Triumeq PD (abacavir sulfate 600 mg dolutegravir sodium 50 mg lamivudine 300 mg) Dailymed

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TRIUMEQ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1‑800‑258‑4263. Risk Summary Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini which together include over 14,000 individuals evaluated during pregnancy show similar prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV-negative individuals (see Data). There are insufficient human data on the use of TRIUMEQ during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the APR with the individual components of TRIUMEQ do not indicate an increased risk of birth defects (see Data). The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal reproduction studies, no evidence of adverse developmental outcomes (including neural tube defects) was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). Oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the RHD. No adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures approximately 9 times the human exposure (AUC) at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at a human exposure (AUC) similar to the RHD; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see Data). Data Human Data:             Dolutegravir:                Observational studies: The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. A subsequent analysis was conducted based on a larger cohort from the birth outcome surveillance study in Botswana and included over 9,460 individuals exposed to dolutegravir at conception, 23,664 individuals exposed to non-dolutegravir-containing regimens, and 170,723 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11% (95% CI: 0.05-0.19%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.11%, 95% CI: 0.07-0.16%), or to HIV-negative individuals (0.06%, 95% CI: 0.05-0.08%). The Eswatini birth outcome surveillance study includes 9,743 individuals exposed to dolutegravir at conception, 1,838 individuals exposed to non-dolutegravir-containing regimens, and 32,259 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08% (95% CI: 0.04-0.16%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%, 95% CI: 0.06-0.56%) or to HIV-negative individuals (0.08%, 95% CI: 0.06-0.12%). The observed prevalence of neural tube defects in infants delivered to individuals taking non-dolutegravir-containing regimens had a wide confidence interval due to low sample size. Limitations of these birth outcome surveillance studies include insufficient data to determine if baseline characteristics were balanced between the study groups or to assess other factors such as the use of folic acid during the preconception or first trimester periods.                Antiretroviral Pregnancy Registry: Based on prospective reports to the APR, of over 1,300 exposures to dolutegravir during pregnancy resulting in live births (including 874 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.2% to 4.7%) following first-trimester exposure to dolutegravir-containing regimens and 5.0% (95% CI: 3.2% to 7.3%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. Dolutegravir has been shown to cross the placenta. In a clinical trial in Uganda and South Africa in women during the last trimester of pregnancy receiving dolutegravir 50 mg once daily, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range 0.51-2.11) (n = 15).                Abacavir: Based on prospective reports to the APR of over 2,800 exposures to abacavir during pregnancy resulting in live births (including 1,455 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.4% to 4.3%) following first trimester exposure to abacavir-containing regimens and 3.0% (95% CI: 2.2% to 4.1%) following second/third trimester exposure to abacavir-containing regimens. Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)].                Lamivudine: Based on prospective reports to the APR of over 13,000 exposures to lamivudine during pregnancy resulting in live births (including 5,613 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater compared with paired maternal serum concentration (n = 8). Animal Data:                Dolutegravir: Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg/kg/day) on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 50 times human exposure at the RHD).                Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg/kg/day) and rabbits (at 125, 350, or 700 mg/kg/day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown‑rump length) were observed in rats at doses up to 1,000 mg/kg/day, resulting in exposures approximately 35 times the human exposure (AUC) at the RHD. No developmental effects were observed in rats at 100 mg/kg/day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg/kg/day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg/kg/day. No developmental effects were observed in rats at 60 mg/kg/day, resulting in exposures (AUC) approximately 4 times the human exposure at the RHD. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the RHD.                Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg/kg/day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.

Pharmacokinetics in Adults One TRIUMEQ tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n = 62). TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension are bioequivalent for the abacavir and lamivudine components, but not for the dolutegravir component. The relative dolutegravir bioavailability of TRIUMEQ PD is approximately 1.7-fold higher than TRIUMEQ; therefore, the 2 dosage forms are not substitutable on a milligram-per-milligram basis [see Dosage and Administration (2.3), Warnings and Precautions (5.7)]. The relative dolutegravir bioavailability is expected to be similar between TRIUMEQ PD and TIVICAY PD. Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour/mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug‑related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′‑carboxylic acid and glucuronyl transferase to form the 5′‑glucuronide. In single-dose trials, the observed elimination half-life (t½) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L/h/kg (mean ± SD). Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5. Dolutegravir is a P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (≥98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis. Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [14C] dolutegravir, 53% of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was <1% of the dose. Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L/h based on population pharmacokinetic analyses. The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. Table 7. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1–Infected Adults Parameter 50 mg Once Daily Geometric Mean (%CV) AUC(0-24) (mcg•h/mL) 53.6 (27) Cmax (mcg/mL) 3.67 (20) Cmin (mcg/mL) 1.11 (46)           Cerebrospinal Fluid (CSF): In 11 treatment-naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng/mL (range: 4 ng/mL to 23.2 ng/mL) 2 to 6 hours postdose after 2 weeks of treatment. The clinical relevance of this finding has not been established. Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple‑dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24‑hour steady‑state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour/mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans‑sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials with plasma sampling up to 48 or 72 hours after dosing, the observed mean elimination half-life (t½) ranged from 13 to 19 hours. In HIV-1–infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). Effect of Food on Oral Absorption TRIUMEQ or TRIUMEQ PD may be taken with or without food. Overall, when compared with fasted conditions, administration of TRIUMEQ to healthy adult subjects with a high-fat meal (53% fat, 869 calories) resulted in decreased Cmax for abacavir and increased Cmax and AUC for dolutegravir. Lamivudine exposures were not affected by food. With a high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively. When compared with fasted conditions, administration of TRIUMEQ PD to healthy adult subjects with a high-fat meal (50% fat, 917 calories) resulted in decreased Cmax for abacavir (55%), dolutegravir (29%) and lamivudine (36%). AUCs for all 3 components were not affected by food. Specific Populations Patients with Renal Impairment: The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components). Patients with Hepatic Impairment: The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components). Pregnant women: Abacavir: Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.           Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Pediatric Patients: The pharmacokinetics of TRIUMEQ, TRIUMEQ PD (abacavir, dolutegravir, and lamivudine) and their individual components have been evaluated in pediatric subjects.           Abacavir, Dolutegravir and Lamivudine: The pharmacokinetics of TRIUMEQ and TRIUMEQ PD were evaluated in the IMPAACT 2019 trial. Steady-state plasma exposure at doses by weight band are summarized in Table 8 [see Use in Specific Populations (8.4), Clinical Studies (14.2)]. Overall, exposures of abacavir, dolutegravir and lamivudine at the recommended doses for TRIUMEQ PD and TRIUMEQ are within the observed exposure ranges at the recommended doses of individual products in adults and pediatrics. Refer to the prescribing information for EPIVIR, TIVICAY, and ZIAGEN for pharmacokinetic information on lamivudine, dolutegravir, and abacavir, respectively, in pediatric patients. Table 8. Summary of Pharmacokinetic Parameters in Pediatric HIV-1–Infected Subjects (IMPAACT 2019 Trial) %CV, coefficient of variation expressed as a percentage. a The relative dolutegravir bioavailability of TRIUMEQ PD tablets for oral suspension is ~1.7-fold that of TRIUMEQ tablets. Drug Weight Band Dosea of single entities in TRIUMEQ or TRIUMEQ PD n Pharmacokinetic Parameter Geometric Mean (%CV) Cmax (mcg/mL) AUC0-24h (mcg∙h/mL) C24h (ng/mL) Abacavir 6 to <10 kg 180 mg once daily TRIUMEQ PD 7 7.30 (20) 17.7 (34) 3 (128) 10 to <14 kg 240 mg once daily TRIUMEQ PD 7 8.36 (44) 19.8 (51) 5 (127) 14 to <20 kg 300 mg once daily TRIUMEQ PD 7 6.26 (31) 15.1 (40) 3 (108) 20 to <25 kg 360 mg once daily TRIUMEQ PD 7 6.65 (28) 17.4 (19) 4 (85) 25 to <40 kg 600 mg once daily TRIUMEQ 7 9.04 (22) 25.7 (15) 11 (229) Dolutegravir 6 to <10 kg 15 mg once daily TRIUMEQ PD 7 7.40 (28) 75.9 (34) 910 (68) 10 to <14 kg 20 mg once daily TRIUMEQ PD 7 8.85 (21) 91.0 (36) 1220 (77) 14 to <20 kg 25 mg once daily TRIUMEQ PD 7 7.04 (17) 71.4 (23) 790 (44) 20 to <25 kg 30 mg once daily TRIUMEQ PD 7 7.29 (17) 84.4 (26) 1350 (95) 25 to <40 kg 50 mg once daily TRIUMEQ 7 6.25 (21) 71.8 (14) 980 (28) Lamivudine 6 to <10 kg 90 mg once daily TRIUMEQ PD 7 2.29 (40) 10.7 (46) 55 (39) 10 to <14 kg 120 mg once daily TRIUMEQ PD 7 3.55 (19) 14.2 (24) 46 (48) 14 to <20 kg 150 mg once daily TRIUMEQ PD 7 2.92 (23) 13.0 (16) 58 (37) 20 to <25 kg 180 mg once daily TRIUMEQ PD 7 2.99 (32) 14.5 (17) 60 (18) 25 to <40 kg 300 mg once daily TRIUMEQ 7 4.15 (29) 21.7 (26) 84 (35) Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years. Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components. Racial Groups: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components. Drug Interaction Studies The drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine. Dosing recommendations as a result of established and other potentially significant drug-drug interactions with the individual components of TRIUMEQ and TRIUMEQ PD are provided in Section 7.3 [see Drug Interactions (7)]. Table 9. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs a The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s) and Dose(s) Dose of Dolutegravir n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00 Cmax AUC Cτ or C24 Ethinyl estradiol  0.035 mg 50 mg twice daily 15 0.99(0.91 to 1.08) 1.03(0.96 to 1.11) 1.02(0.93 to 1.11) Metformin  500 mg twice daily 50 mgonce daily 15a 1.66(1.53 to 1.81) 1.79(1.65 to 1.93) — Metformin  500 mg twice daily 50 mg twice daily 15a 2.11(1.91 to 2.33) 2.45(2.25 to 2.66) — Methadone  16 to 150 mg 50 mg twice daily 11 1.00(0.94 to 1.06) 0.98(0.91 to 1.06) 0.99(0.91 to 1.07) Midazolam  3 mg 25 mgonce daily 10 — 0.95(0.79 to 1.15) — Norelgestromin  0.25 mg 50 mg twice daily 15 0.89(0.82 to 0.97) 0.98(0.91 to 1.04) 0.93(0.85 to 1.03) Rilpivirine  25 mg once daily 50 mgonce daily 16 1.10(0.99 to 1.22) 1.06(0.98 to 1.16) 1.21(1.07 to 1.38) Tenofovir disoproxil fumarate  300 mg once daily 50 mgonce daily 15 1.09(0.97 to 1.23) 1.12(1.01 to 1.24) 1.19(1.04 to 1.35) Table 10. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir a Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. c The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s) and Dose(s) Dose of Dolutegravir n Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 Cmax AUC Cτ or C24 Atazanavir   400 mg once daily 30 mgonce daily 12 1.50(1.40 to 1.59) 1.91(1.80 to 2.03) 2.80(2.52 to 3.11) Atazanavir/ritonavir   300/100 mg once daily 30 mgonce daily 12 1.34(1.25 to 1.42) 1.62(1.50 to 1.74) 2.21(1.97 to 2.47) Darunavir/ritonavir   600/100 mg twice daily 30 mgonce daily 15 0.89(0.83 to 0.97) 0.78(0.72 to 0.85) 0.62(0.56 to 0.69) Efavirenz   600 mg once daily 50 mgonce daily 12 0.61(0.51 to 0.73) 0.43(0.35 to 0.54) 0.25(0.18 to 0.34) Etravirine   200 mg twice daily 50 mgonce daily 16 0.48(0.43 to 0.54) 0.29(0.26 to 0.34) 0.12(0.09 to 0.16) Etravirine + darunavir/ritonavir   200 mg + 600/100 mg twice daily 50 mgonce daily 9 0.88(0.78 to 1.00) 0.75(0.69 to 0.81) 0.63(0.52 to 0.76) Etravirine + lopinavir/ritonavir   200 mg + 400/100 mg twice daily 50 mgonce daily 8 1.07(1.02 to 1.13) 1.11(1.02 to 1.20) 1.28(1.13 to 1.45) Fosamprenavir/ritonavir   700 mg/100 mg twice daily 50 mgonce daily 12 0.76(0.63 to 0.92) 0.65(0.54 to 0.78) 0.51(0.41 to 0.63) Lopinavir/ritonavir   400/100 mg twice daily 30 mgonce daily 15 1.00(0.94 to 1.07) 0.97(0.91 to 1.04) 0.94(0.85 to 1.05) Rilpivirine   25 mg once daily 50 mgonce daily 16 1.13 (1.06 to 1.21) 1.12 (1.05 to 1.19) 1.22 (1.15 to 1.30) Tenofovir   300 mg once daily 50 mgonce daily 15 0.97(0.87 to 1.08) 1.01(0.91 to 1.11) 0.92 (0.82 to 1.04) Tipranavir/ritonavir   500/200 mg twice daily 50 mgonce daily 14 0.54(0.50 to 0.57) 0.41(0.38 to 0.44) 0.24(0.21 to 0.27) Antacid (MAALOX)   simultaneous administration 50 mgsingle dose 16 0.28(0.23 to 0.33) 0.26(0.22 to 0.32) 0.26(0.21 to 0.31) Antacid (MAALOX)   2 h after dolutegravir 50 mgsingle dose 16 0.82(0.69 to 0.98) 0.74(0.62 to 0.90) 0.70(0.58 to 0.85) Boceprevir   800 mg every 8 h 50 mg once daily 13 1.05(0.96 to 1.15) 1.07(0.95 to 1.20) 1.08(0.91 to 1.28) Calcium carbonate 1,200 mg   simultaneous administration (fasted) 50 mgsingle dose 12 0.63(0.50 to 0.81) 0.61(0.47 to 0.80) 0.61(0.47 to 0.80) Calcium carbonate 1,200 mg   simultaneous administration (fed) 50 mgsingle dose 11 1.07(0.83 to 1.38) 1.09(0.84 to 1.43) 1.08(0.81 to 1.42) Calcium carbonate 1,200 mg   2 h after dolutegravir 50 mgsingle dose 11 1.00(0.78 to 1.29) 0.94(0.72 to 1.23) 0.90(0.68 to 1.19) Carbamazepine   300 mg twice daily 50 mgonce daily 16c 0.67(0.61 to 0.73) 0.51(0.48 to 0.55) 0.27(0.24 to 0.31) Ferrous fumarate 324 mg   simultaneous administration (fasted) 50 mgsingle dose 11 0.43(0.35 to 0.52) 0.46(0.38 to 0.56) 0.44(0.36 to 0.54) Ferrous fumarate 324 mg   simultaneous administration (fed) 50 mgsingle dose 11 1.03(0.84 to 1.26) 0.98(0.81 to 1.20) 1.00(0.81 to 1.23) Ferrous fumarate 324 mg   2 h after dolutegravir 50 mgsingle dose 10 0.99(0.81 to 1.21) 0.95(0.77 to 1.15) 0.92(0.74 to 1.13) Multivitamin (One-A-Day)   simultaneous administration 50 mgsingle dose 16 0.65(0.54 to 0.77) 0.67(0.55 to 0.81) 0.68(0.56 to 0.82) Omeprazole   40 mg once daily 50 mgsingle dose 12 0.92(0.75 to 1.11) 0.97(0.78 to 1.20) 0.95(0.75 to 1.21) Prednisone   60 mg once daily with taper 50 mgonce daily 12 1.06(0.99 to 1.14) 1.11(1.03 to 1.20) 1.17(1.06 to 1.28) Rifampina   600 mg once daily 50 mgtwice daily 11 0.57(0.49 to 0.65) 0.46(0.38 to 0.55) 0.28(0.23 to 0.34) Rifampinb   600 mg once daily 50 mgtwice daily 11 1.18(1.03 to 1.37) 1.33(1.15 to 1.53) 1.22(1.01 to 1.48) Rifabutin   300 mg once daily 50 mgonce daily 9 1.16(0.98 to 1.37) 0.95(0.82 to 1.10) 0.70(0.57 to 0.87) Abacavir or Lamivudine: The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities.           Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: OATP1B1/3, BCRP or P-gp, OCT1, OCT2, OCT3 (lamivudine only), or MATE1 and MATE2‑K. Abacavir, Dolutegravir, and Lamivudine: Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving TRIUMEQ is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see Drug Interactions (7.3)].           Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine: In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations. Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed. Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.           Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.           Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.           Methadone: In a trial of 11 HIV‑1–infected subjects receiving methadone‑maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions (7.3)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.           Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV‑1/HCV [hepatitis C virus] virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi‑drug regimen to HIV‑1/HCV co‑infected subjects.           Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 g, 10.2 g, or 13.4 g of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively. Abacavir, Lamivudine, Zidovudine: Fifteen HIV‑1–infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir. Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV‑1–infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 11. Table 11. Effect of Coadministered Drugs on Abacavir or Lamivudine ↑ = Increase; ↔ = No significant change. a The drug-drug interaction was only evaluated in males. Coadministered Drug and Dose Drug and Dose n Concentrations of Abacavir or Lamivudine Concentration of Coadministered Drug AUC Variability Ethanol   0.7 g/kg Abacavir Single 600 mg 24 ↑41% 90% CI: 35% to 48% ↔a Nelfinavir   750 mg every 8 h x 7 to 10 days Lamivudine Single 150 mg 11 ↑10% 95% CI: 1% to 20% ↔ Trimethoprim 160 mg/   Sulfamethoxazole   800 mg daily x 5 days Lamivudine Single 300 mg 14 ↑43% 90% CI: 32% to 55% ↔