Liverpool HIV Interactions

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Potential Interaction

Dolutegravir (DTG)

Metformin

Quality of Evidence: Low

Summary:

Coadministration of metformin (500 mg twice daily) was studied with dolutegravir (50 mg once or twice daily) in 15 subjects. Coadministration with once daily dolutegravir increased metformin Cmax and AUC by 66% and 79%, whereas coadministration with twice daily dolutegravir increased metformin Cmax and AUC by 111% and 145%. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin in order to maintain glycaemic control. The US Prescribing Information suggests limiting the total daily dose of metformin to 1000 mg when starting metformin or dolutegravir. Monitoring renal function during coadministration and monitoring blood glucose when starting and stopping coadministration is recommended. As metformin is eliminated renally, patients with moderate renal impairment may be at increased risk for lactic acidosis due to increased metformin concentrations.

Description:

Coadministration of metformin with once daily dolutegravir (50 mg once daily) increase metformin AUC and Cmin by 79% and 66%. Coadministration with twice daily dolutegravir (50 mg twice daily) increased metformin AUC and Cmax by 145% and 111%. A dose adjustment of metformin should be considered when starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control. Metformin is eliminated renally and therefore it is of importance to monitor renal function when co-treated with dolutegravir. This combination may increase the risk for lactic acidosis in patients with moderate renal impairment (stage 3a creatinine clearance [CrCl] 45– 59 mL/min) and a cautious approach is recommended. Reduction of the metformin dose should be highly considered.
Tivicay Summary of Product Characteristics, ViiV Healthcare, March 2019.

Coadministration of metformin (500 mg twice daily) was studied with dolutegravir (50 mg once or twice daily) in 15 subjects. Coadministration with once daily dolutegravir increased metformin Cmax and AUC by 66% and 79%, whereas coadministration with twice daily dolutegravir increased metformin Cmax and AUC by 111% and 145%. With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or dolutegravir. When stopping dolutegravir, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of dolutegravir is recommended.
Tivicay US Prescribing Information, ViiV Healthcare, July 2019.

Co-administration of metformin (500 mg twice daily) was studied with dolutegravir alone (50 mg once or twice daily) in 15 subjects. Co-administration of dolutegravir 50 mg once daily increased metformin AUC and Cmax by 79% and 66%, respectively, whereas dolutegravir 50 mg twice daily increased metformin area AUC and Cmax by 145% and 111%, respectively. Co-administration of dolutegravir and metformin was well tolerated. In vitro, dolutegravir was not a clinically relevant inhibitor of OCT1, OCT3, multidrug and toxin extrusion protein 1, multidrug and toxin extrusion protein 2-K, or plasma membrane monoamine transporter. Increased metformin plasma exposure can be partially explained by OCT2 inhibition by dolutegravir. It is recommended that dose adjustments of metformin be considered to maintain optimal glycemic control when patients are starting/stopping dolutegravir while taking metformin.

Song IH, Zong J, Borland J, et al. The effect of dolutegravir on the pharmacokinetics of metformin in healthy subjects. J Acquir Immune Defic Syndr. 2016 Aug 1;72(4):400-7.