Inbek

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT INBEC (INBEC)

Composition:

Active substances: abacavir, dolutegravir, and lamivudine;

One film-coated tablet contains: abacavir sulfate equivalent to abacavir 600 mg, dolutegravir sodium equivalent to dolutegravir 50 mg, lamivudine 300 mg;

Excipients: mannite (E 421), microcrystalline cellulose, sodium starch glycolate (type A), povidone, magnesium stearate, Opadry II Blue 85F505121 coating (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, indigo carmine lake (E 132)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, film-coated tablets ranging in color from light blue to blue, with "EM" debossed on one side and "35" on the other.

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

Pharmacological Properties

Pharmacodynamics

Mechanism of action

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

Abacavir and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are sequentially metabolized intracellularly by kinases into their respective 5’-triphosphates (TP), which are the active moieties with extended intracellular half-lives under once-daily dosing (see section "Pharmacokinetics"). Lamivudine-TP (a cytidine analogue) and carbovir-TP (the active triphosphate form of abacavir, a guanosine analogue) are substrates and competitive inhibitors of HIV reverse transcriptase (RT). However, their primary antiviral activity occurs through incorporation of the monophosphate form into the viral DNA chain, leading to chain termination. The triphosphates of abacavir and lamivudine demonstrate 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, lines derived from monocytes/macrophages, primary cultures of activated peripheral blood mononuclear cells, and monocytes/macrophages. The concentration of the drug required to inhibit viral replication by 50% (IC50 – half-maximal inhibitory concentration) varies depending on the virus type and host tissue type.

The IC50 for dolutegravir 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 without significant 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 three 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.

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, the 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.

Isolates of HIV-1 (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 antiretroviral-naïve patients were tested for lamivudine activity and showed high sensitivity.

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

Antiviral activity in combination with other antiviral agents

No antagonistic effect in vitro was observed when dolutegravir was used 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 the protease inhibitor (PI) amprenavir.

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

Effect of human serum

In 100% human serum, the mean shift in dolutegravir activity fold 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-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 noted. These mutations were observed in patients with pre-existing resistance to raltegravir who received dolutegravir (listed as secondary mutations for dolutegravir).

In subsequent selection experiments using clinical isolates of subtype B, R263K mutations were observed in all five isolates (after 20 weeks and beyond). In subtype C (n = 2) and A/G (n = 2) isolates, integrase substitution R263K was detected in one isolate, and G118R in two isolates. R263K has been reported in two separate patients with subtype B and C who received antiretroviral therapy but not integrase inhibitors, without affecting dolutegravir sensitivity in vitro. G118R reduces sensitivity to dolutegravir to 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 these mutations, listed as secondary mutations associated with integrase inhibitors (for raltegravir/elvitegravir), are added to primary mutations (except Q148) in site-directed mutagenesis experiments, dolutegravir sensitivity remains at wild-type levels or approaches it. In viruses with Q148 mutations, increased fold change for dolutegravir correlates with the number of secondary mutations. The impact of Q148-based (H/R/K) mutations also aligns with in vitro passage experiments with site-directed mutants. In serial passage with site-directed 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 (fold change compared to wild-type virus) is not defined; genotypic resistance has been recognized as a 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 receiving dolutegravir + 2 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) receiving dolutegravir in combination with an investigator-selected background regimen (BR). Of these four, two patients showed the unique integrase substitution R263K with a maximum fold change of 1.93, one patient demonstrated the polymorphic integrase substitution V151V/I with a maximum fold change of 0.92, and one patient had pre-existing integrase mutations; the latter is believed to have experienced integrase inhibitor exposure or was infected with an integrase-resistant virus through transmission. The R263K mutation was also selected in vitro (see above).

In vitro and in vivo resistance (abacavir and lamivudine)

Abacavir-resistant HIV-1 isolates in vitro and in vivo are associated with specific genotypic changes in the RT codon region (codons M184V, K65R, L74V, and Y115F). During in vitro selection with abacavir, the M184V mutation occurred first and led to approximately a two-fold increase in IC50 below the clinical cutoff for abacavir at a 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; 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 two-fold increase in resistance to abacavir but does not confer clinical resistance to abacavir.

Isolates resistant to abacavir may also show 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 NNRTIs, is unlikely.

Effect on electrocardiogram

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

Pharmacokinetics

The tablet containing dolutegravir/abacavir/lamivudine demonstrated bioequivalence to the dolutegravir tablet 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 dolutegravir/abacavir/lamivudine (fasting) compared to a 50 mg dolutegravir tablet plus one 600 mg abacavir/300 mg lamivudine tablet (fasting) in healthy volunteers (n = 66). The effect of high-fat food on dolutegravir/abacavir/lamivudine film-coated tablets was studied in a subgroup of patients in this study (n = 12). Plasma maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) of dolutegravir following administration of dolutegravir/abacavir/lamivudine with high-fat food were 37% and 48% higher, respectively, than after administration of dolutegravir/abacavir/lamivudine in the fasting state. This is not considered clinically significant (see "Absorption"). The effect of food on plasma levels of abacavir and lamivudine following administration of dolutegravir/abacavir/lamivudine with high-fat food was very similar to previously obtained results with food effect using ABC/3TC FDC. These results indicate that dolutegravir/abacavir/lamivudine 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 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 50 mg dolutegravir 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, mean (CV) Cmax was 4.26 µg/mL (28%) and mean (CV) AUC∞ was 11.95 µg·h/mL (21%). After oral administration of 300 mg lamivudine once daily for 7 days, mean (CV) steady-state Cmax was 2.04 µg/mL (26%) and mean (CV) AUC24 was 8.87 µg·h/mL (21%).

Plasma Cmax and AUC values of dolutegravir following administration of Inbec with high-fat food were 37% and 48% higher, respectively, than after administration of Inbec in the fasting state. For abacavir, a 23% reduction 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 Inbec can be administered regardless of food intake.

Distribution

The apparent volume of distribution of dolutegravir (after oral administration as a suspension, Vd/F) was calculated as 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 binding to plasma proteins is independent of dolutegravir concentration. The overall blood-to-plasma concentration ratios of radioactivity associated with the drug range from 0.441 to 0.535, indicating minimal binding of radioactivity to blood cellular components. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels (<35 g/L), as observed in patients with moderate hepatic impairment. In vitro plasma protein binding studies indicate that abacavir binds only to a low-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 treatment-naïve patients on a stable regimen of dolutegravir in combination with abacavir/lamivudine, the mean CSF concentration of dolutegravir was 18 ng/mL (compared to unbound plasma concentration and above IC50). Studies with abacavir show that the AUC ratio in CSF to plasma is 30–44%. Peak concentrations observed were 9 times higher than the IC50 of abacavir of 0.08 µg/mL or 0.26 µM when abacavir was administered at 600 mg twice daily. The mean ratio of lamivudine concentrations in CSF to serum 2–4 hours after oral administration was approximately 12%. The extent of lamivudine penetration into the central nervous system and its correlation with clinical efficacy is unknown.

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

Biotransformation

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

Abacavir is primarily metabolized in the liver, with approximately 2% of the administered dose excreted in urine as unchanged component. The primary metabolic pathways in humans are mediated by alcohol dehydrogenase and glucuronidation, resulting in 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 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 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 300 mg lamivudine once daily, the terminal half-life of lamivudine-TP is 16–19 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 in patients with renal impairment demonstrate reduced lamivudine excretion. Dose reduction is required for patients with creatinine clearance (CLcr) < 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 once-daily dosing for abacavir and lamivudine.

Special patient groups

Hepatic impairment

Pharmacokinetic data were obtained for dolutegravir, abacavir, and lamivudine separately. Dolutegravir is primarily metabolized and eliminated via the liver. A single 50 mg dose of dolutegravir was administered to 8 patients with moderate hepatic impairment (Child-Pugh class B) and 8 matched healthy control volunteers. While total plasma concentration was similar, a 1.5–2-fold increase in dolutegravir exposure was observed in patients with moderate hepatic impairment compared to healthy volunteers. No dose adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on dolutegravir pharmacokinetics has not been studied. Abacavir is primarily metabolized in the liver. The pharmacokinetics of abacavir were studied in patients with mild hepatic impairment (5–6 points on the Child-Pugh scale) receiving a single 600 mg dose. The results showed a mean increase in abacavir AUC by 1.89-fold [1.32; 2.70] and abacavir elimination 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 abacavir exposure effects.

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

Based on data from abacavir, the medicinal product Inbec 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 (CLcr < 30 mL/min). No clinically significant difference in pharmacokinetics was observed between patients with severe renal impairment (CLcr < 30 mL/min) and matched healthy volunteers. Dolutegravir has not been studied in patients on dialysis, as no difference in effect was expected.

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

Lamivudine studies demonstrate that plasma concentration (AUC) increases in patients with impaired renal function due to reduced clearance.

Based on lamivudine data, the medicinal product Inbec is not recommended for patients with CLcr < 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

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

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

Polymorphism of drug-metabolizing enzymes

There is no evidence of clinically significant impact of polymorphism of enzymes metabolizing the drug on dolutegravir pharmacokinetics. In a meta-analysis using pharmacogenomic models selected from clinical studies in 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 studies in adult patients did not reveal any clinically significant effect of sex on dolutegravir exposure. There is no evidence to support dose adjustment of dolutegravir, abacavir, or lamivudine based on sex effects on pharmacokinetic parameters.

Race

Population pharmacokinetic analysis using pooled pharmacokinetic data from phase IIb and phase III studies in adult patients did not reveal any 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 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 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 "Pharmacological properties" and "Special instructions").

Prior to 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 instructions"). 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 types of interactions").

Interaction with other medicinal products and other types of interactions

The medicinal product Inbec contains dolutegravir, abacavir, and lamivudine; therefore, any individual interactions associated with these components also apply to Inbec. 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 Inbec with other medicinal products 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 diminish its therapeutic effect (see Table 1).

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

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

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

Abacavir and lamivudine are not significantly metabolized by CYP enzymes.

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

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 coadministered with lopinavir/ritonavir (inhibitors of BCRP and P-gp), and it is unlikely that inhibitors of these transporters significantly alter lamivudine pharmacokinetics given its high bioavailability. In vitro, lamivudine is a substrate of MATE1, MATE2-K, and OCT2. Increased lamivudine plasma concentrations have been observed with trimethoprim (an inhibitor of these 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 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 section "Pharmacokinetics").

In vitro, dolutegravir inhibits the renal transporters OCT2 and MATE1. In vivo, a 10–14% reduction in creatinine clearance (secretory component dependent on OCT2 and MATE1 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 renal uptake of organic anion transporters OAT1 and OAT3. However, due to the lack of effect on the in vivo pharmacokinetics of tenofovir (a substrate of organic anion transporters), in vivo inhibition of OAT1 is unlikely. 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; abacavir shows minimal inhibition of OCT1 and OCT2. Thus, 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 in vitro inhibitor of MATE1, and lamivudine is an in vitro inhibitor of OCT1 and OCT2, their potential to affect plasma concentrations of substrates of these transporters at therapeutic exposure levels (abacavir up to 600 mg, lamivudine 300 mg) is low.

Established and expected interactions with selected antiretroviral and non-antiretroviral medicinal products are 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", and trough concentration as "Cτ"). The table is not exhaustive but is representative of the classes studied.

Table 1

Interaction with other medicinal products

Children

Interaction studies 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 viruses, residual risks cannot be excluded. Preventive measures to avoid virus transmission should be taken in accordance with national regulatory legislation.

Hypersensitivity reactions (see section "Adverse reactions")

Abacavir and dolutegravir are associated with a risk of developing hypersensitivity reactions (see section "Adverse reactions"), characterized by systemic symptoms such as fever and/or rash, along with other symptoms indicating multi-organ involvement. It is not clinically possible to determine whether abacavir and dolutegravir in the drug formulation cause hypersensitivity reactions. Hypersensitivity reactions have been more frequently observed with abacavir use, some of which were life-threatening and occasionally fatal if appropriate medical intervention was not provided promptly. 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, albeit infrequently, in patients who are not carriers of this allele.

Therefore, the following rules must be observed:

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

Clinical presentation of hypersensitivity reactions

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

Hypersensitivity reactions associated with abacavir have been well characterized in clinical trials and post-marketing surveillance. Symptoms typically appear within the first 6 weeks (median time to onset is 11 days) after starting abacavir therapy, but may also occur at any time during treatment.

Almost all abacavir-associated hypersensitivity reactions include fever and/or rash. Other signs and symptoms observed as part of abacavir hypersensitivity reactions are described in detail in the "Adverse reactions" section, including respiratory and gastrointestinal symptoms. It is important to 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 can be life-threatening. These symptoms usually resolve after discontinuation of abacavir.

In rare cases, patients who discontinued abacavir for reasons other than hypersensitivity symptoms have experienced life-threatening reactions within hours of 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 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 accompanied by pancreatitis, hepatic failure, or renal failure.

Lactic acidosis typically occurs after several months of treatment.

Treatment with nucleoside analogues must 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 also be at 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. There is evidence supporting a treatment effect on lipid increases in some cases, whereas evidence for body weight increase is lacking. 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 the medicine have not been evaluated in patients with severe liver disease. The medicine Inbec is not recommended for 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-related disorders during combined antiretroviral therapy and should be monitored according to standard practice. If liver disease progresses, consideration should be given to partial or complete discontinuation of therapy.

Patients with chronic hepatitis B or C

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

The medicine contains lamivudine, which is a component of hepatitis B treatment. Abacavir and dolutegravir do not have such activity. Monotherapy with lamivudine is generally not considered sufficient for hepatitis B treatment due to the high risk of developing resistance to hepatitis B. When prescribing the medicine to patients co-infected with hepatitis B, additional antiviral therapy should be administered. Appropriate product information should be consulted.

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

Immune Reconstitution Inflammatory Syndrome (IRIS)

In HIV-infected patients with advanced immunodeficiency at the initiation of combined antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, potentially causing serious clinical manifestations or worsening symptoms. Such reactions are typically observed within the first few weeks or months after initiating CART. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii-induced 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, although the time to onset is highly variable, and these conditions may manifest many months after starting treatment.

Elevated liver enzymes consistent with immune reconstitution syndrome have been observed in some patients co-infected with hepatitis B and/or C prior to dolutegravir treatment initiation. Monitoring of liver enzyme levels is recommended in patients co-infected with hepatitis B and/or C (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 in utero and/or postnatally, primarily in treatment regimens containing zidovudine. The main reported adverse reactions were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events were often transient. Rare reports of late-onset neurological disorders (hypertension, seizures, behavioral disturbances) have been documented. Whether these neurological disorders are transient or permanent is currently 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 HIV transmission.

Cardiovascular disorders

Observational epidemiological studies have indicated an association between myocardial infarction in patients and abacavir treatment, primarily in those with prior antiretroviral therapy. Clinical trial data identified a limited number of myocardial infarctions, and a small increase in risk cannot be excluded. Overall, data from observational cohorts and randomized trials are somewhat conflicting and cannot confirm or refute a causal relationship between abacavir use and the risk of cardiovascular disorders (particularly myocardial infarction). Currently, there is no established biological mechanism to explain a potential increased risk. Precautions should be taken when prescribing the medicine to minimize all risk factors (such as smoking, arterial hypertension, and hyperlipidemia). Additionally, when treating patients at high risk of cardiovascular disorders, alternative treatment regimens to those 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 progressive HIV infection and/or long-term combined antiretroviral therapy. Patients should be advised to seek medical consultation if they experience joint pain, joint stiffness, or difficulty moving.

Opportunistic infections

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

Use in patients with moderate renal impairment

In patients with CLcr of 30–49 mL/min receiving Inbec, lamivudine AUC may be 1.6–3.3 times higher than in patients with CLcr ≥ 50 mL/min. There are no safety data from randomized controlled trials comparing Inbec (abacavir/dolutegravir/lamivudine) with individual components in patients with CLcr of 30–49 mL/min receiving lamivudine at adjusted doses. In original registration trials of lamivudine in combination with zidovudine, higher lamivudine exposure was associated with a higher incidence of hematological toxicity (neutropenia and anemia), although treatment discontinuation due to neutropenia or anemia occurred in < 1% of patients. Other lamivudine-related adverse reactions (such as gastrointestinal and hepatic disorders) may also occur.

Patients with stable CLcr of 30–49 mL/min receiving Inbec should be monitored for lamivudine-related adverse reactions, particularly hematological toxicity. Dose adjustment of lamivudine according to lamivudine prescribing information is indicated in case of new-onset or worsening neutropenia or anemia, which cannot be achieved with Inbec. In such cases, Inbec should be discontinued and individual components used to construct a treatment regimen.

Drug resistance

Since the recommended dose of dolutegravir for patients with integrase inhibitor resistance is 50 mg twice daily, the use of Inbec 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 the medicine 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").

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

Inbec 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"). 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, CLcr 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").

Inbec should not be used with any medicinal products containing dolutegravir, abacavir, lamivudine, or emtricitabine, except in cases where dose adjustment of dolutegravir is indicated due to drug interaction (see section "Special precautions for use").

Use during pregnancy or breastfeeding

The medicine Inbec may be used during pregnancy only if clinically necessary. Extensive data from pregnant women (over 1000 exposures) indicate no association between dolutegravir use and congenital malformations or fetal/neonatal toxicity. In pregnant women receiving abacavir, a substantial body of data (over 1000 exposures) also shows no evidence of teratogenicity or fetotoxicity/neonatal toxicity. Similar data (over 1000 exposures) are available for lamivudine.

Regarding the use of the triple combination during pregnancy, available data are absent or limited (less than 300 pregnancies).

Two large pregnancy outcome surveillance studies in Botswana (Tsepamo) and Eswatini, along with other sources, do not indicate an increased risk of neural tube defects following dolutegravir exposure. 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%).

The Tsepamo study showed no significant difference in the prevalence of neural tube defects (0.11%) among infants whose mothers received dolutegravir at conception (over 9400 cases) compared to those who received other antiretroviral regimens without dolutegravir (0.11%) or HIV-negative women (0.07%).

The Eswatini study also showed a similar prevalence of neural tube defects (0.08%) among infants born to mothers who received dolutegravir at conception (over 4800 cases) and HIV-negative women (0.08%).

According to the Antiretroviral Pregnancy Registry (APR), analysis of over 1000 first-trimester exposures to dolutegravir, over 1000 first-trimester exposures to abacavir, and over 1000 first-trimester exposures to lamivudine did not show an increased risk of major congenital malformations compared to background rates or HIV-infected women. Regarding the triple combination of dolutegravir + lamivudine + abacavir in pregnancy, APR data are absent or limited (less than 300 first-trimester exposures).

Reproductive toxicity studies in animals with dolutegravir showed no adverse effects on development, including neural tube defects.

Dolutegravir crosses the human placenta. In pregnant women living with HIV, the median concentration of dolutegravir in fetal cord blood was approximately 1.3 times higher than the concentration in maternal plasma.

Currently, there are insufficient data on the impact of dolutegravir on newborns.

Animal studies with abacavir showed embryotoxic and fetotoxic effects in rats but not in rabbits. Animal studies with lamivudine showed increased early embryonic loss in rabbits but not in rats.

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

Mitochondrial dysfunction

Nucleoside and nucleotide analogues have demonstrated various levels of mitochondrial toxicity in vitro and in vivo. 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 small amounts in human breast milk (the average ratio of dolutegravir concentration in breast milk to maternal plasma is 0.033). Data on the effects of dolutegravir on newborns/infants are insufficient.

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

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

HIV-infected pregnant women are not recommended to breastfeed infants under any circumstances to avoid HIV transmission.

Fertility

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

Ability to influence reaction speed when driving vehicles or operating machinery

The medicine Inbec has no effect or a negligible effect on the ability to drive vehicles or operate machinery. Patients should be informed about possible dizziness during dolutegravir treatment. The patient's clinical status and the adverse reaction profile of Inbec should be considered when assessing the patient's ability to drive vehicles or operate machinery.

Method of Administration and Dosage

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

Dosing

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

The recommended dose of the medicinal product for adults and children is 1 tablet once daily.

The medicinal product 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.

The medicinal product is a fixed-dose combination tablet that is not recommended for patients who require dose adjustment. If discontinuation or dose adjustment of any of the active substances is necessary, the specialist may use separate preparations of dolutegravir, abacavir, or lamivudine. In such cases, the physician should follow the instructions for medical use of each of these medicinal products.

Missed doses

A missed dose of the medicinal product can be taken if there is 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 different dosing compared to younger adults (see section "Pharmacological properties"). This age group should be monitored closely due to age-related changes such as reduced renal function and alterations in hematological parameters.

Renal impairment

The medicinal product is not recommended for patients with CLcr < 50 mL/min (see section "Pharmacological properties").

Hepatic impairment

Abacavir is primarily metabolized in the liver. There are no clinical data available in patients with moderate or severe hepatic impairment; therefore, the use of the medicinal product Inbec 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 plasma abacavir levels if necessary (see sections "Pharmacological properties" and "Special precautions for use").

Method of administration

Oral administration.

The medicinal product can be taken with or without food (see section "Pharmacological properties").

Children

The safety and efficacy of the medicinal product 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 treatment should be clinically justified or guided by the national poison control center, where available. There is no specific antidote for the treatment of Inbec overdose. In case of overdose, patients should receive appropriate supportive treatment as necessary, with appropriate monitoring. Since lamivudine may be removed by dialysis, prolonged hemodialysis may be used for managing 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, significant removal by dialysis is unlikely.

Adverse reactions

Short overview of safety profile

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

Many of the adverse reactions listed in Table 2 (such as nausea, vomiting, diarrhoea, fever, fatigue, and rash) occur commonly 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 severe adverse reaction considered possibly related to the use of 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 the components of the medicinal product, based on data from clinical trials and post-marketing use, are listed in Table 2 and classified by system organ class and frequency. 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, based on pooled data from Phase IIb–IIIb clinical trials, are generally consistent with the known 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 data of Phase IIb–IIIb clinical trials and post-marketing use, as well as adverse reactions reported for dolutegravir, abacavir, and lamivudine from clinical studies and post-marketing use when used in combination with other antiretroviral agents

Description of individual adverse reactions

Hypersensitivity reactions

Abacavir and dolutegravir are associated with a risk of hypersensitivity reactions, which were most frequently observed with abacavir. Hypersensitivity reactions for each of these drugs (described below) share some common features such as fever and/or rash, along with other symptoms indicating involvement of multiple organs. Time to onset of reactions associated with abacavir and dolutegravir was usually within 10–14 days, although abacavir-related reactions may develop at any time during treatment. Treatment with Inbec should be discontinued immediately if hypersensitivity cannot be excluded based on clinical findings. Reinitiation of Inbec or other medicinal products containing abacavir and dolutegravir is contraindicated. For detailed information on patient management in case of suspected hypersensitivity to Inbec, 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

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 shown 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 occur without rash or fever. Other key symptoms include gastrointestinal, respiratory, or systemic symptoms such as lethargy and malaise (see Table 3).

Table 3

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

Reinitiating abacavir after hypersensitivity reactions may result in a rapid return of symptoms within several hours. Such recurrent hypersensitivity reactions are generally more severe than those observed at the initial treatment onset and may include episodes of life-threatening hypotension and fatal outcomes. Similar reactions have also occurred infrequently after 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 who restarted treatment without prior hypersensitivity symptoms (i.e., patients who previously demonstrated adequate tolerance to abacavir).

Lactic acidosis

Cases of lactic acidosis, sometimes fatal, generally 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 response to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been observed during immune reconstitution; however, the time to onset of these disorders has been variable, and these events may occur many months after initiation of treatment (see section "Special precautions").

Changes in laboratory parameters

An increase in serum creatinine levels was observed during the first week of dolutegravir 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 week 96 of treatment. These changes are not considered clinically significant, as they do not reflect changes in glomerular filtration rate.

Asymptomatic elevations 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 who were receiving dolutegravir, provided that 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 observed 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 the medicinal product in children are lacking. Individual components of the 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.

The single agents abacavir and lamivudine have been studied separately and in nucleoside combinations, in conjunction 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, except those observed in adult patients.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging

30 or 90 tablets in a plastic bottle containing a silica gel container.

30 or 90 tablets in a plastic bottle containing a silica gel container; 1 plastic bottle in a cardboard package.

Prescription category. Prescription only.

Manufacturer. Emcure Pharmaceuticals Ltd.

Manufacturer's address and location of its business activities

Plot No. P-1 and P-2, ITVT Park, Phase II, MIDC, Hinjewadi, Pune - 411 057, Maharashtra, India.