All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance.
Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration.
The absorption of dolutegravir is reduced by certain anti-acid agents.
In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir does not seem to have an effect on midazolam, a CYP3A4 probe, however, a weak inhibition can presently not be excluded.
Etravirine decreased plasma dolutegravir concentration, which may result in loss of virologic response and possible resistance to dolutegravir. DTV 50 should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir.
The recommended dose of DTV 50 is 50 mg twice daily when co-administered with efavirenz, nevirapine, rifampicin, tipranavir/ritonavir and fosamprenavir/ritonavir with the absence of integrase class resistance. In the presence of integrase class resistance these combinations should be avoided. DTV 50 and dofetilide co-administration is contraindicated due to potential life-threatening toxicity caused by high dofetilide concentration. Co-administration with these enzyme inducers should be avoided. No dose adjustment is necessary. Based on data from other CYP3A4 inhibitors, a marked increase is not expected.
Co-administration with St. John's wort is strongly discouraged.
Magnesium/aluminium-containing antacid should be taken well separated in time from the administration of DTV 50 (minimum 2 hours after or 6 hours before).
Calcium supplements, iron supplements or multivitamins should be taken well separated in time from the administration of DTV 50 (minimum 2 hours after or 6 hours before).
Close monitoring of metformin efficacy and safety is recommended when starting or stopping DTV 50 in patients receiving metformin. A dose adjustment of metformin may be necessary.