INSTRUCTIONS for medical use of the medicinal product TRÍUMEK (TRIUMEQ)

Composition:

Active substances: dolutegravir, abacavir and lamivudine;

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

Excipients: mannitol (E 421), microcrystalline cellulose, povidone K29/32, sodium starch glycolate, magnesium stearate, Opadry II purple 85F90057, containing: polyvinyl alcohol, partially hydrolysed; titanium dioxide (E 171); polyethylene glycol; talc; black iron oxide (E 172); red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: purple, biconvex, film-coated, oval tablets with the imprint «572 Trı» on one side.

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 integrase active site 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 respective 5’-triphosphates (TP), which are the active moieties with extended 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 via 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 several 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 of dolutegravir against various laboratory strains using peripheral blood mononuclear cells was 0.5 nM, and the range using MT-4 cells was 0.7–2 nM. 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 HIV-1 strains ranged from 0.007 to 2.3 µM. The mean IC50 against laboratory HIV-2 strains (LAV2 and EHO) ranged from 1.57 to 7.5 µM for abacavir and from 0.16 to 0.51 µM for lamivudine.

The 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 treatment-naïve 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 patients not receiving antiviral therapy 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 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 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, resulting in 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 the laboratory strain HIVIII was passaged over 112 days, mutations emerged slowly, with substitutions at positions S153Y and F. These mutations were not observed in patients receiving dolutegravir in clinical trials. Using the NL432 strain, mutations E92Q (fold change 3) and G193E (fold change 3) were observed. These mutations were noted in patients with pre-existing resistance to raltegravir who received dolutegravir (listed as secondary mutations for dolutegravir).

In further 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, the integrase substitution R263K was observed in one isolate and G118R in two isolates. R263K has been reported 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 at site-specific mutations (fold change 10), but has not been 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 mutations listed as secondary, associated with integrase inhibitors (for raltegravir/elvitegravir), are added to primary mutations (except Q148) in site-specific mutation experiments, dolutegravir sensitivity remains at wild-type levels or approaches them. In viruses with Q148 mutations, the fold change increase for dolutegravir is considered as the number of secondary mutations increases. The impact of Q148-based (H/R/K) mutations was also consistent with in vitro passage experiments with site-specific mutants. In serial passage with site-specific mutants based on the NL432 strain 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 differences in the number of raltegravir-associated secondary mutations led to accumulation with significant fold change increase to values >10.

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

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

In vivo resistance (dolutegravir)

In treatment-naïve patients who received 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 non-responders to prior therapy who had not previously received integrase inhibitors (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up period 48 weeks) who received 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 was considered 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 with abacavir, the M184V mutation occurred first and led to approximately a 2-fold increase in IC50 below the clinical cutoff for abacavir at 4.5 fold change. Continued passage with increasing drug concentration led to selection of double RT mutants 65R/184V and 74V/184V or the triple RT mutant 74V/115Y/184V. Two mutations accounted for a 7–8-fold increase in abacavir sensitivity, 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 lamivudine-containing antiretroviral therapy. 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 account for 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 substitutions and to viruses with L74V plus M184V/I substitutions.

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

No effects on corrected QT interval were observed with dolutegravir doses approximately three times higher than the therapeutic dose. Similar studies with abacavir or lamivudine were not conducted.

Pharmacokinetics

The Triumeq tablet demonstrated bioequivalence to dolutegravir tablets as a single dose and to the fixed-dose combination tablet of abacavir/lamivudine (ABC/3TC FDC) administered separately. This was demonstrated in a two-way crossover bioequivalence study of single-dose Triumeq (fasted) compared to a dolutegravir tablet 1 × 50 mg plus 1 tablet × 600 mg abacavir/300 mg lamivudine (fasted) in healthy volunteers (n = 66). The effect of high-fat food on Triumeq, film-coated tablets, was studied in a subgroup of patients in this study (n = 12). The Cmax and AUC of dolutegravir in plasma after administration of Triumeq with high-fat food were 37% and 48% higher, respectively, than after administration of Triumeq under fasting conditions. This is not considered clinically significant (see "Absorption"). The effect of food on plasma levels of abacavir and lamivudine after administration of Triumeq with high-fat food was very similar to previously obtained food effect results with ABC/3TC FDC. These results indicate that Triumeq can be administered regardless of food intake.

The pharmacokinetic properties of dolutegravir, lamivudine, and abacavir are described below.

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 serum concentration (tmax) is 2–3 hours (after tablet formulation dose), 1.5 hours, and 1.0 hour for dolutegravir, abacavir, and lamivudine, respectively.

The effect of dolutegravir was generally similar in healthy volunteers and HIV-1-infected patients. In HIV-1-infected adult patients after administration of dolutegravir 50 mg once daily, 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 oral administration of lamivudine 300 mg once daily for 7 days, the mean (CV) steady-state Cmax was 2.04 µg/mL (26%) and the mean (CV) AUC24 was 8.87 µg·h/mL (21%).

The Cmax and AUC of dolutegravir in plasma after administration of Triumeq with high-fat food were 37% and 48% higher, respectively, than after administration of Triumeq under fasting conditions. For abacavir, a 23% decrease in Cmax was observed, while AUC remained unchanged. The effect of lamivudine was similar with food and fasting. These results indicate that Triumeq can be administered regardless of food intake.

Distribution

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

Dolutegravir has a high degree of binding (>99%) to human blood plasma proteins based on in vitro data. Dolutegravir binding to plasma proteins is independent of dolutegravir concentration. The overall ratios of radioactivity concentration associated with the drug in blood and plasma 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 in serum (<35 g/L), which is observed in patients with moderate liver disorders. 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 demonstrates low in vitro plasma protein binding (<36%).

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

In 13 previously untreated patients on a stable regimen of dolutegravir in combination with abacavir/lamivudine, the mean concentration of dolutegravir in CSF was 18 ng/mL (compared to unbound plasma concentration and above IC50). Studies with abacavir demonstrate 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 a dose of 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 CNS and its correlation with clinical efficacy is unknown.

Dolutegravir is present in the genital systems of men and women. The AUC values in vaginal fluid, cervical tissue, and vaginal tissue were 6–10% of the corresponding plasma values at steady state. The AUC was 7% in semen and 17% in rectal mucosa compared to the corresponding plasma values 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 through unabsorbed active substance or through biliary excretion of glucuronide conjugate, which may further degrade to form 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 by the kidneys. The primary metabolic pathways in humans are mediated by alcohol dehydrogenase and glucuronidation, resulting in the formation of 5’-carboxylic acid and 5’-glucuronide, which account for approximately 66% of the administered dose. These metabolites are excreted in urine.

The majority of lamivudine is excreted unchanged, and only a minor portion undergoes 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 interactions

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 half-life of the intracellular active moiety carbovir triphosphate (TP) 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. Abacavir elimination 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 abacavir dose. 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 was 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 transport system. Studies involving patients with renal impairment demonstrate that lamivudine excretion is reduced with renal disorders. Dose reduction is required for patients with creatinine clearance <50 mL/min (see section "Method of administration and dosage").

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 treatment 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 the rationale for once-daily dosing of abacavir and lamivudine.

Special patient groups

Hepatic impairment

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

Dolutegravir is primarily metabolized and excreted 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. The results demonstrated a mean increase in abacavir AUC of 1.89-fold [1.32; 2.70] and abacavir half-life of 1.58-fold [1.22; 2.04]. Dose reduction cannot be recommended for patients with mild hepatic impairment due to significant variability in the impact of different abacavir exposures.

Data obtained in patients with moderate and severe hepatic impairment demonstrate that lamivudine pharmacokinetics are not statistically significantly affected by liver function disorders.

Based on data obtained for abacavir, Triumeq 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 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 kidney function.

Lamivudine studies demonstrate that plasma concentrations (AUC) increase in patients with impaired kidney function due to reduced clearance.

Based on data for lamivudine, Triumeq is not recommended for use in 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 over 65 years of age are limited.

Children

The pharmacokinetics of 50 mg dolutegravir in 10 HIV-1-infected adolescents (aged 12 to 17 years) previously treated with antiretroviral agents 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 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 polymorphism of drug-metabolizing enzymes on dolutegravir pharmacokinetics. In a meta-analysis using pharmacogenomic models selected 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 corresponding values in patients with genotypes associated with normal metabolism via UGT1A1 (n = 41).

Sex

Population pharmacokinetic analysis using pooled pharmacokinetic data from phase IIb and phase III trials involving adult patients revealed no clinically significant effect of sex on dolutegravir exposure. There is no evidence to support the need for dose adjustment 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 involving 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 to support 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 for patients with hepatitis B virus co-infection are limited (see section "Special warnings and precautions for use").

Clinical characteristics.

Indications.

Treatment of adults and children aged 12 years and older with body weight of at least 40 kg who are infected with human immunodeficiency virus (HIV) (see sections "Special precautions" and "Pharmacological properties").

Before initiating therapy with agents 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 precautions"). Abacavir must not be prescribed 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 medicinal products having a narrow therapeutic window that are substrates of the organic cation transporter (OCT2), including fampridine (also known as dalfampridine) (see section "Interaction with other medicinal products and other forms of interactions").

Interaction with other medicinal products and other forms of interactions.

Triumeq contains dolutegravir, abacavir, and lamivudine; therefore, any interactions characteristic of these components individually also apply to Triumeq. 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 metabolism. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP. Concomitant administration of Triumeq with other agents that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may increase dolutegravir plasma concentrations. Medicinal products that induce these enzymes or transporters may reduce dolutegravir plasma concentrations and decrease the therapeutic effect of dolutegravir (see Table 1).

Dolutegravir absorption is reduced by certain antacid agents (see Table 1).

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

Lamivudine is eliminated by the kidneys. Active renal secretion of lamivudine into urine occurs via OCT2 and drug and toxin elimination transporters (MATE1 and MATE2-K). Concomitant use of lamivudine with inhibitors of OCT and MATE may increase lamivudine exposure. Dolutegravir is an inhibitor of OCT2 and MATE1; however, based on results of a cross-study analysis, 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 that modulate these transporters are not expected to affect abacavir plasma levels.

Although in vitro studies indicate that abacavir and lamivudine are substrates of BCRP and P-gp, clinical studies have shown 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 studies show that lamivudine is a substrate of MATE1, MATE2-K, and OCT2. Increased lamivudine plasma concentrations were observed when coadministered with trimethoprim (an inhibitor of the aforementioned transporters); however, this interaction is not considered clinically significant, and dose adjustment of lamivudine is not recommended. Lamivudine is a substrate of the hepatic uptake transporter OCT1. Due to the minor role of the liver in lamivudine elimination, drug interactions via OCT1 inhibition are unlikely to be clinically significant.

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

In vivo, dolutegravir does not affect the activity of midazolam, a CYP3A4 probe. Based on in vitro and/or in vivo data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, or P-gp (see "Pharmacokinetics").

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

In vitro, dolutegravir inhibits renal organic anion transporters OAT1 and OAT3. Due to the lack of in vivo effect on the pharmacokinetics of tenofovir (an organic anion transporter substrate), in vivo inhibition of OAT1 is unlikely. In vivo inhibition of OAT3 has not been studied. Dolutegravir may increase plasma concentrations of medicinal products 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, or 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 inhibition or weak inhibition of drug transporters MATE1 or OCT3, and 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 and lamivudine is an inhibitor of OCT1 and OCT2 in vitro, they have low potential to affect plasma concentrations of substrates of these transporters at therapeutic exposure levels (abacavir up to 600 mg, lamivudine 300 mg).

Information on existing and expected interactions with selected antiretroviral and non-antiretroviral medicinal products is provided in Table 1 (increases are indicated as "↑", decreases as "↓", no change as "↔", area under the concentration-time curve as "AUC", peak concentration as "Cmax", and trough concentration as "Cτ"). 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 upon 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 plasma concentrations of dolutegravir. Since the recommended dose of dolutegravir in patients taking etravirine without concomitant use of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir is 50 mg twice daily, Triumeq is not recommended for use in patients taking etravirine without concomitant use of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir (see below in the table).
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 with efavirenz is 50 mg twice daily, concomitant use with Triumeq is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Nevaripine/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 recommended dose of dolutegravir with nevirapine is 50 mg twice daily, concomitant use of nevirapine with Triumeq 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 is required when Triumeq is used concomitantly with nucleoside reverse transcriptase inhibitors.
Emtricitabine, didanosine, stavudine, zidovudine	Interaction not studied.	Triumeq is not recommended for use in combination with products containing emtricitabine, as both lamivudine (in Triumeq) and emtricitabine are cytidine analogues (i.e., 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 dose of dolutegravir when used concomitantly with tipranavir/ritonavir is 50 mg twice daily, concomitant use of these agents with Triumeq 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 concentrations, but due to limited data, this did not lead to reduced efficacy in phase III studies. Dose adjustment is not mandatory.
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.
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 dose adjustment is necessary.
Anti-infective agents
Trimethoprim/sulfamethoxazole (co-trimoxazole)/abacavir	Interaction not studied	No dose adjustment of Triumeq is required, except in 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 transporter)
Antimycobacterial agents
Rifampicin/dolutegravir	Dolutegravir ↓ AUC ↓ 54 % Cmax↓ 43 % Cτ↓ 72 % (induction of UGT1A1 and CYP3A enzymes)	Since the recommended dose of dolutegravir when used concomitantly with rifampicin is 50 mg twice daily, concomitant use of rifampicin with Triumeq 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 used concomitantly with carbamazepine, use of Triumeq 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 used concomitantly with these metabolic inducers, use of Triumeq is not recommended in patients receiving these metabolic inducers.
Potassium channel blockers
Fampridine (also known as dalfampridine)	Fampridine ↑ (Interaction not studied. Potential increase due to inhibition of OCT2 transporter)	Concomitant use of Triumeq and fampridine is contraindicated due to potentially life-threatening risk from high fampridine concentrations (see section "Contraindications").
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, potentially leading to loss of efficacy of cladribine in clinical combination. Some clinical data also suggest a possible interaction between lamivudine and cladribine.	Concomitant use of Triumeq 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; however, re-titration of methadone may be needed in individual cases.
Retinoid agents
Retinoid mixtures (e.g., isotretinoin)	Interaction not studied. Potential 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 ↔	No dose adjustment required.
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 %	Where possible, prolonged use of lamivudine with medicinal products containing sorbitol should be avoided, or more frequent monitoring of HBV viral load should be considered when prolonged concomitant use cannot be avoided.
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 Triumeq (minimum 2 hours after or 6 hours before administration).
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 Triumeq (minimum 2 hours after or 6 hours before administration).
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 used concomitantly with 50 mg dolutegravir once daily: metformin AUC ↑ 79 % Cmax↑ 66 % When used concomitantly with 50 mg dolutegravir twice daily: metformin AUC ↑ 145 % Cmax↑ 111 %	Dose adjustment of metformin should be considered at initiation and upon discontinuation of concomitant dolutegravir with metformin to maintain glycemic control. For patients with moderate renal impairment, dose adjustment of metformin should be considered when used concomitantly 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 when used concomitantly with St. John's wort is 50 mg twice daily, treatment with Triumeq 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 did not affect the pharmacodynamics of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone. No dose adjustment of Triumeq is required when used concomitantly with oral contraceptives.

Children.

Studies on interactions were conducted only with 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 national regulatory legislation.

Hypersensitivity reactions (see section "Adverse reactions").

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

Therefore, the following rules must be observed:

The HLA-B*5701 status must always be documented before initiating therapy.
Triumeq therapy should not be initiated in patients with a positive HLA-B*5701 status or in patients with a negative HLA-B*5701 status who have a history of suspected hypersensitivity reactions to abacavir in a previous treatment regimen containing abacavir.
Treatment with Triumeq must be discontinued immediately , even in the absence of the HLA-B*5701 allele, if a hypersensitivity reaction is suspected. Delay in discontinuing Triumeq therapy after the onset of a hypersensitivity reaction may lead to progression of the reaction and life-threatening consequences for the patient. Monitoring of clinical status, including liver aminotransferases and bilirubin, is recommended.
After discontinuation of Triumeq due to suspected hypersensitivity reaction, Triumeq or any other medicinal product containing abacavir or dolutegravir must never be restarted .
Reinitiating therapy with abacavir-containing products 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 to dispose of any remaining Triumeq tablets.
Patients should be informed about the necessity of reading 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 have been reported in < 1% of patients receiving dolutegravir in clinical trials, characterized by rash, systemic symptoms, and sometimes organ dysfunction, including severe hepatobiliary reactions.

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

Almost all hypersensitivity reactions associated with abacavir include fever and/or rash. Other signs and symptoms observed as part of abacavir hypersensitivity reactions are described in detail in the section "Adverse reactions," including respiratory and gastrointestinal symptoms. It is important to understand that these symptoms may lead to misinterpretation of hypersensitivity reactions as manifestations of respiratory illness (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 also experienced life-threatening reactions within hours of resuming abacavir therapy (see section "Adverse reactions"). Reinitiation of abacavir in such patients should only occur under conditions where immediate medical assistance is available.

Lactic acidosis.

Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, has been observed with nucleoside analogue therapy. Early symptoms (symptomatic hyperlactataemia) include benign 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 associated with pancreatitis, hepatic or renal failure.

Lactic acidosis typically occurs after several months of treatment.

Treatment with nucleoside analogues should be discontinued in cases of symptomatic hyperlactataemia and 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 are receiving treatment with alpha-interferon and ribavirin may have an increased risk.

Patients at higher risk require careful monitoring.

Body weight and metabolic parameters.

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Factors influencing these levels may also include disease control and lifestyle changes. In some cases, there is evidence supporting a treatment-related effect on lipid levels, 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 disorders should be based on clinical indications.

Liver disease.

The safety and efficacy of Triumeq in patients with severe liver disease have not been evaluated. Triumeq is not recommended for use in patients with moderate or severe hepatic impairment (see section "Dosage and administration").

Patients with pre-existing liver function abnormalities, including chronic active hepatitis, have an increased frequency of liver 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 prescribing concomitant antiviral therapy for hepatitis B or C, the appropriate product information for these medicinal products should be consulted.

Triumeq contains lamivudine, which is a component of hepatitis B treatment. Abacavir and dolutegravir do not have this effect. Lamivudine monotherapy is generally not considered sufficient for the treatment of hepatitis B, as the risk of developing resistance to hepatitis B is high. When Triumeq is used in patients co-infected with hepatitis B, additional antiviral therapy should be prescribed. Appropriate medical guidelines should be followed.

When discontinuing Triumeq in patients co-infected with hepatitis B virus, periodic monitoring of both liver function tests and markers of hepatitis B virus replication is recommended, as withdrawal of lamivudine may lead to hepatitis flare.

Immune reconstitution syndrome.

In HIV-infected patients with advanced immunodeficiency at the time of initiation of combined antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, which may result in serious clinical manifestations or worsening of symptoms. Such 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 (often referred to as 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 of these conditions is highly variable, and thus these events may occur many months after starting treatment.

Elevations in 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, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors during the intrauterine and/or postnatal period, primarily in treatment regimens containing zidovudine. The main adverse reactions reported were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactataemia, hyperlipasaemia). These events were often transient. Rare reports of late-onset neurological disorders (hypertonia, seizures, behavioral abnormalities) have also been documented. Whether these neurological disorders are transient or permanent remains unknown. These disorders should be considered in any child exposed to nucleoside and nucleotide analogues in utero who presents with severe clinical disorders of unknown etiology, particularly neurological disorders. These data do not affect current national recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical transmission of HIV.

Cardiovascular disease.

Although available data from clinical and observational epidemiological studies with abacavir have shown conflicting results, some studies suggest an increased risk of cardiovascular disease (particularly myocardial infarction) in patients receiving abacavir. Therefore, when prescribing Triumeq, precautions should be taken to minimize all risk factors (such as smoking, hypertension, and hyperlipidemia). Additionally, in patients at high risk of cardiovascular disease, an alternative treatment regimen not containing abacavir should be considered.

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 combined 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 be aware that Triumeq or other antiretroviral drugs do not cure HIV infection and that they may still develop infections caused by opportunistic organisms 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 integrase inhibitor resistance is 50 mg twice daily, the use of Triumeq 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 Triumeq 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 forms of interaction").

Triumeq should not be administered together with polyvalent cation-containing antacids. Triumeq should be taken at least 2 hours before or 6 hours after administration of these agents (see section "Interaction with other medicinal products and other forms of interaction").

Triumeq should be taken at least 2 hours before or 6 hours after administration of calcium or iron-containing dietary supplements (see section "Interaction with other medicinal products and other forms of interaction").

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

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

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

Triumeq should not be used with any medicinal products containing dolutegravir, abacavir, lamivudine, or emtricitabine.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Women of childbearing potential should undergo a pregnancy test before starting Triumeq. Women of childbearing potential taking Triumeq should be advised to use effective contraception.

Pregnancy.

In a fertility study in Botswana, 5 cases of neural tube defects were reported among 1683 births (0.3%) in women who received dolutegravir (a component of Triumeq) from conception, compared to 15 cases among 14,792 births (0.1%) in women who received regimens not containing dolutegravir from conception (difference in prevalence 0.20%; 95% CI 0.01–0.59). In the same study, one case of neural tube defect was observed among 3840 births (0.03%) in women who received dolutegravir during pregnancy, compared to three cases among 5952 births in women who received regimens not containing dolutegravir.

The incidence of neural tube defects in the general population ranges from 0.5 to 1 case per 1000 live births (0.05–0.1%). Since neural tube defects occur during the first 4 weeks of fetal development (when neural tubes are forming), this potential risk applies to women who were exposed to dolutegravir at conception and during early pregnancy. Due to the potential risk of neural tube defects associated with dolutegravir, the benefits and risks of continuing Triumeq should be evaluated in women planning pregnancy or who confirm pregnancy in the first trimester, and consideration should be given to switching to alternative antiretroviral regimens.

More than 1000 outcomes of dolutegravir exposure during the second and third trimesters indicate no increased risk of adverse birth outcomes. Triumeq may be used during the second and third trimesters of pregnancy only if the expected benefit to the woman outweighs the potential risk to the fetus.

Reproductive toxicity studies of dolutegravir in animals did not show adverse effects on fetal development, including neural tube defects.

Dolutegravir crosses the human placenta. In HIV-infected pregnant women, the median concentration of dolutegravir in umbilical cord blood was approximately 1.3 times higher than the concentration in maternal peripheral plasma.

There is insufficient information on the effects of dolutegravir on newborns.

Based on data from a moderate number of pregnant women who received abacavir and lamivudine combination therapy, no teratogenic toxicity has been observed (more than 400 outcomes after first-trimester exposure). With lamivudine use, a large amount of data (more than 3000 outcomes after first-trimester exposure) does not indicate teratogenic toxicity. A moderate amount of data (more than 600 outcomes after first-trimester exposure) also does not indicate teratogenic toxicity with abacavir.

Abacavir and lamivudine are capable of inhibiting cellular DNA replication, and abacavir has shown carcinogenic potential in animal studies. The clinical significance of these findings is unknown.

In patients co-infected with hepatitis B who received lamivudine-containing therapy such as Triumeq and subsequently became pregnant, the possibility of hepatitis flare 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.

Dolutegravir is excreted in human breast milk in small amounts (the mean ratio of dolutegravir concentration in breast milk to maternal plasma is 0.033). There is insufficient information on the effects of dolutegravir on newborns/infants.

Abacavir and its metabolites are excreted in the milk of lactating rats. Abacavir is also excreted in human breast milk.

Based on studies of more than 200 mother-infant pairs undergoing HIV treatment, lamivudine concentrations in infant serum from breastfeeding mothers treated for HIV infection are very low (< 4% of concentrations in serum of breastfeeding mothers) and progressively decrease to undetectable levels by the time the infant reaches 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 under any circumstances to avoid transmission of HIV.

Reproductive function.

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

Ability to drive and use machines.

Patients should be informed about the occurrence of dizziness during treatment with dolutegravir. The patient's clinical status and the adverse effect profile of Triumeq should be taken into account when assessing the patient's ability to drive or operate machinery.

Dosage and Administration.

Treatment should be prescribed by a specialist experienced in the management of HIV infection.

Dosage.

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

The recommended dose of Triumeq for adults and children is one tablet once daily.

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

Triumeq is a fixed-dose combination tablet not recommended for patients who require dose adjustments. If discontinuation or dose adjustment of any of the active substances in this medicinal product is necessary, the specialist may use separate preparations of dolutegravir, abacavir, or lamivudine. In such cases, the physician should refer to the respective package leaflets for these medicinal products.

Missed doses.

A missed dose of Triumeq can be taken within 4 hours before the next scheduled dose. If less than 4 hours remain before the next dose, the missed dose should not be taken; continue with the 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 adults (see section "Pharmacological properties"). This age group should be monitored carefully due to age-related changes such as reduced renal function and alterations in hematological parameters.

Renal impairment.

Triumeq is not recommended for 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 the use of Triumeq in patients with moderate or severe hepatic impairment; therefore, its use is not recommended except in cases of special necessity. Close monitoring is required for patients with mild hepatic impairment (Child–Pugh score 5–6), including monitoring of abacavir plasma levels if necessary (see sections "Special precautions for use" and "Pharmacological properties").

Administration method.

Oral administration.

Triumeq can be taken with or without food (see section "Pharmacological properties").

Children.

The safety and efficacy of Triumeq 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 the local national poison control center, if available. There is no specific antidote for Triumeq overdose. In case of overdose, patients should receive appropriate supportive treatment as needed, with appropriate monitoring. Since lamivudine can be removed by dialysis, prolonged hemodialysis may be used to manage overdose, although this has not been specifically studied. It is unknown whether abacavir can be eliminated by peritoneal dialysis or hemodialysis. Because dolutegravir is highly protein-bound, it is unlikely that it will be significantly removed by dialysis.

Adverse reactions.

Short overview of safety profile.

Clinical safety data for Triumeq are currently limited. The most commonly reported adverse reactions considered possibly or probably related to dolutegravir and abacavir/lamivudine (from Phase IIb–IIIb clinical trials, data were collected from 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, lethargy, and rash—occur frequently in patients with 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 possibly related to treatment with dolutegravir and abacavir/lamivudine 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 components of Triumeq, based on data from clinical trials and post-marketing experience, are listed in Table 2 and classified by system organ class and frequency of occurrence. Frequency categories are 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 in pooled analyses of Phase IIb–IIIb clinical trials are 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 compared to individual components.

Table 2

Summary of adverse reactions associated with the combination dolutegravir + abacavir/lamivudine from pooled analyses of Phase IIb–IIIb clinical trials or post-marketing experience, and adverse reactions reported for dolutegravir, abacavir, and lamivudine from clinical studies and post-marketing use when administered with other antiretroviral agents.

Frequency	Adverse reaction
Blood and lymphatic system disorders
Uncommon	Neutropenia¹, anaemia¹, thrombocytopenia¹
Very rare	Pure red cell aplasia¹
Immune system disorders
Common	Hypersensitivity (see section "Special warnings and precautions for use")
Uncommon	Immune reconstitution syndrome (see section "Special warnings and precautions for use")
Metabolism and nutrition disorders
Common	Anorexia¹
Uncommon	Hypertriglyceridaemia, hyperglycaemia
Very rare	Lactic acidosis¹
Psychiatric disorders
Very common	Insomnia
Common	Abnormal dreams, depression, anxiety¹, nightmares, sleep disorders
Uncommon	Suicidal thoughts or attempts (particularly in patients with a history of depression or psychiatric disorders)
Nervous system disorders
Very common	Headache
Common	Dizziness, somnolence, lethargy¹
Very rare	Peripheral neuropathy¹, paraesthesia¹
Respiratory, thoracic and mediastinal disorders
Common	Cough¹, nasal symptoms¹
Gastrointestinal disorders
Very common	Nausea, diarrhoea
Common	Vomiting, flatulence, abdominal pain, upper abdominal pain, abdominal distension, abdominal discomfort, gastroesophageal reflux disease, dyspepsia
Rare	Pancreatitis¹
Hepatobiliary disorders
Uncommon	Hepatitis
Rare	Acute liver failure
Skin and subcutaneous tissue disorders
Common	Rash, pruritus, alopecia¹
Very rare	Multiform erythema¹, Stevens-Johnson syndrome¹, toxic epidermal necrolysis¹
Musculoskeletal and connective tissue disorders
Common	Arthralgia¹, muscle disorders¹ (including myalgia¹)
Rare	Rhabdomyolysis¹
General disorders
Very common	Generalised weakness
Common	Asthenia, chills¹, malaise¹
Investigations
Common	Elevated CPK levels, elevated ALT/AST levels
Rare	Elevated amylase levels¹
¹This adverse reaction was not identified in phase III clinical trials of Triumeq (dolutegravir + abacavir/lamivudine) or dolutegravir, but has been reported in clinical trials or post-marketing experience with dolutegravir, abacavir or lamivudine when used with other antiretroviral agents, or during post-marketing use of Triumeq.

Description of selected adverse reactions.

Hypersensitivity reactions.

Abacavir and dolutegravir are associated with the risk of developing 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 Triumeq should be discontinued immediately if hypersensitivity cannot be ruled out based on clinical findings. Reinitiating therapy with Triumeq or any other medicinal product containing abacavir and dolutegravir is contraindicated. For detailed information on patient management in case of suspected hypersensitivity reaction to Triumeq, see section "Special precautions for use".

Hypersensitivity to dolutegravir

Symptoms included rash, systemic symptoms, and sometimes 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 reported 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; however, reactions may also occur in the absence of rash or fever. Other key signs 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, edema, lymphadenopathy, hypotension, conjunctivitis, anaphylactic reaction
Psychiatric/Nervous system	Headache, paresthesia
Blood and lymphatic system	Lymphopenia
Hepatobiliary system	Elevated liver function tests, hepatitis, hepatic failure
Musculoskeletal and connective tissue	Myalgia, rarely rhabdomyolysis, 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.

Reinitiating abacavir after hypersensitivity reactions may lead to a rapid return of symptoms within several hours. Such recurrent hypersensitivity reactions are usually more severe than the initial reactions and may include life-threatening hypotensive episodes and fatal cases. Similar reactions have also occurred infrequently after re-administration of abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to discontinuation of abacavir; and very rarely have been observed in patients who restarted treatment without prior symptoms of hypersensitivity (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 generally recognized 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 Inflammatory Syndrome

In HIV-infected patients with severe immunodeficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction 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 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 administration, 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 five times the upper limit of normal. Overall, the safety profile in patients co-infected with hepatitis B and/or C virus was similar to that in patients without hepatitis B or C virus co-infection, although AST and ALT levels were higher in the subgroup with hepatitis B and/or C virus co-infection across all treatment groups.

Children

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

Due to limited 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 single agents have been studied separately and in nucleoside combinations, in combination with antiretroviral therapy for the treatment of two groups of HIV-infected children: treatment-naïve and those previously treated (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.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep in the original packaging to protect from moisture. Keep the bottle tightly closed. Do not remove the desiccant (silica gel) from the bottle. Keep out of reach of children.

Packaging.

30 film-coated tablets and a silica gel desiccant in opaque white high-density polyethylene bottles with child-resistant polypropylene caps and a polyethylene protective seal. One bottle per cardboard box.

Prescription category. Prescription only.

Manufacturer. Glaxo Wellcome S.A., Spain.

Manufacturer's address and place of business. Avda. de Extremadura, 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain.

INSTRUCTIONS

for medical use of the medicinal product

TRIUMEQ

(TRIUMEQ)

Composition:

Active substances: dolutegravir, abacavir, and lamivudine;

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

Inactive ingredients: mannitol (E 421), microcrystalline cellulose, povidone K29/32, sodium starch glycolate, magnesium stearate, Opadry II purple 85F90057, which contains: polyvinyl alcohol, partially hydrolyzed; titanium dioxide (E 171); polyethylene glycol; talc; black iron oxide (E 172); red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: purple, biconvex, film-coated, oval tablets with the marking «572 Trı» on one side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for 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 to their respective 5’-triphosphates (TP), which are the active moieties with extended 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 is achieved through incorporation of the monophosphate form into the viral DNA chain, leading to chain termination. The triphosphates of abacavir and lamivudine demonstrate significantly lower affinity for host cell DNA polymerases.

In vitro antiviral activity.

The IC50 for dolutegravir against 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.

Isolates of HIV-1 (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 patients not receiving antiviral therapy 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 with other antiretroviral agents (tested agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, adefovir, and raltegravir). In addition, 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), such as 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 with other antiretroviral agents (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).

Effect of human serum.

In 100% human serum, the mean shift in dolutegravir activity was 75-fold, resulting in 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 selected slowly over 112 days, with substitutions at positions S153Y and F. These mutations have not been observed in patients receiving dolutegravir in clinical trials. Using the NL432 strain, mutations E92Q (3-fold change) and G193E (3-fold change) were observed. These mutations were noted in patients with pre-existing resistance to raltegravir who received dolutegravir (listed as secondary mutations for dolutegravir).

In further 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. R263K has been reported 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 (10-fold change) but has not been 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 mutations listed as secondary, associated with integrase inhibitors (for raltegravir/elvitegravir), are added to primary mutations (except Q148) in site-specific mutation experiments, dolutegravir sensitivity remains at wild-type levels or approaches them. In viruses with Q148 mutations, increased fold change for dolutegravir is considered in proportion to the number of secondary mutations. The impact of Q148-based mutations (H/R/K) was also consistent with in vitro passage experiments with site-specific mutants. In serial passage with site-specific mutants based on the NL432 strain, no further resistance selection was observed with N155H or E92Q (fold change unchanged at 1). In contrast, initial passage of mutants with Q148H mutation (fold change 1) and varying numbers of raltegravir-associated secondary mutations led to accumulation with significant fold change increase to values >10.

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

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

In vivo resistance (dolutegravir).

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

In non-responders to prior therapy who had not previously received integrase inhibitors (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up period 48 weeks) who received 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 was considered to have experienced integrase inhibitor exposure or was infected with 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 with abacavir, the M184V mutation occurred first and led to approximately a 2-fold increase in IC50 below the clinical cutoff for abacavir at 4.5-fold change. Continued passage with increasing drug concentration led to selection of double RT mutants 65R/184V and 74V/184V or the triple RT mutant 74V/115Y/184V. Two mutations accounted for a 7–8-fold increase in abacavir sensitivity, 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 lamivudine-containing antiretroviral therapy. M184V mutants demonstrate markedly 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 demonstrate reduced sensitivity to lamivudine. The combination abacavir/lamivudine demonstrated reduced sensitivity to viruses with K65R substitutions with or without M184V/I substitutions and to viruses with L74V plus M184V/I substitutions.

Effect on electrocardiogram.

No effects on the corrected QT interval were observed when dolutegravir was administered at doses approximately three times higher than the therapeutic dose. Similar studies with abacavir or lamivudine have not been conducted.

Pharmacokinetics.

The Triumeq tablet demonstrated bioequivalence to dolutegravir tablets as a single dose and to the fixed-dose combination tablet of abacavir/lamivudine (ABC/3TC FDC) administered separately. This was demonstrated in a two-way crossover bioequivalence study of single-dose Triumeq (fasting) compared to one 50 mg dolutegravir tablet plus one 600 mg abacavir/300 mg lamivudine tablet (fasting) in healthy volunteers (n = 66). The effect of a high-fat meal on Triumeq, film-coated tablets, was studied in a subgroup of patients in this study (n = 12). The Cmax and AUC of dolutegravir in plasma after administration of Triumeq with a high-fat meal were 37% and 48% higher, respectively, than after administration of Triumeq in the fasting state. This is not considered clinically significant (see "Absorption"). The effect of food on plasma levels of abacavir and lamivudine after administration of Triumeq with a high-fat meal was very similar to previously obtained food effect results with ABC/3TC FDC. These results indicate that Triumeq can be administered regardless of food intake.

The pharmacokinetic properties of dolutegravir, lamivudine, and abacavir are described below.

Absorption.

The effect of dolutegravir was generally similar in healthy volunteers and HIV-1-infected patients. In HIV-1-infected adult patients after administration of 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 oral administration of lamivudine 300 mg once daily for 7 days, the mean (CV) steady-state Cmax was 2.04 µg/mL (26%) and the mean (CV) AUC24 was 8.87 µg·h/mL (21%).

The Cmax and AUC of dolutegravir in plasma after administration of Triumeq with a high-fat meal were 37% and 48% higher, respectively, than after administration of Triumeq in the fasting 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 fasting state. These results indicate that Triumeq can be administered regardless of food intake.

Distribution.

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

Dolutegravir has a high degree of binding (>99%) to human plasma proteins based on in vitro data. Dolutegravir plasma protein binding is independent of dolutegravir concentration. The overall ratios of radioactivity concentration associated with the drug in blood and plasma 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 serum albumin levels (<35 g/L), which is 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 demonstrates low plasma protein binding in vitro (<36%).

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

In 13 previously untreated patients on a stable regimen of dolutegravir in combination with abacavir/lamivudine, the mean concentration of dolutegravir in CSF 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 a dose of 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 CNS and its relationship to clinical efficacy is unknown.

Dolutegravir is present in the genital system of men and women. The AUC values in vaginal fluid, cervical tissue, and vaginal tissue were 6–10% of the corresponding plasma value at steady state. The AUC was 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 the 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 through unabsorbed active substance or through biliary excretion of the glucuronide conjugate, which may further degrade to form the parent mixture 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 in urine as unchanged compound. The primary metabolic pathways in humans are mediated by alcohol dehydrogenase and glucuronidation, resulting in the formation of 5’-carboxylic acid and 5’-glucuronide, which account for approximately 66% of the administered dose. These metabolites are excreted in urine.

The majority of lamivudine is excreted unchanged, and only a minor portion undergoes metabolism. Lamivudine is predominantly 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%).

Interaction with medicinal products.

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 did 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 half-life of the intracellular active moiety carbovir triphosphate (TP) at steady state is 20.6 hours. After multiple oral doses of abacavir (300 mg twice daily), statistically significant accumulation of abacavir was not observed. Abacavir elimination occurs via hepatic metabolism with subsequent excretion of metabolites predominantly in urine. Metabolites and unchanged abacavir in urine account for approximately 83% of the administered abacavir dose. 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 involving patients with renal impairment demonstrate that lamivudine elimination is reduced in renal disorders. For patients with creatinine clearance <50 mL/min, dose reduction is required (see section "Dosage and 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 treatment group.

Intracellular pharmacokinetics.

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. The 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 cannot be recommended for patients with mild hepatic impairment due to significant variability in the impact of different abacavir exposures.

Data obtained in patients with moderate and severe hepatic impairment demonstrate that lamivudine pharmacokinetics are not statistically significantly affected by hepatic function impairment.

Based on data obtained for abacavir, Triumeq is not recommended for patients with moderate and severe hepatic impairment.

Renal impairment

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

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

Based on data for lamivudine, Triumeq is not recommended for use in 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 level 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 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 polymorphism of drug-metabolizing enzymes on dolutegravir pharmacokinetics. In a meta-analysis using pharmacogenomic models selected 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 metabolism via UGT1A1 (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 to support dose adjustment 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 to support 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 precautions").

Clinical characteristics.

Indications.

Treatment of adults and children aged 12 years and older with body weight of at least 40 kg who are infected with human immunodeficiency virus (HIV) (see sections «Special precautions», «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 precautions»). Abacavir must 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 medicinal products having a narrow therapeutic window that are substrates of the organic cation transporter (OCT2), including fampridine (also known as dalfampridine) (see section «Interaction with other medicinal products and other types of interactions»).

Interaction with other medicinal products and other types of interactions.

Triumeq contains dolutegravir, abacavir, and lamivudine; therefore, any interactions associated with these components individually also apply to Triumeq. 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 metabolism. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP. Concomitant administration of Triumeq with other agents that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/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).

Absorption of dolutegravir is reduced by certain antacid agents (see Table 1).

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

Lamivudine is eliminated by the kidneys. Active renal secretion of lamivudine into urine occurs via OCT2 and drug and toxin elimination transporters (MATE1 and MATE2-K). Concomitant use of lamivudine with inhibitors of OCT and MATE may increase lamivudine exposure. Dolutegravir is an inhibitor of OCT2 and MATE1; however, based on results from a cross-study analysis, 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.

Although abacavir and lamivudine are substrates of BCRP and P-gp in in vitro studies, clinical studies indicate no significant changes in abacavir pharmacokinetics when co-administered 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 were observed when co-administered with trimethoprim (an inhibitor of the aforementioned transporters), but this interaction is not considered clinically significant, and dose adjustment of lamivudine is not recommended. Lamivudine is a substrate of the hepatic uptake transporter OCT1. Due to the minor role of the liver in lamivudine elimination, drug interactions via OCT1 inhibition are unlikely to be clinically significant.

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

In vivo, dolutegravir does not affect the activity of 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 fraction dependent on OCT2 and MATE1 transporters) has been observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OCT2 or MATE1 (e.g., fampridine [also known as dalfampridine], metformin) (see Table 1 and section «Contraindications»).

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

Information on existing and expected interactions with selected antiretroviral and non-antiretroviral medicinal products is presented in Table 1 (increases are indicated as «↑», decreases as «↓», no change as «↔», area under the concentration-time curve as «AUC», peak concentration as «Cmax», concentration at the end of the dosing interval as «Cτ»). 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 concomitant use of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is 50 mg twice daily, Triumeq is not recommended for use in patients taking etravirine without concomitant administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir (see below in the table).
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 with efavirenz is 50 mg twice daily, concomitant use with Triumeq is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Nevaripine/dolutegravir	Dolutegravir ↓ (Not studied. A similar reduction in exposure as observed with efavirenz due to induction is expected)	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 dose of dolutegravir with concomitant nevirapine is 50 mg twice daily, concomitant use of nevirapine with Triumeq 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 is required when co-administering Triumeq with nucleoside reverse transcriptase inhibitors.
Emtricitabine, didanosine, stavudine, zidovudine	Interaction not studied.	Triumeq is not recommended for use in combination with products containing emtricitabine, as both lamivudine (in Triumeq) and emtricitabine are cytidine analogues (i.e., 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 with concomitant tipranavir/ritonavir is 50 mg twice daily, concomitant use of these agents with Triumeq 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 concentrations, but limited data did not lead to reduced efficacy in phase III studies. Dose adjustment is not mandatory.
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.
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 dose adjustment is necessary.
Anti-infective agents
Trimethoprim/sulfamethoxazole (co-trimoxazole)/abacavir	Interaction not studied	No dose adjustment of Triumeq is required, except in patients with renal impairment (see section "Posology and method of administration").
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 transporter)
Antimycobacterial agents
Rifampicin/dolutegravir	Dolutegravir ↓ AUC ↓ 54 % Cmax↓ 43 % Cτ↓ 72 % (induction of UGT1A1 and CYP3A enzymes)	Since the recommended dosing of dolutegravir with concomitant rifampicin is 50 mg twice daily, concomitant use of rifampicin with Triumeq 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 Triumeq 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 to be 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 Triumeq is not recommended in patients receiving these metabolic inducers.
Potassium channel blockers
Fampridine (also known as dalfampridine)	Fampridine ↑ (Interaction not studied. Potential increase due to inhibition of OCT2 transporter)	Concomitant use of Triumeq and fampridine is contraindicated due to potentially life-threatening risk from high fampridine concentrations (see section "Contraindications")
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, leading to a potential risk of loss of efficacy of cladribine in clinical combination. Some clinical data also suggest a possible interaction between lamivudine and cladribine	Concomitant use of Triumeq 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 unlikely to be required for most patients; re-titration of methadone may be needed in individual cases.
Retinoid agents
Retinoid combinations (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.
Others
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 ↔	No dose adjustment required.
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 %	Where possible, prolonged use of lamivudine with medicinal products containing sorbitol should be avoided, or more frequent monitoring of HBV viral load should be considered when prolonged concomitant use cannot be avoided.
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 Triumeq (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 Triumeq (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 ↔ With concomitant use of 50 mg dolutegravir once daily: metformin AUC ↑ 79 % Cmax↑ 66 % With concomitant use of 50 mg dolutegravir twice daily: metformin AUC ↑ 145 % Cmax↑ 111 %	Dose adjustment of metformin should be considered at initiation and upon discontinuation of concomitant dolutegravir with metformin to maintain glycemic control. For patients with moderate renal impairment, dose adjustment of metformin should be considered when used concomitantly with dolutegravir, as increased metformin concentrations pose a higher 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 to be 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 Triumeq 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 did not affect the pharmacodynamics of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and progesterone. No dose adjustment of Triumeq is required when used concomitantly with oral contraceptives.

Children.

Interaction studies have been conducted only in adult patients.

Special precautions for use.

HIV transmission.

Although effective antiretroviral therapy has significantly reduced the risk of sexual transmission of viruses, the risk cannot be completely ruled out. Preventive measures to avoid virus transmission should be taken in accordance with national 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 general symptoms such as fever and/or rash, and symptoms indicating multi-organ involvement. It is clinically impossible to determine whether abacavir and dolutegavir in the composition of Triumeq cause hypersensitivity reactions. Hypersensitivity reactions have been more frequently observed with abacavir, some of which were life-threatening and occasionally fatal if patients did not receive appropriate medical care. The risk of developing hypersensitivity reactions is high in patients with positive test results for the HLA-B*5701 allele. However, hypersensitivity reactions to abacavir have been observed in patients who were not carriers of this allele, although at a low frequency.

Therefore, the following rules must be observed:

The HLA-B*5701 status must always be documented before initiating therapy.
Triumeq therapy should not be prescribed to patients with a positive HLA-B*5701 status or to patients with a negative HLA-B*5701 status who have a history of suspected hypersensitivity reactions to abacavir in a previous treatment regimen containing abacavir.
Triumeq treatment must be discontinued immediately, even in the absence of the HLA-B*5701 allele, if a hypersensitivity reaction is suspected. Delay in immediate discontinuation of Triumeq therapy after the onset of a hypersensitivity reaction may lead to progression of the reaction and life-threatening consequences for the patient. Monitoring of clinical status, including liver aminotransferases and bilirubin, is recommended.
After discontinuation of Triumeq due to suspected hypersensitivity reaction, Triumeq 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 lead to recurrence of symptoms within several hours. Such recurrences are usually more severe than during previous treatment and may include life-threatening episodes of arterial 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 Triumeq tablets.
Patients must be informed about the necessity of reading the instruction leaflet and the "Warning Card" that should be removed from the packaging and carried at all times.

Clinical presentation of hypersensitivity reactions.

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

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

Almost all hypersensitivity reactions associated with abacavir 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 understand that such symptoms may lead to misinterpretation of hypersensitivity reactions as manifestations of respiratory illness (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 also experienced life-threatening reactions within several hours after resuming abacavir treatment (see section "Adverse reactions"). Resumption 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 benign 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 associated with pancreatitis, hepatic or renal failure.

Lactic acidosis typically occurs after several months of treatment.

Treatment with nucleoside analogues should be discontinued in cases of symptomatic hyperlactatemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels.

Nucleoside analogues should be prescribed with caution to 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 have an increased risk.

Patients at increased risk require careful monitoring.

Body weight and metabolic parameters.

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Factors influencing these levels may also include disease control and lifestyle changes. In some cases, there is evidence supporting the impact of treatment on increased lipid levels, whereas evidence for increased body weight is lacking. Monitoring of serum lipid and blood glucose levels should be performed according to approved HIV treatment protocols. Treatment of lipid disorders should be based on clinical indications.

Liver disease.

The safety and efficacy of Triumeq in patients with severe liver disease have not been evaluated. Triumeq is not recommended for patients with moderate or severe hepatic impairment (see section "Dosage and administration").

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 adverse hepatic reactions. When prescribing concomitant antiviral therapy for hepatitis B or C, the relevant product information for these medicinal products should be consulted.

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

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

Immune reconstitution syndrome.

In HIV-infected patients with advanced immunodeficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may occur, which can cause serious clinical manifestations or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after starting combination antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jiroveci pneumonia (often known as 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 expected time to onset has greater variability, and thus these events may occur many months after starting treatment.

Elevated liver enzyme levels 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 pronounced when used concomitantly with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors during intrauterine and/or postnatal periods, primarily in treatment regimens including zidovudine. The main adverse reactions reported were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events were often transient. Rare reports of late-onset neurological disorders (hypertonia, seizures, behavioral disturbances) have been documented. Whether these neurological disorders are transient or permanent remains unknown. Such disorders should be considered in any child exposed to nucleoside and nucleotide analogues in utero who presents with severe unexplained clinical disorders, particularly neurological. These data do not affect current national recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical HIV transmission.

Cardiovascular disease.

Although available data from clinical and observational epidemiological studies with abacavir show conflicting results, some studies suggest an increased risk of cardiovascular disease (particularly myocardial infarction) in patients receiving abacavir. Therefore, precautions should be taken when prescribing Triumeq to minimize all risk factors (such as smoking, arterial hypertension, and hyperlipidemia). Additionally, in patients at high risk of cardiovascular disease, an alternative treatment regimen not containing abacavir should be considered.

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 with prolonged 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 Triumeq or other antiretroviral drugs do not cure HIV infection and that they may still develop infections caused by opportunistic organisms and other HIV-related complications. Therefore, patients should remain under close clinical supervision by physicians experienced in treating 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 Triumeq 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 Triumeq with etravirine (without boosted protease inhibitors), efavirenz, nevirapine, rifampicin, tipranavir/ritonavir, carbamazepine, phenytoin, phenobarbital, and St. John's wort is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Triumeq should not be administered together with multivalent cation-containing antacids. Triumeq should be taken 2 hours before or 6 hours after these agents (see section "Interaction with other medicinal products and other forms of interaction").

Triumeq should be taken 2 hours before or 6 hours after calcium or iron-containing dietary supplements (see section "Interaction with other medicinal products and other forms of interaction").

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 forms of interaction").

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

Triumeq is not recommended to be used with any medicinal products containing dolutegravir, abacavir, lamivudine, or emtricitabine.

Use during pregnancy or breastfeeding.

Women of reproductive potential.

Women of reproductive potential should undergo a pregnancy test before starting Triumeq. Women of reproductive potential taking Triumeq should be advised to use effective contraceptive methods.

Pregnancy.

In a Botswana birth outcomes study, 5 cases of neural tube defects were reported among 1683 (0.3%) deliveries in women who received a dolutegravir-containing regimen (a component of Triumeq) from conception, compared to 15 cases among 14,792 (0.1%) deliveries in women who received a regimen not containing dolutegravir (difference in prevalence 0.20%; 95% CI 0.01–0.59). In the same study, one neural tube defect was observed among 3840 (0.03%) newborns of women who took dolutegravir during pregnancy, compared to three cases among 5952 deliveries in women who received a regimen not containing dolutegravir.

The incidence of neural tube defects in the general population ranges from 0.5 to 1 case per 1000 live births (0.05–0.1%). Since neural tube defects occur within the first 4 weeks of fetal development (when neural tubes are forming), this potential risk applies to women who took dolutegravir at conception and during early pregnancy. Due to the potential risk of neural tube defects associated with dolutegravir, the benefits and risks of Triumeq should be evaluated in cases of planned pregnancy or confirmed first-trimester pregnancy during Triumeq treatment, and switching to alternative antiretroviral regimens should be considered.

Reproductive toxicity studies of dolutegravir in animals did not show adverse effects on fetal development, including neural tube defects.

Dolutegravir crosses the human placenta. In pregnant HIV-infected women, the median concentration of dolutegravir in the umbilical cord was approximately 1.3 times higher than the concentration in maternal plasma.

There is insufficient information on the effects of dolutegravir on newborns.

Based on data from a moderate number of pregnant women who self-administered the combination of abacavir and lamivudine, no teratogenic toxicity has been observed (more than 400 outcomes after first-trimester exposure). With lamivudine use, a large amount of data (more than 3000 outcomes after first-trimester exposure) does not indicate teratogenic toxicity. A moderate amount of data (more than 600 outcomes after first-trimester exposure) also does not indicate teratogenic toxicity of abacavir.

Abacavir and lamivudine can inhibit DNA cellular replication, and abacavir has shown carcinogenicity in animal studies. The clinical significance of these findings is unknown.

In patients co-infected with hepatitis B who received lamivudine-containing therapy such as Triumeq and later 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 damage. Mitochondrial dysfunction has been reported in HIV-negative infants exposed to nucleoside analogues in utero and/or after birth (see section "Special precautions for use").

Breastfeeding.

Dolutegravir is excreted in human breast milk in small amounts (the average ratio of dolutegravir concentration in breast milk to maternal plasma is 0.033). There is insufficient information on the effects of dolutegravir on newborns/infants.

Abacavir and its metabolites are excreted in the milk of lactating rats. Abacavir is also excreted in human breast milk.

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

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

Reproductive function.

Ability to affect reaction speed when driving vehicles or operating machinery.

Patients should be informed about possible dizziness during dolutegravir treatment. The patient's clinical status and the adverse effect profile of Triumeq should be considered when assessing the patient's ability to drive vehicles 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 Triumeq for adults and children is one tablet once daily.

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

Triumeq is a fixed-dose combination tablet not recommended for patients who require dose adjustments. If discontinuation or dose adjustment of any of the active substances in this medicinal product is necessary, the physician may consider using separate formulations of dolutegravir, abacavir, or lamivudine. In such cases, the physician should refer to the prescribing information for each of these medicinal products.

Missed doses.

A missed dose of Triumeq can be taken if there are 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; instead, continue with the 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 adults (see section "Pharmacological Properties"). This age group should be monitored closely due to age-related changes such as decreased renal function and alterations in hematological parameters.

Renal impairment.

Triumeq is not recommended for 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 the use of Triumeq in patients with moderate or severe hepatic impairment; therefore, its use is not recommended except in cases of particular necessity. Close monitoring is required for patients with mild hepatic impairment (Child–Pugh score 5–6), including monitoring of abacavir plasma levels if necessary (see sections "Special Warnings and Precautions for Use" and "Pharmacological Properties").

Method of Administration

Oral administration.

Triumeq can be taken with or without food (see section "Pharmacological Properties").

Children

The safety and efficacy of Triumeq 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.

Management should be based on clinical judgment or recommendations from a national poison control center, if available. There is no specific antidote for Triumeq overdose. In case of overdose, appropriate supportive treatment should be initiated as needed, with appropriate monitoring. Since lamivudine can be removed by dialysis, prolonged hemodialysis may be used for management of overdose, although this has not been specifically studied. It is unknown whether abacavir can be eliminated by peritoneal dialysis or hemodialysis. Due to the high plasma protein binding of dolutegravir, it is unlikely that significant amounts will be removed by dialysis.

Adverse reactions.

Short overview of safety profile.

Clinical data on the safety of Triumeq are currently limited. The most commonly reported adverse reactions considered possibly or probably related to dolutegravir and abacavir/lamivudine (data collected from Phase IIb–IIIb clinical trials involving 679 patients receiving the combination 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, lethargy, rash) occur frequently 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, the use of medicinal products containing abacavir must be permanently discontinued.

The most serious adverse reaction likely related to the use of dolutegravir and abacavir/lamivudine observed in individual patients was hypersensitivity reaction, including rash and severe liver 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 components of Triumeq, based on data from clinical studies and post-marketing experience, 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 in pooled analyses of data from Phase IIb–IIIb clinical trials are 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

Summary of adverse reactions associated with the combination of dolutegravir + abacavir/lamivudine from pooled analysis of data obtained during Phase IIb–IIIb clinical trials or post-marketing use, and adverse reactions reported for dolutegravir, abacavir, and lamivudine from clinical studies and post-marketing experience when used in combination with other antiretroviral agents.

Frequency	Adverse reaction
Blood and lymphatic system disorders
Uncommon	Neutropenia¹, anemia¹, thrombocytopenia¹
Very rare	True red cell aplasia¹
Immune system disorders
Common	Hypersensitivity (see section "Special warnings and precautions for use")
Uncommon	Immune reconstitution syndrome (see section "Special warnings and precautions for use")
Metabolism and nutrition disorders
Common	Anorexia¹
Uncommon	Hypertriglyceridemia, hyperglycemia
Very rare	Lactic acidosis¹
Psychiatric disorders
Very common	Insomnia
Common	Abnormal dreams, depression, anxiety¹, night terrors, sleep disorders
Uncommon	Suicidal thoughts or attempts (particularly in patients with a history of depression or psychiatric illness)
Nervous system disorders
Very common	Headache
Common	Dizziness, somnolence, lethargy¹
Very rare	Peripheral neuropathy¹, paraesthesia¹
Respiratory, thoracic and mediastinal disorders
Common	Cough¹, nasal symptoms¹
Gastrointestinal disorders
Very common	Nausea, diarrhea
Common	Vomiting, flatulence, abdominal pain, upper abdominal pain, bloating, abdominal discomfort, gastroesophageal reflux disease, dyspepsia
Uncommon	Pancreatitis¹
Hepatobiliary disorders
Uncommon	Hepatitis
Rare	Acute liver failure
Skin and subcutaneous tissue disorders
Common	Rash, pruritus, alopecia¹
Very rare	Multiform erythema¹, Stevens-Johnson syndrome¹, toxic epidermal necrolysis¹
Musculoskeletal and connective tissue disorders
Common	Arthralgia¹, muscle disorders¹ (including myalgia¹)
Rare	Rhabdomyolysis¹
General disorders
Very common	Generalized weakness
Common	Asthenia, chills¹, malaise¹
Investigations
Common	Increased CPK levels, increased ALT/AST levels
Rare	Increased amylase levels¹
¹This adverse reaction was not identified in Phase III clinical trials of Triumeq (dolutegravir + abacavir/lamivudine) or dolutegravir, but was observed in clinical trials or the post-marketing period for dolutegravir, abacavir or lamivudine when used with other antiretroviral agents, or in the post-marketing period following use of Triumeq.

Description of selected adverse reactions.

Hypersensitivity reactions.

Abacavir and dolutegravir are associated with the risk of developing hypersensitivity reactions, which have been most frequently observed with abacavir. Hypersensitivity reactions to 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 reactions due to abacavir may develop at any time during treatment. Treatment with Triumeq should be discontinued immediately if hypersensitivity cannot be excluded based on clinical findings. Reinitiating therapy with Triumeq or other medicinal products containing abacavir and dolutegravir is contraindicated. For detailed information on patient management in case of suspected hypersensitivity reaction to Triumeq, see section "Special warnings and precautions for use".

Hypersensitivity to dolutegravir

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

Hypersensitivity to abacavir

The signs and symptoms of this hypersensitivity reaction are listed below. They were identified in clinical trials or during post-marketing use. Manifestations reported 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 may occur without rash or fever. Other key signs include gastrointestinal, respiratory, or systemic symptoms such as lethargy and malaise (Table 3).

Table 3

Skin	Rash (usually maculopapular or urticarial)
Gastrointestinal tract	Nausea, vomiting, diarrhea, abdominal pain, oral mucosal ulceration
Respiratory system	Dyspnea, cough, sore throat, adult respiratory distress syndrome, respiratory failure
Other	Chills, lethargy, malaise, edema, lymphadenopathy, hypotension, conjunctivitis, anaphylactic reaction
Psychiatric/Nervous system	Headache, paresthesia
Blood and lymphatic system	Lymphopenia
Hepatobiliary system	Elevated liver function tests, 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.

Reinitiating 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 onset and may include life-threatening hypotensive episodes and fatal outcomes. 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 restarting therapy without prior symptoms of hypersensitivity (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 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 generally recognized risk factors, advanced HIV disease, or long-term use of combined 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 (CART), 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 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 has been observed during the first week of dolutegravir use, and this parameter remained stable over 96 weeks. In the SINGLE trial, 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 co-infection

Phase III studies included patients with hepatitis B and/or C receiving dolutegravir, provided baseline liver function tests did not exceed five times the upper limit of normal. Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that 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.

Paediatric population

Clinical trial data on the use of Triumeq in children are lacking. The individual components of this 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 paediatric patients aged 12 to 17 years, no additional types of adverse reactions have been identified beyond those observed in adult patients.

The individual agents abacavir and lamivudine have been studied separately and in nucleoside combinations, in combination with antiretroviral therapy for the treatment of two groups of antiretroviral-naïve and antiretroviral-experienced HIV-infected children (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.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Store in the original packaging to protect from moisture. Keep the bottle tightly closed. Do not remove the desiccant from the bottle. Keep out of reach of children.

Packaging.

Prescription status. Prescription only.

Manufacturer. Delpharm Poznan S.A., Poland / Delpharm Poznan S.A., Poland.

Manufacturer's address. 189, Grunwaldzka str., 60-322 Poznan, Poland / 189 Grunwaldzka str., 60-322 Poznan, Poland.