This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Film-coated tablet (tablet). Yellow, round, biconvex tablets approximately 9 mm in diameter debossed with 'SV 572' on one side and '50' on the other side.

CLINICAL PARTICULARS

Posology and method of administration

Tivicay should be prescribed by physicians experienced in the management of HIV infection. Posology

Patients infected with HIV-1 without documented or clinically suspected resistance to the integrase class

The recommended dose of dolutegravir is 50 mg (one tablet) orally once daily. Tivicay should be administered twice daily in this population when co-administered with some medicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Please refer to section 4.5.

Patients infected with HIV-1 with resistance to the integrase class (documented or clinically suspected)

The recommended dose of dolutegravir is 50 mg (one tablet) twice daily. The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (see section 5.1). Co-administration of Tivicay with some medicines should be avoided in this population (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Please refer to section 4.4 and 4.5.

If the patient misses a dose of Tivicay, the patient should take Tivicay as soon as possible, providing the next dose is not due within 4 hours. If the next dose is due within 4 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

In adolescents (aged from 12 to 17 years and weighing at least 40 kg) infected with HIV-1 without resistance to the integrase class, the recommended dose of dolutegravir is 50 mg once daily.

There are limited data available on the use of dolutegravir in patients aged 65 years and over. There is no evidence that elderly patients require a different dose than younger adult patients (see section 5.2).

No dosage adjustment is required in patients with mild, moderate or severe (CrCl <30 mL/min, not on dialysis) renal impairment. No data are available in subjects receiving dialysis although differences in pharmacokinetics are not expected in this population (see section 5.2).

No dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh grade A or B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C); therefore dolutegravir should be used with caution in these patients (see section 5.2).

The safety and efficacy of Tivicay in children aged less than 12 years or weighing less than 40 kg has not yet been established. In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose for Tivicay in children and adolescents. Currently available data are described in section 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Oral use. Tivicay can be taken with or without food (see section 5.2). In the presence of integrase class resistance, Tivicay should preferably be taken with food to enhance exposure (particularly in patients with Q148 mutations) (see section 5.2).

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Co-administration with dofetilide (see section 4.5).

Special warnings and precautions for use

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

The decision to use dolutegravir in the presence of integrase class resistance should take into account that the activity of dolutegravir is considerably compromised for viral strains harbouring Q148+>2 secondary mutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides added efficacy in the presence of such integrase class resistance is uncertain.

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir and other suspect agents should be discontinued immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raised liver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubin should be monitored. Delay in stopping treatment with dolutegravir or other suspect active substances after the onset of hypersensitivity may result in a life-threatening allergic reaction.

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' disease) have also been reported to occur in the setting of immune reconstitution, however, the reported time to onset is more variable and these events can occur many months after initiation of treatment. Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liver biochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see section 4.8).

Patients should be advised that dolutegravir or any other antiretroviral therapy does 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 observation by physicians experienced in the treatment of these associated HIV diseases.

Factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. This includes co-administration with medicinal products that reduce dolutegravir exposure (e.g. magnesium/ aluminium-containing antacid, iron and calcium supplements, multivitamins and inducing agents, tipranavir/ritonavir, rifampicin and certain anti-epileptic drugs) (see section 4.5). Metformin concentrations may be increased by dolutegravir. Patients should be monitored during therapy and a dose adjustment of metformin may be required (see section 4.5).

Although the aetiology is considered to be multifactorial (including corticosteroid use, biphosphonates, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported in patients with advanced HIV-disease and/or long-term exposure to CART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Interaction with other medicinal products and other forms of interaction

All factors that decrease dolutegravir exposure should be avoided in the presence of integrase class resistance. Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore medicinal products that induce those enzymes may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 1). Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increase dolutegravir plasma concentration (see Table 1). The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 1). Effect of dolutegravir on the pharmacokinetics of other agents In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 mM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphate glucuronosyl transferase (UGT)1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MATE2-K, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir does not seem to have an effect on midazolam, a CYP3A4 probe, however, a weak inhibition can presently not be excluded. Based on these data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of these enzymes or transporters.

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 or MATE-1 (e.g. dofetilide, metformin) (see Table 1 and section 4.3). In vitro, dolutegravir inhibited the renal uptake transporters (OAT1) and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medical products in which excretion is dependent upon OAT3. Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 1. Interaction table Interactions between dolutegravir and co-administered medicinal products are listed in Table 1 (increase is indicated as "|", decrease as "|", no change as "-", area under the concentration versus time curve as "AUC", maximum observed concentration as "Cmax").

Table 1: Drug Interactions

Fertility, pregnancy and lactation

There are no or limited amount of data from the use of dolutegravir in pregnant women. The effect of dolutegravir on human pregnancy is unknown. In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Tivicay should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus. There are no or limited amount of data from the use of dolutegravir in pregnant women.

It is unknown whether dolutegravir is excreted in human milk. Available toxicological data in animals has shown excretion of dolutegravir in milk. In lactating rats that received a single oral dose of 50 mg/kg at 10 days postpartum, dolutegravir was detected in milk at concentrations typically higher than blood. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility (see section 5.3).

Effects on ability to drive and use machines

There have been no studies to investigate the effect of dolutegravir on driving performance or the ability to operate machines. However, patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of dolutegravir should be borne in mind when considering the patient's ability to drive or operate machinery.

Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from Phase IIb and Phase III clinical studies in 980 previously untreated patients, 357 previously treated patients unexposed to integrase inhibitors and 234 patients with prior treatment failure that included an integrase inhibitor (including integrase class resistance). The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that included rash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adverse reactions were nausea (15%), diarrhoea (16%) and headache (14%). The safety profile was similar across the different treatment populations mentioned above.

Tabulated list of adverse reactions

The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organ class and absolute frequency. Frequencies are defined as 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).

Table 2 Adverse Reactions

Immune system disorders	Uncommon	Hypersensitivity (see section 4.4)
Immune system disorders	Uncommon	Immune Reconstitution Syndrome (see section 4.4) * *
Psychiatric disorders	Common	Insomnia
Psychiatric disorders	Common	Abnormal dreams
Nervous system disorders	Very common	Headache
Nervous system disorders	Common	Dizziness
Gastrointestinal disorders	Very common	Nausea
	Very common	Diarrhoea
	Common	Vomiting
	Common	Flatulence
	Common	Upper abdominal pain
	Common	Abdominal pain
	Common	Abdominal discomfort
Hepatobiliary disorders	Uncommon	Hepatitis
Skin and subcutaneous tissue disorders	Common	Rash
Skin and subcutaneous tissue disorders	Common	Pruritus
General disorders and administration site conditions	Common	Fatigue
Investigations	Common	Alanine aminotransferase (ALT) and/or Aspartate aminotransferase (AST) elevations
Investigations	Common	Creatine phosphokinase (CPK) elevations

* *see below under Description of selected adverse reactions. Description of selected adverse reactions

Changes in laboratory biochemistries

Increases in serum creatinine occurred within the first week of treatment with Tivicay and remained stable through 48 weeks. A mean change from baseline of 9.96 mmol/L was observed after 48 weeks of treatment. Creatinine increases were comparable by various background regimens. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate.

Co-infection with Hepatitis B or C

In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at the start of Tivicay therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (see section 4.4).

Immune response syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Paediatric population

Based on limited available data in adolescents (12 to less than 18 years of age and weighing at least 40 kg), there were no additional types of adverse reactions beyond those observed in the adult population.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Overdose

There is currently limited experience with overdosage in dolutegravir. Limited experience of single higher doses (up to 250 mg in healthy subjects) revealed no specific symptoms or signs, apart from those listed as adverse reactions. Further management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of dolutegravir. If overdose occurs, the patient should be treated supportively with appropriate monitoring, as necessary. As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AX12 Mechanism of action Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Pharmacodynamic effects

The IC50 for dolutegravir in various labstrains using PBMC was 0.5 nM, and when using MT-4 cells it ranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference between subtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 value was 0.2 nM (range 0.02-2.14). The mean IC50 for 3 HIV-2 isolates was 0.18 nM (range 0.09-0.61).

No antagonistic effects in vitro were seen with dolutegravir and other antiretrovirals tested agents: stavudine, abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc and raltegravir. In addition, no antagonistic effects were seen for dolutegravir and adefovir, and ribavirin had no apparent effect on dolutegravir activity.

In 100% human serum, the mean protein fold shift was 75 fold, resulting in protein adjusted IC90 of 0.064 ug/mL.

Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIVIII during passage over 112 days, mutations selected appeared slowly, with substitutions at positions S153Y and F, resulting in a maximal fold change in susceptibility of 4 (range 2-4). These mutations were not selected in patients treated with dolutegravir in the clinical studies. Using strain NL432, mutations E92Q (FC 3) and G193E (also FC 3) were selected. The E92Q mutation has been selected in patients with pre-existing raltegravir resistance who were then treated with dolutegravir (listed as a secondary mutation for dolutegravir). In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all five isolates (after 20 weeks and onwards). In subtype C (n=2) and A/G (n=2) isolates the integrase substitution R263K was selected in one isolate, and G118R in two isolates. R263K was reported from two ART experienced, INI naive individual patients with subtypes B and C in the clinical program, but without effects on dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directed mutants (FC 10), but was not detected in patients receiving dolutegravir in the Phase III program. Primary mutations for raltegravir/elvitegravir (Q148H/R/K, N155H, Y143R/H/C, E92Q and T66I) do not affect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondary integrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to these primary mutations in experiments with site directed mutants, dolutegravir susceptibility is still unchanged (FC <2 vs wild type virus), except in the case of the Q148-mutation, where a FC of 5-10 or higher is seen with the combination of secondary mutations. The effect by the Q148-mutations (H/R/K) was also verified in passage experiments with site directed mutants. In serial passage with strain NL432, starting with site directed mutants harbouring N155H or E92Q, no further selection of resistance was seen (FC unchanged around 1). In contrast, starting with mutants harbouring mutation Q148H (FC 1), a variety of secondary mutations were seen with a consequent increase of FC to values >10. A clinically relevant phenotypic cut-off value (FC vs wild type virus) has not been determined; genotypic resistance was a better predictor for outcome. Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed for susceptibility to dolutegravir. Dolutegravir has a <10 FC against 94% of the 705 clinical isolates.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no development of resistance to the integrase class, or to the NRTI class was seen (n=876, follow-up of 48-96 weeks). In patients with prior failed therapies, but naive to the integrase class (SAILING study), integrase inhibitor substitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which was given in combination with an investigator selected background regimen (BR). Of these four, two subjects had a unique R263K integrase substitution, with a maximum FC of 1.93, one subject had a polymorphic V151V/I integrase substitution, with maximum FC of 0.92, and one subject had pre-existing integrase mutations and is assumed to have been integrase experienced or infected with integrase resistant virus by transmission. The R263K mutation was also selected in vitro (see above). In the presence of integrase class-resistance (VIKING-3 study) the following mutations were selected in 31 patients with protocol defined virological failure through Week 24 and with paired genotypes (all treated with dolutegravir 50 mg twice daily + optimized background agents): L74L/M (n=1), E92Q (n=2), T97A (n=8), E138K/A (n=7), G140S (n=2), Y143H (n=1), S147G (n=1), Q148H/K/R (n=4), and N155H (n=1) and E157E/Q (n=1). Treatment emergent integrase resistance typically appeared in patients with a history of the Q148-mutation (baseline or historic).

No relevant effects were seen on the QTc interval, with doses exceeding the clinical dose by approximately three fold.

The efficacy of Tivicay in HIV-infected, therapy naive subjects is based on the analyses of 48-week data from two randomized, international, double-blind, active-controlled trials, SPRING-2 (ING113086) and SINGLE (ING114467). In SPRING-2, 822 adults were randomized and received at least one dose of either Tivicay 50 mg once daily or raltegravir (RAL) 400 mg twice daily, both administered with fixed-dose dual NRTI therapy (either ABC/3TC or TDF/FTC). At baseline, median patient age was 36 years, 14% were female, 15% non-white, 11% had hepatitis B and/or C co-infection and 2% were CDC Class C, these characteristics were similar between treatment groups. In SINGLE, 833 subjects were randomized and received at least one dose of either Tivicay 50 mg once daily with fixed-dose abacavir-lamivudine (DTG + ABC/3TC) or fixed-dose efavirenz-tenofovir-emtricitabine (EFV/TDF/FTC). At baseline, median patient age was 35 years, 16% were female, 32% non-white, 7% had hepatitis C co-infection and 4% were CDC Class C, these characteristics were similar between treatment groups. Week 48 outcomes (including outcomes by key baseline covariates) for SPRING-2 and SINGLE are shown in Table 3.

Table 3 Response in SPRING-2 and SINGLE at 48 Weeks (Snapshot algorithm, <50 copies/mL)

loss of efficacy and subjects who are >=50 copies in the 48 week window. ++ Adjusted mean treatment difference was statistically significant (p<0.001) In the SINGLE study, virologic suppression (HIV-1 RNA <50 copies/mL) in the Tivicay + ABC/3TC arm was 88%, which was superior to the EFV/TDF/FTC arm (81%), based on the primary analysis (p=0.003). ). This analysis was pre-specified and adjusted for multiplicity. The median time to viral suppression was 28 days in the group receiving Tivicay + ABC/3TC and 84 days in the EFV/TDF/FTC arm in SINGLE at 48 weeks (p<0.0001). This analysis was pre-specified and adjusted for multiplicity. Through 48 weeks in SPRING-2 and SINGLE, no INI-resistant mutations or treatment emergent resistance in background therapy were isolated on the Tivicay-containing arms. In SPRING-2, four subjects on the RAL arm failed with major NRTI mutations and one subject developed raltegravir resistance; in SINGLE, four subjects on the EFV/TDF/FTC arm failed with mutations associated with NNRTI resistance and one developed a major NRTI mutation. Sustained virological response was demonstrated in the SPRING-1 study (ING112276), in which 88% of patients receiving Tivicay 50 mg (n=51) once daily had HIV-1 RNA <50 copies/mL, compared to 72% of patients in the efavirenz group (n=50) at 96 weeks. In patients treated with Tivicay 50 mg once daily, de novo resistance to the integrase class, or the NRTI background agents were not detected during 96 weeks of follow-up.

In the international multicentre, double-blind SAILING study (ING111762), 719 HIV-1 infected, antiretroviral therapy (ART)-experienced adults were randomized and received either Tivicay 50 mg once daily or raltegravir 400 mg twice daily with investigator selected background regimen consisting of up to 2 agents (including at least one fully active agent). At baseline, median patient age was 43 years, 32% were female, 50% non-white, 16% had hepatitis B and/or C co-infection, and 46% were CDC Class C. All patients had at least two class ART resistance, and 49% of subjects had at least 3-class ART resistance at baseline. Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 4.

Table 4 Response in SAILING at 48 Weeks (Snapshot algorithm, <50 copies/mL)

In the SAILING study, virologic suppression (HIV-1 RNA <50 copies/mL) in the Tivicay arm (71%) was statistically superior to the raltegravir arm (64%), at Week 48 (p=0.03). Statistically fewer subjects failed therapy with treatment-emergent integrase resistance on Tivicay (4/354, 1%) than on raltegravir (17/361, 5%) (p=0.003) (refer to section 'Resistance in vivo' above for details).

Patients with prior treatment failure that included an integrase inhibitor (and integrase class resistance)

In the multicentre, open-label, single arm VIKING-3 study (ING112574), HIV-1 infected, ART-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received Tivicay 50 mg twice daily with the current failing background regimen for 7 days but with optimised background ART from Day 8. The study enrolled 183 patients, 133 with INI-resistance at Screening and 50 with only historical evidence of resistance (and not at Screening) resistance. Raltegravir/elvitegravir was part of the current failing regimen in 90/183 patients (part of prior failing therapies in the others). At baseline, median patient age was 48 years, 23% were female, 29% non-white, and 20% had hepatitis B and/or C co-infection. Median baseline CD4+ was 140 cells/mm3, median duration of prior ART was 13 years, and 56% were CDC Class C. Subjects showed multiple class ART resistance at baseline: 79% had >=2 NRTI, 75% >=1 NNRTI, and 71% >=2 PI major mutations; 62% had non-R5 virus. Mean change from baseline in HIV RNA at day 8 (primary endpoint) was -1.4log10 copies/mL (95% CI -1.3 - -1.5log10, p<0.001). Response was associated with baseline INI mutation pathway, as shown in Table 5. Patients who stopped dolutegravir therapy for non-efficacy reasons, or who were protocol deviations for incorrect dolutegravir dosing or prohibited medication use are excluded in the analysis of the Virological Outcome (VO) population.

Table 5 Virologic response (day 8) after 7 days of functional monotherapy, in patients with RAL/EVG as part of current failing regimen, VIKING 3

In patients without a primary mutations detected at baseline (N=60) (i.e. RAL/EVG not part of current failing therapy) there was a 1.63 log10 reduction in viral load at day 8. After the functional monotherapy phase, subjects had the opportunity to re-optimize their background regimen when possible. Based on 24-week data for all 183 patients, 126 (69%) had <50 copies/mL RNA at Week 24 (Snapshot algorithm). Corresponding response for the VO population was 75% (120/161). The response was lower when the Q148-mutation was present at baseline, and in particular in the presence of >=2 secondary mutations, Table 6. The overall susceptibility score (OSS) of the optimised background regimen (OBR) was not associated with Week 24 response.

Table 6 Response by baseline Resistance, Week 24 VO Population (HIV-1 RNA <50 c/mL, Snapshot algorithm)

At Week 24 the median change in CD4+ T cell count from baseline was 61 cells/mm3 for VIKING-3 based on observed data. In the double blind, placebo controlled VIKING-4 study (ING116529), 30 HIV-1 infected, ART-experienced adults with primary genotypic resistance to INIs at Screening, were randomised to receive either dolutegravir 50 mg twice daily or placebo with the current failing regimen for 7 days followed by an open label phase with all subjects receiving dolutegravir. The primary endpoint at Day 8 showed that dolutegravir 50 mg twice daily was superior to placebo, with an adjusted mean treatment difference for the change from Baseline in Plasma HIV-1 RNA of -1.2 log10 copies/mL (95% CI -1.5 - -0.8log10 copies/mL, p<0.001). The day 8 responses in this placebo controlled study were fully in line with those seen in VIKING-3 (not placebo controlled), including by baseline integrase resistance categories.

In a Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokinetic parameters, safety, tolerability and efficacy of Tivicay will be evaluated in combination regimens in HIV-1 infected adolescents. At 24 weeks, 16 of 23 (70%) adolescents (12 to less than 18 years of age) treated with Tivicay once daily (35 mg n=4, 50 mg n=19) plus OBR achieved viral load <50 copies/mL. Four subjects had virologic failure none of which had INI resistance at the time of virologic failure. The European Medicines Agency has deferred the obligation to submit the results of studies with Tivicay in paediatric patients aged 4 weeks to below 12 years with HIV infection (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability of dolutegravir is low to moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC and Cmax ranged from ~20 to 40% and Ct from 30 to 65% across studies. The between-subject PK variability of dolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) is lower than between-subject variability.

Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 2 to 3 hours post dose for tablet formulation. Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravir depends on meal content: low, moderate, and high fat meals increased dolutegravir AUC(0-[?]) by 33%, 41%, and 66%, increased Cmax by 46%, 52%, and 67%, prolonged Tmax to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. These increases may be clinically relevant in the presence of certain integrase class resistance. Therefore, Tivicay is recommended to be taken with food by patients infected with HIV with integrase class resistance (see section 4.2). The absolute bioavailability of dolutegravir has not been established. Distribution Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. The apparent volume of distribution is 17 L to 20 L in HIV-infected patients, based on a population pharmacokinetic analysis. Binding of dolutegravir to plasma proteins is independent of dolutegravir concentration. Total blood and plasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimal association of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasma is increased at low levels of serum albumin (<35 g/L) as seen in subjects with moderate hepatic impairment. Dolutegravir is present in cerebrospinal fluid (CSF). In 13 treatment-naive subjects on a stable dolutegravir plus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable to unbound plasma concentration, and above the IC50). Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue and vaginal tissue were 6-10% of those in corresponding plasma at steady state. AUC in semen was 7% and 17% in rectal tissue of those in corresponding plasma at steady state.

Dolutegravir is primarily metabolized through glucuronidation via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose).

Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately 1L/hr in HIV-infected patients based on a population pharmacokinetic analysis.

The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oral administration of tablet formulations, in general, dolutegravir exhibited nonlinear pharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; however increase in dolutegravir exposure appears dose proportional from 25 mg to 50 mg for the tablet formulation. With 50 mg twice daily, the exposure over 24 hours was approximately doubled compared to 50 mg once daily.

In a randomized, dose-ranging trial, HIV-1-infected subjects treated with dolutegravir monotherapy (ING111521) demonstrated rapid and dose-dependent antiviral activity, with mean declinein HIV-1 RNA of 2.5 log10 at day 11 for 50 mg dose . This antiviral response was maintained for 3 to 4 days after the last dose in the 50 mg group.

The pharmacokinetics of dolutegravir in 10 antiretroviral treatment-experienced HIV-1 infected adolescents (12 to <18 years of age) showed that Tivicay 50 mg once daily oral dosage resulted in dolutegravir exposure comparable to that observed in adults who received Tivicay 50 mg orally once daily.

Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that there was no clinically relevant effect of age on dolutegravir exposure. Pharmacokinetic data for dolutegravir in subjects >65 years of age are limited. Renal impairment Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A study of the pharmacokinetics of dolutegravir was performed in subjects with severe renal impairment (CLcr <30 mL/min) and matched healthy controls. The exposure to dolutegravir was decreased by approximately 40% in subjects with severe renal impairment. The mechanism for the decrease is unknown. No dosage adjustment is considered necessary for patients with renal impairment. Tivicay has not been studied in patients on dialysis.

Dolutegravir is primarily metabolized and eliminated by the liver. A single dose of 50 mg of dolutegravir was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to 8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5- to 2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepatic impairment compared to healthy controls. No dosage adjustment is considered necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of Tivicay has not been studied.

There is no evidence that common polymorphisms in drug metabolising enzymes alter dolutegravir pharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samples collected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n=41).

Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of gender on the exposure of dolutegravir.

Population PK analyses using pooled pharmacokinetic data from Phase IIb and Phase III adult trials revealed no clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravir following single dose oral administration to Japanese subjects appear similar to observed parameters in Western (US) subjects.

Population pharmacokinetic analysis indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection.

Preclinical safety data

Dolutegravir was not mutagenic or clastogenic using in vitro tests in bacteria and cultured mammalian cells, and an in vivo rodent micronucleus assay. Dolutegravir was not carcinogenic in long term studies in the mouse and rat. Dolutegravir did not affect male or female fertility in rats at doses up to 1000 mg/kg/day, the highest dose tested (24 times the 50 mg twice daily human clinical exposure based on AUC). Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (27 times the 50 mg twice daily human clinical exposure based on AUC). Oral administration of dolutegravir to pregnant rabbits at doses up to 1000 mg/kg daily from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity (0.40 times the 50 mg twice daily human clinical exposure based on AUC). In rabbits, maternal toxicity (decreased food consumption, scant/no faeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.40 times the 50 mg twice daily human clinical exposure based on AUC). The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oral dose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect of dolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemic exposures approximately 21 and 0.82 times the 50 mg twice daily human clinical exposure based on AUC, respectively. Because gastrointestinal (GI) intolerance is considered to be due to local active substance administration, mg/kg or mg/m2 metrics are appropriate determinates of safety cover for this toxicity. GI intolerance in monkeys occurred at 15 times the human mg/kg equivalent dose (based on a 50 kg human), and 5 times the human mg/m2 equivalent dose for a clinical dose of 50 mg twice daily.

PHARMACEUTICAL PARTICULARS

List of excipients

Microcrystalline cellulose Povidone K29/32 Sodium starch glycolate Sodium stearyl fumarate

Polyvinyl alcohol-partially hydrolyzed Titanium dioxide (E171) Macrogol Talc Iron oxide yellow (E172)

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

HDPE (high density polyethylene) bottles closed with polypropylene screw closures, with a polyethylene faced induction heat seal liner. The bottles contain 30 or 90 film-coated tablets. Not all pack sizes may be marketed.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

ViiV Healthcare UK Limited 980 Great West Road Brentford Middlesex TW8 9GS United Kingdom

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Medicinal products by therapeutic areas	Interaction Geometric mean change (%)	Recommendations concerning co-administration
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors
Etravirine	Dolutegravir \| AUC \| 71% C m ax \| 52% Ct \| 88% Etravirine - (induction of UGT1A1 and CYP3A enzymes)	Etravirine decreased plasma dolutegravir concentration, which may result in loss of virologic response and possible resistance to dolutegravir. Tivicay should not be used with etravirine without co-administration of atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir (see further below in table).
Efavirenz	Dolutegravir \| AUC \| 57% C m ax \| 39% Ct \| 75% Efavirenz - (historical controls)	The recommended dose of Tivicay is 50 mg twice daily when co-administered with efavirenz. In the presence of integrase class resistance alternative combinations that do not include efavirenz should be considered (see section 4.4).
	(induction of UGT1A1 and CYP3A enzymes)
Nevirapine	Dolutegravir \|	. The recommended dose of Tivicay is 50 mg twice
	(Not studied, a similar	daily when co-administered with nevirapine.
	reduction in exposure as	In the presence of integrase class resistance
	observed with efavirenz is	alternative combinations that do not include
	expected, due to induction)	nevirapine should be considered (see section 4.4).
Rilpivirine	Dolutegravir - AUC \| 12% C m ax \| 13% Ct \| 22% Rilpivirine -	No dose adjustment is necessary.
Nucleoside Reverse Transcriptase Inhibitors
Tenofovir	Dolutegravir - AUC \| 1% C m ax \| 3% Ct \| 8% Tenofovir -	No dose adjustment is necessary.
Protease Inhibitors
Atazanavir	Dolutegravir \| AUC \| 91% C m ax \| 50% Ct \| 180% Atazanavir - (historical controls) (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary.
Atazanavir/ritonavir	Dolutegravir \| AUC \| 62% C m ax \| 34% Ct \| 121% Atazanavir - Ritonavir - (inhibition of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary.
Tipranavir/ritonavir (TPV+RTV)	Dolutegravir \| AUC \| 59% C m ax \| 47% Ct \| 76% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of Tivicay is 50 mg twice daily when co-administered with tipranavir/ritonavir the absence of integrase class resistance. In the presence of integrase class resistance this combination should be avoided (see section 4.4).
Fosamprenavir/ ritonavir (FPV+RTV)	Dolutegravir \| AUC \| 35% C m ax \| 24% Ct \| 49% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary in the absence of integrase class resistance. In the presence of integrase class resistance alternative combinations that do not include fosamprenavir/ritonavir should be considered.
Protease Inhibitor: Nelfinavir	Dolutegravir - (Not studied)	No dose adjustment is necessary.
Protease Inhibitor: Darunavir/ritonavir	Dolutegravir \| AUC \| 32% C m ax \| 11% C 2 4 \| 38%	No dose adjustment is necessary.
	(induction of UGT1A1 and CYP3A enzymes)
Lopinavir/ritonavir	Dolutegravir - AUC \| 3% C m ax - 0% C 2 4 \| 6%	No dose adjustment is necessary.
Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors combinations
Lopinavir/ritonavir + etravirine	Dolutegravir - AUC \| 10% C m ax \| 7% Ct \| 28% LPV - RTV -	No dose adjustment is necessary.
Darunavir/ritonavir + etravirine	Dolutegravir \| AUC \| 25% C m ax \| 12% Ct \| 37% DRV - RTV -	No dose adjustment is necessary.
Other Antiviral agents
Telaprevir	Dolutegravir \| AUC \| 25% C m ax \| 19% Ct \| 37% Telaprevir - (historical controls) (inhibition of CYP3A enzyme)	No dose adjustment is necessary.
Boceprevir	Dolutegravir - AUC \| 7% C m ax \| 5% Ct \| 8%	No dose adjustment is necessary.
Other agents
Antiarrhythmics
Dofetilide	Dofetilide \| (Not studied, potential increase via inhibition of OCT2 transporter)	Tivicay and dofetilide co-administration is contraindicated due to potential life-threatening toxicity caused by high dofetilide concentration (see section 4.3).
Anticonvulsants
Oxcarbamazepine Phenytoin Phenobarbital Carbamazepine	Dolutegravir \| (Not studied, decrease expected due to induction of UGT1A1 and CYP3A enzymes)	Co-administration with these enzyme inducers should be avoided.
Azole anti-fungal agents
Ketoconazole	Dolutegravir -	No dose adjustment is necessary. Based on data
Fluconazole	(Not studied)	from other CYP3A4 inhibitors, a marked increase
Itraconazole		is not expected.
Posaconazole
Voriconazole
Herbal products
St. John's wort	Dolutegravir \| (Not studied, decrease expected due to induction of	Co-administration with St. John's wort is strongly discouraged.
	UGT1A1 and CYP3A enzymes)
Antacids and supplements
Magnesium/ aluminium-containing antacid	Dolutegravir \| AUC \| 74% C m ax \| 72% (Complex binding to polyvalent ions)	Magnesium/ aluminium-containing antacid should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).
Calcium supplements	Dolutegravir \| AUC \| 39% C m ax \| 37% C 2 4 \| 39% (Complex binding to polyvalent ions)	Calcium supplements, iron supplements or multivitamins should be taken well separated in time from the administration of dolutegravir (minimum 2 hours after or 6 hours before).
Iron supplements	Dolutegravir \| AUC \| 54% C m ax \| 57% C 2 4 \| 56% (Complex binding to polyvalent ions)
Multivitamin	Dolutegravir \| AUC \| 33% C m ax \| 35% C 2 4 \| 32% (Complex binding to polyvalent ions)
Corticosteroids
Prednisone	Dolutegravir - AUC \| 11% C m ax \| 6% Ct \| 17%	No dose adjustment is necessary.
Antidiabetics
Metformin	Metformin \| Dolutegravir - (Not studied. Increase of metformin expected, due to inhibition of OCT-2 transporter)	Close monitoring of metformin efficacy and safety is recommended when starting or stopping dolutegravir in patients receiving metformin. A dose adjustment of metformin may be necessary.
Antimycobacterials
Rifampicin	Dolutegravir \| AUC \| 54% C m ax \| 43% Ct \| 72% (induction of UGT1A1 and CYP3A enzymes)	The recommended dose of Tivicay is 50 mg twice daily when co-administered with rifampicin in the absence of integrase class resistance. In the presence of integrase class resistance this combination should be avoided (see section 4.4).
Rifabutin	Dolutegravir - AUC \| 5% C m ax \| 16% Ct \| 30% (induction of UGT1A1 and CYP3A enzymes)	No dose adjustment is necessary.
Oral contraceptives
Ethinyl estradiol (EE) and Norgestromin (NGMN)	Dolutegravir - EE - AUC \| 3%	Dolutegravir had no pharmacodynamic effect on Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and progesterone. No dose
	C m ax \| 1% NGMN - AUC \| 2% C m ax \| 11%	adjustment of oral contraceptives is necessary when co-administered with Tivicay.
Analgesics
Methadone	Dolutegravir - Methadone - AUC \| 2% C m ax - 0% C t \| 1%	No dose adjustment is necessary of either agent.

	SPRING-2		SINGLE
	Tivicay 50 mg Once Daily + 2 NRTI N=411	RAL 400 mg Twice Daily + 2 NRTI N=411	Tivicay 50 mg + ABC/3TC Once Daily N=414	EFV/TDF/FTC Once Daily N=419
HIV-1 RNA <50 copies/mL	88%	85%	88%	81%
Treatment Difference *	2.5% (95% CI: -2.2%, 7.1%)		7.4% (95% CI: 2.5%, 12.3%)
Virologic non-response+	5%	8%	5%	6%
Baseline Viral Load (cps/mL)
<= 100,000	267 / 297 (90%)	264 / 295 (89%)	253 / 280 (90%)	238 / 288 (83%)
>100,000	94 / 114 (82%)	87 / 116 (75%)	111 / 134 (83%)	100 / 131 (76%)
Baseline CD4+ (cells/ mm 3 )
<200	43 / 55 (78%)	34 / 50 (68%)	45 / 57 (79%)	48 / 62 (77%)
200 to <350	128 / 144 (89%)	118 / 139 (85%)	143 / 163 (88%)	126 / 159 (79%)
>= 350	190 / 212 (90%)	199 / 222 (90%)	176 / 194 (91%)	164 / 198 (83%)
NRTI backbone
ABC/3TC	145 / 169 (86%)	142 / 164 (87%)	N/A	N/A
TDF/FTC	216 / 242 (89%)	209 / 247 (85%)	N/A	N/A
Gender
Male	308 / 348 (89%)	305 / 355 (86%)	307 / 347 (88%)	291 / 356 (82%)
Female	53 / 63 (84%)	46 / 56 (82%)	57 / 67 (85%)	47 / 63 (75%)
Race
White	306 / 346 (88%)	301 / 352 (86%)	255 / 284 (90%)	238 /285 (84%)
Non white	55 / 65 (85%)	50 / 59 (85%)	109 / 130 (84%)	99 / 133 (74%)
Age (years)
<50	324/370 (88%)	312/365 (85%)	319/361 (88%)	302/375 (81%)
>= 50	37/41 (90%)	39/46 (85%)	45/53 (85%)	36/44 (82%)
Median CD4 change from baseline	230	230	246++	187++
* Adjusted for baseline stratification factors. + Includes subjects who changed BR to new class or changed BR not permitted per protocol or due to lack of efficacy prior to Week 48 (for SPRING-2 only), subjects who discontinued prior to Week 48 for lack or

Tivicay 50 mg Once Daily + BR N=354SS		RAL 400 mg Twice Daily + BR N=361SS
HIV-1 RNA <50 copies/mL	71%	64%
Adjusted treatment difference++	7.4% (95% CI: 0.7%, 14.2%)
Virologic non-response	20%	28%
Baseline Viral Load (copies/mL)
<= 50,000 copies/mL	186 / 249 (75%)	180 / 254 (71%)
>50,000 copies/mL	65 / 105 (62%)	50 / 107 (47%)
Baseline CD4+ (cells/ mm 3 )
<50	33 / 62 (53%)	30 / 59 (51%)
50 to <200	77 / 111 (69%)	76 / 125 (61%)
200 to <350	64 / 82 (78%)	53 / 79 (67%)
>= 350	77 / 99 (78%)	71 / 98 (73%)
HIV-1 RNA < 50 copies/mL by Background Regimen
Genotypic Susceptibility Score * <2	155 / 216 (72%)	129 / 192 (67%)
Genotypic Susceptibility Score * =2	96 / 138 (70%)	101 / 169 (60%)
Use of DRV without PI mutations
Yes	50 / 72 (69%)	54 / 77 (70%)
No	201 / 282 (71%)	176 / 284 (62%)
HIV-1 RNA <50 copies/mL by Gender
Male	172 / 247 (70%)	156 / 238 (66%)
Female	79 / 107 (74%)	74 / 123 (60%)
HIV-1 RNA <50 copies/mL by Race
White	133 / 178 (75%)	125 / 175 (71%)
Non white	118 / 175 (67%)	105 / 185 (57%)
HIV-1 RNA <50 copies/mL by Age (years)
<50	196 / 269 (73%)	172 / 277 (62%)
>= 50	55 / 85 (65%)	58 / 84 (69%)
HIV-1 RNA <50 copies/mL by HIV sub type
Clade B	173 / 241 (72%)	159 / 246 (65%)
Clade C	34 / 55 (62%)	29 / 48 (60%)
Other+	43 / 57 (75%)	42 / 67 (63%)
Mean increase in CD4+ T cell (cells/mm 3 )	162	153
++ Adjusted for baseline stratification factors. SS 4 subjects were excluded from the efficacy analysis due to data integrity at one study site *The Genotypic Susceptibility Score (GSS) was defined as the total number of ARTs in BR to which a subject's viral isolate showed susceptibility at baseline based upon genotypic resistance tests. +Other clades included: Complex (43), F1 (32), A1 (18), BF (14), all others <10.

Baseline parameters	DTG 50 mg BID N=88
Baseline parameters	n	Mean (SD) Plasma HIV-1 RNA log 10 c/mL	Median
Derived IN mutation group at Baseline with ongoing RAL/EVG
No Q148 a	48	-1.59 (0.47)	-1.64
Q148+1 b	26	-1.14 (0.61)	-1.08
Q148+ >= 2 b	14	-0.75 (0.84)	-0.45
a Included primary IN resistance mutations N155H, Y143C/H/R, T66A, E92Q b Secondary mutations from G140A/C/S, E138A/K/T, L74I.

Derived IN Mutation Group	OSS=0	OSS=1	OSS=2	OSS>2	Total
No primary IN mutation 1	2/2 (100%)	15/20 (75%)	19/21 (90%)	9/12 (75%)	45/55 (82%)
No Q148H/K/R mutations 2	2/2 (100%)	20/20 (100%)	21/27 (78%)	8/10 (80%)	51/59 (86%)
Q148 + 1 secondary mutation 3	2/2 (100%)	8/12 (67%)	10/17 (59%)	-	20/31 (65%)
Q148 +>=2 secondary mutations 3	1/2 (50%)	2/11 (18%)	1/3 (33%)	-	4/16 (25%)
1 Historical or phenotypic evidence of INI resistance only. 2 N155H, Y143C/H/R, T66A, E92Q 3 G140A/C/S, E138A/K/T, L74I OSS: combined genotypic and phenotypic resistance (Monogram Biosciences Net Assessment)

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS