Dovato

Dolutegravir, lamivudine.

Each film-coated tablet contains 50 mg of dolutegravir as dolutegravir sodium and 300 mg of lamivudine.
Excipients/Inactive Ingredients: Tablet Core: Microcrystalline cellulose, Sodium starch glycolate, Magnesium Stearate, Mannitol (E421), Povidone (K29/32), Sodium stearyl fumarate.
Tablet coating: Hypromellose (E464), Macrogol, Titanium dioxide (E171).

Pharmacotherapeutic group: Antiviral for systemic use, Antivirals for treatment of HIV infections, combinations.
PHARMACOLOGY: Pharmacodynamics: Mechanism of action: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC₅₀ values of 2.7 nM and 12.6 nM. In vitro, dolutegravir dissociates slowly from the active site of the wild type integrase-DNA complex (t_½ 71 hours).
Lamivudine is a NRTI, and is a potent, selective inhibitor of HIV-1 and HIV-2. Lamivudine is metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which is the active moiety with an extended intracellular half-life supporting once daily dosing (see Pharmacokinetics: Elimination as follows). Lamivudine-TP is a substrate for and competitive inhibitor of HIV reverse transcriptase (RT). However, its main antiviral activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Lamivudine-TP shows significantly less affinity for host cell DNA polymerases.
Pharmacodynamic Effects: In a randomized, dose-ranging trial, HIV 1-infected subjects treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dose-dependent antiviral activity, with mean declines from baseline to day 11 in HIV-1 RNA of 1.5, 2.0, and 2.5 log10 for dolutegravir 2 mg, 10 mg, and 50 mg once daily, respectively. This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.
Antiviral Activity in cell culture: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of drug necessary to effect viral replication by 50 percent (EC₅₀) values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.
In a viral integrase susceptibility assay using the integrase coding region from 13 clinically diverse clade B isolates, dolutegravir demonstrated antiviral potency similar to laboratory strains, with a mean EC₅₀ of 0.52 nM. When tested in PBMC assays against a panel consisting of 24 HIV-1 clinical isolates [group M (clade A, B, C, D, E, F and G) and group O] and 3 HIV-2 clinical isolates, the geometric mean EC₅₀ was 0.20 nM and EC₅₀ values ranged from 0.02 to 2.14 nM for HIV-1, while the geometric mean EC₅₀ was 0.18 nM and EC₅₀ values ranged from 0.09 to 0.61 nM for HIV-2 isolates.
The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC₅₀ values were in the range of 0.003 to 0.17 μM. The EC₅₀ values of lamivudine against different HIV-1 clades (A-G) ranged from 0.001 to 0.120 μM, and against HIV-2 isolates from 0.002 to 0.120 μM in PBMCs.
Antiviral Activity in combination with other antiviral agents: No drugs with inherent anti-HIV activity were antagonistic with dolutegravir (in vitro assessments were conducted in checkerboard format in combination with stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir and raltegravir). In addition, antivirals without inherent anti-HIV activity (ribavirin) had no apparent effect on dolutegravir activity.
No antagonistic effects in vitro were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).
Effect of Human Serum and Serum Proteins: In vitro studies suggested a 75-fold shift in EC₅₀ of dolutegravir in the presence of 100% human serum (by method of extrapolation), and the protein adjusted EC₉₀ (PA-EC₉₀) in PBMCs was estimated to be 64 ng/mL. Dolutegravir trough concentration for a single 50 mg dose in integrase inhibitor naïve subjects was 1.20 µg/mL, 19 times higher than the estimated PA-EC₉₀. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).
Resistance in vitro and in vivo (dolutegravir): Viruses highly resistant to dolutegravir were not observed during the 112 day passage of strain IIIB, with a 4.1-fold maximum fold change (FC) observed for the passaged resistant virus populations with substitutions at the conserved IN positions S153Y and S153F. Passage of the wild type HIV-1 strain NL432 in the presence of dolutegravir selected for E92Q (passage population virus FC=3.1) and G193E (passage population virus FC=3.2) substitutions on Day 56. Additional passage of wild type clade B, C, and A/G viruses in the presence of dolutegravir selected for G118R (site-directed mutant FC=10), S153T, and R263K (site-directed mutant FC=1.5).
Treatment-naïve HIV-1 infected subjects receiving dolutegravir: No INI-resistant mutations or treatment emergent resistance to the NRTI backbone therapy were isolated with dolutegravir 50 mg once daily in treatment-naive studies.
Resistance in vitro and in vivo (lamivudine): HIV-1 resistance to lamivudine involves the development of a M184I or M184V amino acid change close to the active site of the viral RT. This variant arises both during in vitro selection and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity in vitro.
Resistance in vivo (dolutegravir plus lamivudine): No subjects that met the protocol-defined confirmed virologic withdrawal (CVW) criteria across the pooled GEMINI-1 and GEMINI-2 studies through Week 144 or in the TANGO study through Week 96 had emergent INSTI or NRTI resistance substitutions. In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen. Of these four, two subjects had a unique R263K integrase substitution, with a maximum fold change of 1.93, one subject had a polymorphic V151V/I integrase substitution, with fold change of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission. In patients naïve to the integrase class and failing first line NNRTI + 2 NRTI treatment (DAWNING study) through Week 48, 2/314 subjects treated with dolutegravir had integrase inhibitor G118R pathway substitutions conferring dolutegravir fold changes of 15 and 30, and respective viral replication capacity decreases of 6.6 fold and 18 fold compared with baseline. The G118R and R263K mutations were also selected in vitro (see previous text).
Cross-resistance: Site-directed INSTI mutant virus: Dolutegravir activity was determined against a panel of 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).
Recombinant clinical isolates: Dolutegravir activity was measured for 705 raltegravir resistant recombinant isolates from clinical practice; 93.9% (662/705) of the isolates had a dolutegravir FC ≤10 and 1.8% had a dolutegravir FC >25. Mutants with Y143 and N155 pathway had mean FCs of 1.2 and 1.5, respectively, while Q148 + 1 mutant and Q148 + ≥2 mutants mean FCs were 4.8 and 6.0, respectively.
Cross-resistance conferred by the M184V reverse transcriptase: Cross-resistance is limited within the nucleoside inhibitor class of antiretroviral agents. Zidovudine and stavudine maintain their antiretroviral activities against lamivudine-resistant HIV-1. Abacavir and tenofovir maintain antiretroviral activity against lamivudine-resistant HIV-1 harbouring only the M184V mutation.
Effects on Electrocardiogram: In a randomised, placebo-controlled, cross-over trial, 42 healthy subjects received single dose oral administrations of placebo, dolutegravir 250 mg suspension (exposures approximately 3-fold of the 50 mg once-daily dose at steady state), and moxifloxacin (400 mg, active control) in random sequence. Dolutegravir did not prolong the QTc interval for 24 hours post dose. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) was 1.99 msec (1-sided 95% upper CI: 4.53 msec).
Similar studies were not conducted with lamivudine.
Effects on Renal Function: The effect of dolutegravir on serum creatinine clearance (CrCl), glomerular filtration rate (GFR) using iohexol as the probe and effective renal plasma flow (ERPF) using paraaminohippurate (PAH) as the probe was evaluated in an open-label, randomised, 3 arm, parallel, placebo-controlled study in 37 healthy subjects, who were administered dolutegravir 50 mg once daily (n=12), 50 mg twice daily (n=13) or placebo once daily (n=12) for 14 days. A modest decrease in CrCl was observed with dolutegravir within the first week of treatment, consistent with that seen in clinical studies. Dolutegravir at both doses had no significant effect on GFR or ERPF. These data support in vitro studies which suggest that the small increases in creatinine observed in clinical studies are due to the nonpathologic inhibition of the organic cation transporter 2 (OCT2) in the proximal renal tubules, which mediates the tubular secretion of creatinine.
In the pooled analysis of GEMINI-1 and GEMINI-2 studies in treatment-naïve adult patients at the week 144 analysis, dolutegravir plus lamivudine was associated with lower impact on renal safety parameters compared to dolutegravir plus tenofovir/emtricitabine FDC. The dolutegravir plus lamivudine group had a significantly greater increase in the estimated GFR using cystatin C adjusted CKD-EPI equation, compared with the dolutegravir plus tenofovir/emtricitabine FDC group (adjusted mean change from baseline of 12.2 and 10.6 mL/min/1.73 m², respectively; p=0.008). Change from baseline analysis showed that urine albumin/creatinine and protein/creatinine ratios were lower in the dolutegravir plus lamivudine group compared with the dolutegravir plus tenofovir/emtricitabine FDC group; the difference was statistically significant for the protein/creatinine ratio (urine albumin/creatinine week 144/baseline ratio of 1.046 and 1.104, respectively; p = 0.261 and protein/creatinine week 144/baseline ratio of 0.994 and 1.193, respectively; p <0.001). Withdrawals from study for renal function-related adverse events or for meeting predefined renal toxicity criteria (eGFR <50 ml/min/1.73 m²) were more frequently observed in subjects in the dolutegravir plus tenofovir/emtricitabine FDC group compared with the dolutegravir plus lamivudine group.
Clinical Studies: Antiretroviral naïve subjects: The efficacy of DOVATO is supported by data from 2 identical 148-week, Phase III, randomised, double-blind, multicenter, parallel-group, non-inferiority controlled trials (GEMINI-1 [204861] and GEMINI-2 [205543]). A total of 1,433 HIV-1 infected antiretroviral treatment-naïve adult subjects received treatment in the trials. Subjects were enrolled with a screening plasma HIV-1 RNA of 1,000 c/mL to ≤500,000 c/mL. Subjects were randomised to a two-drug regimen of dolutegravir plus lamivudine administered once daily or dolutegravir plus tenofovir/emtricitabine FDC administered once daily. The primary efficacy endpoint for each GEMINI trial was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm for the ITT-E population).
At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% were female, 69% were white, 9% were CDC Stage 3 (AIDS), 20% had HIV-1 RNA >100,000 copies/mL, and 8% had CD4+ cell count less than 200 cells per mm³; these characteristics were similar between studies and treatment arms.
In the primary week 48 analysis, dolutegravir plus lamivudine was non-inferior to dolutegravir plus tenofovir/emtricitabine FDC in GEMINI-1 and GEMINI-2 studies. This was supported by the pooled analysis, see Table 1.

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At 96 weeks in the GEMINI-1 and GEMINI-2 studies, the dolutegravir plus lamivudine group (86% with plasma HIV-1 RNA < 50 copies/mL [pooled data]) remained non-inferior to the dolutegravir plus tenofovir/emtricitabine FDC group (90% with plasma HIV-1 RNA < 50 copies/mL [pooled data]). The adjusted difference in proportions and 95% CI was -3.4% (-6.7, 0.0). The results of the pooled analysis were in line with those of the individual studies, for which the secondary endpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at Week 96 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir/emtricitabine FDC) was met. The adjusted differences of -4.9 (95% CI: -9.8; 0.0) for GEMINI-1 and -1.8 (95% CI: -6.4; 2.7) for GEMINI-2 were within the prespecified non-inferiority margin of -10%.
The mean increase in CD4+ T-cell counts was 269 cells/mm³ in the DTG+3TC arm and 259 cells/mm³ in the DTG+FTC/TDF arm, at week 96.
At 144 weeks in the GEMINI-1 and GEMINI-2 studies, the dolutegravir plus lamivudine group (82% with plasma HIV-1 RNA < 50 copies/mL [pooled data]) remained non-inferior to dolutegravir plus tenofovir/emtricitabine FDC group (84% with plasma HIV-1 RNA < 50 copies/mL [pooled data]). The results of the pooled analysis were in line with those of the individual studies, for which the secondary endpoint (difference in proportion < 50 copies/mL plasma HIV-1 RNA at Week 144 based on the Snapshot algorithm for dolutegravir plus lamivudine versus dolutegravir plus tenofovir/emtricitabine FDC) was met. The adjusted difference in proportions and 95% CI for the pooled data was -1.8% (-5.8, 2.1). The adjusted differences of -3.6 (95% CI: -9.4, 2.1) for GEMINI-1 and 0.0 (95% CI: -5.3, 5.3) for GEMINI-2 were within the prespecified non-inferiority margin of -10%.
The mean increase in CD4+ T-cell counts was 302 cells/mm³ in the DTG+3TC arm and 300 cells/mm³ in the DTG+FTC/TDF arm, at Week 144.
Virologically suppressed subjects: The efficacy of DOVATO in HIV-infected, antiretroviral therapy experienced, virologically suppressed subjects is supported by data from a 200-week, Phase III, randomised, open-label, multicenter, parallel-group, non-inferiority controlled trial (TANGO [204862]). A total of 741 adult HIV-1 infected subjects who were on a stable suppressive tenofovir alafenamide based regimen (TBR) received treatment in the studies. Subjects were randomised in a 1:1 ratio to receive DOVATO once daily or continue with TBR for up to 200 weeks. Randomisation was stratified by baseline third agent class (protease inhibitor [PI], integrase inhibitor [INSTI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA ≥50 c/mL (virologic non-response) as per the FDA Snapshot category at Week 48 (Snapshot algorithm adjusting for randomization stratification factor: Baseline Third Agent Class [INSTI, PI, NNRTI]).
At baseline the median age of subjects was 39 years, 8% were female and 21% nonwhite, 5% were CDC Class C (AIDS) and 98% subjects had Baseline CD4+ cell count ≥200 cells/mm³; these characteristics were similar between treatment arms. Subjects had been on ART for a median of 2.8 years and 2.9 years prior to Day 1 for the DOVATO and TBR arms, respectively. Most subjects were on INSTI-based TBR, 78% and 80% in the DOVATO and TBR arms, respectively.
In the primary 48 week analysis, DOVATO was non-inferior to TBR, with <1% of subjects in both arms experiencing virologic failure (HIV-1 RNA ≥50 c/mL) based on the Snapshot algorithm (Table 2). (See Table 2.)

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At 96 weeks in the TANGO study, the proportion of subjects with HIV-1 RNA ≥50 c/mL (Snapshot) was 0.3% and 1.1% in the DOVATO and TBR groups, respectively. Based on a non-inferiority margin of 4%, DOVATO remained non-inferior to TBR, as the upper bound of the 95% CI for the adjusted treatment difference (-2.0%, 0.4%) was less than 4% for the ITT E Population.
The median change from baseline in CD4+ T-cell counts at Week 96 was 61 cells/mm³ in the DOVATO arm and 45 cells/mm³ in the TBR arm.
Antiretroviral Pregnancy Registry: The APR has received reports of over 600 exposures to dolutegravir during pregnancy resulting in live births, as of July 2019. These consist of over 370 exposures during the first trimester, over 230 exposures during the second/third trimester and included 12 and 9 birth defects, respectively. The prevalence (95% CI) of defects among live births exposed to dolutegravir in the first trimester was 3.2% (1.7%, 5.5%) and in the second/third trimester, 3.8% (1.7%, 7.0%).
The APR has received reports of over 12,500 exposures to lamivudine during pregnancy resulting in live birth, as of July 2019. These consist of over 5,200 exposures during the first trimester, over 7,400 exposures during the second/third trimester and included 161 and 216 birth defects, respectively. The prevalence (95% CI) of defects among live births exposed to lamivudine in the first trimester was 3.1% (2.6, 3.6%) and in the second/third trimester, 2.9% (2.5, 3.3%).
The available data from the APR shows no significant increase in risk of major birth defects for dolutegravir or lamivudine compared to the background rates in the two population based surveillance systems (Metropolitan Atlanta Congenital Defects Program with defects of 2.72 per 100 live births and the Texas Birth Defects Registry with 4.17 per 100 live births).
Children: There are no clinical study data with DOVATO in the paediatric population.
In a Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of dolutegravir was evaluated in combination regimens in HIV-1 infected infants, children and adolescents.
At 24 weeks, 16 of 23 (69%) adolescents (12 to less than 18 years of age) treated with dolutegravir once daily (35 mg n=4, 50 mg n=19) plus OBR achieved viral load less than 50 copies/mL.
Pharmacokinetics: When administered in fasted state, bioequivalence was achieved for dolutegravir, when comparing the DOVATO tablet to dolutegravir 50 mg co-administered with lamivudine 300 mg, for AUC and C_max.
When administered in fasted state, bioequivalence was achieved for lamivudine AUC, when comparing the DOVATO tablet to lamivudine 300 mg co-administered with dolutegravir 50 mg. Lamivudine C_max for the DOVATO tablet was 32% higher than lamivudine 300 mg co-administered with dolutegravir 50 mg. Following multiple oral doses of DOVATO in HIV-infected, treatment experienced subjects in the Phase III TANGO study, the steady state dolutegravir and lamivudine AUC and C_max were similar to historical exposures.
Absorption: Dolutegravir and lamivudine are rapidly absorbed following oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral lamivudine in adults is 80 to 85%. For DOVATO, the median time to maximal plasma concentrations (t_max) is 2.5 hours for dolutegravir and 1.0 hour for lamivudine, when dosed under fasted conditions.
Following multiple oral doses of dolutegravir 50 mg once daily, the geometric mean steady state pharmacokinetic parameter estimates are 53.6 µg·h/mL for AUC₂₄, 3.67 µg/mL for C_max, and 1.11 µg/mL for C₂₄. Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days the mean steady-state C_max is 2.04 µg/mL and the mean AUC₂₄ is 8.87 µg·h/mL.
Effect of Food: Administration of DOVATO with a high fat meal increased dolutegravir AUC and C_max by 33% and 21%, respectively, and decreased the lamivudine C_max by 30% compared to fasted conditions. The lamivudine AUC was not affected by a high fat meal. These changes are not clinically significant. DOVATO may be administered with or without food.
Distribution: The apparent volume of distribution of dolutegravir (following oral administration of suspension formulation, Vd/F) is estimated at 12.5 L. Intravenous studies with lamivudine showed that the mean apparent volume of distribution is 1.3 L/kg.
Dolutegravir is highly bound (approximately 99.3%) to human plasma proteins based on in vitro data. Binding of dolutegravir to plasma proteins was independent of concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. Free fraction of dolutegravir in plasma is estimated at approximately 0.2 to 1.1% in healthy subjects, approximately 0.4 to 0.5% in subjects with moderate hepatic impairment, and 0.8 to 1.0% in subjects with severe renal impairment and 0.5% in HIV-1 infected patients. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (less than 36%).
Dolutegravir and lamivudine are present in cerebrospinal fluid (CSF). In 12 treatment-naïve subjects receiving a regimen of dolutegravir plus abacavir/lamivudine for 16 weeks, dolutegravir concentration in CSF averaged 15.4 ng/mL at Week 2 and 12.6 ng/mL at Week 16, ranging from 3.7 to 23.2 ng/mL (comparable to unbound plasma concentration). CSF:plasma concentration ratio of dolutegravir ranged from 0.11 to 2.04%. Dolutegravir concentrations in CSF exceeded the IC₅₀, supporting the median reduction from baseline in CSF HIV-1 RNA of 2.2 log after 2 weeks and 3.4 log after 16 weeks of therapy (see Pharmacodynamics as previously mentioned). The mean ratio of CSF/serum lamivudine concentrations 2 to 4 h after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.
Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue, and vaginal tissue were 6 to 10% of that in corresponding plasma at steady-state. AUC was 7% in semen and 17% in rectal tissue, of those in corresponding plasma at steady-state.
Metabolism: Dolutegravir is primarily metabolized via UGT1A1 with a minor CYP3A component (9.7% of total dose administered in a human mass balance study). Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged drug is low (<1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed drug or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-one percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).
Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (less than 10%).
Elimination: Dolutegravir has a terminal half-life of ~14 hours and an apparent clearance (CL/F) of 0.56 L/hr.
The observed half-life of elimination for lamivudine is 18 to 19 hours. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was 16 to 19 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (greater than 70%) via the organic cationic transport system.
Special patient populations: Children: DOVATO has not been studied in the paediatric population.
In a paediatric study including 23 antiretroviral treatment-experienced HIV-1 infected adolescents aged 12 to 18 years of age, the pharmacokinetics of dolutegravir was evaluated in 10 adolescents and showed that dolutegravir 50 mg once daily dosage resulted in dolutegravir exposure in paediatric subjects comparable to that observed in adults who received dolutegravir 50 mg once daily (Table 3). (See Table 3.)

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Limited data are available in adolescents receiving a daily dose of 300 mg of lamivudine. Pharmacokinetic parameters are comparable to those reported in adults.
Elderly: Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure.
Pharmacokinetic data for dolutegravir and lamivudine in subjects of >65 years old are limited.
Renal impairment: Pharmacokinetic data have been obtained for dolutegravir and lamivudine alone. DOVATO should not be used in patients with creatinine clearance of less than 30 mL/min because, whilst no dosage adjustment of dolutegravir is necessary in patients with renal impairment, dose reduction is required for the lamivudine component.
Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance.
Renal clearance of unchanged drug is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min). No clinically important pharmacokinetic differences between subjects with severe renal impairment (CLcr <30 mL/min) and matching healthy subjects were observed.
Hepatic impairment: Pharmacokinetic data has been obtained for dolutegravir and lamivudine individually.
Data obtained for lamivudine in patients with moderate to severe hepatic impairment and for dolutegravir in patients with moderate hepatic impairment show that the pharmacokinetics are not significantly affected by hepatic dysfunction. Dolutegravir is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with moderate hepatic impairment (Child-Pugh category B) to 8 matched healthy adult controls, the single 50 mg dose exposure of dolutegravir was similar between the two groups. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.
Polymorphisms in Drug Metabolising Enzymes: There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41). Polymorphisms in CYP3A4, CYP3A5, and NR1I2 were not associated with differences in the pharmacokinetics of dolutegravir.
Gender: Population pharmacokinetic analyses revealed no clinically relevant effect of gender on the exposure of dolutegravir.
No clinically relevant differences in the pharmacokinetics of lamivudine have been observed between men and women.
Race: Population pharmacokinetic analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials for dolutegravir revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese subjects appear similar to observed parameters in Western (US) subjects.
There is no evidence that a dose adjustment of dolutegravir or lamivudine would be required based on the effects of race on PK parameters.
Co-infection with Hepatitis B or C: Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited pharmacokinetic data on subjects with hepatitis B co-infection (see Precautions).
Pregnancy: The pharmacokinetics of lamivudine during pregnancy are similar to that of non-pregnant adults. In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery.
There are no pharmacokinetic data on the use of dolutegravir in pregnancy.
Toxicology: Pre-clinical Safety Data: Carcinogenesis/mutagenesis: Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Dolutegravir was not carcinogenic in long term studies in the mouse and rat.
Lamivudine was not mutagenic in bacterial tests, but like many nucleoside analogues it shows activity in the in vitro mammalian tests such as the mouse lymphoma assay. This is consistent with the known activity of other nucleoside analogues. The results from two in vivo rat micronucleus tests with lamivudine were negative.
Lamivudine did not show any genotoxic activity in additional in vivo studies in rats (metaphase analysis of bone marrow and unscheduled DNA synthesis). The results of long-term carcinogenicity studies in mice and rats did not show any carcinogenic potential at exposures approximately 12 to 72 times higher than clinical plasma levels.
Reproductive Toxicology: Fertility: Fertility studies in the rat have shown that dolutegravir and lamivudine had no effect on male or female fertility.
Dolutegravir did not affect male or female fertility in rats at doses up to 1,000 mg/kg/day, the highest dose tested (33 times the 50 mg human clinical exposure, based on AUC).
Pregnancy: Dolutegravir and lamivudine were shown to cross the placenta in animal reproductive toxicity studies.
Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (37.9 times the 50 mg human clinical exposure, based on AUC).
Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg/kg daily from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity (0.56 times the 50 mg human clinical exposure, based on AUC). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1,000 mg/kg (0.56 times the 50 mg human clinical exposure, based on AUC).
Lamivudine was not teratogenic in animal studies, but there were indications of an increase in early embryonic deaths in rabbits at exposure levels comparable to those achieved in man. However, there was no evidence of embryonic loss in rats at exposure levels of approximately 32 times the clinical exposure (based on C_max).
Animal toxicology and/or pharmacology: The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oral dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect of dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemic exposures approximately 30 and 1.2 times the 50 mg human clinical exposure based on AUC, respectively. Because gastrointestinal intolerance is considered to be due to local drug administration, mg/kg or mg/m² metrics are appropriate determinates of safety cover for this toxicity. GI intolerance in monkeys occurred at 30 times the human mg/kg equivalent dose (based on 50 kg human), and 11 times the human mg/m² equivalent dose for a total daily clinical dose of 50 mg.

DOVATO is indicated for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents from 12 years of age weighing at least 40 kg, who have no known or suspected resistance to either antiretroviral component.

Therapy should be initiated by a physician experienced in the management of HIV infection.
DOVATO can be taken with or without food.
DOVATO is a fixed-dose tablet and should not be prescribed for patients requiring dosage adjustments, such as those with creatinine clearance less than 30 mL/min.
A separate preparation of dolutegravir (TIVICAY) is available where a dose adjustment is required due to drug-drug interactions (See Interactions).
For patients with integrase inhibitor resistance DOVATO is not recommended. In this case the physician should refer to the TIVICAY product information.
Adults and Adolescents: The recommended dose of DOVATO in adults and adolescents weighing at least 40 kg is one tablet once daily.
Children: DOVATO is not currently recommended for the treatment of children less than 12 years of age as the necessary dose adjustment cannot be made. Clinical data is currently not available for this combination. Physicians should refer to the individual product information for dolutegravir and lamivudine.
Elderly: There are limited data available on the use of dolutegravir and lamivudine in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients (see PHARMACOLOGY: Pharmacokinetics: Special patient populations under Actions). When treating elderly patients, consideration needs to be given to the greater frequency of decreased hepatic and renal function, haematological abnormalities, and concomitant medicinal products or disease.
Renal impairment: Whilst no dosage adjustment of dolutegravir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance. Therefore DOVATO is not recommended for use in patients with a creatinine clearance less than 30 mL/min (see PHARMACOLOGY: Pharmacokinetics: Special patient populations under Actions).
Hepatic impairment: No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade A or B). No data are available for dolutegravir in patients with severe hepatic impairment (Child-Pugh grade C) (see PHARMACOLOGY: Pharmacokinetics: Special patient populations under Actions).

Symptoms and signs: There is currently limited experience with overdosage in dolutegravir. Limited experience of single higher doses (up to 250 mg in healthy subjects) revealed no specific symptoms or signs, apart from those listed as adverse reactions.
No specific symptoms or signs have been identified following acute overdose with lamivudine, apart from those listed as adverse reactions.
Treatment: Further management should be as clinically indicated or as recommended by the national poisons centre, where available.
If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

DOVATO is contraindicated in patients with known hypersensitivity to dolutegravir or lamivudine, or to any of the excipients.
DOVATO must not be administered concurrently with medicinal products with narrow therapeutic windows, that are substrates of organic cation transporter 2 (OCT2), including but not limited to dofetilide, pilsicainide or fampridine (also known as dalfampridine; see Interactions).

The special warnings and precautions relevant to dolutegravir and lamivudine are included in this section. There are no additional precautions and warnings relevant to DOVATO.
Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including liver injury. Discontinue DOVATO and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with DOVATO or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.
Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues either alone or in combination, including lamivudine. A majority of these cases have been in women.
Clinical features which may be indicative of the development of lactic acidosis include generalised weakness, anorexia, and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea).
Caution should be exercised when administering DOVATO particularly to those with known risk factors for liver disease. Treatment with DOVATO should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without hepatitis (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Serum lipids and blood glucose: Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.
Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an atypical presentation.
Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection (see Patients co-infected with hepatitis B virus (HBV) as follows).
Patients co-infected with hepatitis B virus (HBV): Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting therapy with DOVATO in hepatitis B co-infected patients.
Clinical trial and marketed use of lamivudine, have shown that some patients with chronic HBV disease may experience clinical or laboratory evidence of recurrent hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease.
If DOVATO is discontinued in patients co-infected with HBV, periodic monitoring of both liver function tests and markers of HBV replication should be considered.
Opportunistic infections: Patients receiving DOVATO or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.
Transmission of infection: While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Drug Interactions: Caution should be given to co-administering medications (prescription and non-prescription) that may reduce the exposure of dolutegravir, lamivudine or medications that may have their exposure changed by DOVATO (see Interactions).
The recommended dose of dolutegravir is 50 mg twice daily when co-administered with rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir (see Interactions).
Dolutegravir should not be co-administered with polyvalent cation-containing antacids. DOVATO is thus recommended to be administered 2 hours before or 6 hours after these agents (see Interactions).
DOVATO is recommended to be administered 2 hours before or 6 hours after taking calcium or iron supplements, or alternatively, administered with food (see Interactions).
Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be considered when starting and stopping coadministration of DOVATO with metformin, to maintain glycaemic control (see Interactions).
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of DOVATO, on driving performance or the ability to operate machinery. A detrimental effect on such activities would not be anticipated given the pharmacology of these medicinal products. The clinical status of the patient and the adverse event profile of DOVATO should be borne in mind when considering the patient's ability to drive or operate machinery.

Fertility: There are no data on the effects of dolutegravir or lamivudine on human male or female fertility. Animal studies indicate no effects of dolutegravir or lamivudine on male or female fertility (see PHARMACOLOGY: Toxicology: Pre-clinical Safety Data under Actions).
Pregnancy: DOVATO should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the foetus. Women of childbearing potential (WOCBP) should be informed about the potential risk of neural tube defects with dolutegravir and counselled about the use of effective contraception. It is recommended that pregnancy testing is conducted prior to initiation of DOVATO. If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on DOVATO, the risks and benefits of continuing DOVATO versus switching to another antiretroviral regimen should be discussed with the patient. Factors to consider should include feasibility of switching, tolerability, ability to maintain viral suppression, actual gestational age, risk of transmission to the infant and the available data around the potential risk of neural tube defects and other pregnancy outcomes for dolutegravir and alternative antiretroviral drugs.
In a birth outcome surveillance study in Botswana, a numerically higher rate of neural tube defects was identified with exposure to dolutegravir compared to non-dolutegravir-containing antiretroviral regimens at the time of conception, however, the difference was not statistically significant. Seven cases of neural tube defects were reported in 3,591 deliveries (0.19%) to mothers taking dolutegravir-containing regimens at the time of conception, compared with 21 cases in 19,361 deliveries (0.11%) to mothers taking non-dolutegravir-containing regimens at the time of conception (Prevalence Difference 0.09%; 95% CI -0.03, 0.30).
In the same study, an increased risk of neural tube defects was not identified in women who started dolutegravir during pregnancy. Two out of 4,448 deliveries (0.04%) to mothers who started dolutegravir during pregnancy had a neural tube defect, compared with five out of 6,748 deliveries (0.07%) to mothers who started non-dolutegravir-containing regimens during pregnancy.
A causal relationship of these events to the use of dolutegravir has not been established. The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births. As most neural tube defects occur within the first 4 weeks of foetal development (approximately 6 weeks after the last menstrual period) this potential risk would concern women exposed to dolutegravir at the time of conception and in early pregnancy.
Data analysed to date from other sources including the Antiretroviral Pregnancy Registry, clinical trials, and post-marketing data are insufficient to address the risk of neural tube defects with dolutegravir.
More than 1,000 outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.
In animal reproductive toxicity studies with dolutegravir, no adverse development outcomes, including neural tube defects, were identified (see PHARMACOLOGY: Toxicology: Pre-clinical Safety Data under Actions).
Dolutegravir and lamivudine use during pregnancy have been evaluated in the Antiretroviral Pregnancy Registry (APR) in over 600 and 12,500 women, respectively (as of July 2019). Available human data from the APR do not show an increased risk of major birth defects for dolutegravir or lamivudine compared to the background rate (see PHARMACOLOGY: Pharmacodynamics: Clinical Studies under Actions).
Dolutegravir readily crosses the placenta in humans. In HIV-infected pregnant women, the median (range) foetal umbilical cord concentrations of dolutegravir were 1.28 (1.21 to 1.28) fold greater compared with maternal peripheral plasma concentrations.
There is insufficient information on the effects of dolutegravir on neonates.
There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of developmental delay, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure in utero or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Lamivudine was associated with findings in animal reproductive toxicity studies (see PHARMACOLOGY: Toxicology: Pre-clinical Safety Data under Actions).
Lactation: Health experts recommend that where possible HIV infected women do not breast-feed their infants in order to avoid transmission of HIV. In settings where formula feeding is not feasible, local official lactation and treatment guidelines should be followed when considering breast feeding during antiretroviral therapy.
Dolutegravir is excreted in human milk in small amounts. In an open-label randomised study in which HIV-infected treatment-naïve pregnant women were administered a dolutegravir based regimen until two weeks post-partum, the median (range) dolutegravir breast milk to maternal plasma ratio was 0.033 (0.021 to 0.050).
In a study following repeat oral dose of either 150 mg lamivudine twice daily (given in combination with 300 mg zidovudine twice daily) or 300 mg lamivudine twice daily, lamivudine was excreted in human breast milk (0.5 to 8.2 micrograms/mL) at similar concentrations to those found in serum. In other studies following repeat oral dose of 150 mg lamivudine twice daily (given either in combination with 300 mg zidovudine or as COMBID300 or TRIZIVIR) the breast milk:maternal plasma ratio ranged between 0.6 and 3.3. Lamivudine median infant serum concentrations ranged between 18 and 28 ng/mL and were not detectable in one of the studies (assay sensitivity 7 ng/mL). Intracellular lamivudine triphosphate (active metabolite of lamivudine) levels in breastfed infants were not measured therefore the clinical relevance of the serum concentrations of the parent compound measured is unknown.

DOVATO contains dolutegravir and lamivudine, therefore the adverse drug reactions (ADRs) associated with these individual components may be expected (Tables 4 and 5). For many of the adverse events listed it is unclear whether they are related to the active substance, the wide range of other medicinal products used in the management of HIV infection, or whether they are a result of the underlying disease process.
ADRs identified in an analysis of pooled data from Phase 2b and Phase 3 clinical trials of the individual components are listed in Table 4 as follows by MedDRA system organ class and by frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000) and very rare (<1/10,000), including isolated reports.
Clinical Trial Data: Clinical safety data with DOVATO are limited. The ADRs observed for the combination of dolutegravir and lamivudine in an analysis of pooled data from Phase 3 clinical trials (GEMINI-1 and GEMINI-2) conducted in antiretroviral naïve subjects, and from the Phase 3 clinical trial (TANGO) conducted in antiretroviral therapy experienced, virologically suppressed adult subjects who received DOVATO, were generally consistent with the ADR profiles and severities for the individual components when administered with other antiretroviral agents. A single treatment emergent adverse reaction [Nervous system disorders: somnolence; frequency common] was observed with the combination which was not listed in the prescriber information for dolutegravir or lamivudine. There was no difference between the combination and the individual components in severity for any observed adverse reactions. Treatment-emergent ADRs observed in at least 2% of subjects in either treatment arm of the pooled analysis of the GEMINI-1 and GEMINI-2 trials were nausea, headache, diarrhoea, insomnia and dizziness. Insomnia, observed in the DOVATO arm, was the only treatment-emergent ADR observed in at least 2% of subjects in either treatment arm of the TANGO trial. (See Table 4.)

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Changes in laboratory chemistries: Increases in serum creatinine occurred within the first 4 weeks of treatment with dolutegravir plus lamivudine and remained stable through 48 weeks. A mean change from baseline of 10.3 µmol/L (range: -36.3 µmol/L to 55.7 µmol/L) was observed after 48 weeks of treatment. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate (see PHARMACOLOGY: Pharmacodynamics: Pharmacodynamic Effects: Effects on Renal Function under Actions).
Small increases in total bilirubin (without clinical jaundice) were observed with dolutegravir plus lamivudine. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see PHARMACOLOGY: Pharmacokinetics: Metabolism under Actions).
Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with dolutegravir therapy.
Paediatric population: There are no clinical study data with DOVATO in the paediatric population.
Based on limited available data with the dolutegravir single entity used in combination with other antiretroviral agents to treat adolescents (12 to less than 18 years of age), there were no additional types of adverse reactions beyond those observed in the adult population.
Lamivudine has been investigated separately, and as a part of a dual nucleoside backbone, in combination antiretroviral therapy to treat ART-naive and ART-experienced HIV-infected paediatric patients (data available on the use of lamivudine in children less than three months are limited). No additional types of undesirable effects have been observed beyond those characterised for the adult population.
Post-marketing data: In addition to the adverse reactions included from clinical trial data, the adverse reactions listed in Table 5 as follows have been identified during post-approval use of dolutegravir and/or lamivudine in use with other antiretroviral agents. These events have been chosen for inclusion due to a potential causal connection to dolutegravir and/or lamivudine. (See Table 5.)

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As DOVATO contains dolutegravir and lamivudine, any interactions that have been identified with these agents individually may occur with DOVATO. Due to the different routes of metabolism and elimination, no clinically significant drug interactions are expected between dolutegravir and lamivudine.
Effect of Dolutegravir and Lamivudine on the Pharmacokinetics of Other Agents: Dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of cytochrome P450 enzymes, uridine diphosphate glucuronosyl transferase (UGT), or the transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2 or MRP4.
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, UGT1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on these data, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters (e.g., reverse transcriptase and protease inhibitors, abacavir, zidovudine, maraviroc, opioid analgesics, antidepressants, statins, azole antifungals, proton pump inhibitors, erectile dysfunction agents, aciclovir, valaciclovir, sitagliptin, adefovir).
In drug interaction studies, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir, ritonavir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, boceprevir, telaprevir, daclatasvir, and oral contraceptives containing norgestimate and ethinyl estradiol.
In vitro, dolutegravir inhibited the renal OCT2 (IC₅₀ = 1.93 μM), multidrug and toxin extrusion transporter (MATE) 1 (IC₅₀ = 6.34 μM) and MATE2-K (IC₅₀ = 24.8 μM). Given dolutegravir's in vivo exposure, it has a low potential to affect the transport of MATE2-K substrates in vivo. In vivo dolutegravir increases plasma concentrations of drugs in which excretion is dependent upon OCT2 or MATE1 (for example dofetilide, pilsicainide, fampridine [also known as dalfampridine] or metformin) (see Tables 6a, 6b and 6c).
In vitro, dolutegravir inhibited the basolateral renal transporters: OAT1 (IC₅₀ = 2.12 μM) and OAT3 (IC₅₀ = 1.97 μM). However, dolutegravir had no notable effect on the pharmacokinetics in vivo of the OAT substrates tenofovir and para aminohippurate, and therefore has low propensity to cause drug interactions via inhibition of OAT transporters.
Lamivudine does not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6) and demonstrates no or weak inhibition of the drug transporters OATP1B1, OATP1B3, BCRP and Pgp, OCT3, MATE1 or MATE2-K. Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these enzymes or transporters.
Although lamivudine is an inhibitor of OCT1 and OCT2 in vitro, it has low potential to affect the plasma concentrations of substrates of these transporters at the therapeutic dose (300 mg)/exposure.
Effect of Other Agents on the Pharmacokinetics of Dolutegravir and Lamivudine: Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore drugs that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of dolutegravir and other drugs that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or Pgp may increase dolutegravir plasma concentration (see Tables 6a, 6b and 6c).
In vitro, dolutegravir is not a substrate of human organic anion transporting polypeptide (OATP)1B1, OATP1B3, or OCT1, therefore drugs that solely modulate these transporters are not expected to affect dolutegravir plasma concentration.
Rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir each reduced the plasma concentrations of dolutegravir significantly, and require dolutegravir dose adjustment to 50 mg twice daily. A separate preparation of dolutegravir (TIVICAY) is available where a dose adjustment is required due to drug-drug interactions. An additional dose of 50 mg dolutegravir (TIVICAY) should be administered, approximately 12 hours after DOVATO. In these cases the physician should refer to the TIVICAY product information.
The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma protein binding, and almost complete renal clearance. Lamivudine is not significantly metabolised by CYP enzymes. Although lamivudine is a substrate of BCRP and Pgp in vitro, inhibitors of these efflux transporters are unlikely to affect the disposition of lamivudine due to its high bioavailability. Lamivudine is an in vitro substrate of MATE1, MATE2-K and OCT2. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations however; the resulting increase was of such magnitude that a dose adjustment is not recommended as it is not expected to have clinical significance. Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.
Selected drug interactions are presented in Tables 6a, 6b, 6c and 7. Recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. DOVATO is not expected to be co-administered with other HIV-1 antiviral agents and information is provided for reference. (See Tables 6a, 6b, 6c and 7.)

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Incompatibilities: No incompatibilities have been identified.
Instructions for Use/Handling: There are no special requirements for use or handling of this product.

Store up to 30°C.

Antivirals

J05AR25 - lamivudine and dolutegravir ; Belongs to the class of antivirals for treatment of HIV infections, combinations.

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