Dolutegravir

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

Composition:

Active substance: dolutegravir;

One tablet contains dolutegravir (as dolutegravir sodium) equivalent to 50 mg of dolutegravir;

Excipients: mannitol, microcrystalline cellulose, povidone, sodium starch glycolate, sodium stearyl fumarate, talc, magnesium stearate;

Tablet coating: Oparay II 85F565260 brown (polyvinyl alcohol, titanium dioxide (E 171), macrogol, talc, yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, light brown to brown in color, capsule-shaped, with "RL75" imprinted on one side and a break line 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 combination with other antiviral agents.

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

Effect of human serum.

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

Resistance.

In vitro resistance.

Serial passage experiments were used to study the development of in vitro resistance. 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 sensitivity change of 4 (range 2–4). These mutations were not observed in patients receiving dolutegravir during 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 mutation was observed in all five cultures (after 20 weeks or later). In subtype C (n=2) and A/G (n=2) cultures, the integrase substitution R263K 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) and were 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 of 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 from site-directed mutants with pre-existing N155H or E92Q mutations, no resistance was observed (FC values remained unchanged, close to 1). In contrast, starting from site-directed mutants with pre-existing Q148H mutations (FC 1), a variety of secondary mutations emerged, leading to an increase in FC values to >10.

Clinically significant phenotypic values (FC compared to wild-type virus) were not defined; genotypic resistance was a better predictor of outcome.

705 raltegravir-resistant isolates were analyzed for sensitivity to dolutegravir. Dolutegravir showed 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 resistance to integrase inhibitor class drugs or NRTI class drugs was observed (n=1118, follow-up 48–96 weeks). In treatment-naïve patients receiving dolutegravir + lamivudine in the GEMINI studies over 96 weeks (n=716), development of resistance to the integrase or NRTI class was not observed.

In treatment-experienced patients who had not previously received integrase inhibitor class drugs (SAILING study), integrase inhibitor 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 with a maximum FC of 1.93, one patient had the polymorphic integrase substitution V151V/I with a maximum FC of 0.92, and one patient had pre-existing integrase mutations, suggesting prior exposure to integrase inhibitors or infection with integrase inhibitor-resistant virus. The R263K mutation was also identified in vitro (see above).

In the presence of resistance to integrase inhibitor class drugs (VIKING-3 study), at week 24, protocol-defined virologic failure (PDVF) was observed in 32 patients (all receiving dolutegravir 50 mg twice daily plus optimized background therapy), with 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 mutation (baseline or historical control). PDVF was observed in five additional patients between weeks 24 and 28, and treatment-emergent mutations were detected in two of these five. The treatment-emergent mutations or mutation combinations were: L74I (n=1), N155H (n=2).

In the VIKING-4 study, dolutegravir (plus optimized background therapy) was administered to subjects with primary genotypic resistance to integrase inhibitors identified during screening of 30 subjects. The same treatment-emergent mutations were observed as in the VIKING-3 study.

Effect on electrocardiogram.

When administered at a dose approximately three times higher than the recommended dose of dolutegravir, no effect on the QT interval was observed.

Clinical efficacy and safety.

Treatment-naïve patients

The efficacy of dolutegravir in HIV-infected patients who had not previously received treatment is based on 96-week data from two randomized, international, double-blind, active-controlled trials (SPRING-2 [ING113086] and SINGLE [ING114467]), further supported by data from the 96-week open-label, randomized, active-controlled FLAMINGO trial (ING114915) and additional data from the open-label phase of SINGLE up to 144 weeks. The efficacy of dolutegravir in combination with lamivudine in adults is supported by 96-week data from two 148-week, randomized, multicenter, double-blind, non-inferiority trials GEMINI-1 (204861) and GEMINI-2 (205543).

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 or TDF/FTC. Baseline patient characteristics were: mean age 36 years, 14% female, 15% non-Caucasian race, 11% co-infected with hepatitis B and/or C virus, and 2% classified as CDC class C. These characteristics were similar across treatment groups.

In the SINGLE study, 833 patients were randomized to receive at least one dose of dolutegravir 50 mg once daily with fixed-dose abacavir-lamivudine (DTG + ABC/3TC) or fixed-dose efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). Baseline patient characteristics were: mean age 35 years, 16% female, 32% non-Caucasian race, 7% co-infected with hepatitis C virus, 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 baseline independent variables) are shown in Table 1.

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

Table 1

* 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 by 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; analysis was pre-specified and adjusted for multiplicity).

At Week 96, results were consistent with those observed at Week 48. Dolutegravir was non-inferior to raltegravir in the SPRING-2 study (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 remained superior to 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 during the open-label phase of the SINGLE study, virological suppression was maintained: 71% in the dolutegravir + ABC/3TC group, which was higher than in the EFV/TDF/FTC group (63%), with a treatment difference of 8.3 (2.0; 14.6).

In the open-label, randomized, active-controlled FLAMINGO study (ING114915), 484 antiretroviral-naïve HIV-1-infected adults received either dolutegravir 50 mg once daily (n=242) or darunavir/ritonavir (DRV/r) 800 mg/100 mg once daily (n=242), both combined with either ABC/3TC or TDF/FTC. At baseline, the mean age was 34 years, 15% were women, 28% were non-Caucasian, 10% had hepatitis B with or without concomitant hepatitis C infection, and 3% were CDC Class C; these characteristics were similar across treatment groups. Virological suppression (HIV-1 RNA <50 copies/mL) was higher in the dolutegravir group (90%) compared to the DRV/r group (83%) at Week 48 of the study. Adjusted difference in proportion and 95% CI was 7.1% (0.9, 13.2), p=0.025. At Week 96, virological suppression in the dolutegravir group (80%) was higher than in the DRV/r group (68%), with a treatment 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), 1433 antiretroviral-naïve HIV-1-infected adults were randomized to either a two-drug regimen consisting of dolutegravir 50 mg plus lamivudine 300 mg once daily, or a three-drug regimen consisting of dolutegravir 50 mg once daily plus fixed-dose tenofovir/emtricitabine (TDF/FTC). Subjects with plasma HIV-1 RNA levels between 1000 copies/mL and ≤500,000 copies/mL at screening were included. At study entry, in the pooled analysis, the mean age was 33 years, 15% were women, 31% were non-Caucasian, 6% had hepatitis C co-infection, and 9% had CDC Stage 3 disease. Approximately one-third of patients were infected with non-B HIV subtypes; these characteristics were similar across treatment groups. At Week 48, virological suppression (HIV-1 RNA <50 copies/mL) in the group receiving dolutegravir plus lamivudine was non-inferior to the group receiving dolutegravir plus tenofovir/emtricitabine (TDF/FTC), as shown in Table 2. Results from the pooled analysis were consistent with individual study results, meeting the primary endpoint: (difference in proportion with <50 copies/mL HIV-1 RNA in plasma at Week 48 based on snapshot algorithm). Adjusted differences were -2.6% (95% CI -6.7; 1.5) for GEMINI-1 and -0.7% (95% CI: -4.3; 2.9) for GEMINI-2, with a pre-specified non-inferiority margin of 10%.

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

Table 2

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 prior confirmed suppression to <200 copies/mL.

At week 96 of the study, the response rates in the group receiving the combination of dolutegravir + lamivudine (86% < 50 copies/mL HIV-1 RNA in plasma [combined analysis]) were non-inferior to those in the group receiving the combination of dolutegravir + fixed-dose tenofovir/emtricitabine (90% < 50 copies/mL HIV-1 RNA in plasma [combined analysis]). The adjusted difference was -3.4% (95% CI: -6.7, 0.0). Results of the combined analysis were consistent with those of individual studies, meeting the secondary endpoint (difference in 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) for study GEMINI-1 and -1.8 (95% CI: -6.4; 2.7) for GEMINI-2, with a pre-specified non-inferiority margin of -10%. 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 week 96 in studies SPRING-2 and FLAMINGO, and at week 144 of therapy in study SINGLE, no cases of primary resistance emerging during treatment to integrase or NRTI enzyme classes were observed with dolutegravir. For comparison, the same absence of resistance was observed in patients treated with darunavir/ritonavir in the FLAMINGO study. In the SPRING-2 study, among four patients receiving raltegravir, no major NRTI mutations were detected and one mutation conferring resistance to raltegravir was observed. In the SINGLE study, among six patients treated with EFV/TDF/FTC, no mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) were observed, and one patient developed a major NRTI mutation. Over 96 weeks in studies GEMINI-1 and GEMINI-2, no development of resistance to the integrase inhibitor class or to the NRTI class was observed, either in the group receiving the combination dolutegravir + lamivudine (DTG + 3TC) or in the group receiving dolutegravir + tenofovir/emtricitabine (DTG + TDF/FTC).

Patients with prior ineffective treatment who had not received integrase inhibitor class drugs

In the international, multicenter, double-blind SAILING study (ING111762), 719 HIV-infected adult patients who had previously received antiretroviral therapy (ART) were randomized to receive either dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, each combined with an investigator-selected background regimen that 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, 16% co-infected with hepatitis B and/or C, and 46% classified as CDC class C. All patients had resistance to at least two classes of ART drugs, and 49% had resistance to three classes of ART drugs at baseline.

The results of the SAILING study at 48 weeks (including outcomes based on primary endpoints) are presented in Table 3.

Patient response to treatment in the SAILING study at 48 weeks

(Snapshot algorithm, < 50 copies/mL)

Table 3

‡ Balanced for stratification factors.

§ 4 patients were excluded from the efficacy analysis due to missing data discrepancies at a single study 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, virologic suppression (HIV-1 RNA < 50 copies/mL) was statistically greater in the dolutegravir group (71%) compared to the raltegravir group (64%) (p=0.03).

A statistically significantly smaller number of patients experienced treatment failure due to the development 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 integrase inhibitor use (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 virologic failure, and had resistance to raltegravir and/or elvitegravir at present or in their history, received dolutegravir 50 mg twice daily with an optimized background regimen that was failing at baseline for 7 days, with optimization of background ART beginning on Day 8. The study included 183 patients, of whom 133 had integrase strand transfer inhibitor (INI) resistance at screening and 50 had evidence of prior resistance (but not at screening). Raltegravir/elvitegravir was part of the failing regimen at baseline in 98 of the 183 patients (others had prior use of 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, mean duration of prior ART was 14 years, and 56% of patients were CDC Class C. At baseline, patients exhibited multidrug resistance to ARV 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.

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

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

Table 4

* 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 using plasma HIV RNA for assessment.

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 currently failing therapy), 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%) of patients had HIV-1 RNA <50 copies/mL (ITT-E, Snapshot algorithm). Excluding patients who discontinued treatment due to lack of efficacy and those with major protocol deviations (incorrect dosing of dolutegravir, use of prohibited medications), the so-called "virological response population" (VO population), the response rate was 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.

Treatment response by baseline resistance, VIKING-3.

VO population (HIV-1 RNA < 50 copies/mL, Snapshot algorithm)

Table 5

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 study VIKING-4 (ING116529),
30 adult patients infected with HIV-1 who had primary genotypic resistance to INI at screening were randomized to receive dolutegravir 50 mg twice daily or placebo plus an ineffective background regimen 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, the mean duration of prior ART was 13 years, and 63% were CDC class C. At study initiation, subjects demonstrated multi-class resistance to ART: 80% had ≥2 NRTI, 73% – ≥1 NNRTI, and 67% – ≥2 PI primary mutations; 83% had non-R5 virus. 16 out of 30 subjects carried the Q148 virus at study initiation. The primary efficacy endpoint on day 8 showed that dolutegravir 50 mg twice daily was more effective than placebo, with a treatment difference between groups in mean change from baseline in plasma HIV-1 RNA of -1.2 log10 copies/ml (95% CI: -1.5 to -0.8 log10 copies/ml, p < 0.001). Responses on day 8 in this placebo-controlled study were fully consistent with responses in the VIKING-3 study (without placebo control), including categories of baseline resistance to integrase inhibitors. At week 48, 12/30 (40%) subjects had HIV-1 RNA <50 copies/ml (ITT-E, Snapshot algorithm).

In a combined analysis of studies VIKING-3 and VIKING-4 (n=186, VO population), the proportion of subjects with HIV RNA <50 copies/ml at week 48 was 123/186 (66%). The proportion of subjects with HIV RNA <50 copies/ml was 96/126 (76%) in subjects without Q148 mutations, 22/41 (54%) in subjects with Q148+1 secondary mutations, and 5/19 (26%) in subjects with Q148+≥2 secondary mutations.

Children

In a multicenter, open-label 48-week Phase I/II study (P1093/ING112578), pharmacokinetic, safety, tolerability, and efficacy parameters of dolutegravir were evaluated in combination treatment 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) plus an optimized background regimen (OBR).

There are no data on the use of the combination of dolutegravir plus lamivudine 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 in 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. Intra-patient variability (CVw%) is lower than inter-patient variability.

Absorption

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

Food intake increased the extent and slowed the rate of dolutegravir absorption. 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, it is recommended to administer with food to HIV-infected patients with resistance to integrase inhibitor class drugs (see section "Dosage and administration").

The absolute bioavailability of dolutegravir has not been determined.

Distribution

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

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

Dolutegravir is detectable 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, respectively, at steady state.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme and to a minor extent by CYP3A. Dolutegravir circulates predominantly unchanged in plasma; renal excretion of unchanged active substance is 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 related 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 enzymes (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 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 ~14 hours. The apparent total clearance of the drug from plasma (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. After oral administration of the tablet formulation, dolutegravir generally demonstrates non-linear pharmacokinetics with less than dose-proportional increases in plasma drug 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 approximately doubled compared to that with 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 maintained for 3–4 days after the last dose in the group receiving 50 mg.

Special populations

Children

Pharmacokinetics of dolutegravir in 10 children aged 12 years and older infected with HIV-1 and 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 orally once daily.

Elderly 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 of 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 control volunteers. Dose adjustment is not considered necessary for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dolutegravir has not been studied.

Polymorphism of drug-metabolizing enzymes

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

Gender

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

Race

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

Concurrent infection with hepatitis B or C virus

Population pharmacokinetic analysis indicates that concurrent infection with hepatitis C virus has no clinically significant effect on dolutegravir concentration. 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 on bacteria and cultured mammalian 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 in clinical practice, based on AUC).

Oral administration of dolutegravir at doses up to 1000 mg/kg/day from day 6 to 17 of pregnancy in pregnant female rats did not cause toxic effects on the mother or fetus and did not have teratogenic effects (dose 27 times higher than the 50 mg twice daily dose used in humans in clinical practice, based on AUC).

Oral administration of dolutegravir at doses up to 1000 mg/kg/day from day 8 to 18 of pregnancy 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 in clinical practice, based on AUC). In rabbits, toxic effects on the mother (reduced food consumption, low amount/absence of physiological defecation/urination, reduced body weight gain) were observed at a dose of 1000 mg/kg (0.40 times higher than the 50 mg twice daily dose used in humans in clinical practice, based on AUC).

The impact of long-term daily high-dose treatment with 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 with medicinal products that have a narrow therapeutic window and are substrates of organic cation transporter 2 (OCT2), including but not limited to fampridine (also known as dalfampridine) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on the pharmacokinetics of dolutegravir.

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

Dolutegravir is primarily eliminated via metabolism mediated by the enzyme UGT1A1. 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 antacids (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, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, or P-gp.

In vitro, dolutegravir inhibits the renal transporter organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE-1). In vivo, in patients, a 10–14% reduction in creatinine clearance has been observed (the secretory component is dependent on OCT2 and MATE-1 transporters). 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], metformin) (see Table 6).

In vitro, dolutegravir inhibits renal uptake transporters—organic anion transporters OAT1 and OAT3. Given the minimal 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 6, where increase is denoted by ↑, decrease by ↓, no change by ↔, area under the concentration-time curve by AUC, maximum observed concentration by Cmax, and trough concentration by Cτ.

Drug interactions

Table 6

Children.

Studies on interactions were conducted only in adults.

Special precautions for use.

Although effective viral suppression with antiretroviral agents has been shown to substantially reduce the risk of sexual transmission, 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 carrying secondary mutations Q148+ ≥ 2 of G140A/C/S, E138A/K/T, L74I (see section "Pharmacodynamics"). It is unclear whether dolutegravir provides additional efficacy in the presence of such resistance to integrase inhibitors.

Hypersensitivity reactions.

Hypersensitivity reactions, characterized by rash, systemic symptoms, and sometimes organ dysfunction, including severe hepatic reactions, have been reported with dolutegravir. Dolutegravir and other suspected 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 swelling, eosinophilia, or angioedema, but not limited to these). Clinical status should be monitored, including assessment of hepatic aminotransferases and bilirubin levels. Delay in discontinuing dolutegravir or other suspected agents after onset of hypersensitivity reactions may lead to a life-threatening allergic reaction.

Immune reconstitution 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 pathogens may occur, leading to serious clinical manifestations or worsening of symptoms. Such reactions are typically observed within the first few weeks or months after starting cART. Relevant 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 time to onset is more variable, and these events may occur many months after initiation of treatment.

In some patients co-infected with hepatitis B and/or C virus, increased biochemical markers of liver function have been observed at the start of treatment with dolutegravir.

Monitoring of liver function tests is recommended in patients co-infected with hepatitis B and/or C virus. Particular caution is required at the initiation and during maintenance of effective hepatitis B therapy (according to 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 complications of HIV. 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 must be avoided. These include concomitant use of medicinal products that reduce dolutegravir concentrations (such as antacids containing magnesium/aluminum, iron and calcium supplements, multivitamins and stimulants, etravirine [without boosted protease inhibitors], tipranavir/ritonavir, rifampicin, St. John's wort, 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 treatment with dolutegravir and metformin to maintain glycemic control (see section "Interaction with other medicinal products and other forms of interaction"). Metformin is eliminated by the kidneys, and renal function should therefore be monitored during concomitant therapy with dolutegravir. The combination of these agents may increase the risk of lactic acidosis in patients with moderate renal impairment (stage 3a, creatinine clearance [CrCl] 45–59 mL/min), so particular attention is recommended. The physician should consider reducing the dose of metformin.

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 a physician if they experience joint pain, stiffness, or difficulty moving.

Body weight and metabolic parameters.

During antiretroviral therapy, increases in body weight and levels of blood lipids and glucose may occur. These changes may be partly related to improved control of the disease and changes in lifestyle. Regarding increased lipid levels, in some cases, a treatment effect has been demonstrated, while there is no strong evidence linking weight gain directly to therapy. Monitoring of lipid and glucose levels should be performed in accordance with HIV treatment guidelines. Lipid disorders should be managed according to clinical standards.

Lamivudine and dolutegravir.

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

Use during pregnancy or breastfeeding.

Females of reproductive potential.

Females of reproductive potential should be counselled about the potential risk of neural tube defects prior to initiating dolutegravir (see below) and advised to use effective contraception.

If a woman is planning to become pregnant, the benefits and risks of dolutegravir therapy should be evaluated.

Pregnancy.

In a Botswana birth outcomes surveillance study, a small increase in neural tube defects was observed: 7 cases of neural tube defects were reported among 3,591 births (0.19%; 95% CI 0.09%, 0.40%) in mothers who received dolutegravir-containing regimens from conception, compared to 21 cases among 19,361 births (0.11%; 95% CI 0.07%, 0.17%) in mothers who received regimens without dolutegravir from conception.

In the same study, two newborns whose mothers received dolutegravir during pregnancy had neural tube defects among 4,448 births (0.04%), compared to five cases among 6,748 births (0.07%) in mothers receiving regimens without dolutegravir.

The background rate of neural tube defects in the general population ranges from 0.5 to 1 case per 1,000 live births (0.05–0.1%). Most neural tube defects occur 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 therapy, 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 for neural tube development.

Data from the Antiretroviral Pregnancy Registry, analyzing over 600 pregnant women exposed to dolutegravir, do not indicate an increased risk of major congenital malformations. However, these data are insufficient to fully assess the risk of neural tube defects.

In animal reproductive toxicity studies, dolutegravir did not show adverse effects on fetal development, including neural tube defects. Dolutegravir crosses the placenta in animals.

More than 1,000 outcomes of dolutegravir exposure in women during the second and third trimesters indicate no 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 woman outweighs the potential risk to the fetus.

Breastfeeding.

Dolutegravir is excreted in human breast milk in small amounts.

Information on the effects of dolutegravir on infants/infants is limited.

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

Fertility.

There are no data on the effect of dolutegravir on fertility in men and women. Animal studies did not show any effect of dolutegravir on fertility in males or females.

Effects on ability to drive and use machines.

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 treatment with dolutegravir. The patient's clinical status and adverse reaction profile should be considered when determining the patient's ability to drive or operate machinery.

Method of Administration and Dosage

Dolutegravir must be prescribed by a physician experienced in the treatment of HIV infection.

Dosage.

Adults.

HIV-1 infected patients without documented or clinically suspected resistance to integrase inhibitors.

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

Dolutegravir may be administered twice daily when co-administered with certain medications (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 inhibitors (documented or clinically suspected).

The recommended dose of dolutegravir is 50 mg (one tablet) twice daily. When deciding to use dolutegravir in such patients, resistance to integrase inhibitors must be taken into account (see subsection "Pharmacodynamics").

Missed dose.

If a patient misses a dose of dolutegravir, they should take the missed dose 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 regular dosing schedule.

Children aged 12 years and older.

For children (aged 12 to 17 years, with body weight at least 40 kg) infected with HIV-1 and without resistance to integrase inhibitors, 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 adult patients (see subsection "Pharmacokinetics").

Renal impairment.

No dose adjustment is necessary for patients with mild, moderate, or severe renal impairment (CrCl (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 necessary 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"). However, if resistance to integrase inhibitors is present, dolutegravir should be administered with food to enhance 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. The 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 the presence 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. If necessary, further treatment should be based on clinical indications or in accordance with recommendations from the national toxicology center. There is no specific antidote for dolutegravir overdose. In case of overdose, the patient should receive symptomatic treatment with appropriate monitoring, if needed. Since dolutegravir is highly protein-bound in plasma, it is unlikely that significant amounts will be removed by hemodialysis.

Adverse reactions.

Overview of safety profile.

The most severe adverse reaction observed in individual patients was hypersensitivity reaction, including rash and severe hepatic effects (see section "Special precautions"). The most commonly reported adverse reactions during treatment were nausea (13%), diarrhea (18%), and headache (13%).

List of adverse reactions.

Adverse reactions considered possibly related to the use of dolutegravir are listed by system organ classes and organ class frequencies according to absolute frequency of occurrence. Frequency categories are 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".

** - in combination with increased transaminases

Some adverse reactions

Changes in laboratory biochemical test parameters

Elevated 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.

Concurrent hepatitis B or C virus infection

Patients with concurrent hepatitis B and/or C virus infection were allowed in phase III studies provided baseline liver function tests did not exceed five times the upper limit of normal (ULN). Overall, the safety profile in patients with concurrent hepatitis B and/or C virus infection was similar to that in patients without concurrent hepatitis B or C virus infection, although abnormal AST and ALT values were higher in the subgroup with concurrent hepatitis B and/or C virus infection across all treatment groups. Biochemical liver function test elevations consistent with immune reconstitution syndrome were observed in some patients with concurrent hepatitis B and/or C virus infection at the start of dolutegravir treatment, particularly in those who discontinued hepatitis B treatment (see section "Special warnings and precautions").

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency 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 has been more variable, and these events may occur many months after initiation of treatment (see section "Special warnings and precautions").

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").

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.

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

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C, in a dry place protected from moisture and inaccessible to children.

Packaging.

30 or 90 film-coated tablets in a high-density polyethylene bottle.

30 or 90 film-coated tablets in a high-density polyethylene bottle. One bottle per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Sun Pharmaceuticals Industries Limited.

Manufacturer's address and location of operations.

V. Ganguwala, Paonta Sahib, District Sirmour, Himachal Pradesh 173025, India.