BIKTARVY 30mg / 120mg / 15mg film-coated tablets medication leaflet

Biktarvy 30 mg/120 mg/15 mg film-coated tablets

Biktarvy 50 mg/200 mg/25 mg film-coated tablets

Biktarvy 30 mg/120 mg/15 mg film-coated tablets

Each film-coated tablet contains bictegravir sodium equivalent to 30 mg of bictegravir, 120 mg ofemtricitabine, and tenofovir alafenamide fumarate equivalent to 15 mg of tenofovir alafenamide.

Biktarvy 50 mg/200 mg/25 mg film-coated tablets

Each film-coated tablet contains bictegravir sodium equivalent to 50 mg of bictegravir, 200 mg ofemtricitabine, and tenofovir alafenamide fumarate equivalent to 25 mg of tenofovir alafenamide.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Biktarvy 30 mg/120 mg/15 mg film-coated tablets

Pink, capsule-shaped, film-coated tablet, debossed with “BVY” on one side and a score line on theother side of the tablet. Each tablet is approximately 14 mm x 6 mm. The score line is only tofacilitate breaking for ease of swallowing and not to divide into equal doses.

Biktarvy 50 mg/200 mg/25 mg film-coated tablets

Purplish-brown, capsule-shaped, film-coated tablet debossed with “GSI” on one side and “9883” onthe other side of the tablet. Each tablet is approximately 15 mm × 8 mm.

Biktarvy is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection in adultsand paediatric patients at least 2 years of age and weighing at least 14 kg without present or pastevidence of viral resistance to the integrase inhibitor class, emtricitabine or tenofovir (see section 5.1).

Therapy should be initiated by a physician experienced in the management of HIV infection.

Paediatric patients at least 2 years of age and weighing at least 14 kg to less than 25 kg

One 30 mg/120 mg/15 mg tablet to be taken once daily.

Adults and paediatric patients weighing at least 25 kg

One 50 mg/200 mg/25 mg tablet to be taken once daily.

If the patient misses a dose of Biktarvy within 18 hours of the time it is usually taken, the patientshould take Biktarvy as soon as possible and resume the normal dosing schedule. If a patient misses adose of Biktarvy by more than 18 hours, the patient should not take the missed dose and simplyresume the usual dosing schedule.

If the patient vomits within 1 hour of taking Biktarvy another tablet should be taken. If a patientvomits more than 1 hour after taking Biktarvy they do not need to take another dose of Biktarvy untilthe next regularly scheduled dose.

No dose adjustment of Biktarvy is required in patients aged ≥ 65 years (see sections 4.8 and 5.2).

No dose adjustment of Biktarvy is required in patients with mild (Child-Pugh Class A) or moderate(Child-Pugh Class B) hepatic impairment. Biktarvy has not been studied in patients with severehepatic impairment (Child-Pugh Class C), therefore Biktarvy is not recommended for use in patientswith severe hepatic impairment (see sections 4.4 and 5.2).

No dose adjustment of Biktarvy is required in patients weighing ≥ 35 kg with estimated creatinineclearance (CrCl) ≥ 30 mL/min.

No dose adjustment of Biktarvy is required in adult patients with end stage renal disease (estimatedcreatinine clearance < 15 mL/minute) who are receiving chronic haemodialysis. However, Biktarvyshould generally be avoided and only be used in these patients if the potential benefits are consideredto outweigh the potential risks (see sections 4.4 and 5.2). On days of haemodialysis, Biktarvy shouldbe administered after completion of haemodialysis treatment.

Initiation of Biktarvy should be avoided in patients with estimated creatinine clearance ≥15 mL/minand < 30 mL/min, or < 15 mL/min who are not receiving chronic haemodialysis, as the safety of

Biktarvy has not been established in these populations (see section 5.2).

No data are available to make dose recommendations in patients weighing < 35 kg with renalimpairment or in paediatric patients less than 18 years with end stage renal disease.

The safety and efficacy of Biktarvy in children less than 2 years of age or weighing less than 14 kghave not yet been established. No data are available.

Oral use.

Biktarvy can be taken with or without food (see section 5.2).

Due to the bitter taste, it is recommended that the film-coated tablets should not be chewed or crushed.

For patients who are unable to swallow the tablet whole, the tablet may be split in half and both halvestaken one after the other, ensuring that the full dose is taken immediately.

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

Co-administration with rifampicin and St. John’s wort (Hypericum perforatum) (see section 4.5).

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increased risk forsevere and potentially fatal hepatic adverse reactions.

There are limited safety and efficacy data for Biktarvy in patients co-infected with HIV-1 andhepatitis C virus (HCV).

Biktarvy contains tenofovir alafenamide, which is active against hepatitis B virus (HBV).

Discontinuation of Biktarvy therapy in patients co-infected with HIV and HBV may be associatedwith severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue

Biktarvy should be closely monitored with both clinical and laboratory follow-up for at least severalmonths after stopping treatment.

The safety and efficacy of Biktarvy in patients with significant underlying liver disorders have notbeen established.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy (CART) andshould be monitored according to standard practice. If there is evidence of worsening liver disease insuch patients, interruption or discontinuation of treatment must be considered.

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose, reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is mostpronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrialdysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; thesehave predominantly concerned treatment with regimens containing zidovudine. The main adversereactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinicalfindings of unknown aetiology, particularly neurologic findings. These findings do not affect currentnational recommendations to use antiretroviral therapy in pregnant women to prevent verticaltransmission of HIV.

In HIV infected patients with severe immune deficiency at the time of institution of CART, aninflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and causeserious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observedwithin the first few weeks or months of initiation of CART. Relevant examples includecytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystisjirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted whennecessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reactivation; however, the reported time to onset is more variable andthese events can occur many months after initiation of treatment.

Patients should be advised that Biktarvy 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 physiciansexperienced in the treatment of patients with HIV associated diseases.

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly 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, jointstiffness or difficulty in movement.

Post-marketing cases of renal impairment, including acute renal failure and proximal renaltubulopathy have been reported with tenofovir alafenamide-containing products. A potential risk ofnephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing with tenofoviralafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating, therapywith Biktarvy and that it is also monitored during therapy in all patients as clinically appropriate. Inpatients who develop clinically significant decreases in renal function, or evidence of proximal renaltubulopathy, discontinuation of Biktarvy should be considered.

Biktarvy should generally be avoided but may be used in adults with end stage renal disease(estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh thepotential risks (see section 4.2). In a study of emtricitabine + tenofovir alafenamide in combinationwith elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in HIV-1 infected adultswith end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy wasmaintained through 96 weeks but emtricitabine exposure was significantly higher than in patients withnormal renal function. Efficacy was also maintained in the extension phase of the study in which 10patients switched to Biktarvy for 48 weeks. Although no additional adverse reactions were identified,the implications of increased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Co-administration of other medicinal products or supplements

Biktarvy should not be co-administered simultaneously with antacids, oral medications or supplementscontaining magnesium, aluminium or iron under fasted conditions. Biktarvy should be administered atleast 2 hours before, or with food 2 hours after antacids, oral medications or supplements containingmagnesium and/or aluminium. Biktarvy should be administered at least 2 hours before ironsupplements, or taken together with food at any time (see section 4.5).

In pregnant patients, dosage adjustments are recommended for co-administration of polyvalent cation-containing antacids, oral medications or supplements (see section 4.5).

Some medicinal products are not recommended for co-administration with Biktarvy: atazanavir,carbamazepine, ciclosporin (IV or oral use), oxcarbazepine, phenobarbital, phenytoin, rifabutin,rifapentine, or sucralfate.

Biktarvy should not be co-administered with other antiretroviral medicinal products.

Reductions in bone mineral density (BMD ≥ 4%) of the spine and total body less head (TBLH) havebeen reported in patients aged between 3 to < 12 years who received tenofovir alafenamide-containingproducts for 48 weeks (see section 4.8). The long-term effects of changes in BMD on the growingbone, including the risk of fracture, are uncertain. A multidisciplinary approach is recommended todecide the appropriate monitoring during treatment.

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

Interaction studies have only been performed in adults.

Biktarvy should not be administered concomitantly with medicinal products containing tenofoviralafenamide, tenofovir disoproxil, lamivudine or adefovir dipivoxil used for the treatment of

HBV infection.

Bictegravir

Bictegravir is a substrate of CYP3A and UGT1A1. Co-administration of bictegravir and medicinalproducts that potently induce both CYP3A and UGT1A1, such as rifampicin or St. John’s wort, maysignificantly decrease plasma concentrations of bictegravir, which may result in a loss of therapeuticeffect of Biktarvy and development of resistance, therefore co-administration is contraindicated (seesection 4.3). Co-administration of bictegravir with medicinal products that potently inhibit both

CYP3A and UGT1A1, such as atazanavir, may significantly increase plasma concentrations ofbictegravir, therefore co-administration is not recommended.

Bictegravir is both a P-gp and a BCRP substrate. The clinical relevance of this feature is notestablished. Therefore, caution is recommended when bictegravir is combined with medicinalproducts known to inhibit P-gp and/or BCRP (e.g. macrolides, ciclosporin, verapamil, dronedarone,glecaprevir/pibrentasvir) (see also table below).

Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusiontransporter 1 (MATE1) in vitro. Co-administration of Biktarvy with the OCT2 and MATE1 substratemetformin did not result in a clinically significant increase in metformin exposure. Biktarvy may beco-administered with substrates of OCT2 and MATE1.

Bictegravir is not an inhibitor or inducer of CYP in vivo.

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for

CYP-mediated interactions involving emtricitabine with other medicinal products is low.

Co-administration of emtricitabine with medicinal products that are eliminated by active tubularsecretion may increase concentrations of emtricitabine, and/or the co-administered medicinal product.

Medicinal products that decrease renal function may increase concentrations of emtricitabine.

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein(BCRP). Co-administration of Biktarvy with medicinal products that strongly affect P-gp and BCRPactivity may lead to changes in tenofovir alafenamide absorption. Medicinal products that induce

P-gp activity (e.g. rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption oftenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, whichmay lead to loss of therapeutic effect of Biktarvy and development of resistance. Co-administration of

Biktarvy with other medicinal products that inhibit P-gp and BCRP may increase the absorption andplasma concentration of tenofovir alafenamide.

Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo.

Interactions between Biktarvy or its individual component(s) and co-administered medicinal productsare listed in Table 1 below (increase is indicated as “↑”, decrease as “↓” and no change as “↔”; all No

Effect Boundaries are 70%-143%).

Table 1: Interactions between Biktarvy or its individual component(s) and other medicinalproducts

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas/possible levels. co-administration with Biktarvymechanism of interaction Mean percent change in AUC,

Cmax, Cmin

HERBAL PRODUCTS

St. John’s wort (Hypericum Interaction not studied with any of Co-administration with St. John’sperforatum) the components of Biktarvy. wort is contraindicated, due to the

Co-administration may decrease effect of St. John’s wort on the(Induction of CYP3A, UGT1A1, bictegravir and tenofovir bictegravir component ofand P-gp) alafenamide plasma Biktarvy.

concentrations.

ANTI-INFECTIVES

Antimycobacterials

Rifampicin (600 mg once daily), Bictegravir: Co-administration is

Bictegravir1 AUC: ↓ 75% contraindicated due to the effect

Cmax: ↓ 28% of rifampicin on the bictegravir(Induction of CYP3A, UGT1A1, component of Biktarvy.and P-gp) Interaction not studied withtenofovir alafenamide.

Co-administration of rifampicinmay decrease tenofoviralafenamide plasmaconcentrations.

Rifabutin (300 mg once daily), Bictegravir: Co-administration is not

Bictegravir1 AUC: ↓ 38% recommended due to the expected

Cmin: ↓ 56% decrease of tenofovir alafenamide.(Induction of CYP3A and P-gp) Cmax: ↓ 20%

Interaction not studied withtenofovir alafenamide.

Co-administration of rifabutin maydecrease tenofovir alafenamideplasma concentrations.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas/possible levels. co-administration with Biktarvymechanism of interaction Mean percent change in AUC,

Cmax, Cmin

Rifapentine Interaction not studied with any of Co-administration is notthe components of Biktarvy. recommended.(Induction of CYP3A and P-gp) Co-administration of rifapentinemay decrease bictegravir andtenofovir alafenamide plasmaconcentrations.

HIV-1 antiviral agents

Atazanavir (300 mg once daily), Bictegravir: Co-administration is not

Cobicistat (150 mg once daily), AUC: ↑ 306% recommended.

Bictegravir1 Cmax: ↔(Inhibition of CYP3A, UGT1A1,and P-gp/BCRP)

Atazanavir (400 mg once daily), Bictegravir:

Bictegravir1 AUC: ↑ 315%

Cmax: ↔(Inhibition of CYP3A and

UGT1A1)

Hepatitis C virus antiviral agents

Ledipasvir/Sofosbuvir Bictegravir: No dose adjustment is required(90 mg/400 mg once daily), AUC: ↔ upon co-administration.

Bictegravir/Emtricitabine/ Cmin: ↔

Tenofovir alafenamide2 Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmax: ↔

Ledipasvir:

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmin: ↔

Cmax: ↔

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas/possible levels. co-administration with Biktarvymechanism of interaction Mean percent change in AUC,

Cmax, Cmin

Sofosbuvir/Velpatasvir/ Bictegravir: No dose adjustment is required

Voxilaprevir AUC: ↔ upon co-administration.(400/100/100 + 100 mg3 once Cmin: ↔daily), Bictegravir/Emtricitabine/ Cmax: ↔

Emtricitabine:(Inhibition of P-gp/BCRP) AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↑ 57%

Cmax: ↑ 28%

AUC: ↔

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

Antifungals

Voriconazole (300 mg twice Bictegravir: No dose adjustment is requireddaily), Bictegravir1 AUC: ↑ 61% upon co-administration.

Cmax: ↔(Inhibition of CYP3A)

Itraconazole Interaction not studied with any of

Posaconazole the components of Biktarvy.

Co-administration of itraconazole(Inhibition of P-gp/BCRP) or posaconazole may increasebictegravir plasma concentrations.

Macrolides

Azithromycin Interaction not studied. Caution is recommended due to

Clarithromycin Co-administration of azithromycin the potential effect of theseor clarithromycin may increase medicinal products on the(Inhibition of P-gp) bictegravir plasma concentrations. bictegravir component of

Biktarvy.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas/possible levels. co-administration with Biktarvymechanism of interaction Mean percent change in AUC,

Cmax, Cmin

ANTICONVULSANTS

Carbamazepine (titrated from Tenofovir alafenamide: Co-administration is not100 mg to 300 mg twice a day), AUC: ↓ 54% recommended.

Emtricitabine/Tenofovir Cmax: ↓ 57%alafenamide4

Interaction not studied with(Induction of CYP3A, UGT1A1, bictegravir.and P-gp) Co-administration ofcarbamazepine may decreasebictegravir plasma concentrations.

Oxcarbazepine Interaction not studied with any of Co-administration is not

Phenobarbital the components of Biktarvy. recommended.

Phenytoin Co-administration ofoxcarbazepine, phenobarbital, or(Induction of CYP3A, UGT1A1, phenytoin may decreaseand P-gp) bictegravir and tenofoviralafenamide plasmaconcentrations.

ANTACIDS, SUPPLEMENTS AND BUFFERED MEDICINES

Magnesium/aluminium-containing Bictegravir (antacid suspension For non-pregnant patients:antacid suspension (20 mL single 2 hours prior, fasted): Biktarvy should not be takendose5), Bictegravir AUC: ↓ 52% simultaneously with antacids or

Cmax: ↓ 58% supplements containing(Chelation with polyvalent magnesium and/or aluminium duecations) Bictegravir (antacid suspension to the expected substantialafter 2 hours, fasted): decrease of bictegravir exposure

AUC: ↔ (see section 4.4).

Cmax: ↔

Biktarvy should be administered

Bictegravir (simultaneous at least 2 hours before, or withadministration, fasted): food 2 hours after antacids or

AUC: ↓ 79% supplements containing

Cmax: ↓ 80% magnesium and/or aluminium.

Bictegravir (simultaneous For pregnant patients:administration with food): Biktarvy should be administered

AUC: ↓ 47% at least 2 hours before or 6 hours

Cmax: ↓ 49% after taking antacids orsupplements containingaluminium and/or magnesiumwithout regard to food.

Ferrous fumarate (324 mg single Bictegravir (simultaneous For non-pregnant patients:dose), Bictegravir administration, fasted): Biktarvy should be administered

AUC: ↓ 63% at least 2 hours before oral(Chelation with polyvalent Cmax: ↓ 71% medications or supplementscations) containing iron, or taken together

Bictegravir (simultaneous with food at any time.administration with food):

AUC: ↔ For pregnant patients:

Cmax: ↓ 25% Biktarvy should be administeredat least 2 hours before or 6 hoursafter taking oral medications orsupplements containing iron.

Alternatively, Biktarvy and oralmedications or supplementscontaining iron can be takentogether with food at any time.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas/possible levels. co-administration with Biktarvymechanism of interaction Mean percent change in AUC,

Cmax, Cmin

Calcium carbonate (1,200 mg Bictegravir (simultaneous For non-pregnant patients:single dose), Bictegravir administration, fasted): Biktarvy and calcium-containing

AUC: ↓ 33% oral medications or supplements(Chelation with polyvalent Cmax: ↓ 42% can be taken together, withoutcations) regard to food.

Bictegravir (simultaneousadministration with food): For pregnant patients:

AUC: ↔ Biktarvy should be administered

Cmax: ↔ at least 2 hours before or 6 hoursafter taking oral medications orsupplements containing calcium.

Alternatively, Biktarvy and oralmedications or supplementscontaining calcium can be takentogether with food at any time.

Sucralfate Interaction not studied with any of Co-administration notthe components of Biktarvy. recommended.(Chelation with polyvalent Co-administration may decreasecations) bictegravir plasma concentrations.

ANTIDEPRESSANTS

Sertraline (50 mg single dose), Tenofovir alafenamide: No dose adjustment is required

Tenofovir alafenamide6 AUC: ↔ upon co-administration.

Cmax: ↔

Sertraline:

AUC: ↔

Cmax: ↔

No interaction is expected withbictegravir and emtricitabine.

IMMUNOSUPPRESSANTS

Ciclosporin (IV or oral use) Interaction not studied with any of Co-administration of ciclosporinthe components of Biktarvy. (IV or oral use) is not(P-gp inhibition) Co-administration of ciclosporin recommended. If the combination(IV or oral use) is expected to is needed, clinical and biologicalincrease plasma concentrations of monitoring, notably renalboth bictegravir and tenofovir function, is recommended.alafenamide.

ORAL ANTI-DIABETICS

Metformin (500 mg twice daily), Metformin: No dose adjustment is required

Bictegravir/Emtricitabine/ AUC: ↑ 39% upon co-administration in patients

Tenofovir alafenamide Cmin: ↑ 36% with normal renal function.

Cmax: ↔(Inhibition of OCT2/MATE1) In patients with moderate renalimpairment, close monitoringshould be considered whenstarting co-administration ofbictegravir with metformin, due tothe increased risk for lacticacidosis in these patients. A doseadjustment of metformin shouldbe considered if required.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas/possible levels. co-administration with Biktarvymechanism of interaction Mean percent change in AUC,

Cmax, Cmin

ORAL CONTRACEPTIVES

Norgestimate Norelgestromin: No dose adjustment is required(0.180/0.215/0.250 mg once AUC: ↔ upon co-administration.daily)/ Ethinylestradiol (0.025 mg Cmin: ↔once daily), Bictegravir1 Cmax: ↔

Norgestimate(0.180/0.215/0.250 mg once Norgestrel:daily), Ethinylestradiol (0.025 mg AUC: ↔once daily), Cmin: ↔

Emtricitabine/Tenofovir Cmax: ↔alafenamide4

Ethinylestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

SEDATIVES/HYPNOTICS

Midazolam (2 mg, oral syrup, Midazolam: No dose adjustment is requiredsingle dose), AUC: ↔ upon co-administration.

Bictegravir/Emtricitabine/ Cmax: ↔

Tenofovir alafenamide1 This study was conducted using bictegravir 75 mg single dose.2 This study was conducted using bictegravir/emtricitabine/tenofovir alafenamide 75/200/25 mg once daily.3 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV infectedpatients.4 This study was conducted using emtricitabine/tenofovir alafenamide 200/25 mg once daily.5 Maximum strength antacid contained 80 mg aluminium hydroxide, 80 mg magnesium hydroxide, and 8 mgsimethicone per mL.6 This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide 150/150/200/10 mg oncedaily.

Based on drug interaction studies conducted with Biktarvy or the components of Biktarvy, noclinically significant drug interactions are expected with: amlodipine, atorvastatin, buprenorphine,drospirenone, famciclovir, famotidine, fluticasone, methadone, naloxone, norbuprenorphine,omeprazole or rosuvastatin.

A large amount of data on pregnant women (more than 1,000 exposed outcomes) indicate nomalformative or foeto/neonatal toxicity associated with emtricitabine or tenofovir alafenamide. Amoderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate nomalformative or foeto/neonatal toxicity associated with bictegravir.

Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respect tofertility parameters, pregnancy, foetal development, parturition or postnatal development. Studies ofbictegravir and tenofovir alafenamide, administered separately, in animals have shown no evidence ofharmful effects on fertility parameters, pregnancy, or foetal development (see section 5.3).

In a study performed in pregnant women receiving Biktarvy, exposures of bictegravir, emtricitabineand tenofovir alafenamide were lower during pregnancy (see section 5.2).

Therefore, Biktarvy may be used during pregnancy if the potential benefit justifies the potential risk tothe foetus. Moreover, viral load should all the more be monitored closely in accordance withestablished treatment guidelines.

It is not known whether bictegravir or tenofovir alafenamide is excreted in human milk. Emtricitabineis excreted in human milk. In animal studies, bictegravir was detected in the plasma of nursing ratpups likely due to the presence of bictegravir in milk, without effects on nursing pups. In animalstudies it has been shown that tenofovir is excreted in milk.

There is insufficient information on the effects of all the components of Biktarvy in newborns/infants,therefore Biktarvy should not be used during breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with HIV donot breast-feed their infants.

No human data on the effect of Biktarvy on fertility are available. Animal studies indicate no effectsof bictegravir, emtricitabine or tenofovir alafenamide on mating or fertility (see section 5.3).

Biktarvy may have minor influence on the ability to drive and use machines. Patients should beinformed that dizziness has been reported during treatment with the components of Biktarvy (seesection 4.8).

In clinical studies of treatment-naïve patients receiving Biktarvy, the most frequently reportedadverse reactions in the double-blind phase (Week 144) were headache (5%), diarrhoea (5%) andnausea (4%).

The assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studies with

Biktarvy and from post-marketing experience. The adverse reactions in Table 2 are listed by systemorgan class and frequency. Frequencies are defined as follows: common (≥ 1/100 to < 1/10)uncommon (≥ 1/1 000 to < 1/100) and rare (≥ 1/10 000 to < 1/1 000).

Table 2: Tabulated list of adverse reactions1

Frequency Adverse reaction

Uncommon: anaemia2

Common: depression, abnormal dreams

Uncommon: suicidal ideation, suicide attempt (particularly in patients with a pre-existinghistory of depression or psychiatric illness), anxiety, sleep disorders

Common: headache, dizziness

Common: diarrhoea, nausea

Uncommon: vomiting, abdominal pain, dyspepsia, flatulence

Uncommon: hyperbilirubinaemia

Uncommon: angioedema3,4, rash, pruritus, urticaria4

Rare: Stevens-Johnson syndrome5

Frequency Adverse reaction

Uncommon: arthralgia

Common: fatigue1 With the exception of angioedema, anaemia, urticaria and Stevens-Johnson syndrome (see footnotes 2-5), all adversereactions were identified from Biktarvy clinical studies. The frequencies were derived from the double-blind phase(Week 144) of Phase 3 Biktarvy clinical studies in treatment-naïve patients (GS-US-380-1489 and GS-US-380-1490).

2 This adverse reaction was not observed in the clinical studies of emtricitabine + tenofovir alafenamide-containingproducts but identified from clinical studies or post-marketing experience for emtricitabine when used with otherantiretrovirals.

3 This adverse reaction was identified through post-marketing surveillance for emtricitabine-containing products.4 This adverse reaction was identified through post-marketing surveillance for tenofovir alafenamide-containing products.5 This adverse reaction was identified through post-marketing surveillance for Biktarvy. The frequency has been calculatedusing 3/X, where X represent the cumulative number of subjects exposed to Biktarvy in clinical trials (N=3963).

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

In HIV infected patients with severe immune deficiency at the time of initiation of CART, aninflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmunedisorders (such as Graves’ disease and autoimmune hepatitis) have also been reported; however, thereported time to onset is more variable and these events can occur many months after initiation oftreatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown(see section 4.4).

Bictegravir has been shown to increase serum creatinine due to inhibition of tubular secretion ofcreatinine, however these changes are not considered to be clinically relevant since they do not reflecta change in glomerular filtration rate. Increases in serum creatinine occurred by Week 4 of treatmentand remained stable through Week 144. In Studies GS-US-380-1489 and GS-US-380-1490, median(Q1, Q3) serum creatinine increased by 0.11 (0.03, 0.19) mg/dL (9.7 [2.7, 16.8] µmol/L),0.11 (0.04, 0.19) mg/dL (9.7 [3.5, 16.8] µmol/L), and 0.12 (0.06, 0.21) mg/dL(10.6 [5.3, 18.6] μmol/L) from baseline to Week 144 in the Biktarvy,abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups,respectively. There were no discontinuations due to renal adverse reactions through Week 144 inpatients administered Biktarvy in clinical studies.

Changes in bilirubin

In Studies GS-US-380-1489 and GS-US-380-1490, total bilirubin increases were observed in 17% oftreatment-naïve patients administered Biktarvy through Week 144. Increases were primarily Grade 1(12%) and Grade 2 (4%) (≥1.0 to 2.5 x Upper Limit of Normal [ULN]), and were not associated withhepatic adverse reactions or other liver related laboratory abnormalities. Five patients administered

Biktarvy (1%) had grade 3 bilirubin increases that were not considered related to study drug. Therewere no discontinuations due to hepatic adverse reactions through Week 144 in Biktarvy clinicalstudies.

The safety of Biktarvy was evaluated in 50 HIV-1 infected adolescents aged 12 to < 18 years andweighing ≥ 35 kg through Week 96 (48-week main phase and 48-week extension), in 50 children aged6 to < 12 years and weighing ≥ 25 kg through Week 96 (48-week main phase and 48-week extension),and in 22 children ≥ 2 years of age and weighing ≥ 14 to < 25 kg through Week 24 in an open-labelclinical study (GS-US-380-1474). In this study, no new adverse reactions have been observed inpaediatric subjects aged 2 years and older living with HIV-1 as compared to adult subjects living with

HIV-1. Bone mineral density data were not collected in this study. Reductions in BMD of the spineand of the TBLH ≥ 4% have been reported in paediatric patients receiving other tenofovir alafenamidecontaining products for 48 weeks (see section 4.4).

Patients co-infected with hepatitis B

In 16 HIV/HBV co-infected adults administered Biktarvy (8 HIV/HBV treatment-naïve adults in

Study GS-US-380-1490; 8 HIV/HBV suppressed adults in Study GS-US-380-1878), the safety profileof Biktarvy was similar to that in patients with HIV-1 monoinfection (see section 5.1).

Studies GS-US-380-1844, GS-US-380-1878 and the dedicated Study GS-US-380-4449 in patients≥ 65 years old (evaluation of 86 HIV-1 infected, virologically-suppressed subjects ≥ 65 years old)included 111 patients aged ≥ 65 years who received Biktarvy. In these patients, no differences in thesafety profile of Biktarvy were observed.

The safety of emtricitabine + tenofovir alafenamide was evaluated in a single arm, open-label clinicalstudy (GS-US-292-1825), in which 55 virologically-suppressed HIV-1 infected patients with end stagerenal disease (eGFRCG < 15 mL/min) on chronic haemodialysis received emtricitabine + tenofoviralafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination tablet for 96weeks. In an extension phase of Study GS-US-292-1825, 10 patients switched to Biktarvy for 48weeks. No additional adverse reactions were identified in patients with end stage renal disease onchronic haemodialysis in this study (see sections 4.4 and 5.2).

Biktarvy was evaluated in a clinical study of 33 HIV-1 infected virologically suppressed (HIV-1 RNA< 50 copies/mL) pregnant adults administered 50 mg/200 mg/25 mg Biktarvy once daily from thesecond or third trimester through postpartum. There were no new safety findings compared to theknown safety profile of Biktarvy in HIV-1 infected adults.

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. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8). Treatmentof overdose with Biktarvy consists of general supportive measures including monitoring of vital signsas well as observation of the clinical status of the patient.

There is no specific antidote for overdose with Biktarvy. As bictegravir is highly bound to plasmaproteins, it is unlikely that it will be significantly removed by haemodialysis or peritoneal dialysis.

Emtricitabine can be removed by haemodialysis, which removes approximately 30% of theemtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing.

Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections,combinations, ATC code: J05AR20

Mechanism of action and pharmacodynamic effects

Bictegravir is an integrase strand transfer inhibitor (INSTI) that binds to the integrase active site andblocks the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essentialfor the HIV replication cycle. Bictegravir has activity against HIV-1 and HIV-2.

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and analogue of 2’-deoxycytidine.

Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabinetriphosphate inhibits HIV replication through incorporation into viral DNA by the HIV reversetranscriptase (RT), which results in DNA chain-termination. Emtricitabine has activity against HIV-1,

HIV-2 and HBV.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonamidateprodrug of tenofovir (2’-deoxyadenosine monophosphate analogue). Tenofovir alafenamide ispermeable into cells and due to increased plasma stability and intracellular activation throughhydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil in loadingtenofovir into peripheral blood mononuclear cells (PBMCs) (including lymphocytes and other HIVtarget cells) and macrophages. Intracellular tenofovir is subsequently phosphorylated to thepharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIVreplication through incorporation into viral DNA by the HIV RT, which results in DNA chain-termination. Tenofovir has activity against HIV-1, HIV-2 and HBV.

The antiviral activity of bictegravir against laboratory and clinical isolates of HIV-1 was assessed inlymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells, and CD4+ T-lymphocytes.

The 50% effective concentration (EC50) values for bictegravir were in the range of < 0.05 to 6.6 nM.

The protein-adjusted EC95 of bictegravir was 361 nM (0.162 µg/mL) for wild type HIV-1 virus.

Bictegravir displayed antiviral activity in cell culture against HIV-1 group (M, N, O), includingsubtypes A, B, C, D, E, F, and G (EC50 values ranged from < 0.05 to 1.71 nM), and activity against

HIV-2 (EC50 = 1.1 nM).

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed inlymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The EC50 values for emtricitabinewere in the range of 0.0013 to 0.64 µM. Emtricitabine displayed antiviral activity in cell cultureagainst HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 µM) andshowed activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 µM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of HIV-1subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophage cells,and CD4+ T-lymphocytes. The EC50 values for tenofovir alafenamide were in the range of 2.0 to14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups(M, N, O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM) andactivity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).

In vitro

HIV-1 isolates with reduced susceptibility to bictegravir have been selected in cell culture. In oneselection, amino acid substitutions M50I and R263K emerged and phenotypic susceptibility tobictegravir was reduced 1.3-, 2.2-, and 2.9-fold for M50I, R263K, and M50I + R263K, respectively.

In a second selection, amino acid substitutions T66I and S153F emerged and phenotypic susceptibilityto bictegravir was shifted 0.4-, 1.9-, and 0.5-fold for T66I, S153F, and T66I + S153F, respectively.

HIV-1 isolates with reduced susceptibility to emtricitabine have been selected in cell culture and had

M184V/I mutations in HIV-1 RT.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide have been selected in cell cultureand had the K65R mutation in HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has beentransiently observed. HIV-1 isolates with the K65R mutation have low level reduced susceptibility toabacavir, emtricitabine, tenofovir, and lamivudine. In vitro drug resistance selection studies withtenofovir alafenamide have shown no development of high-level resistance after extended culture.

In vivo

In treatment-naïve patients (Studies GS-US-380-1489 and GS-US-380-1490), through Week 144 ofthe double-blind phase or 96 weeks of the open-label extension phase, no patient receiving Biktarvy,with HIV-1 RNA ≥ 200 copies/mL at the time of confirmed virologic failure or early study drugdiscontinuation, had HIV-1 with treatment-emergent genotypic or phenotypic resistance to bictegravir,emtricitabine, or tenofovir alafenamide in the final resistance analysis population (n = 11 with data).

At the time of study entry, one treatment-naïve patient had pre-existing INSTI resistance-associatedmutations Q148H + G140S and had HIV-1 RNA < 50 copies/mL at Week 4 through Week 144. Inaddition, 6 patients had the pre-existing INSTI resistance-associated mutation T97A; all had HIV-1

RNA < 50 copies/mL at Week 144 or the last visit.

In virologically-suppressed patients (Studies GS-US-380-1844 and GS-US-380-1878), no patientsreceiving Biktarvy, with HIV-1 RNA ≥ 200 copies/mL at the time of confirmed virologic failure,

Week 48, or early study drug discontinuation, had HIV-1 with treatment-emergent genotypic orphenotypic resistance to bictegravir, emtricitabine, or tenofovir alafenamide in the final resistanceanalysis population (n = 2).

The susceptibility of bictegravir was tested against 64 INSTI-resistant clinical isolates (20 with singlesubstitutions and 44 with 2 or more substitutions). Of these, all single and double mutant isolateslacking Q148H/K/R and 10 of 24 isolates with Q148H/K/R with additional INSTI resistanceassociated substitutions had ≤ 2.5-fold reduced susceptibility to bictegravir; > 2.5-fold reducedsusceptibility to bictegravir was found for 14 of the 24 isolates that contained G140A/C/S and

Q148H/R/K substitutions in integrase. Of those, 9 of the 14 isolates had additional mutations at

L74M, T97A, or E138A/K. In a separate study, site-directed mutants with G118R and T97A+G118Rhad 3.4- and 2.8-fold reduced susceptibility to bictegravir, respectively. The relevance of thesein vitro cross-resistance data remains to be established in clinical practice.

Bictegravir demonstrated equivalent antiviral activity against 5 nonnucleoside reverse transcriptaseinhibitor (NNRTI)-resistant, 3 NRTI-resistant, and 4 protease inhibitor (PI)-resistant HIV-1 mutantclones compared with the wild-type strain.

Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant to lamivudine, butretained sensitivity to didanosine, stavudine, tenofovir, and zidovudine.

The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine,emtricitabine, and tenofovir, but retain sensitivity to zidovudine. Multinucleoside resistant HIV-1with a T69S double insertion mutation or with a Q151M mutation complex including K65R showedreduced susceptibility to tenofovir alafenamide.

The efficacy and safety of Biktarvy in HIV-1 infected, treatment-naïve adults are based on 48-weekand 144-week data from two randomised, double-blind, active-controlled studies, GS-US-380-1489(n = 629) and GS-US-380-1490 (n = 645). Furthermore, additional efficacy and safety data areavailable from adults who received open-label Biktarvy for an additional 96 weeks after Week 144 inan optional extension phase of these studies (n = 1025).

The efficacy and safety of Biktarvy in virologically-suppressed HIV-1 infected adults are based on48-week data from a randomised, double-blind, active-controlled study, GS-US-380-1844 (n = 563);and a randomised, open-label, active-controlled study, GS-US-380-1878 (n = 577).

In Study GS-US-380-1489, patients were randomised in a 1:1 ratio to receive eitherbictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (n = 314) orabacavir/dolutegravir/lamivudine (600/50/300 mg) (n = 315) once daily. In Study GS-US-380-1490,patients were randomised in a 1:1 ratio to receive either B/F/TAF (n = 320) ordolutegravir + emtricitabine/tenofovir alafenamide (50+200/25 mg) (n = 325) once daily.

In Studies GS-US-380-1489 and GS-US-380-1490, the mean age was 35 years (range 18-77), 89%were male, 58% were White, 33% were Black, and 3% were Asian. Twenty-four percent (24%) ofpatients identified as Hispanic/Latino. The prevalence of different subtypes was comparable across allthree treatment groups, with subtype B predominant in both groups; 11% were non-B subtypes. Themean baseline plasma HIV-1 RNA was 4.4 log10 copies/mL (range 1.3-6.6). The mean baseline CD4+cell count was 460 cells/mm3 (range 0-1,636) and 11% had CD4+ cell counts less than 200 cells/mm3.

Eighteen percent of patients had baseline viral loads greater than 100,000 copies/mL. In both studies,patients were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies/mL, greater than100,000 copies/mL to less than or equal to 400,000 copies/mL, or greater than 400,000 copies/mL), by

CD4+ cell count (less than 50 cells/µL, 50-199 cells/µL, or greater than or equal to 200 cells/µL), andby region (US or ex-US).

Treatment outcomes of Studies GS-US-380-1489 and GS-US-380-1490 through Weeks 48 and 144are presented in Table 3.

Table 3: Pooled virologic outcomes of Studies GS-US-380-1489 and GS-US-380-1490 at

Weeks 48a and 144b

Week 48 Week 144

B/F/TAF ABC/DTG/ DTG + B/F/TAF ABC/DTG/ DTG +(n = 634)c 3TC F/TAF (n = 634)c 3TC F/TAF(n = 315)d (n = 325)e (n = 315)d (n = 325)e

HIV-1 RNA 91% 93% 93% 82% 84% 84%< 50 copies/mL

Treatment - -2.1% -1.9% -2.7% -1.9%difference (-5.9% to (-5.6% to - (-7.8% to (-7.0% to(95% CI) B/F/TAF 1.6%) 1.8%) 2.4%) 3.1%)vs Comparator

HIV-1 RNA 3% 3% 1% 3% 3% 3%≥ 50 copies/mLf

No virologic data at 6% 4% 6% 16% 13% 13%week 48 or 144window

Discontinued <1% 1% 1% 2% 2% 3%study drug due to

AE or deathg

Week 48 Week 144

B/F/TAF ABC/DTG/ DTG + B/F/TAF ABC/DTG/ DTG +(n = 634)c 3TC F/TAF (n = 634)c 3TC F/TAF(n = 315)d (n = 325)e (n = 315)d (n = 325)e

Discontinued 4% 3% 4% 13% 11% 9%study drug due toother reasons andlast available HIV-1 RNA< 50 copies/mLh

Missing data 2% <1% 1% 1% <1% 1%during window buton study drug

Proportion (%) ofpatients with

HIV-1 RNA< 50 copies/mL bysubgroup

By baseline viral load≤ 100,000 copies/ 92% 94% 93% 82% 86% 84%mL 87% 90% 94% 79% 74% 83%> 100,000 copies/mL

By baseline CD4+ cellcount 90% 81% 100% 80% 69% 91%< 200 cells/mm3 91% 94% 92% 82% 86% 83%≥ 200 cells/mm3

HIV-1 RNA 85% 87% 87% 78% 82% 79%< 20 copies/mL

ABC = abacavir DTG = dolutegravir 3TC = lamivudine F/TAF = emtricitabine/tenofovir alafenamidea Week 48 window was between Day 295 and 378 (inclusive).b Week 144 window was between Day 967 and 1050 (inclusive).c Pooled from Study GS-US-380-1489 (n = 314) and Study GS-US-380-1490 (n = 320).d Study GS-US-380-1489.e Study GS-US-380-1490.f Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack orloss of efficacy (n = 0); patients who discontinued for reasons other than an adverse event (AE), death or lack or loss ofefficacy (B/F/TAF n = 12 and 15; ABC/DTG/3TC n = 2 and 7; DTG+F/TAF n = 3 and 6, at Weeks 48 and 144,respectively) and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

g Includes patients who discontinued due to AE or death at any time point from Day 1 through the time window if thisresulted in no virologic data on treatment during the specified window.

h Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g. withdrew consent,loss to follow-up, etc.

B/F/TAF was non-inferior in achieving HIV-1 RNA < 50 copies/mL at both Weeks 48 and 144 whencompared to abacavir/dolutegravir/lamivudine and to dolutegravir + emtricitabine/tenofoviralafenamide, respectively. Treatment outcomes between treatment groups were similar acrosssubgroups by age, sex, race, baseline viral load, baseline CD4+ cell count, and region.

In Studies GS-US-380-1489 and GS-US-380-1490, the mean increase from baseline in CD4+ cellcount at Week 144 was 288, 317, and 289 cells/mm3 in the pooled B/F/TAF,abacavir/dolutegravir/lamivudine, and dolutegravir + emtricitabine/tenofovir alafenamide groups,respectively.

In the optional 96 week open-label extension phase of Studies GS-US-380-1489and GS-US-380-1490, high rates of virologic suppression were achieved and maintained.

HIV-1 infected, virologically -suppressed patients

In Study GS-US-380-1844, the efficacy and safety of switching from a regimen ofdolutegravir + abacavir/lamivudine or abacavir/dolutegravir/lamivudine to B/F/TAF were evaluated ina randomised, double-blind study of virologically-suppressed (HIV-1 RNA < 50 copies/mL) HIV-1infected adults (n = 563). Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) ontheir baseline regimen for at least 3 months prior to study entry. Patients were randomised in a 1:1ratio to either switch to B/F/TAF at baseline (n = 282), or stay on their baseline antiretroviral regimen(n = 281). Patients had a mean age of 45 years (range 20-71), 89% were male, 73% were White, and22% were Black. Seventeen percent (17%) of patients identified as Hispanic/Latino. The prevalenceof different HIV-1 subtypes was comparable between treatment groups, with subtype B predominantin both groups; 5% were non-B subtypes. The mean baseline CD4+ cell count was 723 cells/mm3(range 124-2,444).

In Study GS-US-380-1878, the efficacy and safety of switching from either abacavir/lamivudine oremtricitabine/tenofovir disoproxil fumarate (200/300 mg) plus atazanavir or darunavir (boosted byeither cobicistat or ritonavir) to B/F/TAF were evaluated in a randomised, open-label study ofvirologically-suppressed HIV-1 infected adults (n = 577). Patients must have been stably suppressedon their baseline regimen for at least 6 months and must not have been previously treated with any

INSTI. Patients were randomised in a 1:1 ratio to either switch to B/F/TAF (n = 290), or stay on theirbaseline antiretroviral regimen (n = 287). Patients had a mean age of 46 years (range 20-79), 83%were male, 66% were White, and 26% were Black. Nineteen percent (19%) of patients identified as

Hispanic/Latino. The mean baseline CD4+ cell count was 663 cells/mm3 (range 62-2,582). Theprevalence of different subtypes was comparable across treatment groups, with subtype B predominantin both groups; 11% were non-B subtypes. Patients were stratified by prior treatment regimen. Atscreening, 15% of patients were receiving abacavir/lamivudine plus atazanavir or darunavir (boostedby either cobicistat or ritonavir) and 85% of patients were receiving emtricitabine/tenofovir disoproxilfumarate plus atazanavir or darunavir (boosted by either cobicistat or ritonavir).

Treatment outcomes of Studies GS-US-380-1844 and GS-US-380-1878 through Week 48 arepresented in Table 4.

Table 4: Virologic outcomes of Studies GS-US-380-1844 and GS-US-380-1878 at Week 48a

Study GS-US-380-1844 Study GS-US-380-1878

Baseline ATV-

B/F/TAF ABC/DTG/3TC B/F/TAF or DRV-based(n = 282) (n = 281) (n = 290) regimen(n = 287)

HIV-1 RNA < 50 copies/mL 94% 95% 92% 89%

Treatment difference (95% CI) -1.4% (-5.5% to 2.6%) 3.2% (-1.6% to 8.2%)

HIV-1 RNA ≥ 50 copies/mLb 1% < 1% 2% 2%

Treatment difference (95% CI) 0.7% (-1.0% to 2.8%) 0.0% (-2.5% to 2.5%)

No virologic data at Week 48window 5% 5% 6% 9%

Discontinued study drug due to

AE or death and last available 2% 1% 1% 1%

HIV-1 RNA < 50 copies/mL

Discontinued study drug due toother reasons and last available 2% 3% 3% 7%

HIV-1 RNA < 50 copies/mLc

Missing data during window buton study drug 2% 1% 2% 2%

ABC = abacavir ATV = atazanavir DRV = darunavir DTG = dolutegravir 3TC = lamivudinea Week 48 window was between Day 295 and 378 (inclusive).b Includes patients who had ≥ 50 copies/mL in the Week 48 window; patients who discontinued early due to lack or loss ofefficacy; patients who discontinued for reasons other than lack or loss of efficacy and at the time of discontinuation had aviral value of ≥ 50 copies/mL.

c Includes patients who discontinued for reasons other than an AE, death or lack or loss of efficacy, e.g. withdrew consent,loss to follow-up, etc.

B/F/TAF was non-inferior to the control regimen in both studies. Treatment outcomes betweentreatment groups were similar across subgroups by age, sex, race, and region.

In GS-US-380-1844, the mean change from baseline in CD4+ cell count at Week 48was -31 cells/mm3 in patients who switched to B/F/TAF and 4 cells/mm3 in patients who stayed onabacavir/dolutegravir/lamivudine. In GS-US-380-1878, the mean change from baseline in CD4+ cellcount at Week 48 was 25 cells/mm3 in patients who switched to B/F/TAF and 0 cells/mm3 in patientswho stayed on their baseline regimen.

The number of patients co-infected with HIV and HBV treated with B/F/TAF is limited. In

Study GS-US-380-1490, 8 patients with HIV/HBV co-infection at baseline were randomised toreceive B/F/TAF. At Week 48, 7 patients were HBV suppressed (HBV DNA < 29 IU/mL) and had

HIV-1 RNA < 50 copies/mL. One patient had missing HBV DNA data at Week 48. At Week 144, 5patients were HBV suppressed and had HIV-1 RNA < 50 copies/mL. Three patients had missing

HBV DNA data at Week 144 (1 lost to follow-up from Week 48, 1 lost to follow-up after Week 72,and 1 lost to follow-up after Week 120).

In Study GS-US-380-1878, at Week 48, 100% (8/8) of the patients co-infected with HIV/HBV atbaseline in the B/F/TAF arm maintained HBV DNA < 29 IU/mL (missing = excluded analysis) and

HIV RNA < 50 copies/mL.

In Study GS-US-380-5310, the pharmacokinetics, efficacy and safety of once-daily B/F/TAF wereevaluated in an open-label clinical study of virologically suppressed pregnant adults with HIV-1 fromthe second or third trimester through postpartum (n = 33). All 32 adult participants who completed thestudy maintained viral suppression during pregnancy, at delivery, and through Week 18 postpartum.

The median (Q1, Q3) CD4+ cell count at baseline was 558 (409, 720) cells/μL, and the median(Q1, Q3) change in CD4+ cell count from baseline to Week 12 postpartum was 159 (27, 296) cells/μL.

All 29 neonate participants had negative/nondetectable HIV-1 PCR results at birth and/or 4 to 8 weeksof age.

In Study GS-US-380-1474, the pharmacokinetics, safety and efficacy of B/F/TAF invirologically-suppressed children and adolescents with HIV between the ages of 12 to < 18 years(≥ 35 kg) (n = 50), between the ages of 6 to < 12 years (≥ 25 kg) (n = 50), and ≥ 2 years of age (≥ 14to < 25 kg) (n = 22) were evaluated.

Cohort 1: Virologically-suppressed adolescents (n = 50; 12 to < 18 years; ≥ 35 kg)

Patients in Cohort 1 had a mean age of 14 years (range: 12 to 17) and a mean baseline weight of51.7 kg (range: 35 to 123), 64% were female, 27% were Asian, and 65% were Black. At baseline,median CD4+ cell count was 750 cells/mm3 (range: 337 to 1207), and median CD4+% was 33%(range: 19% to 45%).

After switching to B/F/TAF, 98% (49/50) of patients in Cohort 1 remained suppressed (HIV-1 RNA< 50 copies/mL) at Week 48. The mean change from baseline in CD4+ cell count at Week 48was -22 cells/mm3. Two of 50 subjects met the criteria for inclusion in the resistance analysispopulation through Week 48. No emergent resistance to B/F/TAF was detected through Week 48.

Cohort 2: Virologically-suppressed children (n = 50; 6 to < 12 years; ≥ 25 kg)

Patients in Cohort 2 had a mean age of 10 years (range: 6 to 11) and a mean baseline weight of 31.9 kg(range: 25 to 69), 54% were female, 22% were Asian and 72% were Black. At baseline, median

CD4+ cell count was 898 cells/mm3 (range 390 to 1991) and median CD4+% was 37% (range: 19% to53%).

After switching to B/F/TAF, 98% (49/50) of patients in Cohort 2 remained suppressed (HIV-1 RNA< 50 copies/mL) at Week 48. The mean change from baseline in CD4+ cell count at Week 48was -40 cells/mm3. No patient qualified for resistance analysis through Week 48.

Cohort 3: Virologically-suppressed children (n = 22; ≥ 2 years; ≥ 14 kg to < 25 kg)

Patients in Cohort 3 had a mean age of 5 years (range: 3 to 9) and a mean baseline weight of 18.8 kg(range: 14 to 24), 50% were female, 23% were Asian and 73% were Black. At baseline, median

CD4+ cell count was 962 cells/mm3 (range 365 to 1986) and median CD4+% was 32% (range: 24% to46%).

After switching to B/F/TAF, 91% (20/22) of patients in Cohort 3 remained suppressed (HIV-1 RNA< 50 copies/mL) at Week 24. The mean change from baseline in CD4+ cell count at Week 24 was−126 cells/mm3, and the mean change in CD4+% from baseline to Week 24 was 0.2% (range: -7.7%to 7.5%). No patient qualified for resistance analysis through Week 24.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Biktarvy in one or more subsets of the paediatric population in the treatment of human

HIV-1 infection (see section 4.2 for information on paediatric use).

Bictegravir is absorbed following oral administration with peak plasma concentrations occurring at2.0-4.0 hours after administration of B/F/TAF. Relative to fasting conditions, the administration of

B/F/TAF with either a moderate fat (~600 kcal, 27% fat) or high fat meal (~800 kcal, 50% fat)resulted in an increase in bictegravir AUC (24%). This modest change is not considered clinicallymeaningful and B/F/TAF can be administered with or without food.

Following oral administration of B/F/TAF with or without food in HIV-1 infected adults, the multipledose mean (CV%) pharmacokinetic parameters of bictegravir were Cmax = 6.15 µg/mL (22.9%),

AUCtau = 102 µg*h/mL (26.9%), and Ctrough = 2.61 µg/mL (35.2%).

Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasmaconcentrations occurring at 1.5-2.0 hours after administration of B/F/TAF. The mean absolutebioavailability of emtricitabine from 200 mg hard capsules was 93%. Emtricitabine systemic exposurewas unaffected when emtricitabine was administered with food and B/F/TAF can be administered withor without food.

Following oral administration of B/F/TAF with or without food in HIV-1 infected adults, the multipledose mean (CV%) pharmacokinetic parameters of emtricitabine were Cmax = 2.13 µg/mL (34.7%),

AUCtau = 12.3 µg*h/mL (29.2%), and Ctrough = 0.096 µg/mL (37.4%).

Tenofovir alafenamide is rapidly absorbed following oral administration with peak plasmaconcentrations occurring at 0.5-2.0 hours after administration of B/F/TAF. Relative to fastingconditions, the administration of tenofovir alafenamide with a moderate fat meal (~600 kcal, 27% fat)and a high fat meal (~800 kcal, 50% fat) resulted in an increase in AUClast by 48% and 63%,respectively. These modest changes are not considered clinically meaningful and B/F/TAF can beadministered with or without food.

Following oral administration of B/F/TAF with or without food in HIV-1 infected adults, the multipledose mean (CV%) pharmacokinetic parameters of tenofovir alafenamide were Cmax = 0.121 µg/mL(15.4%), and AUCtau = 0.142 µg*h/mL (17.3%).

In vitro binding of bictegravir to human plasma proteins was > 99% (free fraction ~0.25%). Thein vitro human blood to plasma bictegravir concentration ratio was 0.64.

In vitro binding of emtricitabine to human plasma proteins was < 4% and independent ofconcentration over the range of 0.02 to 200 µg/mL. At peak plasma concentration, the mean plasma toblood emtricitabine concentration ratio was ~1.0 and the mean semen to plasma emtricitabineconcentration ratio was ~4.0.

In vitro binding of tenofovir to human plasma proteins is < 0.7% and is independent of concentrationover the range of 0.01-25 µg/mL. Ex vivo binding of tenofovir alafenamide to human plasma proteinsin samples collected during clinical studies was approximately 80%.

Metabolism is the major clearance pathway for bictegravir in humans. In vitro phenotyping studiesshowed that bictegravir is primarily metabolised by CYP3A and UGT1A1. Following a single doseoral administration of [14C]-bictegravir, ~60% of the dose from faeces included unchanged parent,desfluoro-hydroxy-BIC-cysteine-conjugate, and other minor oxidative metabolites. Thirty-fivepercent of the dose was recovered from urine and consisted primarily of the glucuronide of bictegravirand other minor oxidative metabolites and their phase II conjugates. Renal clearance of the unchangedparent was minimal.

Following administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose wasachieved in urine (~86%) and faeces (~14%). Thirteen percent of the dose was recovered in the urineas three putative metabolites. The biotransformation of emtricitabine includes oxidation of the thiolmoiety to form the 3’-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid toform 2’-O-glucuronide (~4% of dose). No other metabolites were identifiable.

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accounting for> 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide is metabolised totenofovir (major metabolite) by cathepsin A in PBMCs (including lymphocytes and other HIV targetcells) and macrophages; and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide ishydrolysed within cells to form tenofovir (major metabolite), which is phosphorylated to the activemetabolite, tenofovir diphosphate. In human clinical studies, a 25 mg oral dose of tenofoviralafenamide resulted in tenofovir diphosphate concentrations > 4-fold higher in PBMCs and > 90%lower concentrations of tenofovir in plasma as compared to a 245 mg oral dose of tenofovir disoproxil.

Bictegravir is primarily eliminated by hepatic metabolism. Renal excretion of intact bictegravir is aminor pathway (~1% of dose). The plasma bictegravir half-life was 17.3 hours.

Emtricitabine is primarily excreted by the kidneys by both glomerular filtration and active tubularsecretion. The plasma emtricitabine half-life was approximately 10 hours.

Tenofovir alafenamide is eliminated following metabolism to tenofovir. Tenofovir alafenamide andtenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively. Tenofovir iseliminated by the kidneys by both glomerular filtration and active tubular secretion. Renal excretionof intact tenofovir alafenamide is a minor pathway with less than 1% of the dose eliminated in urine.

The multiple dose pharmacokinetics of bictegravir are dose proportional over the dose range of 25 to100 mg. The multiple dose pharmacokinetics of emtricitabine are dose proportional over the doserange of 25 to 200 mg. Tenofovir alafenamide exposures are dose proportional over the dose range of8 mg to 125 mg.

Clinically relevant changes in the pharmacokinetics of bictegravir were not observed in subjects withmoderate hepatic impairment. The pharmacokinetics of emtricitabine have not been studied insubjects with hepatic impairment; however, emtricitabine is not significantly metabolised by liverenzymes, so the impact of liver impairment should be limited. Clinically relevant changes in thepharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were not observed in patientswith mild, moderate, or severe hepatic impairment.

Severe Renal Impairment (estimated creatinine clearance ≥ 15 and < 30 mL/minute)

No clinically relevant differences in bictegravir, tenofovir alafenamide, or tenofovir pharmacokineticswere observed between healthy subjects and subjects with severe renal impairment (estimated

CrCl ≥ 15 mL/min and < 30 mL/min) in Phase 1 Studies. In a separate Phase 1 study of emtricitabinealone, mean systemic emtricitabine exposure was higher in patients with severe renal impairment(CrCl < 30 mL/min) (33.7 µg*h/mL) than in subjects with normal renal function (11.8 µg*h/mL). Thesafety of Biktarvy has not been established in subjects with estimated creatinineclearance ≥ 15 mL/min and < 30 mL/min.

End Stage Renal Disease (estimated creatinine clearance < 15 mL/minute)

Exposures of emtricitabine and tenofovir in 12 patients with end stage renal disease (estimated

CrCl < 15 mL/min) on chronic haemodialysis who received emtricitabine + tenofovir alafenamide incombination with elvitegravir + cobicistat as a fixed dose combination tablet in Study GS-US-292-1825 were significantly higher than in patients with normal renal function. No clinically relevantdifferences in tenofovir alafenamide pharmacokinetics were observed in patients with end stage renaldisease on chronic haemodialysis as compared to those with normal renal function. In the extensionphase of Study GS-US-292-1825, lower bictegravir Ctrough was observed in patients with end stagerenal disease who received Biktarvy compared to patients with normal renal function, but thisdifference was not considered clinically relevant. No additional adverse reactions were identified inpatients with end stage renal disease on chronic haemodialysis in this study (see section 4.8).

There are no pharmacokinetic data on bictegravir, emtricitabine or tenofovir alafenamide in patientswith end stage renal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis. The safetyof Biktarvy has not been established in these patients.

Pharmacokinetics of bictegravir, emtricitabine, and tenofovir have not been fully evaluated in theelderly (≥ 65 years of age). Population analyses using pooled pharmacokinetic data from adult studiesdid not identify any clinically relevant differences due to age, gender or race on the exposures ofbictegravir, emtricitabine, or tenofovir alafenamide.

Mean bictegravir Cmax, and exposures of emtricitabine and tenofovir alafenamide (AUC and/or Cmax),achieved in 50 children between the ages of 6 to < 12 years (≥ 25 kg) who received the50 mg/200 mg/25 mg dose of B/F/TAF and in 22 children ≥ 2 years of age (≥ 14 to < 25 kg) whoreceived the 30 mg/120 mg/15 mg dose of B/F/TAF, in Study GS-US-380-1474 were generally higherthan exposures in adults. The exposures of bictegravir, emtricitabine, tenofovir alafenamide andtenofovir in children, adolescents, and adults are presented in Table 5.

Table 5: Exposures of Bictegravir, Emtricitabine, Tenofovir Alafenamide and Tenofovir in

Children, Adolescents, and Adults

Children aged ≥ 2 Children aged 6 Adolescents aged Adultsbyears to < 12 years 12 to < 18 years≥ 14 to < 25 kga ≥ 25 kga ≥ 35 kga

B/F/TAF B/F/TAF(30 mg/120 mg/15 mg) (50 mg/200 mg/25 mg)n = 12 n = 25 n = 24 n = 77

BIC

AUCtau 108 364.5 (22.9) 121 034.2 (36.4) 109 668.1 (30.6) 94 227.1 (34.7)(ng*h/mL)

Cmax 10 040.0 (19.9) 10 988.8 (28.3) 8 087.1 (29.9) 6 801.6 (30.1)(ng/mL)

C ctau 1 924.5 (78.3) 2 366.6 (78.8)d 2 327.4 (48.6) 2 256.7 (47.3)g(ng/mL)

FTC

AUCtau 14 991.2 (21.9) 17 565.1 (36.9) 13 579.1 (21.7) 12 293.6 (29.2)(ng*h/mL)

Cmax 3 849.2 (34.7) 3 888.4 (31.0) 2 689.2 (34.0) 2 127.0 (34.7)(ng/mL)

C c d htau 210.3 (242.9) 226.7 (322.8) 64.4 (25.0) 96.0 (37.4)(ng/mL)

TAF

AUCtau 305.4 (42.6) 434.5 (94.9)e 347.9 (113.2)f 229.3 (63.0)(ng*h/mL)

Cmax 413.8 (31.0) 581.8 (99.9)d 333.9 (110.6) 276.5 (62.4)(ng/mL)

Ctau N/A N/A N/A N/A(ng/mL)

TFV

AUCtau 326.6 (23.8) 427.7 (28.5) 333.5 (31.5) 292.6 (27.4)i(ng*h/mL)

C imax 21.9 (29.2) 35.5 (89.0) 24.0 (64.2) 15.2 (26.1)(ng/mL)

Ctau 10.3 (30.5)c 14.0 (30.2)d 11.1 (32.4) 10.6 (28.5)i(ng/mL)

BIC = bictegravir; FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TFV = tenofovir

N/A = not applicable; %CV = percentage coefficient of variation

Data are presented as mean (%CV).a Intensive PK data from Study GS-US-380-1474b Intensive PK data from Studies GS-US-380-1489, GS-US-380-1490, GS-US-380-1844, GS-US-380-1878 for BIC, FTCand TAF PK exposures and population PK data from Studies GS-US-292-0104 and GS-US-292-0111 for TFV PKexposuresc n = 11d n = 24e n = 22f n = 23g n = 75h n = 74i n = 841

Plasma exposures of bictegravir, emtricitabine, and tenofovir alafenamide were lower duringpregnancy as compared to postpartum, whereas exposures during postpartum were generally higherthan in non-pregnant adults (Table 6). Exposures were generally similar between the second and thirdtrimesters of pregnancy; exposures were also generally similar between Weeks 6 and 12 postpartum.

Based on exposure-response relationships for bictegravir, emtricitabine, and tenofovir alafenamide,the exposure changes during pregnancy are not considered to be clinically relevant; however, specificdosage adjustments for co-administered oral medications or supplements containing polyvalent cationsare recommended in pregnant patients (see section 4.5).

Table 6: Steady-state PK Parameters of bictegravir, emtricitabine, and tenofovir alafenamide in

HIV-Infected Virologically Suppressed Pregnant Women in the Third Trimester and Week 12

Postpartum Compared to Historical Data in Non-Pregnant Adults with HIV-1

Parameter Third Trimester Week 12 Postpartum Non-Pregnant Adults

Mean (%CV) (N=30) (N=32) with HIV-1

Bictegravir

Cmax(µg per mL) 5.37 (25.9) 11.0 (24.9) 6.15 (22.9)b

AUCtau b(µg*h per mL) 60.2 (29.1) 148 (28.5) 102 (26.9)

Unbound AUC atau(µg*h per mL) 0.219 (33.9) 0.374 (32.2) NA

Ctrough(µg per mL) 1.07 (41.7) 3.64 (34.1) 2.61 (35.2)b

Cmax(µg per mL) 2.59 (26.5) 3.36 (26.9) 2.13 (34.7)c

AUCtau(µg*h per mL) 10.4 (20.3) 15.3 (21.9) 12.3 (29.2)c

Ctrough c(µg per mL) 0.05 (27.2) 0.08 (33.7) 0.096 (37.4)

Tenofovir Alafenamide

Cmax(µg per mL) 0.27 (42.1) 0.49 (52.5) 0.121 (15.4)d

AUCtau d(µg*h per mL) 0.21 (45.0) 0.30 (31.8) 0.142 (17.3)

Unbound AUC atau(µg*h per mL) 0.016 (28.4) 0.017 (23.4) NA

CV = Coefficient of Variation; NA = Not Availablea Calculated by correcting the individual AUCtau estimates by the %unbound fraction.b From Population PK analysis in Studies 1489, 1490, 1844, and 1878; N = 1193.c From Intensive PK analysis in Studies 1489, 1490, 1844, and 1878; N = 77.d From Population PK analysis in Studies 1489 and 1490; N = 486.

Bictegravir was not mutagenic or clastogenic in conventional genotoxicity assays.

Bictegravir was not carcinogenic in a 6-month rasH2 transgenic mouse study (at doses of up to100 mg/kg/day in males and 300 mg/kg/day in females, which resulted in exposures of approximately15 and 23 times, in males and females, respectively, the exposure in humans at the recommendedhuman dose) nor in a 2-year rat study (at doses of up to 300 mg/kg/day, which resulted in exposures ofapproximately 31 times the exposure in humans).

Studies of bictegravir in monkeys revealed the liver as the primary target organ of toxicity.

Hepatobiliary toxicity was described in a 39-week study at a dosage of 1,000 mg/kg/day, whichresulted in exposures of approximately 16 times the exposure in humans at the recommended humandose, and was partially reversible after a 4-week recovery period.

Studies in animals with bictegravir have shown no evidence of teratogenicity or an effect onreproductive function. In offspring from rat and rabbit dams treated with bictegravir duringpregnancy, there were no toxicologically significant effects on developmental endpoints.

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventional studiesof safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity toreproduction and development. Emtricitabine has demonstrated low carcinogenic potential in miceand rats.

Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primarytarget organs of toxicity. Bone toxicity was observed as reduced bone mineral density in rats and dogsat tenofovir exposures at least 43 times greater than those expected after administration of B/F/TAF.

A minimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide andtenofovir exposures of approximately 14 and 43 times greater, respectively, than those expected afteradministration of B/F/TAF.

Tenofovir alafenamide was not mutagenic or clastogenic in conventional genotoxicity assays.

Because there is a lower tenofovir exposure in rats and mice after the administration of tenofoviralafenamide compared to tenofovir disoproxil, carcinogenicity studies and a rat peri-postnatal studywere conducted only with tenofovir disoproxil. No special hazard for humans was revealed inconventional studies of carcinogenic potential and toxicity to reproduction and development.

Reproductive toxicity studies in rats and rabbits showed no effects on mating, fertility, pregnancy orfoetal parameters. However, tenofovir disoproxil reduced the viability index and weight of pups in aperi-postnatal toxicity study at maternally toxic doses.

Microcrystalline cellulose (E460)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Polyvinyl alcohol (E203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Iron oxide red (E172)

Iron oxide black (E172)

Not applicable.

3 years

Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Do notuse if seal over bottle opening is broken or missing.

Store in the original package in order to protect from moisture. Do not use if foil over blister is brokenor pierced.

The following pack configurations are available:

Biktarvy 30 mg/120 mg/15 mg tablets and 50 mg/200 mg/25 mg tablets are packaged in white, highdensity polyethylene (HDPE) bottle with a polypropylene continuous-thread, child-resistant cap, linedwith an induction activated aluminium foil liner containing 30 film-coated tablets. Each bottlecontains silica gel desiccant and polyester coil.

- Outer carton containing 1 bottle of 30 film-coated tablets

- Outer carton containing 90 (3 bottles of 30) film-coated tablets.

Biktarvy 50 mg/200 mg/25 mg blister packs consisting of polyvinylchloride/polyethylene/polychlorotrifluoroethylene (PVC/PE/PCTFE) film, sealed to aluminium foillidding material fitted with a molecular sieve desiccant within each blister cavity.

- Outer carton containing 30 film-coated tablets (4 x blister strips containing 7 film-coatedtablets and 1 x blister strip containing 2 film-coated tablets).

- Outer carton containing 90 (3 blister packs of 30) film-coated tablets.

Not all pack sizes may be marketed.

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

Gilead Sciences Ireland UC

Carrigtohill

County Cork, T45 DP77

Ireland

EU/1/18/1289/001

EU/1/18/1289/002

EU/1/18/1289/003

EU/1/18/1289/004

EU/1/18/1289/005

EU/1/18/1289/006

Date of first authorisation: 21 June 2018

Date of latest renewal: 10 January 2023

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

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