase plasma concentrations of medicinal products that rely on OCT2 or MATE-1 for excretion (e.g., metformin) (see Table 2 and [Contraindications]). In vitro, dolutegravir inhibits the renal uptake of organic anion transporters OAT1 and OAT3. In vivo inhibition of OAT1 is unlikely due to its lack of effect on the pharmacokinetics of the OAT substrate tenofovir. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products that rely on OATB for excretion. In vitro, lamivudine is an inhibitor of OCT1 and OCT2; the clinical consequences are unknown. Pediatric Population Interaction studies have only been conducted in adults.

Dolutegravir sodium. Excipients: D-mannitol, microcrystalline cellulose, povidone, sodium carboxymethyl starch, sodium stearyl fumarate, etc.

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