Dolutegravir

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

Composition:

Active substance: dolutegravir;

1 tablet contains 50 mg of dolutegravir in the form of dolutegravir sodium;

Excipients: mannitol (E 421), microcrystalline cellulose, povidone, sodium stearyl fumarate, sodium starch glycolate;

Coating of the tablet: Opadry II Brown 85F565096 (polyvinyl alcohol, titanium dioxide (E 171), PEG 3350, talc, iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: biconvex, round, film-coated tablets, reddish-brown in color, with an imprint «Т over 50» on one side and smooth on the other.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Other antiviral agents. Dolutegravir.

ATC code J05A X12.

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 deoxyribonucleic acid (DNA), which is essential for the replication cycle of human immunodeficiency virus (HIV).

Antiviral activity in cell culture.

The IC50 value of dolutegravir against various laboratory strains using PBMCs was 0.5 nM, and ranged from 0.7 to 2 nM when using MT-4 cells. Similar IC50 values were observed in cellular isolates without significant differences among subtypes; across a panel of 24 HIV-1 isolates from clades 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).

Antiviral activity in combination with other antiviral agents.

No antagonistic effects were observed in vitro when dolutegravir was used in combination with other studied antiretroviral agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc, and raltegravir. Additionally, no antagonistic effects were observed between dolutegravir and adefovir, and ribavirin had no apparent effect on dolutegravir activity.

Shift in inhibitory concentration in human serum.

In 100% human serum, a mean 75-fold shift in the inhibitory concentration (IC) of dolutegravir was observed, resulting in a protein binding-adjusted IC90 of 0.064 µg/mL.

Resistance.

In vitro resistance.

Serial passage experiments were used to study the development of in vitro resistance. When using the laboratory HIV strain III, mutations emerged slowly over 112 days of passage, with substitutions at positions S153Y and F, leading to a maximum fold change (FC) in sensitivity of 4 (range: 2–4). These mutations were not observed in patients receiving dolutegravir in clinical trials. In the NL432 strain, mutations E92Q (FC 3) and G193E (also FC 3) were observed. The E92Q mutation was found in patients with pre-existing resistance to raltegravir who subsequently received dolutegravir (classified as a secondary mutation for dolutegravir).

In further experiments involving subtype B cultures, the R263K integrase mutation was observed in all five cultures (after 20 weeks or later). In subtype C (n=2) and A/G (n=2) cultures, the R263K substitution was observed in one culture, and G118R in two cultures. The R263K mutation has been reported in two patients receiving antiretroviral therapy who had not received integrase inhibitors (INIs), infected with subtypes B and C, but without impact on in vitro sensitivity to dolutegravir. The G118R mutation reduced sensitivity to dolutegravir in site-directed mutants (FC 10), but was not detected in patients receiving dolutegravir in Phase III trials.

Primary mutations associated with raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, and T66I) did not affect in vitro sensitivity to dolutegravir as single mutations. When secondary mutations associated with integrase inhibitors (for raltegravir/elvitegravir) were added to these primary mutations in site-directed mutant experiments, sensitivity to dolutegravir remained unchanged (FC < 2 compared to wild-type virus), except in cases involving Q148 mutations, where combinations with known secondary mutations resulted in FC values of 5–10 or higher. The impact of Q148 mutations (H/R/K) was also confirmed in passage experiments with site-directed mutants. In serial passage experiments with the NL432 strain, starting with site-directed mutants harboring the N155H or E92Q mutations, no resistance was observed (FC values remained close to 1). In contrast, starting with site-directed mutants harboring Q148H (FC 1), various secondary mutations emerged, leading to an increase in FC values to >10.

A clinically significant phenotypic threshold (FC compared to wild-type virus) has not been established; genotypic resistance was a better predictor of treatment outcome.

705 raltegravir-resistant isolates were analyzed for sensitivity to dolutegravir. Dolutegravir had an FC ≤ 10 in 94% of the 705 clinical isolates.

In vivo resistance.

In treatment-naïve patients receiving dolutegravir in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in Phase IIb and Phase III trials, no development of resistance to integrase inhibitors or NRTIs was observed (n = 1118, follow-up 48–96 weeks). In treatment-naïve patients receiving the combination of dolutegravir + lamivudine in the GEMINI studies over 96 weeks (n = 716), no resistance development to integrase inhibitors or NRTIs was observed.

In treatment-experienced patients without prior use of integrase inhibitors (SAILING study), integrase substitutions were observed in 4 of 354 patients (follow-up 48 weeks) receiving dolutegravir in combination with an investigator-selected background regimen (BR). Of these four patients, two had the unique integrase substitution R263K (maximum FC 1.93), one had the polymorphic integrase substitution V151V/I (maximum FC 0.92), and one had pre-existing integrase mutations, suggesting prior exposure to integrase inhibitors or infection with an integrase inhibitor-resistant virus. The R263K mutation was also identified in vitro (see above).

In patients with pre-existing resistance to integrase inhibitors (VIKING-3 study), at Week 24, 32 patients (all receiving dolutegravir 50 mg twice daily + optimized background therapy) with protocol-defined virological failure (PDVF) had the following mutations identified with paired genotypes: L74L/M (n=1), E92Q (n=2), T97A (n=9), E138K/A/T (n=8), G140S (n=2), Y143H (n=1), S147G (n=1), Q148H/K/R (n=4), N155H (n=1), and E157E/Q (n=1). Resistance to integrase inhibitors emerging during treatment typically occurred in patients with a history of Q148 mutations (baseline or historical). Among five other patients with PDVF between Weeks 24 and 28, two developed on-treatment mutations. The on-treatment mutations, or combinations thereof, were: L74I (n=1), N155H (n=2).

In the VIKING-4 study, dolutegravir (in combination with optimized background therapy) was administered to subjects with primary genotypic resistance to integrase inhibitors identified at screening (n = 30). The same mutations emerged during treatment as in the VIKING-3 study.

Effect on electrocardiogram.

No effect on the QT interval was observed when doses approximately three times higher than the recommended dose of dolutegravir were administered.

Clinical efficacy and safety.

Treatment-naïve patients

The efficacy of dolutegravir in treatment-naïve HIV-infected patients is supported by 96-week data from two randomized, international, double-blind, active-controlled trials (SPRING-2 [ING113086] and SINGLE [ING114467]), data from the 96-week open-label, randomized, active-controlled FLAMINGO study (ING114915), additional data from the open-label phase of the SINGLE study up to 144 weeks, and efficacy of dolutegravir in combination with lamivudine in adults demonstrated in two 148-week, randomized, multicenter, double-blind, non-inferiority trials GEMINI-1 (204861) and GEMINI-2 (205543), with 96-week follow-up.

In the SPRING-2 study, 822 adult patients were randomized and received at least one dose of dolutegravir 50 mg once daily or raltegravir (RAL) 400 mg twice daily. Both drugs were administered with ABC/3TC (abacavir/lamivudine) or TDF/FTC. Baseline patient characteristics were: mean age 36 years, 14% female, 15% non-Caucasian, 11% co-infected with hepatitis B and/or C, and 2% classified as CDC Class C. These characteristics were similar across treatment groups.

In the SINGLE study, 833 patients were randomized to receive either dolutegravir 50 mg once daily with fixed-dose abacavir-lamivudine (DTG + ABC/3TC) or a fixed-dose combination of efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). Baseline patient characteristics were: mean age 35 years, 16% female, 32% non-Caucasian, 7% co-infected with hepatitis C, and 4% classified as CDC Class C. These characteristics were similar across treatment groups.

Primary endpoints and other outcomes from SPRING-2 and SINGLE at 48 weeks (including results based on the primary outcome independent review) are shown in Table 1.

Table 1

Patient response to treatment in the SPRING-2 and SINGLE studies at 48 weeks (Snapshot algorithm, < 50 copies/mL)

* Balanced for baseline stratification factors.

† Includes patients who switched ART to a new drug class or switched ART not permitted by protocol or due to lack of efficacy by Week 48 (for SPRING-2 study only), as well as patients who discontinued treatment before Week 48 due to lack or loss of efficacy, and patients who had ≥50 copies in the 48-week window.

‡ The adjusted mean difference between treatment groups was statistically significant (p < 0.001).

Dolutegravir was non-inferior to raltegravir at Week 48, and in the SINGLE study, dolutegravir + ABC/3TC was superior to efavirenz/TDF/FTC (p=0.003), see Table 1. In the SINGLE study, the median time to viral suppression was shorter with dolutegravir treatment (28 vs. 84 days, p < 0.0001; the analysis was pre-specified and adjusted for multiplicity).

At Week 96, results were consistent with those at Week 48. In the SPRING-2 study, dolutegravir was non-inferior to raltegravir (viral suppression in 81% vs. 76% of patients) with a mean change in CD4 cell count of 276 vs. 264 cells/mm³, respectively. In the SINGLE study, dolutegravir + ABC/3TC continued to show superiority over EFV/TDF/FTC (viral suppression in 80% vs. 72%, treatment difference 8.0% (2.3, 13.8), p=0.006), with an adjusted mean change in CD4 cell count of 325 vs. 281 cells/mm³, respectively.

At Week 144 in the open-label phase of the SINGLE study, virological suppression was maintained: in the dolutegravir + ABC/3TC group it was 71%, which was higher than in the EFV/TDF/FTC group (63%), with a between-group difference of 8.3 (2.0; 14.6).

In the open-label, randomized, active-controlled FLAMINGO study (ING114915), 484 antiretroviral-naïve HIV-1-infected adult patients were randomized to receive one of two treatment regimens: either dolutegravir 50 mg once daily (n = 242) or darunavir/ritonavir (DRV/r) 800 mg / 100 mg once daily (n = 242), both administered with either ABC/3TC or TDF/FTC. At baseline, the mean age of patients was 34 years, 15% were women, 28% were non-Caucasian, 10% had hepatitis B with or without hepatitis C co-infection, and 3% were CDC class C; these characteristics were similar across treatment groups. Virological suppression (HIV-1 RNA < 50 copies/mL) in the dolutegravir group (90%) was higher than in the DRV/r group (83%) at Week 48 of the study. The adjusted difference in proportions and 95% CI was 7.1% (0.9, 13.2), p=0.025. At Week 96, virological suppression in the dolutegravir group (80%) remained higher than in the DRV/r group (68%), with a between-group difference [DTG-(DRV+RTV)] of 12.4%; 95% CI: [4.7, 20.2].

In two identical 148-week, randomized, double-blind studies, GEMINI-1 (204861) and GEMINI-2 (205543), 1,433 antiretroviral-naïve HIV-1-infected adult subjects were randomized into two treatment groups: a two-drug regimen of dolutegravir 50 mg + lamivudine 300 mg once daily, or a three-drug regimen of dolutegravir 50 mg once daily plus fixed-dose tenofovir/emtricitabine (TDF/FTC). Subjects were enrolled with plasma HIV-1 RNA levels between 1,000 and ≤500,000 copies/mL at screening. At baseline, according to the pooled analysis, the mean age was 33 years, 15% were women, 31% were non-Caucasian, 6% had hepatitis C co-infection, and 9% were CDC stage 3. Approximately one-third of patients were infected with non-B subtypes of HIV; population characteristics were similar across treatment groups. At Week 48, virological suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir + lamivudine group was non-inferior to the dolutegravir + tenofovir/emtricitabine (TDF/FTC) group, as shown in Table 2. The results of the pooled analysis were consistent with those of the individual studies, meeting the primary endpoint (difference in proportion with plasma HIV-1 RNA <50 copies/mL at Week 48 based on snapshot algorithm). The adjusted difference was –2.6% (95% CI: –6.7; 1.5) in the GEMINI-1 study and –0.7% (95% CI: –4.3; 2.9) in the GEMINI-2 study, with a pre-specified non-inferiority margin of 10%.

Table 2

Response (<50 copies/mL, snapshot analysis) in GEMINI-1 and GEMINI-2 — pooled data.

a Adjusted for baseline stratification factors: HIV-1 RNA in plasma (≤ 100,000 copies/mL vs. >100,000 copies/mL) and CD4+ cell count (≤ 200 cells/mm³ vs. >200 cells/mm³).

b Confirmed HIV-1 RNA in plasma ≥ 200 copies/mL after previously confirmed suppression to <200 copies/mL.

At 96 weeks of the study, the values in the group receiving the combination of dolutegravir + lamivudine (86% < 50 copies/mL HIV-1 RNA in plasma [pooled analysis]) were not different from those in the group receiving the combination of dolutegravir + fixed-dose tenofovir/emtricitabine (90% < 50 copies/mL HIV-1 RNA in plasma [pooled analysis]). The adjusted difference was –3.4% (95% CI: –6.7, 0.0). The results of the pooled analysis were consistent with the results of individual studies in which the secondary endpoint was met (difference in the proportion with < 50 copies/mL HIV-1 RNA in plasma at week 96 based on snapshot algorithm). The adjusted difference was –4.9 (95% CI: –9.8; 0.0) in study GEMINI-1 and –1.8 (95% CI: –6.4; 2.7) in study GEMINI-2, with a pre-specified non-inferiority margin of –10%. The mean increase in CD4+ T-cell count at week 96 was 269 in the dolutegravir + lamivudine group and 259 in the dolutegravir + fixed-dose tenofovir/emtricitabine (FTC/TDF) group.

Resistance that emerged during treatment in previously untreated patients

At 96 weeks in studies SPRING-2 and FLAMINGO, and at 144 weeks of therapy in study SINGLE, no cases of primary resistance emerging during treatment to integrase or NRTI enzyme classes were observed with dolutegravir. A similar absence of resistance was observed in patients receiving darunavir/ritonavir within the FLAMINGO study. In the SPRING-2 study, among four patients receiving raltegravir, no major mutations associated with NRTI resistance were detected, and one mutation associated with raltegravir resistance was observed. In the SINGLE study, among six patients receiving EFV/TDF/FTC treatment, no mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) emerged, and one patient developed a major mutation associated with NRTI resistance. Over 96 weeks in studies GEMINI-1 and GEMINI-2, there were no cases of development of resistance to the integrase inhibitor class or to the NRTI class in either the group receiving dolutegravir + lamivudine (DTG + 3TC) or the group receiving dolutegravir + tenofovir/emtricitabine (DTG + TDF/FTC).

Patients with prior virological failure who had not received integrase inhibitor class drugs

In the international, multicenter, double-blind SAILING study (ING111762), 719 HIV-infected adult patients with prior antiretroviral therapy (ART) experience were randomized to receive either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each combined with an optimized background regimen selected by the investigator, which could include up to 2 drugs (including at least one fully active agent). Baseline patient characteristics were as follows: mean age 43 years, 32% female, 50% non-Caucasian race, 16% co-infected with hepatitis B and/or C virus, and 46% classified as CDC class C. All patients had resistance to at least two classes of ART drugs, and 49% had baseline resistance to three classes of ART drugs.

The results of the SAILING study at 48 weeks (including results based on primary baseline variables) are shown in Table 3.

Table 3

Patient response to treatment in the SAILING study at 48 weeks

(Snapshot algorithm, < 50 copies/mL)

‡ Balanced for baseline stratification factors.

§ 4 patients were excluded from the efficacy analysis due to missing data at a single investigative site.

* Genotypic susceptibility score (GSS) was defined as the total number of ARV drugs in the background regimen to which the patient's virus cultures showed susceptibility at baseline, based on genotypic resistance testing.

† Other subtypes included CRF (43), F1 (32), A1 (18), BF (14), all others < 10.

In the SAILING study at Week 48, virological suppression (HIV-1 RNA < 50 copies/mL) in the Dolutegravir group (71%) was statistically greater (p=0.03) compared to the raltegravir group (64%).

A statistically significantly smaller number of patients experienced treatment failure due to the emergence of resistance to Dolutegravir during treatment (4/354, 1%) compared to raltegravir (17/361, 5%) (p=0.003) (for detailed information, see section "In vivo Resistance").

Patients with prior treatment failure including use of an integrase inhibitor (and presence of resistance to integrase inhibitor class drugs)

In the multicenter, open-label, single-arm study VIKING-3 (ING112574), adult patients infected with HIV-1 who had previously received antiretroviral therapy (ART), had experienced virological failure, and had resistance to raltegravir and/or elvitegravir either currently or in their history, received Dolutegravir 50 mg twice daily with an optimized background regimen for 7 days, followed by optimization of the background ART starting on Day 8. The study included 183 patients, of whom 133 had INI resistance at screening and 50 had evidence of prior resistance (but not at screening). Raltegravir/elvitegravir was part of the current failing regimen in 98 out of 183 patients (others had prior exposure to raltegravir/elvitegravir). Baseline patient characteristics were as follows: mean age was 48 years, 23% were female, 29% were non-Caucasian, and 20% were co-infected with hepatitis B and/or C virus. The mean baseline CD4+ T-cell count was 140 cells/mm³, the mean duration of prior ART was 14 years, and 56% of patients were CDC class C. At baseline, patients exhibited multidrug resistance to ARV drug classes: 79% had resistance to ≥2 NRTIs, 75% to ≥1 NNRTI, and 71% had ≥2 major PI resistance-associated mutations; 62% had non-R5 virus.

The mean change in HIV-1 RNA from baseline at Day 8 (primary endpoint) was -1.4 log10 copies/mL (95% CI: -1.3 to -1.5 log10, p<0.001). Response was associated with the baseline INI mutation pathway, as shown in Table 4.

Table 4

Virological response (Day 8) after 7 days of functional monotherapy in patients in whom RAL/EVG was part of the current failing regimen, VIKING-3 study

* Of the 98 patients receiving RAL/EVG as part of a failing regimen, 88 had detectable primary INI resistance mutations at baseline and on Day 8 when plasma HIV RNA was assessed.

a Including primary integrase resistance mutations N155H, Y143C/H/R, T66A, E92Q.

b Secondary mutations G140A/C/S, E138A/K/T, L74I.

In patients without baseline detectable primary mutations (N=60) (i.e., RAL/EVG not part of the current failing regimen), a reduction in viral load was observed (1.63 log10 copies/mL by Day 8).

After the functional monotherapy phase, patients had the opportunity to re-optimize their background regimen if possible. The overall response rate at 24 weeks of treatment was 69% (126/183), which was generally maintained at 48 weeks—116/183 (63%) patients had HIV-1 RNA <50 copies/mL (ITT-E, Snapshot algorithm). When patients who discontinued treatment due to lack of efficacy and those with major protocol violations (incorrect dosing of dolutegravir, use of prohibited medications) were excluded, the so-called virological response (VO) population showed a response rate of 75% (120/161) at Week 24 and 69% (111/160) at Week 48.

Response was reduced when the Q148 mutation was present at baseline, particularly in the presence of ≥2 secondary mutations (Table 5). The overall phenotypic susceptibility score (OSS) of the optimized background regimen (OBR) was not associated with response at either Week 24 or Week 48.

Table 5

Treatment response by baseline resistance, VIKING-3. VO population (HIV-1 RNA < 50 copies/mL, Snapshot algorithm)

1 Only evidence of resistance to integrase inhibitors in history or phenotypically.

2 N155H, Y143C/H/R, T66A, E92Q.

3 G140A/C/S, E138A/K/T, L74I.

OSS: combined genotypic and phenotypic resistance (overall assessment by Monogram Biosciences).

Based on data from the VIKING-3 study, the mean change in CD4+ T-lymphocyte count from baseline was 61 cells/mm³ at Week 24 and 110 cells/mm³ at Week 48.

In the double-blind, placebo-controlled VIKING-4 study (ING116529), 30 adult patients infected with HIV-1 and with primary genotypic resistance to INI at screening were randomized to receive dolutegravir 50 mg twice daily or placebo plus an optimized background regimen (OBR) for 7 days, followed by an open-label phase in which all patients received dolutegravir.

At study entry, the mean patient age was 49 years, 20% were women, 58% were non-Caucasian, and 23% had hepatitis B and/or C co-infection. The mean baseline CD4+ count was 160 cells/mm³, and the mean duration of prior ART was 13 years; 63% of participants were classified as CDC Class C. At baseline, subjects had multi-class resistance to antiretroviral drugs: 80% had resistance to at least two NRTIs, 73% had resistance to one or more NNRTIs, 67% had at least two major protease inhibitor resistance-associated mutations; 83% had non-R5 virus. Sixteen out of 30 participants were carriers of Q148 virus at baseline. The primary efficacy endpoint on Day 8 showed that dolutegravir 50 mg twice daily was more effective than placebo: the adjusted mean difference between treatment groups in reduction of plasma HIV-1 RNA levels was –1.2 log₁₀ copies/mL (95% CI: –1.5; –0.8 log₁₀ copies/mL, p < 0.001). Responses on Day 8 in this placebo-controlled study were fully consistent with responses observed in the VIKING-3 study (without placebo control), including categories of baseline integrase inhibitor resistance. At Week 48, 12/30 (40%) subjects had HIV-1 RNA <50 copies/mL (ITT-E, Snapshot algorithm).

Based on pooled analysis of the VIKING-3 and VIKING-4 studies (n = 186, VO population), the proportion of participants with HIV RNA <50 copies/mL at Week 48 was 123/186 (66%). The proportion of participants with HIV RNA <50 copies/mL was 96/126 (76%) among subjects without the Q148 mutation, 22/41 (54%) among those with the Q148 mutation combined with one secondary mutation, and 5/19 (26%) among participants with Q148 combined with two or more secondary mutations.

Children

A multicenter, open-label, 48-week Phase I/II study (P1093/ING112578) evaluated the pharmacokinetic, safety, tolerability, and efficacy parameters of dolutegravir in combination regimens in children infected with HIV-1.

Subjects were stratified by age and received dolutegravir (70 mg: 35 mg twice daily, n = 1; 50 mg once daily, n = 5; 35 mg once daily, n = 6; 25 mg once daily, n = 8; 20 mg once daily, n = 3) in combination with an optimized background regimen (OBR).

There are no data on the use of the dolutegravir + lamivudine combination as a two-drug regimen in children.

Pharmacokinetics.

The pharmacokinetics (PK) of dolutegravir are similar in healthy and HIV-infected individuals. The PK variability of dolutegravir is low to moderate. In Phase I studies among healthy volunteers, the CVb% for AUC and Cmax ranged from ~20 to 40%, and Cτ ranged from 30 to 65% across all studies. PK variability of dolutegravir was higher in HIV-infected patients compared to healthy volunteers. The within-patient variability (CVw%) is lower than inter-patient variability.

Bioequivalence data for 50 mg tablets compared to five 10 mg tablets are not equivalent. Therefore, the 50 mg once-daily regimen cannot be substituted with five 10 mg tablets once daily.

Absorption

Dolutegravir is rapidly absorbed after oral administration, with a median Tmax of 2–3 hours after tablet intake.

Food intake increases the extent and slows the rate of absorption of dolutegravir. The bioavailability of dolutegravir depends on the composition of food: low-, medium-, and high-fat meals increased AUC(0–∞) of dolutegravir by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, and prolonged Tmax to 3, 4, and 5 hours, respectively, compared to 2 hours under fasting conditions. This increase in pharmacokinetic parameters may be clinically significant in patients with existing resistance to integrase inhibitor class drugs. Therefore, dolutegravir is recommended to be taken with food in HIV-infected patients with resistance to integrase inhibitor class drugs (see section "Method of administration and dosage").

Absolute bioavailability of dolutegravir has not been determined.

Distribution

Dolutegravir has high plasma protein binding (>99%), as determined from in vitro data. The apparent volume of distribution is 17–20 L in HIV-infected patients based on population pharmacokinetic analysis. The total blood-to-plasma ratio of radioactivity associated with the drug ranges from 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels (<35 g/L), which may be observed in patients with moderate hepatic impairment.

Dolutegravir is detected in cerebrospinal fluid (CSF). In 13 treatment-naïve patients currently on a stable dolutegravir regimen in combination with abacavir/lamivudine, the concentration of dolutegravir in CSF averaged 18 ng/mL (at the level of unbound drug concentration in plasma or higher than IC50).

Dolutegravir is detected in the genital tract of men and women. AUC in cervical-vaginal secretions, cervical tissue, and vaginal tissue was 6–10% of the corresponding plasma value at steady state. AUC in semen and rectal tissue was 7% and 17% of the corresponding plasma value at steady state, respectively.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme, with minor contribution from CYP3A. Dolutegravir circulates predominantly unchanged in plasma; renal excretion of unchanged active substance is very low (<1% of dose). 53% of the total orally administered dose is excreted unchanged in feces. It is unknown whether this is fully or partially due to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently be hydrolyzed to form the parent compound in the intestinal lumen. 32% of the total orally administered dose is excreted in urine as dolutegravir glucuronide (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and metabolite formed by oxidation at the benzyl carbon (3% of total dose).

Drug interactions

In vitro, dolutegravir did not show direct or weak inhibition (IC50 > 50 µM) of cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate-glucuronosyltransferases (UGT)1A1 or UGT2B7, or transporters Pgp, 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 impact 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 ~14 hours. The apparent total plasma clearance (CL/F) is approximately 1 L/hour in HIV-infected patients, as determined from population pharmacokinetic analysis.

Linearity/non-linearity

The linearity of dolutegravir pharmacokinetics depends on dose and dosage form. Following oral administration of the tablet formulation, dolutegravir generally exhibits non-linear pharmacokinetics with less than dose-proportional increases in plasma concentrations at doses from 2 to 100 mg; however, dolutegravir concentration increases are dose-proportional when doses from 25 mg to 50 mg (for tablets) are administered. When administered at 50 mg twice daily, the 24-hour concentration was approximately doubled compared to 50 mg once daily.

Pharmacokinetic-pharmacodynamic relationship

In a randomized dose-finding study, HIV-1-infected patients received 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. This antiviral response was sustained for 3–4 days after the last dose in the 50 mg group.

Comparison of pharmacokinetic and pharmacodynamic data using pooled data from various clinical trials in patients with resistance to integrase inhibitor class drugs suggests that increasing the dose from 50 mg twice daily to 100 mg twice daily may increase the efficacy of dolutegravir. It is predicted that over 24 weeks, the proportion of patients with Q148 + ≥2 secondary mutations from G140A/C/S, E138A/K/T, L74I (HIV-1 RNA <50 copies/mL) will increase by approximately 4–18%. Although these theoretical results have not been confirmed in clinical trials, dose escalation may theoretically be considered for treating this patient group. However, clinical data on the safety and efficacy of 100 mg twice daily are not available. Concomitant use of atazanavir significantly increases dolutegravir exposure and should not be used with dose escalation of dolutegravir, as safety has not been established.

Special patient populations

Children

Pharmacokinetics of dolutegravir in 10 HIV-1-infected children aged 12 years and older receiving antiretroviral therapy indicate that an oral dose of dolutegravir 50 mg once daily results in dolutegravir concentrations comparable to those observed in adults receiving dolutegravir 50 mg once daily orally.

Geriatric patients

Population pharmacokinetic analysis of dolutegravir using data from HIV-1-infected adults showed no clinically significant effect of age on dolutegravir concentrations.

Pharmacokinetic data for dolutegravir in patients over 65 years of age are limited.

Renal impairment

Renal clearance of unchanged active substance is a minor elimination pathway for dolutegravir. A pharmacokinetic study of dolutegravir was conducted in patients with severe renal impairment (CLcr < 30 mL/min) and healthy control volunteers. Dolutegravir concentrations decreased by approximately 40% in patients with severe renal impairment. The mechanism of this phenomenon is unknown. Dose adjustment is not considered necessary for patients with renal impairment. Dolutegravir has not been studied in patients on dialysis.

Hepatic impairment

Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir was administered to 8 patients with moderate hepatic impairment (Child-Pugh Class B) and 8 healthy control volunteers. Although total plasma dolutegravir concentrations were similar, patients with moderate hepatic impairment showed a 1.5- to 2-fold increase in unbound dolutegravir concentration compared to healthy controls. Dose adjustment is not considered necessary for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on dolutegravir pharmacokinetics has not been studied.

Polymorphism of drug-metabolizing enzymes

There is no evidence that common polymorphisms in drug-metabolizing enzymes have a significant clinical impact on dolutegravir pharmacokinetics. In a meta-analysis using pharmacogenomic samples collected from clinical trials in healthy volunteers, individuals with UGT1A1 genotypes (n=7) associated with reduced dolutegravir metabolism had a 32% lower clearance and 46% higher AUC compared to individuals with genotypes associated with normal UGT1A1-mediated metabolism (n=41).

Sex

Population PK analysis using pooled pharmacokinetic data from Phase IIb and Phase III studies in adults did not reveal a clinically significant effect of sex on dolutegravir concentrations.

Race

Population PK analysis using pooled pharmacokinetic data from Phase IIb and Phase III studies in adults did not reveal a clinically significant effect of race on dolutegravir concentrations.

Concurrent infection with hepatitis B or C virus

Population pharmacokinetic analysis indicates that concurrent hepatitis C virus infection has no clinically significant effect on dolutegravir concentrations. Data in patients with concurrent hepatitis B virus infection are limited.

Preclinical safety data

Dolutegravir did not show mutagenic or clastogenic properties in in vitro tests in bacteria and mammalian cultured cells, or in the in vivo micronucleus test in rats. Dolutegravir did not show carcinogenic properties in long-term studies in mice and rats.

Dolutegravir did not affect reproductive function in male or female rats at doses up to 1000 mg/kg/day, the highest dose tested (24 times higher than the 50 mg twice daily dose used in humans clinically, based on AUC).

Oral administration of dolutegravir at doses up to 1000 mg/kg/day from Day 6 to Day 17 of gestation in pregnant female rats did not cause toxic effects on the mother or fetus and showed no teratogenic effects (dose 27 times higher than the 50 mg twice daily dose used in humans clinically, based on AUC).

Oral administration of dolutegravir at doses up to 1000 mg/kg/day from Day 8 to Day 18 of gestation in pregnant female rabbits did not cause toxic effects on the fetus or teratogenic effects (dose 0.40 times higher than the 50 mg twice daily dose used in humans clinically, based on AUC). In rabbits, toxic effects on the mother (reduced food intake, low/absent fecal output/urination, reduced body weight gain) were observed at 1000 mg/kg (0.40 times higher than the 50 mg twice daily dose used in humans clinically, based on AUC).

The impact of long-term daily treatment with high doses of dolutegravir was evaluated in repeat-dose oral toxicity studies in rats (up to 26 weeks) and monkeys (up to 38 weeks). In rats and monkeys, the main effect of dolutegravir at doses producing systemic exposure approximately 21 and 0.82 times higher, respectively, than the clinically used human dose of 50 mg twice daily (based on AUC), was associated with gastrointestinal (GI) intolerance or irritation. Since GI intolerance is related to local exposure of the active substance, mg/kg or mg/m² units are appropriate safety metrics for this toxicity. GI intolerance in monkeys occurred at a dose 15 times higher than the human equivalent dose expressed in mg/kg (based on a 50 kg human) and 5 times higher than the human equivalent dose expressed in mg/m², for the therapeutic dose of 50 mg twice daily.

Clinical characteristics.

Indications.

Dolutegravir is indicated in combination with other antiretroviral medicinal products for the treatment of adults and children aged 12 years and older infected with human immunodeficiency virus (HIV).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use is contraindicated with medicinal products that have a narrow therapeutic window and are substrates of the organic cation transporter 2 (OCT2), particularly 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.

Effect of other medicinal products on the pharmacokinetics of dolutegravir.

If resistance to integrase inhibitor class drugs exists, factors that reduce dolutegravir concentrations must be avoided.

Dolutegravir is primarily eliminated via metabolism mediated by the UGT1A1 enzyme. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-gp, and BCRP (breast cancer resistance protein); therefore, medicinal products that induce these enzymes may reduce dolutegravir plasma concentrations and diminish its therapeutic effect (see Table 6). Concomitant administration of dolutegravir with other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentrations (see Table 6).

The absorption of dolutegravir is reduced by certain antacid medicinal products (see Table 6).

Effect of dolutegravir on the pharmacokinetics of other medicinal products

In vivo, dolutegravir does not affect midazolam—a CYP3A4 probe. Based on in vivo and in vitro 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.

In vitro, dolutegravir inhibits the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE-1). In vivo, a 10–14% reduction in creatinine clearance (secretory fraction dependent on OCT2 and MATE-1 transporters) has been observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OCT2 or MATE-1, such as fampridine (also known as dalfampridine) and metformin (see Table 6 and section "Contraindications").

In vitro, dolutegravir inhibits renal uptake transporters, organic anion transporters (OAT1 and OAT3). Given the limited effect of tenofovir substrate on OAT pharmacokinetics in vivo, inhibition of OAT1 in vivo is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products whose elimination depends on OAT3.

Established and potential interactions with specific antiretroviral and other medicinal products are listed in Table 5, where increase is denoted by the symbol ↑, decrease by ↓, no change by ↔, area under the concentration-time curve by AUC, maximum observed concentration by Cmax, and concentration at the end of the dosing interval by Cτ.

Table 6

Drug interactions

Children.

Studies on interactions were conducted only in adult patients.

Special precautions for use.

Although effective viral suppression with antiretroviral agents has been shown to substantially reduce the risk of sexual transmission of HIV, residual risk cannot be excluded. Preventive measures to avoid transmission of the virus should be taken in accordance with national guidelines.

Resistance to integrase inhibitor class drugs, which is of particular concern.

When considering the use of Dolutegravir in the presence of resistance to integrase inhibitor class drugs, it should be noted that the antiviral activity of Dolutegravir is significantly reduced in patients infected with viral strains harboring secondary mutations Q148+≥2 from G140A/C/S, E138A/K/T, or L74I (see section "Pharmacodynamics"). It is unclear to what extent Dolutegravir provides additional efficacy in the presence of such resistance to integrase inhibitors.

Hypersensitivity reactions.

Hypersensitivity reactions, characterized by rash and organ dysfunction, sometimes including severe hepatic reactions, have been reported with Dolutegravir. Dolutegravir and other suspected causative agents should be discontinued immediately if signs or symptoms of hypersensitivity occur (including severe rash or rash accompanied by elevated liver enzymes, fever, malaise, fatigue, muscle or joint pain, blistering, oral lesions, conjunctivitis, facial edema, eosinophilia, or angioedema, but not limited to these). Clinical status should be closely monitored, including regular assessment of liver aminotransferases and bilirubin levels. Delay in discontinuing Dolutegravir or other suspected causative agents after onset of hypersensitivity reactions may lead to life-threatening allergic reactions.

Immune Reconstitution Inflammatory Syndrome (IRIS).

In HIV-infected patients with advanced immunodeficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, leading to severe clinical symptoms or worsening of existing conditions. Such reactions are typically observed within the first few weeks or months of initiating cART. Typical examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated, and treatment initiated if necessary. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported during immune recovery. However, the reported onset of these conditions is more variable, and they may manifest many months after starting treatment.

In some patients co-infected with hepatitis B and/or C virus, increases in liver biochemistry parameters have been observed at the beginning of Dolutegravir treatment. Monitoring of liver function tests is recommended in patients with hepatitis B and/or C co-infection. Particular caution is required at the initiation and during maintenance therapy for hepatitis B (according to current treatment guidelines) when Dolutegravir-based therapy is started in patients co-infected with hepatitis B virus (see section "Adverse reactions").

Opportunistic infections.

Patients should be informed that Dolutegravir or any other antiretroviral agent does not cure HIV infection and that they may still develop opportunistic infections and other HIV-related complications. Therefore, patients should remain under close clinical supervision by physicians experienced in managing HIV-associated diseases.

Drug interactions.

In patients with resistance to integrase inhibitor class drugs, factors that reduce the effect of Dolutegravir should be avoided. These include concomitant use of medicinal products that decrease Dolutegravir concentrations, such as magnesium/aluminum-containing antacids, iron and calcium supplements, multivitamins, stimulants, etravirine (without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, and certain antiepileptic drugs (see section "Interaction with other medicinal products and other forms of interaction").

Dolutegravir increases metformin concentrations. Dose adjustment of metformin may be required at the initiation and upon discontinuation of concomitant therapy with Dolutegravir and metformin to maintain glycemic control (see section "Interaction with other medicinal products and other forms of interaction"). Since metformin is excreted by the kidneys, renal function should be monitored when used concomitantly with Dolutegravir. The combination increases the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance [CrCl] 45–59 mL/min), and therefore special attention is recommended. The physician should consider reducing the metformin dose.

Osteonecrosis.

Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, bisphosphonates, alcohol consumption, severe immunosuppression, and high body mass index), cases have been reported in patients with advanced HIV disease and/or long-term exposure to cART. Patients should be advised to consult their physician if they experience joint pain, stiffness, or difficulty in movement.

Body weight and metabolic parameters.

Increases in body weight and elevations in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly attributable to improved control of the disease and lifestyle changes. Lipid elevations in some cases may reflect treatment effect, while a direct link between antiretroviral therapy and weight gain has not been established. Monitoring of lipid and glucose levels should be performed in accordance with current HIV treatment guidelines. Lipid abnormalities should be managed according to clinical standards.

Lamivudine and Dolutegravir.

Two large randomized, double-blind trials, GEMINI-1 and GEMINI-2 (see section "Pharmacological properties"), evaluated a two-drug regimen consisting of Dolutegravir 50 mg once daily and lamivudine 300 mg once daily. This regimen is indicated only for the treatment of HIV-1 infection in the absence of resistance to integrase inhibitors or lamivudine, or suspicion thereof.

Use during pregnancy or breastfeeding.

Women of childbearing potential.

Women of childbearing potential should be informed about the potential risk of neural tube defects in the fetus prior to initiating Dolutegravir (see below) and advised to use effective contraception.

If a woman plans to become pregnant, the benefits and risks of Dolutegravir therapy should be evaluated.

Pregnancy.

In an observational study conducted in Botswana, which assessed the impact of antiretroviral therapy during pregnancy, a slightly higher incidence of neural tube defects was observed: 7 cases out of 3,591 live births (0.19%; 95% CI 0.09%, 0.40%) among women who received Dolutegravir-containing regimens from conception, compared to 21 cases out of 19,361 live births (0.11%; 95% CI 0.07%, 0.17%) among women who received regimens without Dolutegravir from conception.

In the same study, two infants born to mothers who took Dolutegravir during pregnancy had neural tube defects out of 4,448 births (0.04%), compared to 5 cases out of 6,748 births (0.07%) among women receiving regimens without Dolutegravir.

The background rate of neural tube defects in the general population is 0.5–1 per 1,000 live births (0.05–0.1%). Most neural tube defects develop within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If pregnancy is confirmed during the first trimester while on Dolutegravir, the benefits and risks of continuing Dolutegravir should be evaluated, and switching to alternative antiretroviral regimens should be considered, taking into account gestational age and the critical period of neural tube development.

Data from the Antiretroviral Pregnancy Registry, covering over 600 women exposed to Dolutegravir during pregnancy, do not indicate an increased risk of congenital malformations. However, these data are insufficient to definitively assess the risk of neural tube defects.

In animal reproductive toxicity studies, no adverse effects on fetal development, including neural tube defects, were observed with Dolutegravir. Dolutegravir crosses the placenta in animals.

Data from over 1,000 cases of Dolutegravir use during the second and third trimesters of pregnancy do not suggest an increased risk of fetal/neonatal toxicity. Dolutegravir may be used during the second and third trimesters of pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding.

Dolutegravir is excreted in human breast milk in small amounts.

There is insufficient information regarding the effects of Dolutegravir on newborns/infants.

HIV-infected women should not breastfeed under any circumstances to prevent transmission of HIV to the infant.

Fertility.

There are no data on the effect of Dolutegravir on fertility in men and women. Animal studies have not shown any effect of Dolutegravir on fertility in males or females.

Effect on ability to drive or operate machinery.

No studies have been conducted to assess the effect of Dolutegravir on the ability to drive or operate machinery. However, patients should be informed about the possibility of dizziness during Dolutegravir treatment. The patient's clinical status and adverse reaction profile should be taken into account when determining their ability to drive or operate machinery.

Method of Administration and Dosage

Dolutegravir should be prescribed by a physician experienced in the management of HIV infection.

Adults

HIV-1 infected patients without documented or clinically suspected resistance to integrase inhibitor class drugs.

The recommended dose of dolutegravir is 50 mg (1 tablet) orally once daily.

Dolutegravir may be administered twice daily when co-administered with certain medicinal products (such as efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin) (see section "Interaction with other medicinal products and other forms of interaction").

HIV-1 infected patients with resistance to integrase inhibitor class drugs (documented or clinically suspected).

The recommended dose of dolutegravir is 50 mg (1 tablet) twice daily. In patients with documented resistance to Q148 + ≥2 secondary mutations G140A/C/S, E138A/K/T, and L74I, consideration should be given to using doses higher than recommended (provided that fewer than two antiretroviral medicinal products are used), due to resistance to multiple antiretroviral agents (see subsection "Pharmacokinetics"). When deciding to use dolutegravir in such patients, resistance to integrase inhibitors should be taken into account (see subsection "Pharmacodynamics").

Concomitant administration of dolutegravir with certain medicinal products (such as efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin) should be avoided (see sections "Special Warnings and Precautions for Use" and "Interaction with other medicinal products and other forms of interaction").

Missed Dose

If a patient misses a dose of dolutegravir, they should take it as soon as possible, provided that the next dose is not due within the following 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and should resume their normal dosing schedule.

Children aged 12 years and older

For children (aged 12 to 18 years, with body weight at least 40 kg) infected with HIV-1 without resistance to integrase inhibitor class drugs, the recommended dose of dolutegravir is 50 mg once daily.

Elderly Patients

There is limited data on the use of dolutegravir in patients aged 65 years and older. There is no evidence that elderly patients require a different dosage than younger adults (see subsection "Pharmacokinetics").

Renal Impairment

No dose adjustment is required for patients with mild, moderate, or severe renal impairment (creatinine clearance < 30 mL/min, not on dialysis). Data in patients on dialysis are lacking, although no differences in pharmacokinetics are expected in this population (see subsection "Pharmacokinetics").

Hepatic Impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh class A or B). Data in patients with severe hepatic impairment (Child-Pugh class C) are lacking; therefore, dolutegravir should be used with caution in such patients (see subsection "Pharmacokinetics").

Method of Administration

Oral administration.

Dolutegravir can be administered regardless of food intake (see subsection "Pharmacokinetics"). If resistance to integrase inhibitor class drugs is present, dolutegravir should be administered with food to increase its effect (particularly in patients with Q148 mutations) (see subsection "Pharmacokinetics").

Children

The medicinal product is indicated for use in children aged 12 years and older. Safety and efficacy of dolutegravir in children under 12 years of age or with body weight less than 40 kg have not been established. In cases of resistance to integrase inhibitors, there is insufficient data to recommend the use of dolutegravir in children.

Overdose

Experience with dolutegravir overdose is currently limited.

Based on limited experience with single high doses (up to 250 mg in healthy volunteers), no additional specific symptoms or signs were observed beyond those listed as adverse reactions. There is no specific antidote for dolutegravir overdose. In case of overdose, the patient should receive symptomatic treatment with appropriate monitoring, if necessary. Since dolutegravir is highly protein-bound in plasma, it is unlikely to be significantly removed by hemodialysis.

Adverse reactions.

Overview of safety profile.

The safety profile is based on pooled data from Phase IIb and Phase III clinical trials involving 1222 treatment-naïve patients, 357 treatment-experienced but integrase inhibitor-naïve patients, and 264 patients with prior treatment failure including use of an integrase inhibitor (including resistance to integrase inhibitor class drugs). The most severe adverse reaction observed in individual patients was hypersensitivity reaction, including rash and severe hepatic effects (see section "Special warnings and precautions for use"). The most commonly occurring adverse reactions during treatment were nausea (13%), diarrhea (18%), and headache (13%).

The safety profile was similar across the different treatment populations mentioned above.

List of adverse reactions.

Adverse reactions considered possibly related to the use of Dolutegravir are listed by system organ classes, organ class terms, and absolute frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Table 7

*See below in the section "Some adverse reactions".

Some adverse reactions

Changes in laboratory biochemical parameters

Increased serum creatinine levels occurred during the first week of treatment with dolutegravir and persisted for 48 weeks. After 48 weeks of treatment, the mean change from baseline was 9.96 µmol/L. The increase in creatinine levels was similar across different background regimens. These changes are not considered clinically significant, as they do not reflect changes in glomerular filtration rate.

Concomitant hepatitis B or C virus infection

In phase III studies, patients with concomitant hepatitis B and/or C virus infection were allowed to participate provided that baseline liver function biochemical parameters did not exceed five times the upper limit of normal. Overall, the safety profile in patients with concomitant hepatitis B and/or C virus infection was similar to that in patients without concomitant hepatitis B or C virus infection, although abnormal AST and ALT values were higher in the subgroup with concomitant hepatitis B and/or C virus infection across all treatment groups. Elevations in liver function biochemical parameters consistent with immune reconstitution syndrome were observed in some patients with concomitant hepatitis B and/or C virus infection at the initiation of dolutegravir treatment, particularly in those who had discontinued hepatitis B treatment (see section "Special warnings and precautions for use").

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the start 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 reported; however, the reported time to onset of these disorders is more variable, and such events may occur many months after initiation of treatment (see section "Special warnings and precautions for use").

Metabolic parameters

During antiretroviral therapy, increases in body weight and elevations in blood lipid and glucose levels may occur (see section "Special warnings and precautions for use").

Children

Based on limited data in children aged 12 years and older with body weight of at least 40 kg, no additional types of adverse reactions were observed beyond those identified in adults.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging, protected from light, at temperatures not exceeding 30°C. Keep out of the reach and sight of children.

Packaging. 30 film-coated tablets in an opaque white high-density polyethylene bottle with a polypropylene screw cap with child-resistant closure and a polyethylene protective seal. One bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer. Aurobindo Pharma Limited, Unit-VII/Aurobindo Pharma Limited – Unit VII.

Manufacturer's address and place of business.

Special Economic Zone, TSIIC, Plot No.S1, Sy. Nos. 411, 425, 434, 435 & 458, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahaboobnagar District, Telangana State, 509302, India.