TIVICAY 25mg tablets medication leaflet

Tivicay 10 mg film-coated tablets

Tivicay 25 mg film-coated tablets

Tivicay 50 mg film-coated tablets

Tivicay 10 mg film-coated tablets

Each film-coated tablet contains dolutegravir sodium equivalent to 10 mg dolutegravir.

Tivicay 25 mg film-coated tablets

Each film-coated tablet contains dolutegravir sodium equivalent to 25 mg dolutegravir.

Tivicay 50 mg film-coated tablets

Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Tivicay 10 mg film-coated tablets

White, round, biconvex tablets approximately 6 mm in diameter debossed with ‘SV 572’ on one side and‘10’ on the other side.

Tivicay 25 mg film-coated tablets

Pale yellow, round, biconvex tablets approximately 7 mm in diameter debossed with ‘SV 572’ on one sideand ‘25’ on the other side.

Tivicay 50 mg film-coated tablets

Yellow, round, biconvex tablets approximately 9 mm in diameter debossed with ‘SV 572’ on one side and‘50’ on the other side.

Tivicay is indicated in combination with other anti-retroviral medicinal products for the treatment of Human

Immunodeficiency Virus (HIV) infected adults, adolescents and children of at least 6 years of age or olderand weighing at least 14 kg.

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

The recommended dose of dolutegravir is 50 mg orally once daily.

Dolutegravir should be administered twice daily in this population when co-administered with somemedicines (e.g. efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin). Please refer to section 4.5.

The recommended dose of dolutegravir is 50 mg twice daily.

In the presence of documented resistance that includes Q148 + ≥2 secondary mutations from G140A/C/S,

E138A/K/T, L74I, modelling suggests that an increased dose may be considered for patients with limitedtreatment options (less than 2 active agents) due to advanced multi class resistance (see section 5.2).

The decision to use dolutegravir for such patients should be informed by the integrase resistance pattern (seesection 5.1).

Adolescents aged 12 and above, to less than 18 years, and weighing at least 20 kg

In patients infected with HIV-1 without resistance to the integrase class, the recommended dose ofdolutegravir is 50 mg once daily. Alternatively, if preferred 25 mg may be taken twice daily (see section5.2). In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose fordolutegravir in adolescents.

Children aged 6 and above, to less than 12 years, and weighing at least 14 kg

In patients infected with HIV-1 without resistance to the integrase class, the recommended dose ofdolutegravir is determined according to the weight of the child (see Table 1 and section 5.2).

Table 1 Paediatric dose recommendations for film-coated tablets

Body weight (kg) Dose14 to less than 20 40 mg once daily20 or greater 50 mg once daily

Alternatively, if preferred the dose may be divided equally into 2 doses, with one dose taken in the morningand one dose taken in the evening (see Table 2 and section 5.2).

Table 2 Alternative paediatric dose recommendations for film-coated tablets

Body weight (kg) Dose14 to less than 20 20 mg twice daily20 or greater 25 mg twice daily

In the presence of integrase inhibitor resistance, there are insufficient data to recommend a dose fordolutegravir in children.

Dispersible Tablets

Tivicay is available as film-coated tablets for patients aged 6 years and above and weighing at least 14 kg.

Tivicay is also available as dispersible tablets for patients aged 4 weeks and above and weighing at least 3kg, or for patients in whom film-coated tablets are not appropriate. Patients can change between film-coatedtablets and dispersible tablets. However, the bioavailability of film-coated tablets and dispersible tablets isnot comparable, therefore they are not interchangeable on a milligram per milligram basis (see section 5.2).

For example, the recommended adult dose for film-coated tablets is 50 mg versus 30 mg for dispersibletablets. Patients changing between film-coated and dispersible tablets should follow the dosingrecommendations that are specific for the formulation.

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

There are limited data available on the use of dolutegravir in patients aged 65 years and over. There is noevidence 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 ondialysis) renal impairment. No data are available in subjects receiving dialysis although differences inpharmacokinetics 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 Aor B). No data are available in patients with severe hepatic impairment (Child-Pugh grade C); thereforedolutegravir should be used with caution in these patients (see section 5.2).

Dolutegravir is also available in dispersible tablets for children aged 4 weeks and above and weighing atleast 3 kg. However, the safety and efficacy of dolutegravir in children aged less than 4 weeks or weighingless than 3 kg have not yet been established. In the presence of integrase inhibitor resistance, there areinsufficient data to recommend a dose for dolutegravir in children and adolescents. Currently available dataare 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 Q148mutations) (see section 5.2).

To reduce the risk of choking, patients should not swallow more than one tablet at a time, and wherepossible, children weighing 14 to less than 20 kg should preferentially take the dispersible tablet formulation.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Medicinal products with narrow therapeutic windows that are substrates of organic cation transporter 2(OCT2), including but not limited to fampridine (also known as dalfampridine; see section 4.5).

The decision to use dolutegravir in the presence of integrase class resistance should take into account that theactivity of dolutegravir is considerably compromised for viral strains harbouring Q148+≥2 secondarymutations from G140A/C/S, E138A/K/T, L74I (see section 5.1). To what extent dolutegravir provides addedefficacy in the presence of such integrase class resistance is uncertain (see section 5.2).

Hypersensitivity reactions have been reported with dolutegravir, and were characterized by rash,constitutional findings, and sometimes, organ dysfunction, including severe liver reactions. Dolutegravir andother suspect medicinal products should be discontinued immediately if signs or symptoms ofhypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by raisedliver enzymes, fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis,facial oedema, eosinophilia, angioedema). Clinical status including liver aminotransferases and bilirubinshould be monitored. Delay in stopping treatment with dolutegravir or other suspect active substances afterthe 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 combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticpathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, suchreactions have been observed within the first few weeks or months of initiation of CART. Relevant examplesare Cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveciipneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to occurin the setting of immune reconstitution, however, the reported time to onset is more variable and these eventscan occur many months after initiation of treatment.

Liver biochemistry elevations consistent with immune reconstitution syndrome were observed in somehepatitis B and/or C co-infected patients at the start of dolutegravir therapy. Monitoring of liverbiochemistries is recommended in patients with hepatitis B and/or C co-infection. Particular diligenceshould 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 infectionand 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 theseassociated 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, etravirine(without boosted protease inhibitors), tipranavir/ritonavir, rifampicin, St. John’s wort and certain anti-epileptic medicinal products) (see section 4.5).

When taken with food, Tivicay and supplements or multivitamins containing calcium, iron or magnesiumcan be taken at the same time. If Tivicay is administered under fasting conditions, supplements ormultivitamins containing calcium, iron or magnesium are recommended to be taken 2 hours after or 6 hoursbefore Tivicay (see section 4.5).

Dolutegravir increased metformin concentrations. A dose adjustment of metformin should be consideredwhen starting and stopping coadministration of dolutegravir with metformin, to maintain glycaemic control(see section 4.5). Metformin is eliminated renally and, therefore, it is of importance to monitor renal functionwhen co-treated with dolutegravir. This combination may increase the risk for lactic acidosis in patients withmoderate renal impairment (stage 3a creatinine clearance [CrCl] 45- 59 mL/min) and a cautious approach isrecommended. Reduction of the metformin dose should be highly considered.

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

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Suchchanges may in part be linked to disease control and lifestyle. For lipids and weight, there is in some casesevidence for a treatment effect. For monitoring of blood lipids and glucose reference is made to established

HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

The two-drug regimen of dolutegravir 50 mg once daily and lamivudine 300 mg once daily was explored intwo large randomized and blinded studies, GEMINI 1 and GEMINI 2 (see section 5.1). This regimen is onlysuitable for the treatment of HIV-1 infection where there is no known or suspected resistance to the integraseinhibitor class, or to lamivudine.

Tivicay contains less than 1 mmol sodium (23 mg) per tablet, that is to say is essentially ‘sodium free’.

All factors that decrease dolutegravir exposure should be avoided in the presence of integrase classresistance.

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 maydecrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir (see Table 3).

Co-administration of dolutegravir and other medicinal products that inhibit these enzymes may increasedolutegravir plasma concentration (see Table 3).

The absorption of dolutegravir is reduced by certain anti-acid agents (see Table 3).

In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitrodata, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates ofany major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see section 5.2).

In vitro, dolutegravir inhibited the renal organic cation transporter 2 (OCT2) and multidrug and toxinextrusion transporter (MATE) 1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction isdependent on OCT2 and MATE-1 transport) was observed in patients. In vivo, dolutegravir may increaseplasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE-1(e.g. fampridine [also known as dalfampridine], metformin) (see Table 3).

In vitro, dolutegravir inhibited the renal uptake transporters, organic anion transporters (OAT1) and OAT3.

Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibitionof OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasmaconcentrations of medicinal products in which excretion is dependent upon OAT3.

Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinalproducts are listed in Table 3.

Interactions between dolutegravir and co-administered medicinal products are listed in Table 3 (increase isindicated as “↑”, decrease as “↓”, no change as “↔”, area under the concentration versus time curve as“AUC”, maximum observed concentration as “Cmax”, concentration at end of dosing interval as “Cτ”).

Table 3: Drug Interactions

Medicinal products Interaction Recommendations concerningby therapeutic areas Geometric mean change co-administration(%)

HIV-1 Antiviral Agents

Non-nucleoside Reverse Transcriptase Inhibitors

Etravirine without Dolutegravir ↓ Etravirine without boosted protease inhibitorsboosted protease AUC ↓ 71% decreased plasma dolutegravir concentration. Theinhibitors Cmax ↓ 52% recommended adult dose of dolutegravir is 50 mg

Cτ ↓ 88% twice daily when co-administered with etravirinewithout boosted protease inhibitors. In paediatric

Etravirine ↔ patients the weight-based once daily dose should(induction of UGT1A1 and be administered twice daily. Dolutegravir should

CYP3A enzymes) not be used with etravirine without co-administration of atazanavir/ritonavir,darunavir/ritonavir or lopinavir/ritonavir in INI-resistant patients (see further below in table).

Lopinavir/ritonavir + Dolutegravir ↔ No dose adjustment is necessary.etravirine AUC ↑ 11%

Cmax ↑ 7%

Cτ ↑ 28%

LPV ↔

RTV ↔

Darunavir/ritonavir + Dolutegravir ↓ No dose adjustment is necessary.etravirine AUC ↓ 25%

Cmax ↓ 12%

Cτ ↓ 36%

DRV ↔

RTV ↔

Efavirenz Dolutegravir ↓ The recommended adult dose of dolutegravir is

AUC ↓ 57% 50 mg twice daily when co-administered with

Cmax ↓ 39% efavirenz. In paediatric patients the weight-based

Cτ ↓ 75% once daily dose should be administered twicedaily.

Efavirenz ↔ (historical In the presence of integrase class resistancecontrols) alternative combinations that do not include(induction of UGT1A1 and efavirenz should be considered (see section 4.4).

CYP3A enzymes)

Nevirapine Dolutegravir ↓ The recommended adult dose of dolutegravir is(Not studied, a similar 50 mg twice daily when co-administered withreduction in exposure as nevirapine. In paediatric patients the weight-basedobserved with efavirenz is once daily dose should be administered twiceexpected, due to induction) daily.

In the presence of integrase class resistancealternative combinations that do not includenevirapine should be considered (see section 4.4).

Rilpivirine Dolutegravir ↔ No dose adjustment is necessary.

AUC ↑ 12%

Cmax ↑ 13%

Cτ ↑ 22%

Rilpivirine ↔

Nucleoside Reverse Transcriptase Inhibitors

Tenofovir Dolutegravir ↔ No dose adjustment is necessary.

AUC ↑ 1%

Cmax ↓ 3%

Cτ ↓ 8%

Tenofovir ↔

Protease Inhibitors

Atazanavir Dolutegravir ↑ No dose adjustment is necessary.

AUC ↑ 91%

Cmax ↑ 50% Tivicay should not be dosed higher than 50 mg

Cτ ↑ 180% twice daily in combination with atazanavir (seesection 5.2) due to lack of data.

Atazanavir ↔ (historicalcontrols)(inhibition of UGT1A1 and

CYP3A enzymes)

Atazanavir/ritonavir Dolutegravir ↑ No dose adjustment is necessary.

AUC ↑ 62%

Cmax ↑ 34% Tivicay should not be dosed higher than 50 mg

Cτ ↑ 121% twice daily in combination with atazanavir (seesection 5.2) due to lack of data.

Atazanavir ↔

Ritonavir ↔(inhibition of UGT1A1 and

CYP3A enzymes)

Tipranavir/ritonavir Dolutegravir ↓ The recommended adult dose of dolutegravir is(TPV+RTV) AUC ↓ 59% 50 mg twice daily when co-administered with

Cmax ↓ 47% tipranavir/ritonavir. In paediatric patients the

Cτ ↓ 76% weight-based once daily dose should be(induction of UGT1A1 and administered twice daily.

CYP3A enzymes) In the presence of integrase class resistance thiscombination should be avoided (see section 4.4).

Fosamprenavir/ Dolutegravir ↓ No dose adjustment is necessary in the absence ofritonavir (FPV+RTV) AUC ↓ 35% integrase class resistance.

Cmax ↓ 24% In the presence of integrase class resistance

Cτ ↓ 49% alternative combinations that do not include(induction of UGT1A1 and fosamprenavir/ritonavir should be considered.

CYP3A enzymes)

Darunavir/ritonavir Dolutegravir ↓ No dose adjustment is necessary.

AUC ↓ 22%

Cmax ↓ 11%

C24 ↓ 38%(induction of UGT1A1 and

CYP3A enzymes)

Lopinavir/ritonavir Dolutegravir ↔ No dose adjustment is necessary.

AUC ↓ 4%

Cmax ↔ 0%

C24 ↓ 6%

Other Antiviral agents

Daclatasvir Dolutegravir ↔ Daclatasvir did not change dolutegravir plasma

AUC ↑ 33% concentration to a clinically relevant extent.

Cmax ↑ 29% Dolutegravir did not change daclatasvir plasma

Cτ ↑ 45% concentration. No dose adjustment is necessary.

Daclatasvir ↔

Other agents

Potassium channel blocker

Fampridine (also Fampridine ↑ Co-administration of dolutegravir has the potentialknown as to cause seizures due to increased fampridinedalfampridine) plasma concentration via inhibition of OCT2transporter; co-administration has not been studied.

Fampridine co-administration with dolutegravir iscontraindicated.

Anticonvulsants

Carbamazepine Dolutegravir ↓ The recommended adult dose of dolutegravir is 50

AUC ↓ 49% mg twice daily when co-administered with

Cmax ↓ 33% carbamazepine. In paediatric patients the weight-

Cτ ↓ 73% based once daily dose should be administeredtwice daily. Alternatives to carbamazepine shouldbe used where possible for INI resistant patients.

Oxcarbazepine Dolutegravir ↓ The recommended adult dose of dolutegravir is 50

Phenytoin (Not studied, decrease mg twice daily when co-administered with these

Phenobarbital expected due to induction of metabolic inducers. In paediatric patients the

UGT1A1 and CYP3A weight-based once daily dose should beenzymes, a similar reduction administered twice daily. Alternativein exposure as observed combinations that do not include these metabolicwith carbamazepine is inducers should be used where possible in INI-expected) resistant patients.

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 ↓ The recommended adult dose of dolutegravir is 50(Not studied, decrease mg twice daily when co-administered with St.expected due to induction of John’s wort. In paediatric patients the weight-

UGT1A1 and CYP3A based once daily dose should be administeredenzymes, a similar reduction twice daily. Alternative combinations that do notin exposure as observed include St. John’s wort should be used wherewith carbamazepine is possible in INI-resistant patients.expected)

Antacids and supplements

Magnesium/ Dolutegravir ↓ Magnesium/ aluminium-containing antacid shouldaluminium-containing AUC ↓ 74% be taken well separated in time from theantacid Cmax ↓ 72% administration of dolutegravir (minimum 2 hours(Complex binding to after or 6 hours before).polyvalent ions)

Calcium supplements Dolutegravir ↓ - When taken with food, Tivicay and supplements(fasted intake) AUC ↓ 39% or multivitamins containing calcium, iron or

Cmax ↓ 37% magnesium can be taken at the same time.

C24 ↓ 39% - If Tivicay is taken in a fasted state, such(Complex binding to supplements should be taken a minimum 2 hourspolyvalent ions) after or 6 hours before the intake of Tivicay.

Iron supplements Dolutegravir ↓(fasted intake) AUC ↓ 54% The stated reductions in dolutegravir exposure

Cmax ↓ 57% were observed with the intake of dolutegravir and

C24 ↓ 56% these supplements during fasted conditions. In fed(Complex binding to state, the changes in exposure following intakepolyvalent ions) together with calcium or iron supplements were

Multivitamin Dolutegravir ↓ modified by the food effect, resulting in an(containing calcium, AUC ↓ 33% exposure similar to that obtained with dolutegraviriron and magnesium) Cmax ↓ 35% administered in the fasted state.(fasted intake) C24 ↓ 32%(Complex binding topolyvalent ions)

Prednisone Dolutegravir ↔ No dose adjustment is necessary.

AUC ↑ 11%

Cmax ↑ 6%

Cτ ↑ 17%

Antidiabetics

Metformin Metformin ↑ A dose adjustment of metformin should be

When co-administered with considered when starting and stoppingdolutegravir 50mg once coadministration of dolutegravir with metformin,daily: to maintain glycaemic control. In patients with

Metformin moderate renal impairment a dose adjustment of

AUC ↑ 79% metformin should be considered when

Cmax ↑ 66% coadministered with dolutegravir, because of the

When co-administered with increased risk for lactic acidosis in patients withdolutegravir 50mg twice moderate renal impairment due to increaseddaily: metformin concentration (section 4.4).

AUC ↑ 145 %

Cmax ↑ 111%

Antimycobacterials

Rifampicin Dolutegravir ↓ The recommended adult dose of dolutegravir is

AUC ↓ 54% 50 mg twice daily when co-administered with

Cmax ↓ 43% rifampicin in the absence of integrase class

Cτ ↓72% resistance. In paediatric patients the weight-based(induction of UGT1A1 and once daily dose should be administered twice

CYP3A enzymes) daily.

In the presence of integrase class resistance thiscombination should be avoided (see section 4.4).

Rifabutin Dolutegravir ↔ No dose adjustment is necessary.

AUC ↓ 5%

Cmax ↑ 16%

Cτ ↓ 30%(induction of UGT1A1 and

CYP3A enzymes)

Ethinyl estradiol (EE) Dolutegravir ↔ Dolutegravir had no pharmacodynamic effect onand Norelgestromin EE ↔ Luteinizing Hormone (LH), Follicle Stimulating(NGMN) AUC ↑ 3% Hormone (FSH) and progesterone. No dose

Cmax ↓ 1% adjustment of oral contraceptives is necessarywhen co-administered with dolutegravir.

NGMN ↔

AUC ↓ 2%

Cmax ↓ 11%

Analgesics

Methadone Dolutegravir ↔ No dose adjustment is necessary of either agent.

Methadone ↔

AUC ↓ 2%

Cmax ↔ 0%

Cτ ↓ 1%

Interaction studies have only been performed in adults.

Tivicay can be used during pregnancy if clinically needed.

A large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformativenor feto/ neonatal toxicity.

Two large birth outcome surveillance studies (more than 14,000 pregnancy outcomes) in Botswana(Tsepamo) and Eswatini, and other sources, do not indicate an increased risk for neural tube defects afterdolutegravir exposure.

The incidence of neural tube defects in the general population ranges from 0.5-1 case per 1,000 live births(0.05-0.1%).

Data from the Tsepamo study show no significant difference in the prevalence of neural tube defects (0.11%)in infants whose mothers were taking dolutegravir at conception (more than 9,400 exposures) compared tothose taking non-dolutegravir containing antiretroviral regimens at conception (0.11%), or compared towomen without HIV (0.07%).

Data from the Eswatini study show the same prevalence of neural tube defects (0.08%) in infants whosemothers were taking dolutegravir at conception (more than 4,800 exposures), as infants of women without

HIV (0.08%).

Data analysed from the Antiretroviral Pregnancy Registry (APR) of more than 1000 pregnancies with firsttrimester dolutegravir treatment do not indicate an increased risk of major birth defects compared to thebackground rate or women with HIV.

In animal reproductive toxicity studies, no adverse development outcomes, including neural tube defects,were identified (see section 5.3).

Dolutegravir crosses the placenta in humans. In pregnant women living with HIV, the median foetalumbilical cord concentration of dolutegravir was approximately 1.3-fold greater compared with the maternalperipheral plasma concentration.

There is insufficient information on the effects of dolutegravir on neonates.

Dolutegravir is excreted in human milk in small amounts (a median dolutegravir breast milk to maternalplasma ratio of 0.033 has been shown). There is insufficient information on the effects of dolutegravir inneonates/infants.

It is recommended that women living with HIV do not breast-feed their infants in order to avoid transmissionof HIV.

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

Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinicalstatus of the patient and the adverse reaction profile of dolutegravir should be borne in mind whenconsidering the patient's ability to drive or operate machinery.

The most severe adverse reaction, seen in an individual patient, was a hypersensitivity reaction that includedrash and severe liver effects (see section 4.4). The most commonly seen treatment emergent adversereactions were nausea (13%), diarrhoea (18%) and headache (13%).

The adverse reactions considered at least possibly related to dolutegravir are listed by body system, organclass 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 4 Adverse Reactions

Immune system Uncommon Hypersensitivity (see section 4.4)disorders Uncommon Immune Reconstitution Syndrome (see section 4.4)**

Psychiatric disorders Common Insomnia

Common Abnormal dreams

Common Depression

Common Anxiety

Uncommon Panic attack

Uncommon Suicidal ideation*, suicide attempt*

*particularly in patients with a pre-existing history ofdepression or psychiatric illness.

Rare Completed suicide*

*particularly in patients with a pre-existing history ofdepression or psychiatric illness.

Nervous system Very common Headachedisorders Common Dizziness

Gastrointestinal Very common Nauseadisorders Very common Diarrhoea

Common Vomiting

Common Flatulence

Common Upper abdominal pain

Common Abdominal pain

Common Abdominal discomfort

Hepatobiliary Common Alanine aminotransferase (ALT) and/or Aspartatedisorders aminotransferase (AST) elevations

Uncommon Hepatitis

Rare Acute hepatic failure, increased bilirubin***

Skin and Common Rashsubcutaneous tissue Common Pruritusdisorders

Musculoskeletal and Uncommon Arthralgiaconnective tissue Uncommon Myalgiadisorders

General disorders Common Fatigueand administrationsite conditions

Investigations Common Creatine phosphokinase (CPK) elevations, weightincreased

**see below under Description of selected adverse reactions.

***in combination with increased transaminases

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

In Phase III studies patients with hepatitis B and/or C co-infection were permitted to enrol provided thatbaseline liver chemistry tests did not exceed 5 times the upper limit of normal (ULN). Overall, the safetyprofile in patients co-infected with hepatitis B and/or C was similar to that observed in patients withouthepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroupwith hepatitis B and/or C co-infection for all treatment groups. Liver chemistry elevations consistent withimmune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection atthe start of dolutegravir therapy, particularly in those whose anti-hepatitis B therapy was withdrawn (seesection 4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviraltherapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise.

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 can occur many months after initiationof treatment (see section 4.4).

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Based on available data from the ongoing P1093 (ING112578) and ODYSSEY (201296) studies in 172infants, children and adolescents (aged 4 weeks and above, to less than 18 years, and weighing at least 3 kg)who received the recommended doses of film-coated tablets or dispersible tablets once daily, there were noadditional types of adverse reactions beyond those observed in the adult population.

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

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 symptomsor 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, thepatient should be treated supportively with appropriate monitoring, as necessary. As dolutegravir is highlybound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Pharmacotherapeutic group: Antivirals for systemic use, other antivirals, ATC code: J05AJ03

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transferstep of retroviral Deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle.

The IC50 for dolutegravir in various labstrains using PBMC was 0.5 nM, and when using MT-4 cells itranged from 0.7-2 nM. Similar IC50s were seen for clinical isolates without any major difference betweensubtypes; in a panel of 24 HIV-1 isolates of clades A, B, C, D, E, F and G and group O the mean IC50 valuewas 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: stavudine,abacavir, efavirenz, nevirapine, lopinavir, amprenavir, enfuvirtide, maraviroc and raltegravir. In addition, noantagonistic effects were seen for dolutegravir and adefovir, and ribavirin had no apparent effect ondolutegravir activity.

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

Serial passage is used to study resistance evolution in vitro. When using the lab-strain HIV-1 IIIB duringpassage 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 inpatients 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-existingraltegravir resistance who were then treated with dolutegravir (listed as a secondary mutation fordolutegravir).

In further selection experiments using clinical isolates of subtype B, mutation R263K was seen in all fiveisolates (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 ARTexperienced, INI naive individual patients with subtypes B and C in the clinical program, but without effectson dolutegravir susceptibility in vitro. G118R lowers the susceptibility to dolutegravir in site directedmutants (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 notaffect the in vitro susceptibility of dolutegravir as single mutations. When mutations listed as secondaryintegrase inhibitor associated mutations (for raltegravir/elvitegravir) are added to these primary mutations inexperiments with site directed mutants, dolutegravir susceptibility is still unchanged (FC <2 vs wild typevirus), except in the case of Q148-mutations, where a FC of 5-10 or higher is seen with combinations ofcertain secondary mutations. The effect by the Q148-mutations (H/R/K) was also verified in passageexperiments with site directed mutants. In serial passage with strain NL432, starting with site directedmutants 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 wereseen 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; genotypicresistance was a better predictor for outcome.

Seven hundred and five raltegravir resistant isolates from raltegravir experienced patients were analyzed forsusceptibility to dolutegravir. Dolutegravir has a less than or equal to 10 FC against 94% of the 705 clinicalisolates.

In previously untreated patients receiving dolutegravir + 2 NRTIs in Phase IIb and Phase III, no developmentof resistance to the integrase class, or to the NRTI class was seen (n=1118 follow-up of 48-96 weeks). Inpreviously untreated patients receiving dolutegravir + lamivudine in the GEMINI studies through week 144(n=716), no development of resistance to the integrase class, or to the NRTI class was seen.

In patients with prior failed therapies, but naïve to the integrase class (SAILING study), integrase inhibitorsubstitutions were observed in 4/354 patients (follow-up 48 weeks) treated with dolutegravir, which wasgiven in combination with an investigator selected background regimen (BR). Of these four, two subjectshad 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 integrasemutations and is assumed to have been integrase experienced or infected with integrase resistant virus bytransmission. 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 32patients with protocol defined virological failure (PDVF) through Week 24 and with paired genotypes (alltreated with dolutegravir 50 mg twice daily + optimized background agents): 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), and N155H(n=1) and E157E/Q (n=1). Treatment emergent integrase resistance typically appeared in patients with ahistory of the Q148-mutation (baseline or historic). Five further subjects experienced PDVF between weeks24 and 48, and 2 of these 5 had treatment emergent mutations. Treatment-emergent mutations or mixtures ofmutations observed were L74I (n=1), N155H (n=2).

The VIKING-4 study examined dolutegravir (plus optimized background therapy) in subjects with primarygenotypic resistance to INIs at Screening in 30 subjects. Treatment-emergent mutations observed wereconsistent with those observed in the VIKING-3 study.

In paediatric patients with prior failed therapies, but naïve to the integrase class, the integrase inhibitorsubstitution G118R was observed in 5/159 patients treated with dolutegravir, given in combination with aninvestigator selected background regimen. Of these five, 4 participants had additional integrase associatedsubstitutions as follows: L74M, E138E/K, E92E/Q and T66I. Four of the 5 participants with emergent

G118R had phenotypic data available. Dolutegravir FC (fold change as compared to wildtype virus) for thesefour participants ranged from 6 to 25-fold.

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

The efficacy of dolutegravir in HIV-infected, therapy naïve subjects is based on the analyses of 96-week datafrom two randomized, international, double-blind, active-controlled trials, SPRING-2 (ING113086) and

SINGLE (ING114467). This is supported by 96 week data from an open-label, randomized and active-controlled study FLAMINGO (ING114915) and additional data from the open-label phase of SINGLE to144 weeks. The efficacy of dolutegravir in combination with lamivudine in adults is supported by 144-weekdata from two identical 148-week, randomised, multicentre, double-blind, non-inferiority studies GEMINI-1(204861) and GEMINI-2 (205543).

In SPRING-2, 822 adults were randomized and received at least one dose of either dolutegravir 50 mg oncedaily or raltegravir (RAL) 400 mg twice daily, both administered with either ABC/3TC or TDF/FTC. Atbaseline, median patient age was 36 years, 14% were female, 15% non-white, 11% had hepatitis B and/or Cco-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 dolutegravir 50 mg oncedaily with fixed-dose abacavir-lamivudine (Dolutegravir + 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 similarbetween treatment groups.

The primary endpoint and other week 48 outcomes (including outcomes by key baseline covariates) for

SPRING-2 and SINGLE are shown in Table 5.

Table 5 Response in SPRING-2 and SINGLE at 48 Weeks (Snapshot algorithm, <50 copies/mL)

SPRING-2 SINGLE

Dolutegravir RAL 400 mg Dolutegravir EFV/TDF/FTC50 mg Once Twice Daily + 2 50 mg + Once Daily

Daily + 2 NRTI NRTI ABC/3TC Once N=419

N=411 N=411 Daily

N=414

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%

HIV-1 RNA <50 copies/mL by baseline covariates

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/ mm3)<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

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%)

White 306/346 (88%) 301/352 (86%) 255/284 (90%) 238 /285 (84%)

African-America/African

Heritage/Other 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 frombaseline 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 lackof efficacy prior to Week 48 (for SPRING-2 only), subjects who discontinued prior to Week 48 for lack orloss of efficacy and subjects who are ≥50 copies in the 48 week window.‡ Adjusted mean treatment difference was statistically significant (p<0.001)

At week 48, dolutegravir was non-inferior to raltegravir in the SPRING-2 study, and in the SINGLE studydolutegravir + ABC/3TC was superior to efavirenz/TDF/FTC (p=0.003), table 5 above. In SINGLE, themedian time to viral suppression was shorter in the dolutegravir treated patients (28 vs 84 days, (p<0.0001,analysis pre-specified and adjusted for multiplicity).

At week 96, results were consistent with those seen at week 48. In SPRING-2, dolutegravir was still non-inferior to raltegravir (viral suppression in 81% vs 76% of patients), and with a median change in CD4 countof 276 vs 264 cells/mm3, respectively. In SINGLE, dolutegravir + ABC/3TC was still superior to

EFV/TDF/FTC (viral suppression in 80% vs 72%, treatment difference 8.0% (2.3, 13.8), p=0.006, and withan adjusted mean change in CD4 count of 325 vs 281 cells/ mm3, respectively. At 144 weeks in the open-label phase of SINGLE, virologic suppression was maintained, the dolutegravir + ABC/3TC arm (71%) wassuperior to the EFV/TDF/FTC arm (63%), treatment difference was 8.3% (2.0, 14.6).

In FLAMINGO (ING114915), an open-label, randomised and active-controlled study, 484 HIV-1 infectedantiretroviral naïve adults received one dose of either dolutegravir 50 mg once daily (n=242) ordarunavir/ritonavir (DRV/r) 800 mg/100 mg once daily (n=242), both administered with either ABC/3TC or

TDF/FTC. At baseline, median patient age was 34 years, 15% were female, 28% non-white, 10% hadhepatitis B and/or C co-infection, and 3% were CDC Class C; these characteristics were similar betweentreatment groups. Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir group (90%) wassuperior to the DRV/r group (83%) at 48 weeks. The adjusted difference in proportion and 95% CI were7.1% (0.9, 13.2), p=0.025. At 96 weeks, virologic suppression in the dolutegravir group (80%) was superiorto the DRV/r group (68%), (adjusted treatment difference [Dolutegravir-(DRV+RTV)]: 12.4%; 95% CI:[4.7, 20.2].

In GEMINI-1 (204861) and GEMINI-2 (205543), identical 148-week, randomised, double-blind studies,1433 adult HIV-1 infected antiretroviral naïve subjects were randomised to either a two-drug regimen ofdolutegravir 50 mg plus lamivudine 300 mg once daily, or to a three-drug regimen of dolutegravir 50 mgonce daily with fixed dose TDF/FTC. Subjects were enrolled with a screening plasma HIV-1 RNA of 1000c/mL to ≤500,000 c/mL. At baseline, in the pooled analysis, median patient age was 33 years, 15% werefemale, 31% non-white, 6% had hepatitis C co-infection and 9% were CDC Stage 3. Approximately onethird of the patients were infected with an HIV non-B subtype; these characteristics were similar betweentreatment groups. Virologic suppression (HIV-1 RNA <50 copies/mL) in the dolutegravir plus lamivudinegroup was non-inferior to the dolutegravir plus TDF/FTC group at 48 weeks, as shown in Table 6. Theresults of the pooled analysis were in line with those of the individual studies, for which the primaryendpoint (difference in proportion <50 copies/mL plasma HIV-1 RNA at week 48 based on the Snapshotalgorithm) was met. 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 prespecified non-inferiority margin of 10%.

Table 6 Response (<50 cps/ml, snapshot) in GEMINI 1 + 2, pooled data at Week 48.

Dolutegravir + 3TC Dolutegravir +(N=716) TDF/FTCn/N (%) (N=717)n/N (%)

All patients 655/716 (91) 669/717 (93)adjusted diff -1.7% (CI95-4.4, 1.1) a

By BL HIV-1 RNA≤100,000 cps/mL 526/576 (91) 531/564 (94)>100,000 cps/mL 129/140 (92) 138/153 (90)

By CD4+≤200 c/ mm3 50/63 (79) 51/55 (93)>200 c/ mm3 605/653 (93) 618/662 (93)

By HIV-1 subtype

B 424/467 (91) 452/488 (93)

Non-B 231/249 (93) 217/229 (95)

Rebound up to week 48 b 6 (<1) 4 (<1)

Mean change in CD4 count frombaseline at Week 48, c/ mm3 224 217a adjusted for BL stratification factors: Plasma HIV-1 RNA (≤100,000 cps/mL vs. >100,000 cps/mL) and CD4+cell count (≤200 cells/mm3 vs. >200 cells/mm3).b Confirmed plasma HIV-1 RNA levels to ≥200 cps/mL after prior confirmed suppression to <200 cps/mL.

At 96 weeks and at 144 weeks in the GEMINI studies, the lower bound of the 95% confidence interval forthe adjusted treatment difference of proportion of subjects with HIV-1 RNA <50 copies/mL (snapshot) wasgreater than the non-inferiority margin of -10%, for the individual studies as well as pooled analysis, see

Table 7.

Table 7 Virologic Outcomes (snapshot algorithm) in GEMINI 1 + 2, pooled data at Weeks 96 and 144

GEMINI-1 and GEMINI-2 Pooled Data*

DTG + DTG + DTG + DTG +3TC TDF/FTC 3TC TDF/FTC

N=716 N=717 N=716 N=717

Week 96 Week 144

HIV-1 RNA <50 copies/mL 86% 90% 82% 84%

Treatment Difference†(95% confidence intervals) -3.4% (-6.7, 0.0) -1.8% (-5.8; 2.1)

Virologic non response 3% 2% 3% 3%

Reasons

Data in window, ≥50 cps/mL <1% <1% <1% <1%

Discontinued, lack of efficacy 1% <1% 1% <1%

Discontinued, other reasons, ≥50 cps/mL <1% <1% <1% 2%

Change in ART <1% <1% <1% <1%

No virologic data at Week 96/Week 144 11% 9% 15% 14%window

Reasons

Discontinued study due to AE or death 3% 3% 4% 4%

Discontinued study for other reasons 8% 5% 11% 9%

Loss to follow-up 3% 1% 3% 3%

Withdrew consent 3% 2% 4% 3%

Protocol deviations 1% 1% 2% 1%

Physicians decision 1% <1% 2% 1%

Missing data in window, on study 0% <1% <1% <1%

DTG=Dolutegravir

* The results of the pooled analysis are in line with those of the individual studies.† Based on CMH-stratified analysis adjusting for the following baseline stratification factors: Plasma HIV-1

RNA (≤100,000 c/mL vs. >100,000 c/mL) and CD4+ cell count (≤200 cells/mm3 vs. >200 cells/mm3).

Pooled analysis also stratified by study. Assessed using a non-inferiority margin of 10%.

N = Number of subjects in each treatment group

The mean increase in CD4+ T-cell counts through week 144 was 302 cells/mm3 in the dolutegravir pluslamivudine arm and 300 cells/mm3 in the dolutegravir plus tenofovir/emtricitabine arm.

Through 96 weeks in SPRING-2 and FLAMINGO and 144 weeks in SINGLE, no cases of treatmentemergent primary resistance to the integrase- or NRTI-class were seen in the dolutegravir-containing arms.

For the comparator arms, the same lack of treatment emergent resistance was also the case for patientstreated with darunavir/r in FLAMINGO. In SPRING-2, four patients in the RAL-arm failed with major

NRTI mutations and one with raltegravir resistance; in SINGLE, six patients in the EFV/TDF/FTC-armfailed with mutations associated with NNRTI resistance, and one developed a major NRTI mutation.

Through 144 weeks in the GEMINI-1 and GEMINI-2 studies, no cases of emergent resistance to theintegrase- or NRTI-class were seen in either the Dolutegravir+3TC or comparator Dolutegravir+TDF/FTCarms.

In the international multicentre, double-blind SAILING study (ING111762), 719 HIV-1 infected,antiretroviral therapy (ART)-experienced adults were randomized and received either dolutegravir 50 mgonce daily or raltegravir 400 mg twice daily with investigator selected background regimen consisting of upto 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. Allpatients had at least two class ART resistance, and 49% of subjects had at least 3-class ART resistance atbaseline.

Week 48 outcomes (including outcomes by key baseline covariates) for SAILING are shown in Table 8.

Table 8 Response in SAILING at 48 Weeks (Snapshot algorithm, <50 copies/mL)

Dolutegravir 50 mg RAL 400 mg Twice

Once Daily + BR Daily + BR

N=354§ N=361§

HIV-1 RNA <50 copies/mL 71% 64%

Adjusted treatment difference‡ 7.4% (95% CI: 0.7%, 14.2%)

Virologic non-response 20% 28%

HIV-1 RNA <50 copies/mL by baseline covariates

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/ mm3)<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 (72%)

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 in background regimen

No DRV use 143/214 (67%) 126/209 (60%)

DRV use with primary PI mutations 58/68 (85%) 50/75 (67%)

DRV use without primary PI mutations 50/72 (69%) 54/77 (70%)

Male 172/247 (70%) 156/238 (66%)

Female 79/107 (74%) 74/123 (60%)

White 133/178 (75%) 125/175 (71%)

African-America/African Heritage/Other 118/175 (67%) 105/185 (57%)

Age (years)<50 196/269 (73%) 172/277 (62%)≥50 55/85 (65%) 58/84 (69%)

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/mm3) 162 153‡ Adjusted for baseline stratification factors.§ 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 whicha 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.

In the SAILING study, virologic suppression (HIV-1 RNA <50 copies/mL) in the Tivicay arm (71%) wasstatistically 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).

In the multicentre, open-label, single arm VIKING-3 study (ING112574), HIV-1 infected, ART-experiencedadults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistancereceived Tivicay 50 mg twice daily with the current failing background regimen for 7 days but withoptimised 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). Raltegravir/elvitegravirwas part of the current failing regimen in 98/183 patients (part of prior failing therapies in the others). Atbaseline, median patient age was 48 years, 23% were female, 29% non-white, and 20% had hepatitis Band/or C co-infection. Median baseline CD4+ was 140 cells/mm3, median duration of prior ART was 14years, 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 9.

Table 9 Virologic response (day 8) after 7 days of functional monotherapy, in patients with RAL/EVGas part of current failing regimen, VIKING 3

Baseline parameters Dolutegravir 50 mg BID

N=88*n Mean (SD) Plasma HIV- Median1 RNA log10 c/mL

Derived IN mutation group at

Baseline with ongoing RAL/EVG

Primary mutation other than 48 -1.59 (0.47) -1.64

Q148H/K/Ra

Q148+1 secondary mutationb 26 -1.14 (0.61) -1.08

Q148+≥2 secondary mutationsb 14 -0.75 (0.84) -0.45

*Of 98 on RAL/EVG as part of current failing regimen, 88 had detectable primary INI mutations at

Baseline and a Day 8 Plasma HIV-1 RNA outcome for evaluationa Included primary IN resistance mutations N155H, Y143C/H/R, T66A, E92Qb Secondary mutations from G140A/C/S, E138A/K/T, L74I.

In patients without a primary mutation detected at baseline (N=60) (i.e. RAL/EVG not part of current failingtherapy) 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 backgroundregimen when possible. The overall response rate through 24 weeks of therapy, 69% (126/183), wasgenerally sustained through 48 weeks with 116/183 (63%) of patients with HIV-1 RNA <50c/mL (ITT-E,

Snapshot algorithm). When excluding patients who stopped therapy for non-efficacy reasons, and those withmajor protocol deviations (incorrect dolutegravir dosing, intake of prohibited co-medication), namely, “the

Virological Outcome (VO)-population)”, the corresponding response rates were 75% (120/161, week 24)and 69% (111/160, week 48).

The response was lower when the Q148-mutation was present at baseline, and in particular in the presence of≥2 secondary mutations, Table 10. The overall susceptibility score (OSS) of the optimised backgroundregimen (OBR) was not associated with Week 24 response, nor with the week 48 response.

Table 10 Response by baseline Resistance, VIKING-3. VO Population (HIV-1 RNA <50 c/mL,

Snapshot algorithm)

Week 24 (N=161) Week 48(N=160)

Derived IN Mutation Total

Group OSS=0 OSS=1 OSS=2 OSS>2 Total

No primary IN mutation1 45/55 38/552/2 (100%) 15/20 (75%) 19/21 (90%) 9/12 (75%) (82%) (69%)

Primary mutation other 51/59 50/58than Q148H/K/R2 2/2 (100%) 20/20 (100%) 21/27 (78%) 8/10 (80%) (86%) (86%)

Q148 + 1 secondary 20/31 19/31mutation3 2/2 (100%) 8/12 (67%) 10/17 (59%) - (65%) (61%)

Q148 +≥2 secondarymutations 3 1/2 (50%) 2/11 (18%) 1/3 (33%) - 4/16 (25%) 4/16 (25%)1 Historical or phenotypic evidence of INI resistance only.2 N155H, Y143C/H/R, T66A, E92Q3 G140A/C/S, E138A/K/T, L74I

OSS: combined genotypic and phenotypic resistance (Monogram Biosciences Net Assessment)

The median change in CD4+ T cell count from baseline for VIKING-3 based on observed data was61 cells/mm3 at Week 24 and 110 cells/mm3 at Week 48.

In the double blind, placebo controlled VIKING-4 study (ING116529), 30 HIV-1 infected, ART-experiencedadults with primary genotypic resistance to INIs at Screening, were randomised to receive either dolutegravir50 mg twice daily or placebo with the current failing regimen for 7 days followed by an open label phasewith all subjects receiving dolutegravir. At baseline, median patient age was 49 years, 20% were female,58% non-white, and 23% had hepatitis B and/or C co-infection. Median baseline CD4+ was 160 cells/mm3,median duration of prior ART was 13 years, and 63% were CDC Class C. Subjects showed multiple class

ART resistance at baseline: 80% had ≥2 NRTI, 73% ≥1 NNRTI, and 67% ≥2 PI major mutations; 83% hadnon-R5 virus. Sixteen of 30 subjects (53%) harboured Q148 virus at baseline. The primary endpoint at Day8 showed that dolutegravir 50 mg twice daily was superior to placebo, with an adjusted mean treatmentdifference 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 withthose seen in VIKING-3 (not placebo controlled), including by baseline integrase resistance categories. Atweek 48, 12/30 (40%) subjects had HIV-1 RNA <50 copies/mL (ITT-E, Snapshot algorithm).

In a combined analysis of VIKING-3 and VIKING-4 (n=186, VO population), the proportion of subjectswith 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 No Q148 mutations, 22/41 (54%) for Q148+1 and 5/19 (26%) for

Q148+≥2 secondary mutations.

In an ongoing Phase I/II 48 week multicentre, open-label study (P1093/ING112578), the pharmacokineticparameters, safety, tolerability and efficacy of dolutegravir film-coated tablets and dispersible tabletsfollowing once daily dosing were evaluated in combination regimens in HIV-1 infected infants, children andadolescents aged ≥ 4 weeks to < 18 years, the majority of whom were treatment-experienced.

The efficacy results (Table 11) include participants who received the recommended once daily doses ofeither film-coated tablets or dispersible tablets.

Table 11 Antiviral and Immunological Activity Through Week 24 and Week 48 in Paediatric Patients

Week 24 Week 48

N=75 N=66n/N % (95% CI) n/N % (95% CI)

Proportion of participants with HIV 56 65.2

RNA <50 c/mLa, b 42/75 (44.1, 67.5) 43/66 (52.4, 76.5)

Proportion of participants with HIV 82.7 80.3

RNA <400 c/mLb 62/75 (72.2, 90.4) 53/66 (68.7, 89.1)

Median (n) (Q1, Q3) Median (n) (Q1, Q3)

Change from baseline in CD4+ cellcount (cells/mm3) 145 (72) (-64, 489) 184 (62) (-179, 665)

Change from baseline in CD4+percent 6 (72) (2.5, 10) 8 (62) (0.4, 11)

Q1, Q3= First and third quartiles, respectively.a Results of <200 c/mL from HIV-1 RNA testing using an LLOD of 200 c/mL were censored to >50 c/mL in thisanalysisb Snapshot algorithm was used in the analyses

In participants experiencing virologic failure, 5/36 acquired integrase inhibitor substitution G118R. Of thesefive, 4 participants had additional integrase associated substitutions as follows: L74M, E138E/K, E92E/Qand T66I. Four of the 5 participants with emergent G118R had phenotypic data available. Dolutegravir FC(fold change as compared to wildtype virus) for these four participants ranged from 6 to 25-fold.

The European Medicines Agency has deferred the obligation to submit the results of studies with Tivicay inpaediatric patients aged 4 weeks to below 6 years with HIV infection (see section 4.2 for information onpaediatric use).

There are no data available on the use of dolutegravir plus lamivudine as a two-drug regimen in paediatricpatients.

Dolutegravir pharmacokinetics are similar between healthy and HIV-infected subjects. The PK variability ofdolutegravir is low to moderate. In Phase I studies in healthy subjects, between-subject CVb% for AUC and

Cmax ranged from ~20 to 40% and Cτ from 30 to 65% across studies. The between-subject PK variability ofdolutegravir was higher in HIV-infected subjects than healthy subjects. Within-subject variability (CVw%) islower than between-subject variability.

Film-coated tablets and dispersible tablets do not have the same bioavailability. The relative bioavailabilityof dispersible tablets is approximately 1.6-fold higher as compared to film-coated tablets. Thus, a 50 mgdolutegravir dose administered as film-coated tablet(s) will have similar exposure to a 30 mg dolutegravirdose administered as six 5 mg dispersible tablets. Similarly, a 40 mg dolutegravir dose administered as four10 mg film-coated tablets will provide comparable exposure to a 25 mg dolutegravir dose administered asfive 5 mg dispersible tablets.

Dolutegravir is rapidly absorbed following oral administration, with median Tmax at 1 to 3 hours post dose forfilm-coated tablet or dispersible tablet formulations.

Food increased the extent and slowed the rate of absorption of dolutegravir. Bioavailability of dolutegravirdepends 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 underfasted conditions, respectively for the film-coated tablet. These increases may be clinically relevant in thepresence of certain integrase class resistance. Therefore, Tivicay is recommended to be taken with food bypatients infected with HIV with integrase class resistance (see section 4.2).

The absolute bioavailability of dolutegravir has not been established.

Dolutegravir is highly bound (>99%) to human plasma proteins based on in vitro data. The apparent volumeof 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 andplasma drug-related radioactivity concentration ratios averaged between 0.441 to 0.535, indicating minimalassociation of radioactivity with blood cellular components. The unbound fraction of dolutegravir in plasmais 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-naïve subjects on a stable dolutegravirplus abacavir/lamivudine regimen, dolutegravir concentration in CSF averaged 18 ng/mL (comparable tounbound plasma concentration, and above the IC50).

Dolutegravir is present in the female and male genital tract. AUC in cervicovaginal fluid, cervical tissue andvaginal 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 CYP3Acomponent. Dolutegravir is the predominant circulating compound in plasma; renal elimination ofunchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excretedunchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliaryexcretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in thegut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronideof dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metaboliteformed by oxidation at the benzylic carbon (3.0% of total dose).

In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50>50 μM) of the enzymes cytochrome

P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP3A, uridine diphosphateglucuronosyl 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. Based on this data, dolutegravir is not expected to affect the pharmacokinetics of medicinalproducts that are substrates of major enzymes or transporters (see section 4.5).

In vitro, dolutegravir was not a substrate of human OATP 1B1, OATP 1B3 or OCT 1.

Dolutegravir has a terminal half-life of ~14 hours. The apparent oral clearance (CL/F) is approximately1L/hr in HIV-infected patients based on a population pharmacokinetic analysis.

The linearity of dolutegravir pharmacokinetics is dependent on dose and formulation. Following oraladministration of film-coated tablet formulations, in general, dolutegravir exhibited nonlinearpharmacokinetics with less than dose-proportional increases in plasma exposure from 2 to 100 mg; howeverincrease in dolutegravir exposure appears dose proportional from 25 mg to 50 mg for the film-coated tabletformulation. With 50 mg film-coated tablet twice daily, the exposure over 24 hours was approximatelydoubled compared to 50 mg film-coated tablet 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 decline in HIV-1 RNA of2.5 log10 at day 11 for 50 mg dose. This antiviral response was maintained for 3 to 4 days after the last dosein the 50 mg film-coated tablet group.

PK/PD modelling using pooled data from clinical studies in integrase resistant patients suggest thatincreasing the dose from 50 mg film-coated tablet twice daily to 100 mg film-coated tablet twice daily mayincrease the effectiveness of dolutegravir in patients with integrase resistance and limited treatment optionsdue to advanced multi class resistance. The proportion of responders (HIV-1 RNA <50 c/mL) at week 24was predicted to increase around 4-18% in the subjects with Q148 + ≥2 secondary mutations from

G140A/C/S, E138A/K/T, L74I. Although these simulated results have not been confirmed in clinical trials,this high dose may be considered in the presence of the Q148 + ≥2 secondary mutations from G140A/C/S,

E138A/K/T, L74I in patients with overall limited treatment options due to advanced multi class resistance.

There is no clinical data on the safety or efficacy of the 100 mg film-coated tablet twice daily dose. Co-treatment with atazanavir increases the exposure of dolutegravir markedly, and should not be used incombination with this high dose, since safety with the resulting dolutegravir exposure has not beenestablished.

The pharmacokinetics of dolutegravir given once daily as film-coated and dispersible tablets in HIV-1infected infants, children and adolescents aged ≥ 4 weeks to < 18 years were evaluated in two on-goingstudies (P1093/ING112578 and ODYSSEY/201296). Steady state simulated plasma exposure at once dailyweight band doses is summarized in Table 12.

Table 12 Summary of Simulated Dolutegravir PK Parameters at Once Daily Doses by Weight Band in

Paediatric HIV-1 Infected Subjects

PK Parameter

Weight Band Dolutegravir Once Daily Geometric Mean (90% CI)(kg) Dosage

Forma Dose (mg) Cmax AUC0-24h C24h(µg/mL) (µg*h/mL) (ng/mL)4.02 49.4 10703 to <6 DT 5(2.12, 7.96) (21.6, 115) (247, 3830)6 to <10b 5.90 67.4 1240

DT 10(3.23, 10.9) (30.4, 151) (257, 4580)6.67 68.4 9646 to <10c DT 15(3.75, 12.1) (30.6, 154) (158, 4150)6.61 63.1 71910 to <14 DT 20(3.80, 11.5) (28.9, 136) (102, 3340)7.17 69.5 824

DT 25(4.10, 12.6) (32.1, 151) (122, 3780)14 to <206.96 72.6 972

FCT 40(3.83, 12.5) (33.7, 156) (150, 4260)7.37 72.0 881

DT 30(4.24, 12.9) (33.3, 156) (137, 3960)20 to <257.43 78.6 1080

FCT 50(4.13, 13.3) (36.8, 171) (178, 4690)6.74 71.4 99725 to <30 FCT 50(3.73, 12.1) (33.2, 154) (162, 4250)6.20 66.6 94430 to <35 FCT 50(3.45, 11.1) (30.5, 141) (154, 4020)4.93 54.0 814≥35 FCT 50(2.66, 9.08) (24.4, 118) (142, 3310)

Target: Geometric Mean 46 (37-134) 995 (697-2260)

DT=dispersible tablet

FCT=film-coated tablet

a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT.

b. <6 months of age

c. ≥6 months of age

Steady state simulated plasma exposure at alternative twice daily weight band doses are summarized in Table13. In contrast to once daily dosing, simulated data for alternative twice daily dosing have not beenconfirmed in clinical trials.

Table 13 Summary of Simulated Dolutegravir PK Parameters at Alternative Twice Daily Doses by

Weight Band in Paediatric HIV-1 Infected Subjects

PK Parameter

Weight Band Dolutegravir Twice

Geometric Mean (90% CI)(kg) Dosage Daily Dose

Forma (mg) Cmax AUC0-12h C12h(µg/mL) (µg*h/mL) (ng/mL)b 4.28 31.6 17606 to <10 DT 5(2.10, 9.01) (14.6, 71.4) (509, 5330)6.19 43.6 21906 to <10c DT 10(3.15, 12.6) (19.4, 96.9) (565, 6960)4.40 30.0 140010 to <14 DT 10(2.27, 8.68) (13.5, 66.0) (351, 4480)5.78 39.6 1890

DT 15(2.97, 11.4) (17.6, 86.3) (482, 6070)14 to <204.98 35.9 1840

FCT 20(2.55, 9.96) (16.5, 77.4) (496, 5650)5.01 34.7 1690

DT 15(2.61, 9.99) (15.8, 76.5) (455, 5360)20 to <255.38 39.2 2040

FCT 25(2.73, 10.8) (18.1, 85.4) (567, 6250)4.57 32.0 1580

DT 15(2.37, 9.05) (14.6, 69.1) (414, 4930)25 to <304.93 35.9 1910

FCT 25(2.50, 9.85) (16.4, 77.4) (530, 5760)4.54 33.3 177030 to <35 FCT 25(2.31, 9.10) (15.3, 72.4) (494, 5400)3.59 26.8 1470≥35 FCT 25(1.76, 7.36) (12.1, 58.3) (425, 4400)

DT=dispersible tablet

FCT=film-coated tablet

a. The bioavailability of dolutegravir DT is ~1.6-fold dolutegravir FCT.

b. <6 months of age

c. ≥6 months of age

Population pharmacokinetic analysis of dolutegravir using data in HIV-1 infected adults showed that therewas no clinically relevant effect of age on dolutegravir exposure.

Pharmacokinetic data for dolutegravir in subjects >65 years of age are limited.

Renal clearance of unchanged active substance is a minor pathway of elimination for dolutegravir. A studyof the pharmacokinetics of a single 50 mg dose of dolutegravir film-coated tablets was performed in subjectswith severe renal impairment (CLcr <30 mL/min) and matched healthy controls. The exposure todolutegravir was decreased by approximately 40% in subjects with severe renal impairment. The mechanismfor the decrease is unknown. No dosage adjustment is considered necessary for patients with renalimpairment. Tivicay has not been studied in patients on dialysis.

Dolutegravir is primarily metabolized and eliminated by the liver. A single 50 mg dose of dolutegravir film-coated tablets was administered to 8 subjects with moderate hepatic impairment (Child-Pugh class B) and to8 matched healthy adult controls. While the total dolutegravir concentration in plasma was similar, a 1.5- to2-fold increase in unbound exposure to dolutegravir was observed in subjects with moderate hepaticimpairment compared to healthy controls. No dosage adjustment is considered necessary for patients withmild 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 dolutegravirpharmacokinetics to a clinically meaningful extent. In a meta-analysis using pharmacogenomics samplescollected in clinical studies in healthy subjects, subjects with UGT1A1 (n=7) genotypes conferring poordolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared withsubjects 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 revealedno 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 revealedno clinically relevant effect of race on the exposure of dolutegravir. The pharmacokinetics of dolutegravirfollowing 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 relevanteffect on the exposure to dolutegravir. There are limited data on subjects with hepatitis B co-infection.

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 themouse and rat.

Dolutegravir did not affect male or female fertility in rats at doses up to 1000 mg/kg/day, the highest dosetested (24 times the 50 mg twice daily human clinical exposure based on AUC).

In reproductive toxicity studies in animals, dolutegravir was shown to cross the placenta.

Oral administration of dolutegravir to pregnant rats at doses up to 1000 mg/kg daily from days 6 to 17 ofgestation did not elicit maternal toxicity, developmental toxicity or teratogenicity (27 times the 50 mg twicedaily 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 ofgestation did not elicit developmental toxicity or teratogenicity (0.40 times the 50 mg twice daily humanclinical exposure based on AUC). In rabbits, maternal toxicity (decreased food consumption, scant/nofaeces/urine, suppressed body weight gain) was observed at 1000 mg/kg (0.40 times the 50 mg twice dailyhuman clinical exposure based on AUC).

In a juvenile toxicity study in rats, dolutegravir administration resulted in two preweanling deaths at75 mg/kg/day. Over the preweaning treatment period, mean body weight gain was decreased in this groupand the decrease persisted throughout the entire study for females during the postweaning period. Thesystemic exposure at this dose (based on AUC) to dolutegravir was ~17-20-fold higher than humans at therecommended pediatric exposure. There were no new target organs identified in juveniles compared toadults. In the rat pre/post-natal development study, decreased body weight of the developing offspring wasobserved during lactation at a maternally toxic dose (approximately 27 times human exposure at themaximum recommended human dose).

The effect of prolonged daily treatment with high doses of dolutegravir has been evaluated in repeat oraldose toxicity studies in rats (up to 26 weeks) and in monkeys (up to 38 weeks). The primary effect ofdolutegravir was gastrointestinal intolerance or irritation in rats and monkeys at doses that produce systemicexposures 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 substanceadministration, mg/kg or mg/m2 metrics are appropriate determinates of safety cover for this toxicity. GIintolerance 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.

Mannitol (E421)

Microcrystalline cellulose

Povidone

Sodium starch glycolate

Sodium stearyl fumarate

Poly(vinyl alcohol) partially hydrolyzed

Titanium dioxide (E171)

Macrogol

Talc

Iron oxide yellow (E172) (for 25 mg and 50 mg tablets)

Not applicable.

Tivicay 10 mg film-coated tablets5 years

Tivicay 25 mg film-coated tablets4 years

Tivicay 50 mg film-coated tablets5 years

Tivicay 10 mg film-coated tablets

Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do not removethe desiccant. Do not swallow the desiccant.

Tivicay 25 mg and 50 mg film-coated tablets

This medicinal product does not require any special storage conditions.

This medicinal product does not require any special temperature storage conditions.

HDPE (high density polyethylene) bottles closed with child resistant polypropylene screw closures, with apolyethylene faced induction heat seal liner. The bottles contain 30 or 90 film-coated tablets.

Tivicay 10 mg film-coated tablets

Each bottle contains a desiccant.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

ViiV Healthcare BV

Van Asch van Wijckstraat 55H3811 LP Amersfoort

Netherlands

EU/1/13/892/001

EU/1/13/892/002

EU/1/13/892/003

EU/1/13/892/004

EU/1/13/892/005

EU/1/13/892/006

Date of first authorisation: 16 January 2014

Date of latest renewal: 21 September 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.