Daltrex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DALTRAX

Composition:

Active substances: abacavir, dolutegravir, and lamivudine;

One tablet contains 600 mg of abacavir (as abacavir sulfate), 50 mg of dolutegravir (as dolutegravir sodium), and 300 mg of lamivudine;

Excipients: microcrystalline cellulose, mannitol, sodium starch glycolate (type A), povidone, magnesium stearate, Opadry II Beige 85F570009 [polyvinyl alcohol (E 1203), polyethylene glycol (E 1521), titanium dioxide (E 171), talc (E 553b), yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)].

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: beige, oval-shaped, biconvex, film-coated tablets with the inscription "H" on one side and "A60" on the other.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for the treatment of HIV infection, combinations. ATC code J05AR13.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Dolutegravir inhibits HIV integrase by binding to the active site of the integrase enzyme and blocking the integration step of retroviral DNA, which is essential for the replication cycle of human immunodeficiency virus (HIV).

Abacavir and lamivudine are potent, selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are sequentially metabolized intracellularly by kinases into their corresponding 5’-triphosphates (TP), which are the active moieties with prolonged intracellular half-lives under once-daily dosing conditions (see “Pharmacokinetics”). Lamivudine-TP (a cytidine analogue) and carbovir-TP (the active triphosphate form of abacavir, a guanosine analogue) are substrates and competitive inhibitors of HIV reverse transcriptase (RT). However, their primary antiviral activity occurs through incorporation of the monophosphate form into the viral DNA chain, leading to chain termination. The triphosphates of abacavir and lamivudine exhibit significantly lower affinity for host cell DNA polymerases.

In vitro antiviral activity.

Dolutegravir, abacavir, and lamivudine demonstrated inhibition of replication of laboratory strains and clinical isolates of HIV in various cell types, including transformed T-lymphocyte lines, monocyte/macrophage-derived lines, primary cultures of activated peripheral blood mononuclear cells, and monocytes/macrophages. The concentration of drug required to inhibit viral replication by 50% (IC50 — half-maximal inhibitory concentration) varies depending on the virus type and host tissue type.

The IC50 for dolutegravir in various laboratory strains using peripheral blood mononuclear cells was 0.5 nM, and ranged from 0.7 to 2 nM using MT-4 cells. Similar IC50 values were observed for clinical isolates, with no major differences between subtypes; in a panel of 24 HIV-1 isolates from groups A, B, C, D, E, F, G, and group O, the mean IC50 was 0.2 nM (range: 0.02–2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range: 0.09–0.61).

The mean IC50 for abacavir against laboratory strains HIV-1IIIB and HIV-1HXB2 ranged from 1.4 to 5.8 µM. The median mean IC50 for lamivudine against laboratory strains of HIV-1 ranged from 0.007 to 2.3 µM. The mean IC50 against laboratory strains of HIV-2 (LAV2 and EHO) ranged from 1.57 to 7.5 µM for abacavir and from 0.16 to 0.51 µM for lamivudine.

IC50 values for abacavir against HIV-1 group M subtypes (A–G) ranged from 0.002 to 1.179 µM, against group O from 0.022 to 1.21 µM, and against HIV-2 isolates from 0.024 to 0.49 µM. For lamivudine, IC50 values against HIV-1 subtypes (A–G) ranged from 0.001 to 0.170 µM, against group O from 0.030 to 0.160 µM, and against HIV-2 isolates from 0.002 to 0.120 µM in peripheral blood mononuclear cells.

HIV-1 isolates (CRF01_AE, n = 12; CRF02_AG, n = 12; and subtype C or CRF_AC, n = 13) from 37 untreated patients in Africa and Asia demonstrated sensitivity to abacavir (IC50 fold-change < 2.5) and lamivudine (IC50 fold-change < 3.0), except for two CRF02_AG isolates with fold-changes of 2.9 and 3.4 for abacavir. Group O isolates from antiretroviral-naïve patients were tested for lamivudine activity and showed high sensitivity.

The combination of abacavir and lamivudine demonstrated antiviral activity in cell cultures against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity to subtype B isolates.

Antiviral activity in combination with other antiviral agents.

No antagonistic effect in vitro was observed when dolutegravir was used in combination with other antiretroviral agents (tested agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir, and raltegravir). Additionally, ribavirin did not significantly affect the activity of dolutegravir.

The antiviral activity of abacavir in cell culture was not antagonized when combined with nucleoside reverse transcriptase inhibitors (NRTIs), including didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine, or with non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine, or with the protease inhibitor (PI) amprenavir.

No antagonistic effect in vitro was observed when lamivudine was used in combination with other antiretroviral agents (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).

Effect of human serum.

In 100% human serum, the mean fold-shift in dolutegravir activity was 75-fold, leading to a protein-adjusted IC90 of 0.064 µg/mL. In vitro plasma protein binding studies indicate that abacavir binds only to a low-to-moderate extent (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics within the therapeutic range and shows low plasma protein binding (less than 36%).

Resistance.

In vitro resistance (dolutegravir). Serial passage is used to study the evolution of resistance in vitro. When using the laboratory strain HIVIII, mutations emerged slowly over 112 days of passage, with substitutions at positions S153Y and F. These mutations were not observed in patients receiving dolutegravir in clinical trials. Using strain NL432, mutations E92Q (fold-change 3) and G193E (fold-change 3) were noted. These mutations were observed in patients with pre-existing resistance to raltegravir who received dolutegravir (listed as secondary mutations for dolutegravir).

In subsequent selection experiments using clinical isolates of subtype B, R263K mutations were observed in all five isolates (after 20 weeks and beyond). In subtype C (n = 2) and A/G (n = 2) isolates, integrase substitution R263K was observed in one isolate and G118R in two isolates. The presence of R263K was detected in two separate patients with subtype B and subtype C who were receiving antiretroviral therapy but not integrase inhibitors, with no impact on dolutegravir sensitivity in vitro. G118R reduces sensitivity to dolutegravir to site-specific mutations (fold-change 10), but was not detected in patients receiving dolutegravir in phase III trials.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, T66I) do not affect dolutegravir sensitivity in vitro as single mutations. When secondary mutations associated with integrase inhibitors (for raltegravir/elvitegravir) are added to primary mutations (except Q148) in site-directed mutagenesis experiments, dolutegravir sensitivity remains at wild-type levels or close to it. In viruses with Q148 mutations, the fold-change increase for dolutegravir correlates with the number of added secondary mutations. The impact of Q148-based (H/R/K) mutations was consistent with in vitro passage experiments and site-directed mutagenesis. In serial passage with site-directed mutants based on strain NL432 with N155H or E92Q, no further resistance selection was observed (fold-change unchanged at 1). In contrast, initial passage of mutants with Q148H mutation (fold-change 1) and varying numbers of secondary mutations associated with raltegravir led to accumulation with significant fold-change increases > 10.

The clinically significant phenotypic cutoff (fold-change compared to wild-type virus) is not defined; genotypic resistance has been recognized as a better prognostic factor for outcomes.

705 raltegravir-resistant isolates from patients previously treated with raltegravir were analyzed for dolutegravir sensitivity. Dolutegravir showed a fold-change < 10 in 94% of the 705 clinical isolates.

In vivo resistance (dolutegravir). In antiretroviral-naïve patients receiving dolutegravir + 2 nucleoside reverse transcriptase inhibitors (NRTIs) in phase IIb and phase III trials, no development of resistance to the integrase class or NRTI class was observed (n = 876, follow-up period 48–96 weeks).

In treatment-experienced non-responders who had not previously received integrase inhibitors (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up period 48 weeks) receiving dolutegravir in combination with an investigator-selected background regimen (BR). Of these four, two patients showed the unique integrase substitution R263K, with a maximum fold-change of 1.93; one patient demonstrated the polymorphic integrase substitution V151V/I with a maximum fold-change of 0.92; and one patient had pre-existing integrase mutations. The latter is believed to have experienced integrase inhibitor exposure or was infected with an integrase-resistant virus through transmission. The R263K mutation was also selected in vitro (see above).

In vitro and in vivo resistance (abacavir and lamivudine). Abacavir-resistant HIV-1 isolates in vitro and in vivo are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V, and Y115F). During in vitro selection of abacavir, the M184V mutation occurred first and led to approximately a 2-fold increase in IC50 below the clinical cutoff for abacavir at a fold-change of 4.5. Continued passage with increasing drug concentration led to selection of double RT mutants 65R/184V and 74V/184V or the triple mutant 74V/115Y/184V. Two mutations accounted for a 7–8-fold increase in abacavir resistance, and a combination of three mutations was required for more than an 8-fold change in sensitivity.

HIV-1 resistance to lamivudine involves the development of amino acid changes M184I or M184V near the active site of the viral reverse transcriptase. This variant arises both in vitro and in HIV-1-infected patients receiving antiretroviral therapy containing lamivudine. M184V mutants exhibit substantially reduced sensitivity to lamivudine and reduced viral replicative capacity in vitro. M184V is associated with a 2-fold increase in resistance to abacavir but does not confer clinical resistance to abacavir.

Isolates resistant to abacavir may also exhibit reduced sensitivity to lamivudine. The combination of abacavir/lamivudine demonstrated reduced sensitivity to viruses with K65R substitutions with or without M184V/I and to viruses with L74V plus M184V/I.

Cross-resistance between dolutegravir or abacavir or lamivudine and antiretroviral agents of other classes, such as protease inhibitors or non-nucleoside reverse transcriptase inhibitors, is unlikely.

Effect on electrocardiogram.

When administered at a dose approximately three times higher than the therapeutic dose, dolutegravir showed no effect on the corrected QT interval. Similar studies with abacavir or lamivudine have not been conducted.

Pharmacokinetics.

Absorption.

Dolutegravir, abacavir, and lamivudine are rapidly absorbed after oral administration. The absolute bioavailability of dolutegravir has not been established. The absolute bioavailability of oral abacavir and lamivudine in adults is approximately 83% and 80–85%, respectively. The median time to reach maximum plasma concentration (tmax) is 2–3 hours (after tablet administration), 1.5 hours, and 1 hour for dolutegravir, abacavir, and lamivudine, respectively.

The pharmacokinetic profile of dolutegravir was generally similar in healthy volunteers and HIV-1-infected patients. In HIV-1-infected adult patients receiving dolutegravir 50 mg once daily, the steady-state pharmacokinetic parameters (geometric mean [% CV]) based on population pharmacokinetic analysis were: AUC(0–24) — 53.6 (27) µg·h/mL, Cmax — 3.67 (20) µg/mL, and Cmin — 1.11 (46) µg/mL. After a single 600 mg dose of abacavir, the mean (CV) Cmax was 4.26 µg/mL (28%) and the mean (CV) AUC∞ was 11.95 µg·h/mL (21%). After 7 days of once-daily 300 mg oral lamivudine, the mean (CV) steady-state Cmax was 2.04 µg/mL (26%) and the mean (CV) AUC24 was 8.87 µg·h/mL (21%).

Plasma Cmax and AUC values for dolutegravir after administration of the fixed-dose combination tablet of abacavir/dolutegravir/lamivudine with a high-fat meal were 37% and 48% higher, respectively, than after administration of the same tablets in the fasted state. For abacavir, a 23% decrease in Cmax was observed, while AUC remained unchanged. The effect of lamivudine was similar when administered with food or in the fasted state. These results indicate that Dolutegravir/Abacavir/Lamivudine (Daltrax) can be administered regardless of food intake.

Distribution.

The apparent volume of distribution of dolutegravir (after oral administration as a suspension, Vd/F) is 12.5 L. Intravenous administration studies of abacavir and lamivudine demonstrated mean apparent volumes of distribution of 0.8 and 1.3 L/kg, respectively.

Dolutegravir is highly bound (>99%) to human plasma proteins, based on in vitro data. Dolutegravir binding to plasma proteins is independent of its concentration. The overall blood-to-plasma concentration ratios of radioactivity associated with the drug range from 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma increases at low albumin levels (<35 g/L), as observed in patients with moderate hepatic impairment. In vitro plasma protein binding studies indicate that abacavir binds only to a low-to-moderate extent (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics within the therapeutic range and shows low in vitro plasma protein binding (<36%).

Dolutegravir, abacavir, and lamivudine are present in cerebrospinal fluid (CSF).

In 13 antiretroviral-naïve patients receiving a stable regimen of dolutegravir in combination with abacavir/lamivudine, the mean CSF concentration of dolutegravir was 18 ng/mL (compared to unbound plasma concentration and above IC50). Studies with abacavir show that the AUC ratio in CSF to plasma is 30–44%. Peak concentrations observed were 9 times higher than the IC50 of abacavir of 0.08 µg/mL or 0.26 µM when abacavir was administered at 600 mg twice daily. The mean ratio of lamivudine concentrations in CSF to serum 2–4 hours after oral administration was approximately 12%. The extent of lamivudine penetration into the central nervous system and its correlation with clinical efficacy is unknown.

Dolutegravir is present in the genital tract of men and women. AUC values in vaginal fluid, cervical tissue, and vaginal tissue were 6–10% of the corresponding plasma value at steady state. AUC values were 7% in semen and 17% in rectal mucosa compared to the corresponding plasma value at steady state.

Biotransformation.

Dolutegravir is primarily metabolized via UGT1A1, to a lesser extent via CYP3A (9.7% of total administered dose in a human mass balance study). Dolutegravir is the predominant circulating component in plasma; renal excretion of unchanged active substance is low (<1% of dose). 53% of the total oral dose is excreted unchanged in feces. It is unknown whether this occurs partially or completely via unabsorbed active substance or via biliary excretion of glucuronide conjugate, which may further degrade to reform the parent compound in the intestinal lumen. 23% of the total oral dose is excreted in urine as either dolutegravir glucuronide (18.9% of total dose), N-dealkylated metabolite (3.6% of total dose), or metabolite formed by oxidation at the benzylcarbinol (3.0% of total dose).

Abacavir is primarily metabolized in the liver, with approximately 2% of the administered dose excreted unchanged in urine. The primary metabolic pathways in humans are mediated by alcohol dehydrogenase and glucuronidation, resulting in the formation of 5’-carboxylic acid and 5’-glucuronide, accounting for approximately 66% of the administered dose. These metabolites are excreted in urine.

The majority of lamivudine is excreted unchanged, with only a minor portion undergoing metabolism. Lamivudine is primarily excreted unchanged by the kidneys. The likelihood of metabolic interactions of other substances with lamivudine is low due to low hepatic metabolism rate (5–10%).

Drug interaction.

In vitro, dolutegravir did not show direct or weak inhibition (IC50 > 50 µM) of cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate-glucuronosyltransferases UGT1A1 or UGT2B7, or transporters P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2, or MRP4. In vitro, dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. Based on these data, no effect of dolutegravir on the pharmacokinetics of drugs that are substrates of major enzymes or transporters is expected (see section “Interaction with other medicinal products and other forms of interaction”).

In vitro, dolutegravir was not a substrate of human OATP1B1, OATP1B3, or OCT1.

Elimination.

The elimination half-life of dolutegravir is approximately 14 hours. Total clearance (CL/F) is approximately 1 L/h in HIV-infected patients based on population pharmacokinetic analysis.

The mean elimination half-life of abacavir is 1.5 hours. The mean geometric terminal intracellular half-life of the active moiety carbovir triphosphate at steady state is 20.6 hours. After multiple oral doses of abacavir (300 mg twice daily), no statistically significant accumulation of abacavir was observed. Elimination of abacavir occurs via hepatic metabolism, with subsequent excretion of metabolites primarily in urine. Metabolites and unchanged abacavir in urine account for approximately 83% of the administered dose of abacavir. The remainder is excreted in feces.

The expected elimination half-life of lamivudine is 5 to 7 hours. For patients receiving lamivudine 300 mg once daily, the terminal half-life of lamivudine-TP ranged from 16 to 19 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, primarily via renal clearance (>70%) through the organic cation transporter system. Studies in patients with renal impairment demonstrate that lamivudine clearance is reduced in renal disorders. Dose reduction is required for patients with creatinine clearance < 50 mL/min (see section “Posology and method of administration”).

Pharmacokinetic/pharmacodynamic relationship.

In a randomized dose-ranging study in HIV-1-infected patients receiving dolutegravir as monotherapy (ING111521), rapid and dose-dependent antiviral activity was demonstrated, with a mean reduction in HIV-1 RNA of 2.5 log10 on day 11 for the 50 mg dose. Antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.

Intracellular pharmacokinetics.

The mean geometric terminal intracellular half-life of carbovir-TP at steady state is 20.6 hours, compared to the mean geometric plasma half-life of abacavir of 2.6 hours. The terminal intracellular half-life of lamivudine-TP was prolonged to 16–19 days, compared to the plasma half-life of lamivudine of 5–7 hours, supporting once-daily dosing for abacavir and lamivudine.

Special patient groups.

Hepatic impairment

Pharmacokinetic data were obtained for dolutegravir, abacavir, and lamivudine separately.

Dolutegravir is primarily metabolized and eliminated via the liver. A single 50 mg dose of dolutegravir was administered to 8 patients with moderate hepatic impairment (Child-Pugh class B) and 8 matched healthy control volunteers. While total plasma concentration was similar, a 1.5–2-fold increase in dolutegravir exposure was observed in patients with moderate hepatic impairment compared to healthy volunteers. No dose adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on dolutegravir pharmacokinetics has not been studied.

Abacavir is primarily metabolized in the liver. The pharmacokinetics of abacavir were studied in patients with mild hepatic impairment (5–6 points on the Child-Pugh scale) who received a single 600 mg dose. Results showed a mean increase in abacavir AUC by 1.89-fold [1.32; 2.70] and abacavir half-life by 1.58-fold [1.22; 2.04]. Dose reduction in patients with mild hepatic impairment cannot be recommended due to significant variability in the impact of different abacavir concentrations.

Data from patients with moderate and severe hepatic impairment show that lamivudine pharmacokinetics are not statistically significantly affected by hepatic dysfunction.

Based on data from abacavir use, Daltrax is not recommended for patients with moderate and severe hepatic impairment.

Renal impairment

Pharmacokinetic data were obtained for dolutegravir, abacavir, and lamivudine separately.

Only a minor portion of dolutegravir active substance is metabolized by the kidneys. A pharmacokinetic study of dolutegravir was conducted in patients with severe renal impairment (creatinine clearance (CLcr) < 30 mL/min). No clinically significant differences in pharmacokinetics were observed between patients with severe renal impairment (CLcr < 30 mL/min) and matched healthy volunteers. Dolutegravir has not been studied in patients on dialysis, as no difference in effect was expected.

Abacavir is primarily metabolized in the liver, with approximately 2% of abacavir excreted unchanged in urine. The pharmacokinetics of abacavir in patients with end-stage renal disease are similar to those in patients with normal renal function.

Lamivudine studies demonstrate that plasma concentrations (AUC) increase in patients with renal dysfunction due to reduced clearance.

Based on lamivudine data, Daltrax is not recommended for patients with creatinine clearance < 50 mL/min.

Elderly patients

Population analysis of HIV-1-infected patients showed no clinically significant effect of age on dolutegravir pharmacokinetics.

Pharmacokinetic data for dolutegravir, abacavir, and lamivudine in patients aged >65 years are limited.

Children

The pharmacokinetics of 50 mg dolutegravir in 10 antiretroviral-experienced HIV-1-infected adolescents (aged 12 to 17 years) were shown to be comparable in exposure levels to those in adults receiving dolutegravir 50 mg once daily.

Data for adolescents receiving a daily dose of 600 mg abacavir and 300 mg lamivudine are currently limited. Pharmacokinetic parameters are comparable to those observed in adult patients.

Polymorphism of drug-metabolizing enzymes

There is no evidence of clinically significant impact of polymorphisms in drug-metabolizing enzymes on dolutegravir pharmacokinetics. In a meta-analysis using pharmacogenomic models from clinical trials involving healthy volunteers with UGT1A1 genotypes (n = 7), a 32% decrease in dolutegravir clearance and a 46% increase in AUC were observed compared to those with genotypes associated with normal UGT1A1 metabolism (n = 41).

Sex

Population pharmacokinetic analysis using pooled pharmacokinetic data from phase IIb and phase III trials in adult patients revealed no clinically significant effect of sex on dolutegravir exposure. There is no evidence for the need to adjust the dose of dolutegravir, abacavir, or lamivudine based on sex-related effects on pharmacokinetic parameters.

Race

Population pharmacokinetic analysis using pooled pharmacokinetic data from phase IIb and phase III trials in adult patients revealed no clinically significant effect of race on dolutegravir exposure. The pharmacokinetics of a single dose of dolutegravir in Japanese subjects are comparable to those in US citizens. There is no evidence supporting the need for dose adjustment of dolutegravir, abacavir, or lamivudine based on race-related effects on pharmacokinetic parameters.

Hepatitis B or C virus co-infection

Population pharmacokinetic analysis indicates that hepatitis C virus co-infection has no clinically significant effect on dolutegravir exposure. Pharmacokinetic data in patients with hepatitis B virus co-infection are limited (see section “Special warnings and precautions for use”).

Clinical characteristics.

Indications.

Dolutegravir/abacavir/lamivudine (Daltravex) is indicated for the treatment of human immunodeficiency virus (HIV)-infected adults and children aged 12 years and older with body weight of at least 40 kg (see sections "Special warnings and precautions for use" and "Pharmacological properties").

Before initiating therapy with products containing abacavir, all HIV-infected patients must be screened for the presence of the HLA-B*5701 allele regardless of racial origin (see section "Special warnings and precautions for use"). Abacavir should not be administered to patients who are carriers of the HLA-B*5701 allele.

Contraindications.

Hypersensitivity to dolutegravir, abacavir, lamivudine or to any excipient of the medicinal product.

Concomitant use with dofetilide (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Daltravex contains dolutegravir, abacavir and lamivudine; therefore, any individual interactions associated with these components also apply to Daltravex. No clinically significant drug interactions between dolutegravir, abacavir and lamivudine are expected.

Effect of other substances on the pharmacokinetics of dolutegravir, abacavir and lamivudine.

Dolutegravir is primarily eliminated via UGT1A1-mediated metabolism. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp and BCRP. Concomitant administration of Daltravex with other agents that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4 or P-gp may increase plasma concentrations of dolutegravir. Medicinal products that induce these enzymes or transporters may reduce plasma concentrations of dolutegravir and diminish its therapeutic effect (see Table 1).

The absorption of dolutegravir is reduced by certain antacids (see Table 1).

Abacavir is metabolized by UDP-glucuronosyltransferase (UGT) enzymes and alcohol dehydrogenase; concomitant use of inducers or inhibitors of UGT enzymes or substances metabolized by alcohol dehydrogenase may alter abacavir exposure.

Lamivudine is eliminated via the kidneys. Active renal secretion of lamivudine into urine occurs through the organic cation transporter (OCT2) and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Concomitant use of lamivudine with inhibitors of OCT or MATE transporters may increase lamivudine exposure. Dolutegravir is an inhibitor of OCT2 and MATE1; however, in a crossover study, lamivudine concentrations were similar with or without concomitant dolutegravir, indicating that dolutegravir does not affect lamivudine exposure in vivo.

Abacavir and lamivudine are not significantly metabolized by CYP enzymes.

In vitro studies show that abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4. Therefore, medicinal products modulating these transporters are not expected to affect plasma levels of abacavir.

Although abacavir and lamivudine are substrates of BCRP and P-gp in vitro, clinical studies indicate no significant changes in abacavir pharmacokinetics when coadministered with lopinavir/ritonavir (inhibitors of BCRP and P-gp), and it is unlikely that inhibitors of these transporters significantly alter lamivudine pharmacokinetics, given its high bioavailability. In vitro, lamivudine is a substrate of MATE1, MATE2-K and OCT2. Increased plasma concentrations of lamivudine have been observed with trimethoprim (an inhibitor of these transporters), but this interaction is not considered clinically significant, and dose adjustment of lamivudine is not recommended. Lamivudine is also a substrate of the hepatic uptake transporter OCT1. However, due to the minor role of the liver in lamivudine elimination, drug interactions via OCT1 inhibition are unlikely to be clinically relevant.

Effect of dolutegravir, abacavir and lamivudine on the pharmacokinetics of other substances.

In vivo, dolutegravir does not affect midazolam, a CYP3A4 probe. Based on in vitro and/or in vivo data, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9 or P-gp is expected (see "Pharmacokinetics").

In vitro, dolutegravir inhibits the renal transporters OCT2 and MATE1. In vivo, a 10–14% reduction in creatinine clearance (secretory component dependent on OCT2 and MATE1) has been observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OCT2 or MATE1 (e.g., dofetilide, metformin) (see Table 1 and section "Contraindications").

In vitro, dolutegravir inhibits renal uptake of organic anion transporters OAT1 and OAT3. However, due to the lack of effect on the in vivo pharmacokinetics of tenofovir (a substrate of organic anion transporters), in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 in vivo has not been studied. Dolutegravir may increase plasma concentrations of drugs whose secretion depends on OAT3.

Abacavir and lamivudine do not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6) and show no inhibition or weak inhibition of OATP1B3, BCRP, P-gp and MATE2-K. In vitro data suggest that inhibition of P-gp and BCRP by abacavir cannot be excluded at the intestinal level. Lamivudine shows no or weak inhibition of drug transporters MATE1 or OCT3, while abacavir shows minimal inhibition of OCT1 and OCT2. Therefore, abacavir and lamivudine are not expected to alter plasma concentrations of medicinal products that are substrates of these enzymes or transporters. In vitro, lamivudine inhibits OCT1 and OCT2.

Although abacavir is an inhibitor of MATE1 in vitro, and lamivudine inhibits OCT1 and OCT2 in vitro, their potential to affect plasma concentrations of substrates of these transporters at therapeutic concentrations (abacavir up to 600 mg, lamivudine 300 mg) is low.

Known and potential interactions with selected antiretroviral and non-antiretroviral medicinal products are summarized in Table 1 (increases are indicated as "↑", decreases as "↓", no change as "↔", area under the concentration-time curve as "AUC", peak concentration as "Cmax"). The table is not exhaustive but is representative of the classes studied.

Table 1

Interaction with other medicinal products

Medicinal products classified by therapeutic area	Geometric mean change in interaction (%)		Recommendations for concomitant use
Antiretroviral medicinal products
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Etravirine without boosted protease inhibitors / dolutegravir	Dolutegravir ↓ AUC ↓ 71 % Cmax ↓ 52 % Cτ ↓ 88 % Etravirine ↔ (induction of UGT1A1 and CYP3A enzymes)	Etravirine without boosted protease inhibitors reduces dolutegravir plasma concentrations. Since the recommended dose of dolutegravir for patients taking etravirine without boosted protease inhibitors is 50 mg twice daily, Daltex is not recommended for use in patients taking etravirine without concomitant use of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir (see table below).
Lopinavir + ritonavir + etravirine/dolutegravir	Dolutegravir ↔ AUC ↑ 11 % Cmax ↑ 7 % Cτ ↑ 28 % Lopinavir ↔ Ritonavir ↔ Etravirine ↔	No dose adjustment required.
Darunavir + ritonavir + etravirine/dolutegravir	Dolutegravir ↔ AUC ↓ 25 % Cmax ↓ 12 % Cτ ↓ 36 % Darunavir ↔ Ritonavir ↔ Etravirine ↔	No dose adjustment required.
Efavirenz/dolutegravir	Dolutegravir ↓ AUC ↓ 57 % Cmax ↓ 39 % Cτ ↓ 75 % Efavirenz ↔ (historical control) (induction of UGT1A1 and CYP3A enzymes)	Since the dosing of dolutegravir when co-administered with efavirenz is 50 mg twice daily, concomitant use with Daltex is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Nevirapine/dolutegravir	Dolutegravir ↓ (Not studied. Similar reduction in exposure expected as observed with efavirenz, due to induction)	Concomitant use with nevirapine, which may reduce dolutegravir plasma concentrations due to enzyme induction, has not been studied. The effect of nevirapine on dolutegravir exposure is likely similar to or less than that of efavirenz. Since the dosing of dolutegravir when co-administered with nevirapine is 50 mg twice daily, concomitant use of nevirapine with Daltex is not recommended.
Rilpivirine	Dolutegravir ↔ AUC ↑ 12 % Cmax ↑ 13 % Cτ ↑ 22 % Rilpivirine ↔	No dose adjustment required.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Tenofovir	Dolutegravir ↔ AUC ↑ 1 % Cmax ↓ 3 % Cτ ↓ 8 % Tenofovir ↔		No dose adjustment required when Daltex is co-administered with nucleoside reverse transcriptase inhibitors.
Emtricitabine, didanosine, stavudine, zidovudine	Interaction not studied.		Daltex is not recommended for use in combination with products containing emtricitabine, as both lamivudine (in Daltex) and emtricitabine are cytidine analogues, thus there is a risk of intracellular interactions (see section "Interaction with other medicinal products and other forms of interaction").
Protease inhibitors
Atazanavir/dolutegravir	Dolutegravir ↑ AUC ↑ 91 % Cmax ↑ 50 % Cτ ↑ 180 % Atazanavir ↔ (historical control) (inhibition of UGT1A1 and CYP3A enzymes)		No dose adjustment required.
Atazanavir + ritonavir/dolutegravir	Dolutegravir ↑ AUC ↑ 62 % Cmax ↑ 34 % Cτ ↑ 121 % Atazanavir ↔ Ritonavir ↔		No dose adjustment required.
Tipranavir + ritonavir/dolutegravir	Dolutegravir ↓ AUC ↓ 59 % Cmax ↓ 47 % Cτ ↓ 76 % Tipranavir ↔ Ritonavir ↔ (induction of UGT1A1 and CYP3A enzymes)		Since the recommended dosing of dolutegravir when co-administered with tipranavir/ritonavir is 50 mg twice daily, concomitant use of these agents with Daltex is not recommended.
Fosamprenavir + ritonavir/dolutegravir	Dolutegravir ↓ AUC ↓ 35 % Cmax ↓ 24 % Cτ ↓ 49 % Fosamprenavir ↔ Ritonavir ↔ (induction of UGT1A1 and CYP3A enzymes)		Fosamprenavir/ritonavir reduces dolutegravir concentration, but according to some data, this did not lead to reduced efficacy in phase III studies. Dose adjustment is not mandatory.
Nelfinavir/dolutegravir	Dolutegravir ↔ (interaction not studied)		No dose adjustment required.
Lopinavir + ritonavir/dolutegravir	Dolutegravir ↔ AUC ↓ 4 % Cmax ↔ 0 % C24 ↓ 6 % Lopinavir ↔ Ritonavir ↔		No dose adjustment required.
Darunavir + ritonavir/dolutegravir	Dolutegravir ↓ AUC ↓ 22 % Cmax ↓ 11 % Cτ ↓ 38 % Darunavir ↔ Ritonavir ↔ (induction of UGT1A1 and CYP3A enzymes)		No dose adjustment required.
Other antiviral agents
Telaprevir	Dolutegravir ↑ AUC ↑ 25 % Cmax ↑ 19 % Cτ ↑ 37 % Telaprevir ↔ (historical control) (inhibition of CYP3A enzyme)		No dose adjustment required.
Boceprevir	Dolutegravir ↔ AUC ↑ 7 % Cmax ↑ 5 % Cτ ↑ 8 % Boceprevir ↔ (historical control)		No dose adjustment required.
Daclatasvir/dolutegravir	Dolutegravir ↔ AUC ↑ 33 % Cmax ↑ 29 % Cτ ↑ 45 % Daclatasvir ↔		Daclatasvir does not significantly alter dolutegravir plasma concentrations. Dolutegravir does not alter daclatasvir plasma concentrations. No need for dose adjustment.
Antimicrobial agents
Trimethoprim/sulfamethoxazole (co-trimoxazole)/abacavir	Interaction not studied		No dose adjustment of Daltex is required, except for patients with renal impairment (see section "Method of administration and dosage").
Trimethoprim/ sulfamethoxazole (co-trimoxazole)/lamivudine (160 mg / 800 mg once daily for 5 days / 300 mg, single dose)	Lamivudine AUC ↑ 43 % Cmax ↑ 7 % Trimethoprim AUC ↔ Sulfamethoxazole AUC ↔ (inhibition of organic cation transport)
Antimycobacterial agents
Rifampicin/dolutegravir	Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 43 % Cτ ↓ 72 % (induction of UGT1A1 and CYP3A enzymes)		Since the recommended dosing of dolutegravir when co-administered with rifampicin is 50 mg twice daily, concomitant use of rifampicin with Daltex is not recommended.
Rifabutin	Dolutegravir ↔ AUC ↓ 5 % Cmax ↑ 16 % Cτ ↓ 30 % (induction of UGT1A1 and CYP3A enzymes)		No dose adjustment required.
Antiepileptic agents
Carbamazepine/dolutegravir	Dolutegravir ↓ AUC ↓ 49 % Cmax ↓ 33 % Cτ ↓ 73 %		Since the recommended dose of dolutegravir is 50 mg twice daily when co-administered with carbamazepine, use of Daltex is not recommended in patients receiving carbamazepine.
Phenobarbital/dolutegravir Phenytoin/dolutegravir Oxcarbazepine/dolutegravir	Dolutegravir ↓ (interaction not studied, reduction expected due to induction of UGT1A1 and CYP3A enzymes, reduction in exposure expected similar to that observed with carbamazepine)		Since the recommended dose of dolutegravir is 50 mg twice daily when co-administered with these metabolic inducers, use of Daltex is not recommended in patients receiving these metabolic inducers.
Antihistamines (H2-histamine receptor blockers)
Ranitidine	Interaction not studied. Clinically significant interaction unlikely.		No dose adjustment required.
Cimetidine	Interaction not studied. Clinically significant interaction unlikely.		No dose adjustment required.
Cytotoxic agents
Cladribine/lamivudine	Interaction not studied. In vitro, lamivudine inhibits intracellular phosphorylation of cladribine, posing a risk of loss of cladribine efficacy in clinical combination. Some clinical data also suggest a possible interaction between lamivudine and cladribine.		Concomitant use of Daltex with cladribine is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Opioid agents
Methadone/abacavir (40–90 mg once daily for 14 days / 600 mg single dose, then 600 mg twice daily for 14 days)	Abacavir AUC ↔ Cmax ↓ 35 % Methadone CL/F ↑ 22 %		Dose adjustment of methadone is likely not required for most patients; in individual cases, re-titration of methadone may be needed.
Retinoid agents
Retinoid mixtures (e.g., isotretinoin)	Interaction not studied. Possible interaction due to shared elimination pathway via alcohol dehydrogenase (abacavir-containing component).		Dose adjustment recommendation not possible due to insufficient evidence.
Other
Alcohol
Alcohol/dolutegravir Alcohol/lamivudine	Interaction not studied (inhibition of alcohol dehydrogenase).		No dose adjustment required.
Alcohol/abacavir (0.7 g/kg, single dose / 600 mg, single dose)	Abacavir AUC ↑ 41 % Alcohol AUC ↔
Sorbitol solution
Sorbitol solution (3.2 g, 10.2 g, 13.4 g)	Single dose of lamivudine 300 mg Lamivudine: AUC ↓ 14 %; 32 %; 36 % Cmax ↓ 28 %; 52 %; 55 %		Long-term use of lamivudine with medicinal products containing sorbitol should be avoided, or more frequent monitoring of hepatitis B viral load should be performed when concomitant long-term use cannot be avoided.
Antiarrhythmic agents
Dofetilide/dolutegravir	Dofetilide ↑ (not studied, potential increase due to inhibition of OCT2 transport)		Concomitant use of Daltex and dofetilide is contraindicated due to potentially life-threatening toxicity caused by high dofetilide concentrations (see section "Contraindications").
Antacids and dietary supplements
Magnesium/aluminum-containing antacids / dolutegravir	Dolutegravir ↓ AUC ↓ 74 % Cmax ↓ 72 % (binding to polyvalent ions)		Administration of magnesium/aluminum-containing antacids should be separated in time from Daltex (minimum 2 hours after or 6 hours before intake).
Calcium supplements / dolutegravir	Dolutegravir ↓ AUC ↓ 39 % Cmax ↓ 37 % C24 ↓ 39 % (binding to polyvalent ions)		Administration of calcium, iron supplements or multivitamins should be separated in time from Daltex (minimum 2 hours after or 6 hours before intake).
Iron supplements / dolutegravir	Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 57 % C24 ↓ 56 % (binding to polyvalent ions)
Multivitamins / dolutegravir	Dolutegravir ↓ AUC ↓ 33 % Cmax ↓ 35 % C24 ↓ 32 %
Corticosteroids
Prednisone	Dolutegravir ↔ AUC ↑ 11 % Cmax ↑ 6 % Cτ ↑ 17 %		No dose adjustment required.
Antidiabetic agents
Metformin/dolutegravir	Metformin ↑ Dolutegravir ↔ When co-administered with 50 mg dolutegravir once daily: metformin AUC ↑ 79 % Cmax ↑ 66 % When co-administered with 50 mg dolutegravir twice daily: metformin AUC ↑ 145 % Cmax ↑ 111 %		Dose adjustment of metformin should be considered at the initiation and upon discontinuation of concomitant dolutegravir to maintain glycemic control. For patients with moderate renal impairment, dose adjustment of metformin should be considered when co-administered with dolutegravir, as increased metformin concentrations pose an increased risk of lactic acidosis in patients with moderate renal impairment (see section "Special warnings and precautions for use").
Herbal medicinal products
St. John's wort/dolutegravir	Dolutegravir ↓ (not studied. Reduction expected due to induction of UGT1A1 and CYP3A enzymes, reduction in exposure expected similar to that observed with carbamazepine)		Since the recommended dose of dolutegravir is 50 mg twice daily when co-administered with St. John's wort, treatment with Daltex is not recommended.
Oral contraceptives
Ethinylestradiol (EE) and norelgestromin (NGMN) / dolutegravir	Effect of dolutegravir: EE ↔ AUC ↑ 3 % Cmax ↓ 1 % Effect of dolutegravir: NGMN ↔ AUC ↓ 2 % Cmax ↓ 11 %		Dolutegravir had no effect on the pharmacodynamics of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone. No dose adjustment of Daltex is required when used concomitantly with oral contraceptives.

Children.

Studies on interactions were conducted only in adult patients.

Special precautions for use.

HIV transmission.

Although effective antiretroviral therapy has significantly reduced the risk of sexual transmission of HIV, the risk cannot be completely excluded. Preventive measures to avoid transmission of the virus should be taken in accordance with regulatory legislation.

Hypersensitivity reactions (see section "Adverse reactions").

The use of abacavir and dolutegravir is associated with a risk of developing hypersensitivity reactions (see section "Adverse reactions"), characterized by systemic symptoms such as fever and/or rash, along with other symptoms indicating multi-organ involvement. It is clinically impossible to determine whether abacavir and dolutegravir in the composition of Dolutrav cause hypersensitivity reactions. Hypersensitivity reactions have been more frequently observed with abacavir use, some of which were life-threatening and occasionally fatal if patients did not receive appropriate medical intervention. The risk of developing hypersensitivity reactions is high in patients who test positive for the HLA-B*5701 allele. Hypersensitivity reactions to abacavir have been observed in patients who are not carriers of this allele, but at a low frequency.

Therefore, the following rules must be observed:

• The HLA-B*5701 status must always be documented before initiating therapy.
• Dolutrav therapy should not be prescribed to patients with a positive HLA-B*5701 status or to patients with a negative HLA-B*5701 status but with a history of suspected hypersensitivity reactions to abacavir in a previous antiretroviral regimen containing abacavir.
• Dolutrav treatment must be discontinued immediately, even in the absence of the HLA-B*5701 allele, if a hypersensitivity reaction is suspected. Delay in immediately stopping Dolutrav therapy after the onset of a hypersensitivity reaction may lead to progression of the reaction and life-threatening consequences. Monitoring of clinical status, including liver aminotransferases and bilirubin, is recommended.
• After discontinuation of Dolutrav due to suspected hypersensitivity reaction, Dolutrav or any other medicinal product containing abacavir or dolutegravir must never be restarted.
• Reinitiating therapy with abacavir-containing agents after a suspected hypersensitivity reaction may result in recurrence of symptoms within hours. Such recurrences are usually more severe than during prior treatment and may include life-threatening episodes of hypotension and fatal outcomes.
• To avoid re-exposure to abacavir and dolutegravir, patients who have experienced suspected hypersensitivity reactions should be instructed on proper disposal of any remaining Dolutrav tablets.
• Patients should be informed of the necessity to read the package leaflet and the "Warning card," which should be removed from the packaging and carried at all times.

Clinical presentation of hypersensitivity reactions.

Hypersensitivity reactions were observed in < 1% of patients receiving dolutegravir in clinical trials, characterized by rash, systemic disturbances, and sometimes organ dysfunction, including severe hepatobiliary reactions.

Hypersensitivity reactions associated with abacavir use have been well documented in clinical trials and post-marketing surveillance. Symptoms typically appear within the first six weeks (median time to onset: 11 days) after starting abacavir treatment, but may occur at any time during therapy.

Almost all abacavir-related hypersensitivity reactions include fever and/or rash. Other signs and symptoms observed as part of abacavir hypersensitivity reactions are described in detail in the "Adverse reactions" section, including respiratory and gastrointestinal symptoms. It is important to recognize that these symptoms may lead to misdiagnosis of hypersensitivity reactions as respiratory infections (pneumonia, bronchitis, pharyngitis) or gastroenteritis. Symptoms associated with hypersensitivity reactions may worsen with continued treatment and may be life-threatening. These symptoms usually resolve after discontinuation of abacavir.

In rare cases, patients who discontinued abacavir for reasons other than hypersensitivity symptoms have experienced life-threatening reactions within hours of reinitiating abacavir therapy (see section "Adverse reactions"). Reintroduction of abacavir in such patients should only occur under conditions where immediate medical assistance is available.

Lactic acidosis.

Lactic acidosis has been observed with nucleoside analogues, usually associated with hepatomegaly and hepatic steatosis. Early symptoms (symptomatic hyperlactatemia) include mild gastrointestinal symptoms (nausea, vomiting, abdominal pain), general weakness, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including motor weakness).

Lactic acidosis is associated with high mortality and may be accompanied by pancreatitis, hepatic failure, or renal failure.

Lactic acidosis typically occurs after several months of treatment.

Nucleoside analogue therapy should be discontinued in cases of symptomatic hyperlactatemia, metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels.

Nucleoside analogues should be used with caution in any patient (particularly women with excess body weight) who has hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain medications and alcohol). Patients co-infected with hepatitis C virus who have received treatment with alpha-interferon and ribavirin may be at increased risk.

Patients at higher risk require close monitoring.

Body weight and metabolic parameters.

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Contributing factors may include disease control and lifestyle changes. Evidence supports a treatment-related effect on lipid levels in some cases, whereas such evidence is lacking for weight gain. Monitoring of serum lipid and blood glucose levels should be performed according to established HIV treatment guidelines. Treatment of lipid abnormalities should be based on clinical indications.

Liver disease.

The safety and efficacy of fixed-dose combination tablets of abacavir/dolutegravir/lamivudine have not been evaluated in patients with severe liver disease. Dolutrav is not recommended for patients with moderate or severe hepatic impairment (see section "Method of administration and dosage").

Patients with pre-existing liver function abnormalities, including chronic active hepatitis, have an increased frequency of liver-related disorders during combined antiretroviral therapy and should be monitored according to standard practice. If liver disease progresses, consideration should be given to partial or complete discontinuation of therapy.

Patients with chronic hepatitis B or C.

Patients with chronic hepatitis B or C receiving combined antiretroviral therapy are at risk of severe and potentially fatal hepatic adverse reactions. When concomitant antiviral therapy for hepatitis B or C is prescribed, the appropriate product information for these medicinal products should be followed.

Dolutrav contains lamivudine, which is a component of hepatitis B treatment. Abacavir and dolutegravir do not have this effect. Lamivudine monotherapy is generally not considered adequate treatment for hepatitis B due to a high risk of developing resistance to hepatitis B virus. When Dolutrav is prescribed to patients co-infected with hepatitis B, additional antiviral therapy should be administered. Appropriate product information should be consulted.

Upon discontinuation of Dolutrav in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and hepatitis B viral replication markers is recommended, as discontinuation of lamivudine may lead to hepatitis flare.

Immune reconstitution syndrome.

In HIV-infected patients with advanced immunodeficiency at the initiation of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, leading to serious clinical manifestations or worsening of symptoms. These reactions are typically observed within the first few weeks or months after starting cART. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia (PCP). Any inflammatory symptoms should be evaluated and treated as necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been observed during immune reconstitution; however, the time to onset is highly variable, and these conditions may manifest many months after starting treatment.

Elevated liver enzymes consistent with immune reconstitution syndrome have been observed in some patients co-infected with hepatitis B and/or C prior to starting dolutegravir. In patients co-infected with hepatitis B and/or C, monitoring of liver enzyme levels is recommended (see "Patients with chronic hepatitis B or C" and section "Adverse reactions").

Mitochondrial dysfunction.

Nucleoside and nucleotide analogues may cause mitochondrial dysfunction of varying severity, particularly when used concomitantly with stavudine, didanosine, or zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors during the prenatal and/or postnatal period, primarily in regimens containing zidovudine. The main adverse reactions reported include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Rare reports of delayed neurological disorders (hypertonia, seizures, behavioral disturbances) have been documented. It is currently unknown whether these neurological disorders are transient or permanent. The possibility of such disorders should be considered in any infant exposed to nucleoside and nucleotide analogues in utero who presents with severe clinical symptoms of unknown etiology, particularly neurological symptoms. These data do not affect current recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical transmission of HIV.

Cardiovascular events.

Although clinical and observational data on abacavir are conflicting, some studies suggest an increased risk of cardiovascular events (particularly myocardial infarction) in patients receiving abacavir. Therefore, when prescribing Dolutrav, measures should be taken to minimize all modifiable risk factors (e.g., smoking, hypertension, hyperlipidemia). Additionally, alternative treatment regimens not containing abacavir should be considered for patients with high cardiovascular risk.

Osteonecrosis.

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, and increased body mass index), cases of osteonecrosis have been reported in patients with advanced HIV infection and/or long-term use of combination antiretroviral therapy. Patients should be advised to seek medical consultation if they experience joint pain, joint stiffness, or difficulty moving.

Infections caused by opportunistic organisms.

Patients should understand that Dolutrav or other antiretroviral drugs do not cure HIV infection and that they may still develop opportunistic infections and other HIV-related complications. Therefore, patients should remain under close clinical supervision by physicians experienced in managing HIV-associated diseases.

Drug resistance.

Since the recommended dose of dolutegravir for patients with resistance to integrase inhibitors is 50 mg twice daily, the use of Dolutrav is not recommended in patients with resistance to integrase inhibitors.

Interaction with other medicinal products.

Since the recommended dose of dolutegravir is 50 mg twice daily, concomitant use of Dolutrav with etravirine (without boosted protease inhibitors), efavirenz, nevirapine, rifampicin, tipranavir/ritonavir, carbamazepine, phenytoin, phenobarbital, or St. John's wort is not recommended (see section "Interaction with other medicinal products and other types of interactions").

Dolutrav should not be co-administered with polyvalent cation-containing antacids. Dolutrav should be administered at least 2 hours before or 6 hours after these agents (see section "Interaction with other medicinal products and other types of interactions").

Dolutrav should be administered at least 2 hours before or 6 hours after calcium or iron-containing dietary supplements (see section "Interaction with other medicinal products and other types of interactions").

Dolutegravir increases metformin concentrations. The physician should consider adjusting the metformin dose at the initiation and discontinuation of concomitant dolutegravir therapy to maintain glycemic control (see section "Interaction with other medicinal products and other types of interactions").

Metformin is eliminated by the kidneys; therefore, renal function should be monitored during concomitant therapy with dolutegravir. The combination of these medicinal products increases the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance [CrCl] 45–59 mL/min) — special attention is recommended. The physician should consider the need to reduce the metformin dose.

The combination of lamivudine with cladribine is not recommended (see section "Interaction with other medicinal products and other types of interactions").

Dolutrav should not be used concomitantly with any medicinal product containing dolutegravir, abacavir, lamivudine, or emtricitabine.

This medicinal product contains sodium. Caution should be exercised when prescribing to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy. When selecting antiretroviral agents for treating HIV in pregnant women and reducing the risk of vertical transmission to the newborn, data from animal studies and clinical experience in pregnant women should be considered.

Currently, there are no data on the use of fixed-dose combination tablets of abacavir/dolutegravir/lamivudine in pregnant women.

Data on the use of dolutegravir in pregnant women are lacking or limited. The effect of dolutegravir on pregnancy is unknown. According to information from pregnant women who self-administered the combination of abacavir and lamivudine, no teratogenic toxicity was observed (over 400 outcomes after first-trimester exposure). A large amount of data on lamivudine use (over 3000 outcomes after first-trimester exposure) does not indicate teratogenic toxicity. Available data on abacavir use (over 600 outcomes after first-trimester exposure) also do not indicate teratogenic toxicity of abacavir.

In reproductive toxicity studies in animals, dolutegravir crossed the placenta. Animal studies do not indicate a direct or indirect harmful effect on reproductive function. Abacavir and lamivudine are capable of inhibiting cellular DNA replication, and abacavir has shown carcinogenicity in animal studies. The clinical significance of these findings is unknown.

Dolutrav may be used during pregnancy only if the expected benefit outweighs the potential risks to the fetus.

In patients co-infected with hepatitis B who received lamivudine-containing therapy such as Dolutrav and subsequently became pregnant, the possibility of hepatitis relapse upon discontinuation of lamivudine should be considered.

Mitochondrial dysfunction. Nucleoside and nucleotide analogues have demonstrated in vitro and in vivo various levels of mitochondrial injury. Mitochondrial dysfunction has been reported in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally (see section "Special precautions for use").

Breastfeeding. It is unknown whether dolutegravir is excreted in human breast milk. Available toxicological data in animals indicate excretion of dolutegravir into milk. When dolutegravir was administered to animals during lactation at a dose of 50 mg/kg/day for 10 days postpartum, dolutegravir concentrations in milk were higher than those in blood.

Abacavir and its metabolites are excreted in rat milk. Abacavir is also excreted in human breast milk.

In studies involving more than 200 mother-infant pairs undergoing HIV treatment, abacavir concentrations in infant serum were very low (< 4% of maternal serum concentrations) and progressively decreased to undetectable levels by 24 weeks of age. There are no data on the safety of abacavir and lamivudine in children under 3 months of age.

HIV-infected women should not breastfeed their infants under any circumstances to avoid HIV transmission.

Reproductive function. There are no data on the effects of dolutegravir, abacavir, or lamivudine on male or female reproductive function. Animal studies did not demonstrate effects of dolutegravir, abacavir, or lamivudine on reproductive function in males or females.

Ability to influence reaction speed when driving or operating machinery.

Patients should be informed about possible dizziness during dolutegravir use. The patient's clinical status and the adverse reaction profile of Dolutrav should be considered when assessing the patient's ability to drive or operate machinery.

Method of Administration and Dosage

Therapy should be prescribed by a specialist experienced in the treatment of HIV infection.

Dosing.

Adults and children (with body weight of 40 kg or more).

The recommended dose of Dolutrav for adults and children is 1 tablet once daily.

Dolutrav should not be prescribed to adults and children with body weight less than 40 kg, as the tablet contains a fixed therapeutic dose that cannot be reduced.

Dolutrav is a fixed-dose tablet formulation not recommended for patients who require dose adjustments. If discontinuation or dose adjustment of any of the active ingredients is necessary, the specialist may consider using separate formulations of dolutegravir, abacavir, or lamivudine. In such cases, the physician should follow the instructions for medical use of each of these medicinal products.

Missed doses.

A missed dose of Dolutrav can be taken if there is still at least 4 hours before the next scheduled dose. If less than 4 hours remain before the next dose, the missed dose should not be taken—patients should continue with their regular dosing schedule.

Elderly patients.

Data on the use of dolutegravir, abacavir, and lamivudine in patients aged 65 years and older are limited. There is no evidence that elderly patients require a different dosage regimen compared to younger adult patients (see section "Pharmacological properties"). This age group should be monitored carefully due to age-related changes such as decreased renal function and alterations in hematological parameters.

Renal impairment.

Dolutrav is not recommended for use in patients with creatinine clearance < 50 mL/min (see section "Pharmacological properties").

Hepatic impairment.

Abacavir is primarily metabolized in the liver. There are no clinical data available on patients with moderate or severe hepatic impairment; therefore, Dolutrav is not recommended unless absolutely necessary. Close monitoring is required for patients with mild hepatic impairment (Child–Pugh score 5–6), including plasma abacavir level monitoring when necessary (see sections "Special precautions" and "Pharmacological properties").

Method of administration.

Oral administration.

Dolutrav can be taken regardless of food intake (see section "Pharmacological properties").

Children.

The safety and efficacy of Dolutrav in children under 12 years of age have not been established.

Overdose.

No specific symptoms or signs of acute overdose with dolutegravir, abacavir, or lamivudine have been identified beyond those listed in the adverse reactions section.

Further management should be clinically appropriate or guided by a poison control center, if available. There is no specific antidote for Dolutrav overdose. In case of overdose, patients should receive supportive treatment as needed, with appropriate monitoring. Since lamivudine can be removed by dialysis, prolonged hemodialysis may be used for overdose management, although this has not been studied. It is unknown whether abacavir can be eliminated by peritoneal dialysis or hemodialysis. Because dolutegravir is highly protein-bound, it is unlikely to be significantly removed by dialysis.

Adverse reactions

Clinical safety data for fixed-dose combination tablets of abacavir/dolutegravir/lamivudine are currently limited. The most frequently reported adverse reactions, which were possibly or probably related to dolutegravir and abacavir/lamivudine (based on data collected from Phase IIb–IIIb clinical trials involving 679 patients receiving combinations of dolutegravir, abacavir, and lamivudine who had not previously received antiretroviral therapy), were nausea (12%), insomnia (7%), dizziness (6%), and headache (6%).

Many of the adverse reactions listed in Table 2—such as nausea, vomiting, diarrhea, fever, fatigue, and rash—commonly occur in patients experiencing hypersensitivity to abacavir. Therefore, patients presenting with any of these symptoms should be carefully evaluated for abacavir hypersensitivity (see section "Special warnings and precautions for use"). Very rare cases of erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis have been reported when abacavir hypersensitivity could not be ruled out. In such cases, medications containing abacavir must be permanently discontinued.

The most serious adverse reaction, probably associated with the use of dolutegravir and abacavir/lamivudine and observed in individual patients, was a hypersensitivity reaction including rash and severe hepatic injury (see section "Special warnings and precautions for use" and subsection "Description of selected adverse reactions" in this section).

Adverse reactions considered at least possibly related to treatment with the components of fixed-dose combination tablets of abacavir/dolutegravir/lamivudine, based on data from clinical studies and post-marketing use, are listed in Table 2 and classified by system organ class and frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Adverse reactions observed with the combination of dolutegravir + abacavir/lamivudine, based on pooled data analysis from Phase IIb–IIIb clinical trials, were generally consistent with the adverse reaction profiles of the individual components—dolutegravir, abacavir, and lamivudine.

There were no differences in the severity of any adverse reactions when the combination was used compared to the individual components.

Table 2

Adverse reactions associated with the combination dolutegravir + abacavir/lamivudine observed during Phase IIb–IIIb clinical trials or post-marketing use, and adverse reactions to dolutegravir, abacavir, and lamivudine observed during clinical studies and post-marketing use in combination with other antiretroviral agents.

Frequency	Adverse reaction
From the blood and lymphatic system
Uncommon	Neutropenia1, anemia1, thrombocytopenia1
Very rare	True red cell aplasia1
From the immune system
Common	Hypersensitivity (see section "Special precautions")
Uncommon	Immune reconstitution syndrome (see section "Special precautions")
From the metabolism and nutrition
Common	Anorexia1
Uncommon	Hypertriglyceridemia, hyperglycemia
Very rare	Lactic acidosis1
From the mental sphere
Very common	Insomnia
Common	Unusual dreams, depression, anxiety1, night terrors, sleep disturbances
Uncommon	Suicidal thoughts or attempts (especially in patients with history of depression or psychiatric disorders), panic attack
From the nervous system
Very common	Headache
Common	Dizziness, somnolence, lethargy1
Very rare	Peripheral neuropathy1, paresthesia1
From the respiratory, thoracic and mediastinal system
Common	Cough1, nasal symptoms1
From the gastrointestinal tract
Very common	Nausea, diarrhea
Common	Vomiting, flatulence, abdominal pain, upper abdominal pain, bloating, abdominal discomfort, gastroesophageal reflux disease, dyspepsia
Rare	Pancreatitis1
From the hepatobiliary system
Uncommon	Hepatitis
Rare	Acute liver failure
From the skin and subcutaneous tissues
Common	Rash, pruritus, alopecia1
Very rare	Multiform erythema1, Stevens-Johnson syndrome1, toxic epidermal necrolysis1
From the musculoskeletal and connective tissue system
Common	Arthralgia1, muscle disorders1 (including myalgia1)
Rare	Rhabdomyolysis1
General disorders
Very common	General weakness
Common	Asthenia, chills1, malaise1
Laboratory data
Common	Elevated levels of creatine phosphokinase (CPK), alanine aminotransferase (ALT), aspartate aminotransferase (AST)
Rare	Elevated amylase levels1
1This adverse reaction was not identified in phase III clinical trials for the combination (dolutegravir + abacavir/lamivudine) or dolutegravir alone, but was observed in clinical trials or during the post-marketing period for dolutegravir, abacavir, or lamivudine when used with other antiretroviral agents, or in the post-marketing period following use of the fixed-dose combination.

Description of selected adverse reactions

Hypersensitivity reactions

Abacavir and dolutegravir are associated with the risk of hypersensitivity reactions, which have been most frequently observed with abacavir. Hypersensitivity reactions for each of these drugs (described below) share some common features such as fever and/or rash, accompanied by other symptoms indicating multi-organ involvement. The time to onset of reactions associated with abacavir and dolutegravir is usually 10–14 days, although abacavir-related reactions may develop at any time during treatment. Treatment with Dolutrakx should be discontinued immediately if hypersensitivity cannot be ruled out based on clinical findings. Reinitiating therapy with Dolutrakx or any other medicinal product containing abacavir and dolutegravir is contraindicated. For detailed recommendations on patient management in case of suspected hypersensitivity to Dolutrakx, see section "Special warnings and precautions for use".

Hypersensitivity to dolutegravir

Symptoms included rash, systemic symptoms, and occasionally organ dysfunction, including severe hepatic reactions.

Hypersensitivity to abacavir

Signs and symptoms of this hypersensitivity reaction are listed below. They were identified in clinical trials or during post-marketing use. Manifestations observed in at least 10% of patients are indicated in bold.

Almost all patients who develop hypersensitivity reactions have fever and/or rash (usually maculopapular or urticarial) as part of this syndrome, although reactions have occurred in the absence of rash or fever. Other key symptoms include gastrointestinal, respiratory, or systemic symptoms such as lethargy and malaise (Table 3).

Table 3

Skin	Rash (usually maculopapular or urticarial)
Gastrointestinal system	Nausea, vomiting, diarrhea, abdominal pain, oral mucosal ulceration
Respiratory system	Dyspnea, cough, sore throat, adult respiratory distress syndrome, respiratory failure
Other	Chills, lethargy, malaise, swelling, lymphadenopathy, hypotension, conjunctivitis, anaphylactic reaction
Psychiatric / Nervous system	Headache, paresthesia
Blood and lymphatic system	Lymphopenia
Hepatobiliary system	Elevated liver enzyme levels, hepatitis, hepatic failure
Musculoskeletal and connective tissue	Myalgia, rarely — myolysis, arthralgia, elevated creatine phosphokinase levels
Renal and urinary system	Elevated creatinine levels, renal failure

Symptoms associated with hypersensitivity reactions may worsen with continued treatment, may be life-threatening, and in rare cases may be fatal.

Restarting abacavir after hypersensitivity reactions may result in a rapid return of symptoms within several hours. Such recurrent hypersensitivity reactions are usually more severe than at initial treatment and may include life-threatening hypotensive episodes and fatal cases. Similar reactions have also occurred infrequently upon re-administration of abacavir in patients who previously experienced only one of the key symptoms of hypersensitivity (see above) prior to discontinuation of abacavir; and very rarely have been observed in patients without prior hypersensitivity symptoms who restarted treatment (i.e., patients who previously demonstrated adequate tolerance to abacavir).

Lactic acidosis

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported during treatment with nucleoside analogues (see section "Special precautions").

Metabolic parameters.

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy (see section "Special precautions").

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with well-known risk factors, advanced HIV disease, or long-term use of combination antiretroviral therapy. The frequency of this phenomenon is unknown (see section "Special precautions").

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been observed during immune reconstitution; however, the time to onset of these disorders has been variable and these events may occur many months after initiation of treatment (see section "Special precautions").

Changes in laboratory parameters

An increase in serum creatinine levels was observed during the first week of dolutegravir use, and this parameter remained stable over 96 weeks. In the SINGLE study, a mean change from baseline of 12.6 µmol/L was observed at 96 weeks of treatment. These changes are not considered clinically significant, as they do not reflect changes in glomerular filtration rate.

Asymptomatic increases in creatine phosphokinase (CPK) levels have also been reported, primarily associated with physical exertion during dolutegravir use.

Hepatitis B or C virus co-infection

Phase III studies included patients with hepatitis B and/or C receiving dolutegravir, provided baseline liver function tests did not exceed the upper limit of normal by more than 5 times. Overall, the safety profile in patients co-infected with hepatitis B and/or C virus was similar to that observed in patients without hepatitis B or C co-infection, although AST and ALT levels were higher in the subgroup with hepatitis B and/or C co-infection across all treatment groups.

Children

Clinical trial data on the use of Dolutegravir in children are lacking. Individual components of the medicinal product have been studied in adolescents aged 12 to 17 years.

Due to the limited amount of available data on the use of dolutegravir alone in combination with other antiretroviral agents for the treatment of pediatric patients aged 12 to 17 years, no additional types of adverse reactions have been identified beyond those observed in adult patients.

Abacavir and lamivudine as individual monotherapy agents have been studied separately and in nucleoside combinations, in combination with antiretroviral therapy for the treatment of two groups of HIV-infected children who were either antiretroviral treatment-naïve or antiretroviral treatment-experienced (data on use of abacavir and lamivudine in infants under 3 months of age are limited). No additional types of adverse reactions have been reported beyond those observed in adult patients.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 30 tablets in a container; 1 container with a "Warning Card" in a cardboard box.

Prescription status. Prescription only.

Manufacturer. HETERO LABS LIMITED.

Manufacturer's address and location of its business operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.