Tivikei

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIVICAY™ (TIVICAY™)

Composition:

Active substance: dolutegravir;

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

Excipients: mannitol (E 421), microcrystalline cellulose, povidone K29/32, sodium stearyl fumarate, sodium starch glycolate;

tablet film coating: Opadry® II Yellow 85F92461.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: yellow, round, biconvex tablets with the imprint «SV 572» on one side and «50» on the other side.

Pharmacotherapeutic group. Antiviral agents for systemic use. Direct-acting antiviral agents. Integrase inhibitors. Dolutegravir. 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 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 dolutegravir activity.

Effect of human serum

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

Resistance

In vitro resistance

Serial passage experiments were used to investigate the development of in vitro resistance. When using the laboratory HIV strain III, mutations appeared slowly over 112 days, 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 in clinical trials. In the NL432 strain, mutations E92Q (FC 3) and G193E (also FC 3) were observed. The E92Q mutation was found in patients with pre-existing resistance to raltegravir who subsequently received dolutegravir (classified as a secondary mutation for dolutegravir).

In subsequent 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 (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 for 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 with site-directed mutants harboring N155H or E92Q mutations, no resistance was observed (FC values remained unchanged, close to 1). In contrast, starting with site-directed mutants harboring Q148H mutations (FC 1), various secondary mutations emerged, leading to an increase in FC values to >10.

The clinically significant threshold for the phenotypic FC (vs. wild-type virus) has not been established; 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 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), no development of resistance to the integrase or NRTI class was observed.

In patients with prior treatment failure who had not received integrase inhibitor class drugs (SAILING study), integrase substitutions were observed in 4 out 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 had the polymorphic integrase substitution V151V/I with a maximum FC of 0.92, and one 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, 32 patients (all receiving dolutegravir 50 mg twice daily + optimized background regimens) with protocol-defined virological failure (PDVF) had the following mutations identified with paired genotypes: L74L/M (n = 1), E92Q (n = 2), T97A (n = 9), E138K/A/T (n = 8), G140S (n = 2), Y143H (n = 1), S147G (n = 1), Q148H/K/R (n = 4), N155H (n = 1), and E157E/Q (n = 1). Resistance to integrase inhibitors emerging during treatment typically occurred in patients with a history of Q148 mutation (baseline or historical control). PDVF was observed in five additional patients between Weeks 24 and 28, and treatment-emergent mutations were observed in 2 of these 5 patients. 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 at screening of 30 subjects. The same treatment-emergent mutations were observed as in the VIKING-3 study.

Effect on electrocardiogram

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

Clinical efficacy and safety

Treatment-naïve patients

The efficacy of dolutegravir in treatment-naïve HIV-infected patients 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 the SINGLE trial up to 144 weeks. The efficacy of dolutegravir in combination with lamivudine in adults is further 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, 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, 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 the SPRING-2 and SINGLE studies at 48 weeks (including results based on the primary intent-to-treat population) are shown in Table 1.

Table 1

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

* Balanced for baseline stratification factors.

† Includes patients who switched ART to a new class of medicinal products or switched ART not permitted by protocol, or due to lack of efficacy by Week 48 (only for SPRING-2 study), 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 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 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 be 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 in the open-label phase of the SINGLE study, virological suppression was maintained: it was 71% in the dolutegravir + ABC/3TC group and 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 study FLAMINGO (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 in combination 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 studies GEMINI-1 (204861) and GEMINI-2 (205543), 1433 antiretroviral-naïve HIV-1 infected subjects were randomized into two groups: a two-drug regimen group receiving dolutegravir 50 mg plus lamivudine 300 mg once daily, or a three-drug regimen group receiving 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 combined analysis, the mean age was 33 years, 15% of participants were women, 31% were non-Caucasian, 6% had hepatitis C co-infection, and 9% were CDC stage 3. Approximately one-third of patients were infected with non-B 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 combined analysis were consistent with individual study results, both meeting the primary endpoint (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

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 level in blood plasma ≥ 200 copies/mL after previously confirmed suppression to < 200 copies/mL.

At week 96 of the study, the proportion in the group receiving the combination of dolutegravir + lamivudine (86% < 50 copies/mL HIV-1 RNA in blood plasma [combined analysis]) was non-inferior to that in the group receiving the combination of dolutegravir + fixed-dose tenofovir/emtricitabine (90% < 50 copies/mL HIV-1 RNA in blood 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, which achieved the secondary endpoint (difference in proportion with < 50 copies/mL HIV-1 RNA in blood 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 treatment-naive 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 enzymes 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 raltegravir-resistance mutation 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 major NRTI mutation emerged. Over 96 weeks in studies GEMINI-1 and GEMINI-2, no development of resistance to the integrase inhibitor class or 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 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 two drugs (including at least one fully active agent). Baseline patient characteristics were as follows: mean age 43 years, 32% were female, 50% were non-Caucasian, 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 results based on the 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)

‡ Balanced for stratification factors.

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

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

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

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

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

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

In the multicenter, open-label, single-arm study VIKING-3 (ING112574), adult patients infected with HIV-1 who had previously received antiretroviral therapy (ART), had experienced virological failure, and had resistance to raltegravir and/or elvitegravir currently or in their history, received Tivicay 50 mg twice daily with a failing background regimen for 7 days, after which the background ART was optimized starting on Day 8. The study included 183 patients, of whom 133 had integrase inhibitor (INI) resistance at screening and 50 had historical evidence of resistance (but not at screening). Raltegravir/elvitegravir was part of the failing regimen in 98 of the 183 patients (others had prior failing regimens). Baseline patient characteristics were as follows: mean age was 48 years, 23% of patients 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 the following ARV classes: 79% had resistance to ≥2 NRTIs, 75% to ≥1 NNRTI, and 71% had ≥2 major resistance-associated mutations to PIs; 62% had non-R5 virus.

The mean change in HIV-1 RNA from baseline at Day 8 (primary endpoint) was -1.4 log₁₀ copies/mL (95% CI: -1.3 to -1.5 log₁₀, p < 0.001). Response was associated with baseline INI resistance mutation pathways, 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 time of analysis, VIKING-3 study

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

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

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

In patients without baseline detectable primary mutations (N = 60) (i.e., RAL/EVG was not part of the failing regimen at analysis), a reduction in viral load was observed (1.63 log10 copies/mL at 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), and this response was generally maintained at 48 weeks – 116/183 (63%) patients achieved 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 violations (incorrect dosing of dolutegravir, use of prohibited medications) were excluded, the so-called "virological response population" (VO population), the response rate was 75% (120/161, Week 24) and 69% (111/160, 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 sensitivity score (PSS) of the optimized background regimen (OBR) was not associated with response at either Week 24 or Week 48.

Table 5

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

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

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

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

CVR – 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 a double-blind, placebo-controlled study VIKING-4 (ING116529), 30 adult patients infected with HIV-1 who were receiving ART with primary genotypic resistance to INIs 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% belonged to CDC class C. At baseline, subjects showed multi-class resistance to ART: 80% had ≥2 NRTIs, 73% had ≥1 NNRTI, and 67% had ≥2 PI major 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 (non-placebo-controlled), 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 pooled analysis of VIKING-3 and VIKING-4 studies (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%) for subjects without Q148 mutations, 22/41 (54%) for subjects with Q148 + 1 secondary mutation, and 5/19 (26%) for 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 Tivicay in combination regimens were evaluated in children infected with HIV-1. Subjects were stratified by age to receive Tivicay (70 mg/day as 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

Pharmacokinetics (PK) of dolutegravir are similar in healthy and HIV-infected individuals. PK variability of dolutegravir is low to moderate. In Phase I studies in healthy volunteers, 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, Tivicay is recommended to be taken with food in 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 to plasma proteins (>99%), as established from in vitro data. The apparent volume of distribution based on population pharmacokinetic analysis is 17–20 L in HIV-infected patients. The overall blood-to-plasma 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 on a stable dolutegravir regimen in combination with abacavir/lamivudine at the time of analysis, 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 male and female genital tracts. AUC in cervical-vaginal secretions, cervical tissue, and vaginal tissue was 6–10% of the corresponding plasma value at steady state. AUC in semen and rectal tissue was 7% and 17% of the corresponding plasma value at steady state, respectively.

Biotransformation

Dolutegravir is primarily metabolized via glucuronidation by the UGT1A1 enzyme and to a minor 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 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 showed no direct or weak inhibition (IC50 > 50 µM) of cytochrome P450 (CYP) enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 3A, uridine diphosphate-glucuronosyltransferases (UGT) 1A1 or 2B7, or transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2, or MRP4. In vitro, dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4 enzymes. Based on these data, no impact of dolutegravir on the pharmacokinetics of drugs that are substrates of major enzymes or transporters is expected (see section "Interaction with other medicinal products and other forms of interaction").

In vitro, dolutegravir was not a substrate of human OATP1B1, OATP1B3, or OCT1.

Elimination

The elimination half-life of dolutegravir is ~14 hours. The apparent total plasma clearance (CL/F) is approximately 1 L/hour in HIV-infected patients, as determined from population pharmacokinetic analysis.

Linearity/Non-linearity

The linearity of dolutegravir pharmacokinetics depends on dose and dosage form. 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 the dose of 50 mg twice daily is administered, the 24-hour concentration is 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 by Day 11 with the 50 mg dose. This antiviral response was maintained for 3–4 days after the last dose in the 50 mg group.

There are no clinical data on the safety and efficacy of the 100 mg twice daily dose. Concomitant treatment with atazanavir significantly increases dolutegravir exposure and should not be used in combination with such a high dose, as the safety of the resulting dolutegravir exposure is not established.

Special populations

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 Tivicay 50 mg once daily results in dolutegravir concentrations comparable to those observed in adults receiving Tivicay 50 mg once daily orally.

Elderly patients

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

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

Renal impairment

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

Polymorphism of metabolizing enzymes

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

Sex

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

Race

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

Concurrent infection with hepatitis B or C virus

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

Preclinical safety data

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

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

In animal reproductive toxicity studies, it was established that dolutegravir crosses the placenta.

Oral administration of dolutegravir at doses up to 1000 mg/kg/day from Day 6 to 17 of gestation in pregnant female rats showed no toxic effects on the dam or fetus and no 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 gestation in pregnant female rabbits showed no toxic effects on the fetus and no 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 dam (reduced food consumption, low/absent fecal output/urination, reduced body weight gain) were observed at the 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).

In a toxicity study in juvenile rats, administration of dolutegravir led to two deaths before weaning at the dose of 75 mg/kg/day. During treatment before weaning, mean body weight gain in this group was reduced, with this reduction persisting throughout the study in females after weaning. Systemic exposure to dolutegravir at this dose (based on AUC) was approximately 17–20 times higher than in the pediatric human population receiving the recommended dose. No new target organs were identified in juvenile animals compared to adults. At the NOAEL (no observed adverse effect level) dose of 2 mg/kg/day, AUC values in juvenile rats on Day 13 after birth were approximately 3–6 times higher than in pediatric patients weighing 3 to <10 kg (aged from 4 weeks to >6 months).

The impact of long-term daily treatment with high doses of dolutegravir was evaluated in repeat-dose toxicity studies with oral dosing 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 50 mg twice daily dose clinically used in humans (based on AUC), was associated with gastrointestinal tract intolerance or irritation. Since gastrointestinal tract (GI) intolerance is related to local exposure of the active substance, mg/kg or mg/m² are appropriate safety indicators for such 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

Tivicay 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 index and are substrates of the organic cation transporter 2 (OCT2), including, in particular, fampridine (also known as dalfampridine) (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Effect of other medicinal products on the pharmacokinetics of dolutegravir

If resistance to integrase inhibitor class drugs exists, factors that reduce dolutegravir concentrations 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, no effect of dolutegravir on the pharmacokinetics of medicinal products that are substrates of major enzymes or transporters such as CYP3A4, CYP2C9, or P-gp is expected.

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

In vitro, dolutegravir inhibits renal uptake transporters, organic anion transporters OAT1 and OAT3. Given the limited effect of tenofovir substrate on OAT pharmacokinetics in vivo, in vivo inhibition of OAT1 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 presented in Table 6, where increases are indicated by the symbol ↑, decreases by ↓, and no change by ↔. AUC denotes area under the plasma concentration-time curve, Cmax the maximum observed concentration, and Cτ the concentration at the end of the dosing interval.

Table 6

Drug interactions

Children

Interaction studies have been conducted only in adults.

Special precautions for use

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

Resistance to integrase inhibitor class drugs 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 activity of dolutegravir is significantly reduced in patients infected with viral strains harboring secondary mutations Q148+ ≥ 2 from G140A/C/S, E138A/K/T, L74I (see section "Pharmacodynamics"). It is unclear to what extent dolutegravir provides additional efficacy in the presence of such resistance to integrase inhibitor class drugs.

Hypersensitivity reactions

Hypersensitivity reactions, characterized by rash, structural changes, and sometimes organ dysfunction, including severe hepatic reactions, have been reported with dolutegravir. Dolutegravir and other agents suspected of causing hypersensitivity reactions must be discontinued immediately if signs or symptoms of hypersensitivity occur (including, in particular, 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). Clinical status, including assessment of liver aminotransferases and bilirubin levels, should be monitored. Delay in discontinuing dolutegravir or other causative agents after onset of hypersensitivity reactions may lead to life-threatening allergic reactions.

Immune reconstitution syndrome

In HIV-infected patients with advanced immunodeficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, leading to severe clinical manifestations or worsening of symptoms. Such reactions are typically observed within the first few weeks or months of initiating 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 to occur during immune recovery. However, the reported onset of these conditions is more variable, and they may manifest many months after starting therapy.

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

Monitoring of liver function tests is recommended in patients co-infected with hepatitis B and/or C virus. Particular caution is required when initiating and maintaining effective hepatitis B therapy (in accordance with treatment guidelines) in patients infected with hepatitis B virus who are starting dolutegravir-based therapy (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, 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 discontinuation of concomitant treatment with dolutegravir and metformin to maintain glycemic control (see section "Interaction with other medicinal products and other forms of interaction"). Since metformin is eliminated by the kidneys, renal function should be monitored during concomitant use with dolutegravir. This combination 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 metformin dose.

Osteonecrosis

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

Body weight and metabolic parameters

Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to controlled disease and lifestyle changes. Regarding increased lipid levels, treatment effect has been demonstrated in some cases, while there is no strong evidence linking weight gain 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 requirements.

Lamivudine and dolutegravir

A two-drug regimen of dolutegravir 50 mg once daily and lamivudine 300 mg once daily was evaluated in two large randomized, blinded trials, GEMINI 1 and GEMINI 2 (see section "Pharmacological properties"). 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.

Excipients

The product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Women of childbearing potential

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

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

Pregnancy

In a birth outcomes study in Botswana, a small increase in neural tube defect cases was observed: 7 cases of neural tube defects were reported among 3591 live births (0.19%; 95% CI 0.09%, 0.40%) in infants whose mothers received dolutegravir-containing regimens from the time of conception, compared to 21 cases among 19,361 live births (0.11%; 95% CI 0.07%, 0.17%) in infants whose mothers received regimens not containing dolutegravir from conception.

The background rate of neural tube defects in the general population ranges from 0.5 to 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, the benefits and risks of continuing dolutegravir should be assessed, and switching to alternative antiretroviral regimens should be considered, taking into account gestational age and the critical period of neural tube development.

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

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

More than 1000 outcomes of dolutegravir exposure in the second and third trimesters of pregnancy 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.

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

Information on the effects of dolutegravir on neonates is limited.

Breastfeeding

Dolutegravir is excreted in human breast milk in small amounts (the mean ratio of dolutegravir concentration in breast milk to maternal plasma has been shown to be 0.033).

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

HIV-infected women should under no circumstances breastfeed their infants to avoid 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.

Ability to influence the ability to drive and use machines

Studies on the ability of dolutegravir to influence reaction speed while driving or operating machinery have not been conducted. However, patients should be informed about possible 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

Tivicay should be prescribed by a physician experienced in the management 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) administered orally once daily.

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

HIV-1 infected patients with resistance to integrase inhibitors (documented or clinically suspected)

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

In the presence of documented resistance including secondary mutations Q148 + ≥ 2 from G140A/C/S, E138A/K/T, L74I, modelling suggests that dose escalation may be considered for patients with limited treatment options (fewer than 2 active agents) due to progressive multi-class resistance (see subsection "Pharmacokinetics").
When making decisions regarding the use of dolutegravir in such patients, resistance to integrase inhibitors should be taken into account (see subsection "Pharmacodynamics").

Missed dose

If a patient misses a dose of Tivicay, the patient should take the 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 the following 4 hours, the patient should not take the missed dose and should return to the regular dosing schedule.

Children aged 12 years and older

For children aged 12 to 17 years weighing at least 40 kg and infected with HIV-1 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 these patients (see subsection "Pharmacokinetics").

Method of administration

Oral administration.

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

Children

The medicinal product is intended for use in children aged 12 years and older. The safety and efficacy of Tivicay in children under 12 years of age or weighing less than 40 kg have not been established. Insufficient data are available to recommend the use of Tivicay in children with resistance to integrase inhibitors.

Overdose

Experience with dolutegravir overdose is limited to date.

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

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 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 class and absolute frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Table 7

* Particularly in patients with a history of depression or psychiatric illness.

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

*** In combination with elevated transaminase levels.

Some adverse reactions

Changes in laboratory biochemical test parameters

An increase in 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

Phase III studies included patients with concurrent hepatitis B and/or C virus infection provided baseline liver function biochemical parameters did not exceed the upper limit of normal (ULN) by more than 5 times. 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 elevated AST and ALT levels were more frequent in the subgroup with concurrent hepatitis B and/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 and/or C virus infection at the initiation of dolutegravir treatment, particularly in those who had discontinued hepatitis B treatment (see section "Special precautions").

Immune Reconstitution Syndrome

In HIV-infected patients with severe immunodeficiency at the start of combination antiretroviral therapy (cART), an inflammatory response to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable, and these events may occur many months after initiation of treatment (see section "Special precautions").

Metabolic parameters

During antiretroviral therapy, increases in body weight as well as elevations in blood lipid and glucose levels may occur (see section "Special 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 have been identified beyond those observed in adults.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions

Store at temperatures not exceeding 30 °C. Keep out of reach and sight of children.

Packaging. 30 or 90 film-coated tablets in an opaque white high-density polyethylene bottle with a polypropylene screw cap with child-resistant closure and a polyethylene protective seal. One bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer. Glaxo Wellcome S.A., Spain.

Manufacturer's address and place of business

Glaxo Wellcome S.A., Avenida de Extremadura 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain.

Glaxo Wellcome S.A., Avenida de Extremadura 3, Pol. Ind. Allendeduero, 09400 Aranda de Duero, Burgos, Spain.

Marketing Authorization Holder's Representative

TOV "GlaxoSmithKline Pharmaceuticals Ukraine".

Address of the Marketing Authorization Holder's Representative

1-V Pavla Tychyny Avenue, Kyiv, 02152, Ukraine. Tel: (044) 585-51-85, Fax: (044) 585-51-92.

Reports of all suspected adverse reactions and lack of efficacy may also be submitted to TOV "GlaxoSmithKline Pharmaceuticals Ukraine" via the 24-hour hotline (044) 585-51-85 or by email at [email protected].