Dolutegravir

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

Composition:

Active substance: dolutegravir;

One film-coated tablet contains sodium dolutegravir 52.6 mg, equivalent to dolutegravir 50 mg;

Excipients: mannite, microcrystalline cellulose, sodium starch glycolate (type A), povidone K-30, sodium stearyl fumarate;

Film coating: Opadry II brown 85F565142 (polyvinyl alcohol partially hydrolyzed; titanium dioxide (E 171), macrogol 4000, talc, red iron oxide (E 172), black iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: pink, round, biconvex, film-coated tablet with beveled edges, marked with "M" on one side and "DT5" on the other side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Integrase inhibitors. ATC code J05A J03.

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 effects were observed in vitro when dolutegravir was used in combination with other investigated antiretroviral agents: 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 the presence of 100% human serum, there was an average 75-fold shift in IC (inhibitory concentration), resulting in a protein binding-adjusted IC90 of 0.064 µg/mL.

Resistance.

Resistance in vitro.

Serial passage experiments were used to investigate the development of resistance in vitro. 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 during clinical trials. In the NL432 strain, mutations E92Q (FC 3) and G193E (also FC 3) were observed. The E92Q mutation was noted 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 was reported in two patients receiving antiretroviral therapy who had not received integrase inhibitors, with subtypes B and C, but without impact on dolutegravir sensitivity in vitro. The G118R mutation reduced sensitivity to dolutegravir in site-directed mutants (FC 10), but was not observed in patients receiving dolutegravir in phase III trials.

Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q, and T66I) did not affect in vitro sensitivity to dolutegravir as individual 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 for 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 serial passage experiments of site-directed mutants. In serial passage of the NL432 strain, starting with site-directed mutants harboring N155H or E92Q mutations, no further resistance selection was observed (FC values remained unchanged, close to 1). In contrast, starting with site-directed mutants harboring Q148H mutations (FC 1), a variety of secondary mutations emerged, leading to an increase in FC values to >10.

Clinically significant phenotypic thresholds (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 had an FC ≤ 10 in 94% of the 705 clinical isolates.

Resistance in vivo.

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

In patients with prior failed antiretroviral therapy who had not received 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. Of these four patients, two had the unique integrase substitution R263K with a maximum FC of 1.93, one had the polymorphic integrase substitution V151V/I with a maximum FC of 0.92, and one had pre-existing integrase mutations and was considered to have previously received integrase inhibitors or been infected with 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, among 32 patients (all receiving dolutegravir 50 mg twice daily + optimized background regimens) with protocol-defined virologic failure (PDVF), the following mutations with paired genotypes were identified: 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 that emerged during treatment typically occurred in patients with a history of Q148 mutation (baseline or historical control). In five additional patients with PDVF between weeks 24 and 28, mutations emerging during treatment were observed in two of these five. The mutations emerging during treatment or mutation combinations were L74I (n=1) and 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.

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

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]). It is further supported by 96-week data from the open-label, randomized, active-controlled FLAMINGO study (ING114915) and additional data from the open-label phase of the SINGLE study up to 144 weeks.

The efficacy of dolutegravir in combination with lamivudine in adults is confirmed by primary endpoint data at week 48 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, 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 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 virus, and 4% classified as CDC class C. These characteristics were similar across treatment groups.

Primary endpoints and other results from SPRING-2 and SINGLE at 48 weeks (including outcomes based on key baseline independent variables) 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)

Patient groups by characteristics	SPRING-2		SINGLE
	50 mg dolutegravir once daily + 2 NRTIs, N = 411	RAL 400 mg twice daily + 2 NRTIs, N = 411	50 mg dolutegravir + ABC/3TC once daily, N = 414	EFV/TDF/FTC once daily, N = 419
HIV-1 RNA < 50 copies/mL	88 %	85 %	88 %	81 %
Difference between groups comparison *	2.5 % (95 % CI: -2.2 %; 7.1 %)		7.4 % (95 % CI: 2.5 %; 12.3 %)
Lack of virological response †	5 %	8 %	5 %	6 %
HIV-1 RNA < 50 copies/mL with baseline variables
Baseline viral load (copies/mL)
≤ 100000 > 100000	267/297 (90 %) 94/114 (82 %)	264/295 (89 %) 87/116 (75 %)	253/280 (90 %) 111/134 (83 %)	238/288 (83 %) 100/131 (76 %)
Baseline CD4+ count (cells/mm³)
< 200 200 to < 350 ≥ 350	43/55 (78 %) 128/144 (89 %) 190/212 (90 %)	34/50 (68 %) 118/139 (85 %) 199/222 (90 %)	45/57 (79 %) 143/163 (88 %) 176/194 (91 %)	48/62 (77 %) 126/159 (79 %) 164/198 (83 %)
Background NRTI therapy
ABC/3TC TDF/FTC	145/169 (86 %) 216/242 (89 %)	142/164 (87 %) 209/247 (85 %)	N/A (no data) N/A	N/A N/A
Sex
Male Female	308/348 (89 %) 53/63 (84 %)	305/355 (86 %) 46/56 (82 %)	307/347 (88 %) 57/67 (85 %)	291/356 (82 %) 47/63 (75 %)
Race
Caucasian Other	306/346 (88 %) 55/65 (85 %)	301/352 (86 %) 50/59 (85 %)	255/284 (90 %) 109/130 (84 %)	238/285 (84 %) 99/133 (74 %)
Age (years)
< 50 ≥ 50	324/370 (88 %) 37/41 (90 %)	312/365 (85 %) 39/46 (85 %)	319/361 (88 %) 45/53 (85 %)	302/375 (81 %) 36/44 (82 %)
Mean change in CD4+ count from baseline	230	230	246‡	187‡

* Balanced for baseline stratification factors.

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

‡ The balanced 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 observed at Week 48. Dolutegravir in the SPRING-2 study 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 outperform EFV/TDF/FTC (viral suppression in 80% vs. 72%, treatment difference 8.0% (2.3 to 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%, 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 hepatitis C co-infection, and 3% were CDC class C; these characteristics were similar between 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 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 GEMINI-1 (204861) and GEMINI-2 (205543) studies, 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 were included if screening plasma HIV-1 RNA levels were between 1,000 copies/mL and ≤500,000 copies/mL. 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 subtypes of HIV; these characteristics were similar across treatment groups. At Week 48, virological suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir plus lamivudine group was non-inferior to the dolutegravir plus tenofovir/emtricitabine (TDF/FTC) group, as shown in Table 2. Results from the pooled analysis were consistent with individual study results, with the primary endpoint achieved: (difference in proportion with <50 copies/mL HIV-1 RNA in plasma at Week 48 based on snapshot algorithm). The adjusted difference was -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%.

Table 2

Response (<50 copies/mL, snapshot analysis) in GEMINI 1+2, pooled data at Week 48

	Dolutegravir + lamivudine (DTG + 3TC) (N=716) n/N (%)	Dolutegravir + tenofovir/emtricitabine (DTG + TDF/FTC) (N=717) n/N (%)
All patients	655/716 (91)	669/717 (93)
	adjusted difference -1.7% (95% CI -4.4, 1.1) a
By baseline HIV-1 RNA level
≤ 100,000 copies/ml	526/576 (91)	531/564 (94)
> 100,000 copies/ml	129/140 (92)	138/150 (92)
By CD4+ cell count
≤ 200 cells/mm³	50/63 (79)	51/55 (93)
> 200 cells/mm³	605/653 (93)	618/662 (93)
By HIV-1 subtype
Subtype B	424/467 (91)	452/488 (93)
Non-B subtype	231/249 (93)	217/229 (95)
Relapse by Week 48b	6 (<1)	4 (<1)
Mean change in CD4 cell count at Week 48 compared to baseline, cells/mm³	224	217

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 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 results from individual studies, both 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%. 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 emerging 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 class drugs were observed with dolutegravir. For comparison, the same absence of resistance was observed in patients treated with darunavir/ritonavir in study FLAMINGO. In study SPRING-2, among four patients receiving raltegravir, no major NRTI mutations were detected and one mutation conferring resistance to raltegravir was observed. In study SINGLE, among six patients treated with EFV/TDF/FTC, no mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) were observed, and one patient developed a major NRTI mutation. Over 144 weeks in studies GEMINI-1 and GEMINI-2, no development of resistance to the integrase inhibitor class or to the NRTI class was observed in either the group receiving dolutegravir + lamivudine (DTG + 3TC) or the group receiving dolutegravir + tenofovir/emtricitabine (DTG + TDF/FTC).

Patients with prior ineffective treatment who have 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 was 43 years, 32% were female, 50% were of non-Caucasian race, 16% were co-infected with hepatitis B and/or C virus, and 46% were 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 primary outcome measures) are presented in Table 3.

Table 3

Patient response to treatment in the SAILING study at 48 weeks

(Snapshot algorithm, < 50 copies/ml)

Subgroups by characteristics	50 mg dolutegravir once daily + OBT N=354§	RAL 400 mg twice daily + OBT N=361§
HIV-1 RNA < 50 copies/ml	71 %	64 %
Difference between treatment groups‡	7.4 % (95 % CI: 0.7 %, 14.2 %)
Lack of virological response	20 %	28 %
HIV-1 RNA < 50 copies/ml by baseline variables
Baseline viral load (copies/ml)
≤ 50,000 copies/ml > 50,000 copies/ml	186/249 (75 %) 65/105 (62 %)	180/254 (71 %) 50/107 (47 %)
Baseline CD4+ count (cells/mm³)
< 50 50 to < 200 200 to < 350 ≥ 350	33/62 (53 %) 77/111 (69 %) 64/82 (78 %) 77/99 (78 %)	30/59 (51 %) 76/125 (61 %) 53/79 (67 %) 71/98 (73 %)
Background regimen
Genotypic sensitivity score* < 2 Genotypic sensitivity score* = 2 Use of DRV (darunavir) in background regimen No use of DRV Use of DRV with primary integrase mutations Use of DRV without primary integrase mutations	155/216 (72 %) 96/138 (70 %) 143/214 (67 %) 58/68 (85 %) 50/72 (69 %)	129/192 (67 %) 101/169 (60 %) 126/209 (60 %) 50/75 (67 %) 54/77 (70 %)
Sex
Male Female	172/247 (70 %) 79/107 (74 %)	156/238 (66 %) 74/123 (60 %)
Race
White Other	133/178 (75 %) 118/175 (67 %)	125/175 (71 %) 105/185 (57 %)
Age (years)
< 50 ≥ 50	196/269 (73 %) 55/85 (65 %)	172/277 (62 %) 58/84 (69 %)
HIV subtype
Group B Group C Other†	173/241 (72 %) 34/55 (62 %) 43/57 (75 %)	159/246 (65 %) 29/48 (60 %) 42/67 (63 %)
Mean increase in CD4+ T-lymphocytes (cells/mm³)	162	153

‡ Balanced for stratification factors.

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

* Genotypic susceptibility score (GSS) was defined as the total number of ART drugs in the background regimen to which the patient's virus isolates 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) was statistically greater in the dolutegravir group (71%) compared to the raltegravir group (64%) (p=0.03).

A statistically significantly smaller proportion of patients experienced treatment failure with 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 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 virological failure, and had current or historical resistance to raltegravir and/or elvitegravir, received dolutegravir 50 mg twice daily with an optimized background regimen that was failing at baseline, with optimization of background ART starting on Day 8. The study included 183 patients, of whom 133 had integrase inhibitor (INI) resistance at screening and 50 had evidence of historical resistance (but not at screening). Raltegravir/elvitegravir was part of the failing regimen at baseline in 98 of the 183 patients (others had prior treatment failure). 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. 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 ART classes: 79% had resistance to ≥2 NRTIs, 75% to ≥1 NNRTI, and 71% had ≥2 major protease inhibitor 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 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 failing regimen at baseline,

study VIKING-3

Baseline characteristics	DTG 50 mg twice daily, N = 88*
	N	Mean plasma HIV-1 RNA level, log10 copies/mL	Mean change
Integrase inhibitor-resistant mutation group at baseline continuing RAL/EVG
Primary mutation other than Q148H/K/Ra	48	-1.59 (0.47)	-1.64
Q148 + 1 secondary mutationb	26	-1.14 (0.61)	-1.08
Q148 + ≥2 secondary mutationsb	14	-0.75 (0.84)	-0.45

* Of the 98 patients on RAL/EVG as part of their failing regimen, 88 had detectable primary INI resistance mutations at baseline and on day 8 when blood 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 primary mutations detected at baseline (N=60) (i.e., RAL/EVG not part of the current 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). When patients who discontinued therapy due to lack of efficacy and those with major protocol deviations (incorrect dosing of dolutegravir, use of prohibited medications) were excluded, the so-called virological response (VO) population, the response rate was 75% (120/161) at week 24 and 69% (111/160) at week 48.

Response was weaker 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)

Integrase mutation group	Week 24 (N=161)					Week 48 (N=160)
	OSS = 0	OSS = 1	OSS = 2	OSS > 2	Total	Total
No primary integrase mutation1	2/2 (100 %)	15/20 (75 %)	19/21 (90 %)	9/12 (75 %)	45/55 (82 %)	38/55 (69 %)
Primary mutation other than Q148H/K/R2	2/2 (100 %)	20/20 (100 %)	21/27 (78 %)	8/10 (80 %)	51/59 (86 %)	50/58 (86 %)
Q148 + 1 secondary mutation3	2/2 (100 %)	8/12 (67 %)	10/17 (59 %)	-	20/31 (65 %)	19/31 (61 %)
Q148 + ≥ 2 secondary mutations3	1/2 (50 %)	2/11 (18 %)	1/3 (33 %)	-	4/16 (25 %)	4/16 (25 %)

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 who had 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 age of patients 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 baseline, subjects exhibited multi-class resistance to ART: 80% had ≥2 NRTI, 73% had ≥1 NNRTI, and 67% had ≥2 PI primary mutations; 83% had non-R5 virus. 16 out of 30 subjects were carriers of the Q148 virus at baseline. The primary efficacy endpoint on Day 8 showed that dolutegravir 50 mg twice daily was more effective than placebo, with a balanced mean difference between treatment groups in 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 observed 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 the VIKING-3 and VIKING-4 studies (n = 186, VO population), the proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 48 was 123/186 (66%). The proportion of subjects with HIV-1 RNA < 50 copies/mL was 96/126 (76%) for subjects without Q148 mutations, 22/41 (54%) for subjects with Q148 plus one secondary mutation, and 5/19 (26%) for subjects with Q148 plus ≥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 in combination regimens were evaluated 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).

No data are available on the use of the dolutegravir plus 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 in healthy volunteers, the CVb% for AUC and Cmax ranged from ~20 to 40%, and for Cτ 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 absorption of dolutegravir. The bioavailability of dolutegravir depends on the composition of food: low-, medium-, and high-fat meals increased the 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 administered with food to HIV-infected patients with resistance to integrase inhibitor class drugs (see section "Dosage and administration").

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 concentration ratios of radioactivity associated with the drug range from 0.441 to 0.535, indicating minimal binding of radioactivity to blood cellular components. The unbound fraction of dolutegravir in plasma increases with low serum albumin levels (<35 g/L), 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 regimen of dolutegravir in combination with abacavir/lamivudine, the concentration of dolutegravir in CSF averaged 18 ng/mL (at the level of unbound drug concentration in plasma and above 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 determined at steady state. AUC in semen and rectal tissue was 7% and 17%, respectively, of the corresponding plasma value determined at steady state.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme and to a lesser extent by CYP3A. Dolutegravir circulates predominantly 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 related to unabsorbed drug or biliary excretion of the glucuronide conjugate, which may subsequently be degraded to 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).

Interaction with medicinal products

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 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 clearance of the drug from plasma (CL/F) is approximately 1 L/hour in HIV-infected patients, as determined by 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 exhibits non-linear pharmacokinetics with less than dose-proportional increases in plasma concentrations at doses from 2 to 100 mg; however, increases in dolutegravir concentration are dose-proportional when doses from 25 mg to 50 mg (for tablets) are administered. When administered at 50 mg twice daily, the concentration over 24 hours approximately doubled compared to that with 50 mg once daily.

Pharmacokinetic/pharmacodynamic relationship

In a randomized dose-finding study, patients infected with HIV-1 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 by 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 patient groups

Children

Pharmacokinetics of dolutegravir in 10 children aged 12 years and older infected with HIV-1 who were receiving antiretroviral therapy showed that an oral dose of dolutegravir 50 mg once daily results in dolutegravir exposure comparable to that in adults receiving dolutegravir 50 mg once daily orally.

Elderly patients

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

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 (creatinine clearance) < 30 mL/min) and healthy control volunteers. Dolutegravir exposure 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. Total plasma concentrations of dolutegravir were similar. However, in patients with moderate hepatic impairment, unbound dolutegravir concentrations increased 1.5–2 times 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 have 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 of the drug via UGT1A1 (n=41).

Sex

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

Race

Population pharmacokinetic 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 exposure.

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 exposure. 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 to pregnant female rats from Day 6 to Day 17 of gestation, a dose 27 times higher than the 50 mg twice daily dose used in humans in clinical practice (based on AUC), did not cause toxic effects on maternal organism, fetal development, or teratogenic effects.

Oral administration of dolutegravir at doses up to 1000 mg/kg/day from Day 6 to Day 18 of gestation in pregnant female rabbits did not cause toxic effects on fetal development or teratogenic effects (a 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 maternal organism (reduced food intake, 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 effects of long-term daily treatment with high doses of dolutegravir were evaluated in studies in rats (up to 26 weeks) and monkeys (up to 38 weeks). At doses providing systemic exposure in rats and monkeys approximately 21 times and 0.82 times, respectively, higher than exposure in humans (based on AUC) at the 50 mg twice daily dose, the main findings were gastrointestinal intolerance or irritation. Since gastrointestinal intolerance is associated with local effects of the active substance, mg/kg or mg/m² are appropriate units for safety endpoints for such toxicity. Gastrointestinal 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.

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 dolutegravir or to any of the excipients.

Concomitant use with medicinal products having a narrow therapeutic index that 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 reducing dolutegravir concentrations must be avoided.

Dolutegravir is primarily eliminated via metabolism mediated by the enzyme uridine diphosphate-glucuronosyltransferase (UGT1A1). Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP); 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).

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/or 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 (for further details, see section "Pharmacokinetics").

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

In vitro, dolutegravir inhibits renal substrate uptake transporters, organic anion transporters OAT1 and OAT3. However, due to 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 6, where increase is denoted by ↑, decrease by ↓, and 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

Medicinal product interactions

Drug classes	Interaction, mean geometric change (%)	Recommendations for co-administration
Antiretroviral drugs against HIV-1
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Etravirine (without boosted protease inhibitors)	Dolutegravir ↓ AUC ↓ 71 % Cmax ↓ 52 % Cτ ↓ 88 % Etravirine ↔ (stimulation of UGT1A1 and CYP3A enzymes)	Etravirine without boosted protease inhibitors reduces plasma concentrations of dolutegravir. The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with etravirine without boosted protease inhibitors. Dolutegravir should not be used with etravirine without concomitant administration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir in patients with resistance to integrase inhibitors (see below in the table).
Lopinavir/ ritonavir + etravirine	Dolutegravir ↔ AUC ↑ 11 % Cmax ↑ 7 % Cτ ↑ 28 % LPV ↔ RTV ↔	No dose adjustment necessary.
Darunavir/ ritonavir + etravirine	Dolutegravir ↓ AUC ↓ 25 % Cmax ↓ 12 % Cτ ↓ 36 % DRV ↔ RTV ↔	No dose adjustment necessary.
Efavirenz	Dolutegravir ↓ AUC ↓ 57 % Cmax ↓ 39 % Cτ ↓ 75 % Efavirenz ↔ (historical controls) (stimulation of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with efavirenz. If resistance to integrase inhibitors is present, alternative combinations not including efavirenz should be considered (see section "Special warnings and precautions").
Nevaripine	Dolutegravir ↓ (not studied, similar reduction in exposure expected as with efavirenz due to induction)	The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with nevirapine. If resistance to integrase inhibitors is present, alternative combinations not including nevirapine should be considered (see section "Special warnings and precautions").
Rilpivirine	Dolutegravir ↔ AUC ↑ 12 % Cmax ↑ 13 % Cτ ↑ 22 % Rilpivirine ↔	No dose adjustment necessary.
Nucleoside reverse transcriptase inhibitors (NRTIs)
Tenofovir	Dolutegravir ↔ AUC ↑ 1 % Cmax ↓ 3 % Cτ ↓ 8 % Tenofovir ↔	No dose adjustment necessary.
Protease inhibitors
Atazanavir	Dolutegravir ↑ AUC ↑ 91 % Cmax ↑ 50 % Cτ ↑ 180 % Atazanavir ↔ (historical controls) (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment necessary. Dolutegravir should not be used at doses higher than 50 mg twice daily in combination with atazanavir due to lack of data (see section "Pharmacokinetics").
Atazanavir/ ritonavir	Dolutegravir ↑ AUC ↑ 62 % Cmax ↑ 34 % Cτ ↑ 121 % Atazanavir ↔ Ritonavir ↔ (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment necessary. Dolutegravir should not be used at doses higher than 50 mg twice daily in combination with atazanavir due to lack of data (see section "Pharmacokinetics").
Tipranavir/ritonavir	Dolutegravir ↓ AUC ↓ 59 % Cmax ↓ 47 % Cτ ↓ 76 % (stimulation of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with tipranavir/ritonavir. This combination should be avoided if resistance to integrase inhibitors is present (see section "Special warnings and precautions").
Fosamprenavir/ritonavir	Dolutegravir ↓ AUC ↓ 35 % Cmax ↓ 24 % Cτ ↓ 49 % (stimulation of UGT1A1 and CYP3A enzymes)	No dose adjustment necessary in the absence of resistance to integrase inhibitors. If resistance to integrase inhibitors is present, alternative combinations not including fosamprenavir/ritonavir should be considered.
Darunavir/ ritonavir	Dolutegravir ↓ AUC ↓ 22 % Cmax ↓ 11 % C24h ↓ 38 % (stimulation of UGT1A1 and CYP3A enzymes)	No dose adjustment necessary.
Lopinavir/ ritonavir	Dolutegravir ↔ AUC ↓ 4 % Cmax ↔ 0 % C24h ↓ 6 %	No dose adjustment necessary.
Other antiviral drugs
Daclatasvir	Dolutegravir ↔ AUC ↑ 33 % Cmax ↑ 29 % Cτ ↑ 45 % Daclatasvir ↔	Daclatasvir does not clinically significantly alter plasma concentrations of dolutegravir. Dolutegravir does not alter plasma concentrations of daclatasvir. No dose adjustment necessary.
Other drugs
Antituberculosis drugs
Rifampicin	Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 43 % Cτ ↓ 72 % (stimulation of UGT1A1 and CYP3A enzymes)	The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with rifampicin in the absence of resistance to integrase inhibitors. This combination should be avoided if resistance to integrase inhibitors is present (see section "Special warnings and precautions").
Rifabutin	Dolutegravir ↔ AUC ↓ 5 % Cmax ↑ 16 % Cτ ↓ 30 % (stimulation of UGT1A1 and CYP3A enzymes)	No dose adjustment necessary.
Azole antifungal agents
Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole	Dolutegravir ↔ (not studied)	No dose adjustment necessary. Based on data from other CYP3A4 inhibitors, a significant increase is not expected.
Anticonvulsants
Carbamazepine	Dolutegravir ↓ AUC ↓ 49 % Cmax ↓ 33 % Cτ ↓ 73 %	The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with carbamazepine. Alternative agents to carbamazepine should be prescribed for patients with resistance to integrase inhibitors.
Oxcarbazepine Phenytoin Phenobarbital	Dolutegravir ↓ (not studied, reduction expected due to stimulation of UGT1A1 and CYP3A enzymes, reduction in exposure expected similar to that observed with carbamazepine)	The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with these enzyme inducers. Alternative agents to these metabolic inducers should be prescribed for patients with resistance to integrase inhibitors.
Potassium channel blockers
Fampridine (also known as dalfampridine)	Fampridine ↑	Concomitant use of dolutegravir may cause seizures due to increased plasma concentrations of fampridine via inhibition of the OCT2 transporter. Concomitant use has not been studied and is contraindicated.
Antacids and dietary supplements
Antacids containing magnesium or aluminium	Dolutegravir ↓ AUC ↓ 74 % Cmax ↓ 72 % (chelation with polyvalent ions)	Antacids containing magnesium or aluminium should be taken separately from dolutegravir (at least 2 hours after or 6 hours before administration).
Calcium-containing supplements	Dolutegravir ↓ AUC ↓ 39 % Cmax ↓ 37 % C24h ↓ 39 % (chelation with polyvalent ions)	Calcium, iron, or multivitamin supplements should be taken separately from dolutegravir (at least 2 hours after or 6 hours before administration).
Iron-containing supplements	Dolutegravir ↓ AUC ↓ 54 % Cmax ↓ 57 % C24h ↓ 56 % (chelation with polyvalent ions)
Multivitamins	Dolutegravir ↓ AUC ↓ 33 % Cmax ↓ 35 % C24h ↓ 32 % (chelation with polyvalent ions)
Antidiabetic agents
Metformin	Metformin ↑ Co-administration with dolutegravir 50 mg once daily Metformin parameters: AUC ↑ 79 % Cmax ↑ 66 % Co-administration with dolutegravir 50 mg twice daily Metformin parameters: AUC ↑ 145 % Cmax ↑ 111 %	Dose adjustment of metformin is required at the start and upon discontinuation of concomitant dolutegravir therapy in patients taking metformin to maintain glycemic control. In patients with moderate renal impairment, consider dose adjustment of metformin when co-administered with dolutegravir due to increased risk of lactic acidosis from elevated metformin concentrations (see section "Special warnings and precautions").
Oral contraceptives
Ethinylestradiol and norelgestromin	Dolutegravir ↔ Ethinylestradiol ↔ AUC ↑ 3 % Cmax ↓ 1 % Norelgestromin ↔ AUC ↓ 2 % Cmax ↓ 11 %	Dolutegravir has no pharmacodynamic effect on luteinizing hormone, follicle-stimulating hormone, or progesterone. No dose adjustment of oral contraceptives is necessary when co-administered with dolutegravir.
Corticosteroids
Prednisone	Dolutegravir ↔ AUC ↑ 11 % Cmax ↑ 6 % Cτ ↑ 17 %	No dose adjustment necessary.
Analgesics
Methadone	Dolutegravir ↔ Methadone ↔ AUC ↓ 2 % Cmax ↔ 0 % Cτ ↓ 1 %	No dose adjustment necessary for either drug.
Herbal products
St. John's wort	Dolutegravir ↓ (not studied, reduction expected due to stimulation of UGT1A1 and CYP3A enzymes, reduction in exposure expected similar to that observed with carbamazepine)	The recommended dose of dolutegravir in adults is 50 mg twice daily when co-administered with St. John's wort. Alternative agents to St. John's wort should be prescribed for patients with resistance to integrase inhibitors.

Children.

Studies on interactions were conducted only in adult patients.

Special precautions for use.

Effective suppression of the virus by antiretroviral agents can substantially reduce the risk of sexual transmission. However, the risk cannot be completely eliminated. Preventive measures to avoid transmission of the virus should be taken in accordance with national and other authorized recommendations.

Resistance to integrase inhibitors of particular concern

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

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 medicinal products should be discontinued immediately if signs or symptoms of hypersensitivity reactions 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, and angioedema, but not limited to these). Clinical status, including assessment of liver aminotransferases and bilirubin levels, should be monitored. 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 and may result in serious clinical symptoms or deterioration of symptoms. Such reactions are typically observed within the first few weeks or months after initiation of 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 to occur in the setting of immune reconstitution. However, the time to onset of such disorders is more variable, and these events may occur many months after initiation of treatment.

In some patients co-infected with hepatitis B or C virus, increased biochemical markers of liver function have been observed at the start of dolutegravir treatment together with immune reconstitution syndrome. 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 (refer to instructions for medical use) when dolutegravir-based therapy is initiated in patients co-infected with hepatitis B virus (see section "Adverse reactions").

Opportunistic infections

Patients should be advised that dolutegravir and any other antiretroviral therapy do not cure HIV infection and that they may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical supervision by physicians experienced in managing HIV-related diseases.

Drug interactions

In patients with resistance to integrase inhibitor class drugs, factors that reduce the effect of dolutegravir should be avoided. Such factors include concomitant use of medicinal products that decrease dolutegravir concentrations (such as magnesium/aluminum-containing antacids, 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 therefore renal function should 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 special attention is recommended. The physician should consider reducing the dose of metformin.

Osteonecrosis

Although the etiology may be multifactorial and include corticosteroid use, bisphosphonates, excessive alcohol intake, severe immunosuppression, and high body weight, cases of osteonecrosis have been reported in patients with advanced HIV disease and/or after prolonged combination antiretroviral therapy. Patients should be advised to consult a physician if they experience joint pain, stiffness, or difficulty in movement.

Body weight and metabolic parameters

Increases in body weight and levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may be partly associated with control of the disease and lifestyle changes. Regarding increases in lipid levels and body weight, in some cases, a treatment effect has been demonstrated. Monitoring of lipid and glucose levels should be performed in accordance with HIV treatment guidelines. Lipid disorders should be managed according to clinical requirements.

Lamivudine and dolutegravir

Two large randomized, blinded trials, GEMINI 1 and GEMINI 2 (see section "Pharmacological properties"), evaluated a two-drug regimen 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 known or suspected resistance to integrase inhibitors or to lamivudine.

Excipients

Each film-coated tablet contains mannitol, which may have a mild laxative effect.

Each tablet also contains 5.2 mg (0.2 mmol) of sodium, which is less than 1 mmol of sodium (23 mg) per tablet, meaning the product is practically sodium-free.

The content of excipients in all medicinal products taken by the patient should be considered.

Use during pregnancy or breastfeeding.

Women of reproductive age

Women of reproductive age should be counselled regarding the potential risk of neural tube defects associated with dolutegravir (see below), including consideration of effective contraceptive measures.

If a woman is planning pregnancy, the benefits and risks of continuing dolutegravir treatment should be discussed with the patient.

Pregnancy

Human experience from a birth outcomes study in Botswana indicates a slightly increased frequency of neural tube defects: 7 cases out of 3591 live births (0.19%; 95% CI 0.09%, 0.40%) in mothers who were receiving dolutegravir-containing regimens at conception, compared with 21 cases out of 19,361 live births (0.11%; 95% CI 0.07%, 0.17%) in women who were receiving regimens without dolutegravir at conception.

In the general population, the frequency of neural tube defects is 0.5–1 case per 1000 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 treatment, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient, taking into account gestational age and the critical period for neural tube defect development.

Data analyzed from the Antiretroviral Pregnancy Registry do not indicate an increased risk of major birth defects in over 600 women who received dolutegravir during pregnancy, but currently these data are insufficient to assess the risk of neural tube defects.

In reproductive toxicity studies in animals, no adverse developmental effects, including neural tube defects, were observed. Dolutegravir has been shown to cross the placenta in animals.

More than 1000 exposures during the second and third trimesters of pregnancy do not indicate an increased risk of fetal/neonatal toxicity. Dolutegravir may be used during the second and third trimesters of pregnancy when the expected benefit justifies the potential risk to the fetus.

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

Data on the effect of dolutegravir on the infant are limited.

Breastfeeding

Dolutegravir is excreted in small amounts in human breast milk (the median ratio of dolutegravir concentration in breast milk to plasma concentration has been shown to be 0.033). Information on the effects of dolutegravir on neonates/infants is limited.

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

Fertility

There are no data on the effect of dolutegravir on reproductive function in men and women. Animal studies do not show an effect of dolutegravir on fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted to assess the ability of dolutegravir to affect reaction speed when driving or operating machinery. Patients should be informed that dolutegravir may cause dizziness. The patient's clinical status and the adverse effects of dolutegravir should be taken into account when deciding whether the patient is able to drive or operate machinery.

Method of Administration and Dosage

Dolutegravir (sodium) 50 mg tablets should be prescribed by a physician experienced in managing HIV infection.

Dosage

Adults

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

The recommended dose of dolutegravir in adults infected with HIV-1 without resistance to integrase inhibitors is 50 mg (one tablet) once daily.

The dose should be increased to 50 mg twice daily when dolutegravir is co-administered with 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.

In cases of documented resistance involving Q148 + ≥2 secondary mutations at G140A/C/S, E138A/K/T, or L74I, modeling results suggest that dose escalation may be considered for patients with limited treatment options (fewer than two active agents) due to extensive multi-class resistance (see subsection "Pharmacokinetics").

When deciding to use dolutegravir in such patients, the specific pattern of integrase inhibitor resistance should be taken into account (see subsection "Pharmacodynamics").

Children aged 12 years and older

The recommended dose of dolutegravir in children aged 12 years and older with body weight of at least 40 kg, infected with HIV-1 without resistance to integrase inhibitors, is 50 mg (one tablet) once daily.

Use is not recommended in the presence of integrase inhibitor resistance due to lack of appropriate data.

Older patients

There is insufficient information regarding the use of dolutegravir in patients aged 65 years and older. There is no evidence to suggest that older patients require a different dosage from younger adults (see section "Pharmacokinetics").

Renal impairment

No dose adjustment is required in patients with mild, moderate, or severe renal impairment (creatinine clearance, Clcr < 30 mL/min) who are not on dialysis. Dolutegravir has not been studied in patients on dialysis; however, no significant differences in pharmacokinetics are expected in this population (see section "Pharmacokinetics").

Hepatic impairment

No dosage adjustment is necessary in 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 these patients (see section "Pharmacokinetics").

Missed doses

If a patient misses a dose of dolutegravir, they should take the missed dose as soon as possible, provided that at least 4 hours remain before the next scheduled dose. If the next dose is due within 4 hours, the missed dose should be skipped and the next dose taken at the usual time.

Method of administration

For oral use.

Dolutegravir can be taken with or without food (see section "Pharmacokinetics"). If there is HIV-1 resistance to integrase inhibitors, dolutegravir should preferably be taken with food to enhance absorption (particularly in patients with Q148 mutations) (see section "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 integrase inhibitor resistance, there are insufficient data to recommend the use of dolutegravir in children.

Overdose.

Experience with dolutegravir overdose is limited. Single high doses up to 250 mg administered to healthy volunteers did not result in specific symptoms or signs other than those listed as adverse reactions. There is no specific antidote for dolutegravir overdose. In case of overdose, patients should receive symptomatic treatment with appropriate monitoring, if necessary. Because dolutegravir is highly protein-bound, it is unlikely that it will be significantly removed by hemodialysis.

Adverse Reactions.

Safety profile overview.

The most severe adverse reaction observed in individual patients was a 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%).

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 categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000).

Immune system disorders

Uncommon: hypersensitivity (see section "Special Warnings and Precautions for Use"), immune reconstitution syndrome (see section "Special Warnings and Precautions for Use" and "Description of selected adverse reactions" below).

Psychiatric disorders

Common: insomnia, abnormal dreams, depression, anxiety.

Uncommon: suicidal ideation or suicide attempts (particularly in patients with a history of depression or psychiatric disorders), panic attack.

Rare: completed suicide (particularly in patients with a history of depression or psychiatric disorders).

Nervous system disorders

Very common: headache.

Common: dizziness.

Gastrointestinal disorders

Very common: nausea, diarrhea.

Common: vomiting, flatulence, upper abdominal pain, abdominal pain, abdominal discomfort.

Hepatobiliary disorders

Common: increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels.

Uncommon: hepatitis.

Rare: acute liver failure, increased bilirubin (in combination with elevated transaminases).

Skin and subcutaneous tissue disorders

Common: rash, pruritus.

Musculoskeletal and connective tissue disorders

Uncommon: arthralgia, myalgia.

General disorders

Common: fatigue.

Laboratory or other test abnormalities

Common: increased creatine phosphokinase (CPK) levels, weight gain.

Description of selected adverse reactions

Changes in laboratory biochemical parameters

An increase in serum creatinine levels occurred within the first week of dolutegravir treatment and persisted for 48 weeks. After 48 weeks of treatment, the mean change from baseline was 9.96 µmol/L. The increase in creatinine 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 permitted in phase III studies provided baseline liver function biochemical parameters did not exceed five times the upper limit of normal. 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. However, abnormally elevated AST and ALT levels were higher in patients with concurrent hepatitis B or C virus infection across all treatment groups. Biochemical liver function test abnormalities consistent with immune reconstitution syndrome were observed in some patients with concurrent hepatitis B or C virus infection at the initiation of dolutegravir treatment, particularly in those who 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 reaction to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the time to onset reported is more variable, and these 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 levels of lipids and blood glucose may occur (see section "Special Warnings and Precautions for Use").

Paediatric population

Limited data available in children (aged 12 years and older with body weight at least 40 kg) indicate no additional adverse reactions beyond those identified in adults.

Reporting of suspected adverse reactions

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

Shelf life. 36 months.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging.

30 tablets in a bottle, 1 bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Mylan Laboratories Limited.

Manufacturer's address and place of business.

Plot No. 11, 12 and 13, Indore SEZ, Pharma Zone, Phase II, Sector III, District Dhar, Pithampur, Madhya Pradesh, 454775, India.

The medicinal product was manufactured under license from the Medicines Patent Pool.