GENVOYA 150mg / 150mg / 200mg / 10mg film-coated tablets medication leaflet

Genvoya 150 mg/150 mg/200 mg/10 mg film-coated tablets

Genvoya 90 mg/90 mg/120 mg/6 mg film-coated tablets

Genvoya 150 mg/150 mg/200 mg/10 mg film-coated tablets

Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine andtenofovir alafenamide fumarate equivalent to 10 mg of tenofovir alafenamide.

Each tablet contains 58 mg lactose (as monohydrate).

Genvoya 90 mg/90 mg/120 mg/6 mg film-coated tablets

Each tablet contains 90 mg of elvitegravir, 90 mg of cobicistat, 120 mg of emtricitabine and tenofoviralafenamide fumarate equivalent to 6 mg of tenofovir alafenamide.

Each tablet contains 35 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Genvoya 150 mg/150 mg/200 mg/10 mg film-coated tablets

Green, capsule-shaped, film-coated tablet of dimensions 19 mm x 8.5 mm, debossed with “GSI” onone side of the tablet and “510” on the other side of the tablet.

Genvoya 90 mg/90 mg/120 mg/6 mg film-coated tablets

Green, capsule-shaped, film-coated tablet of dimensions 16 mm x 7 mm, debossed with “GSI” on oneside of the tablet and scored on the other side of the tablet.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Genvoya is indicated for the treatment of human immunodeficiency virus-1 (HIV-1) infection withoutany known mutations associated with resistance to the integrase inhibitor class, emtricitabine ortenofovir in adults and paediatric patients aged from 2 years and with body weight at least 14 kg.

See sections 4.2 and 5.1.

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

Adults and paediatric patients weighing at least 25 kg

One 150 mg/150 mg/200 mg/10 mg tablet to be taken once daily with food.

Paediatric patients aged 2 years and older, weighing at least 14 kg to less than 25 kg

One 90 mg/90 mg/120 mg/6 mg tablet to be taken once daily with food.

If the patient misses a dose of Genvoya within 18 hours of the time it is usually taken, the patientshould take Genvoya with food as soon as possible and resume the normal dosing schedule. If apatient misses a dose of Genvoya by more than 18 hours, the patient should not take the missed doseand simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Genvoya another tablet should be taken.

No dose adjustment of Genvoya is required in elderly patients (see sections 5.1 and 5.2).

No dose adjustment of Genvoya is required in adults or adolescents (aged at least 12 years and of atleast 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 30 mL/min. Genvoya should bediscontinued in patients with estimated CrCl that declines below 30 mL/min during treatment (seesection 5.2).

No dose adjustment of Genvoya is required in adults with end stage renal disease (estimated

CrCl < 15 mL/min) on chronic haemodialysis; however, Genvoya should generally be avoided butmay be used in these patients if the potential benefits are considered to outweigh the potential risks(see sections 4.4 and 5.2). On days of haemodialysis, Genvoya should be administered aftercompletion of haemodialysis treatment.

Genvoya should be avoided in patients with estimated CrCl ≥ 15 mL/min and < 30 mL/min, or< 15 mL/min who are not on chronic haemodialysis, as the safety of Genvoya has not been establishedin these populations.

No data are available to make dose recommendations in children aged less than 12 years with renalimpairment or in children less than 18 years with end stage renal disease.

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

The safety and efficacy of Genvoya in children younger than 2 years of age, or weighing < 14 kg, havenot yet been established. No data are available.

Genvoya should be taken orally, once daily with food (see section 5.2). Due to the bitter taste, it isrecommended that the film-coated tablet not be chewed or crushed. For patients who are unable toswallow the tablet whole, the tablet may be split in half and both halves taken 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 medicinal products that are highly dependent on CYP3A for clearance and forwhich elevated plasma concentrations are associated with serious or life-threatening adverse reactions.

Therefore, Genvoya should not be co-administered with medicinal products that include, but are notlimited to, the following (see sections 4.4 and 4.5):

* alpha 1-adrenoreceptor antagonists: alfuzosin

* antiarrhythmics: amiodarone, quinidine

* ergot derivatives: dihydroergotamine, ergometrine, ergotamine

* gastrointestinal motility agents: cisapride

* HMG Co-A reductase inhibitors: lovastatin, simvastatin

* lipid-modifying agent: lomitapide

* neuroleptics/antipsychotics: pimozide, lurasidone

* PDE-5 inhibitors: sildenafil for the treatment of pulmonary arterial hypertension

* sedatives/hypnotics: orally administered midazolam, triazolam

Co-administration with medicinal products that are strong inducers of CYP3A due to the potential forloss of virologic response and possible resistance to Genvoya. Therefore, Genvoya should not beco-administered with medicinal products that include, but are not limited to, the following (seesections 4.4 and 4.5):

* anticonvulsants: carbamazepine, phenobarbital, phenytoin

* antimycobacterials: rifampicin

* herbal products: St. John’s wort (Hypericum perforatum)

Co-administration with dabigatran etexilate, a P-glycoprotein (P-gp) substrate (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.

The safety and efficacy of Genvoya in patients co-infected with HIV-1 and hepatitis C virus (HCV)have not been established.

Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of Genvoya therapyin patients co-infected with HIV and HBV may be associated with severe acute exacerbations ofhepatitis. Patients co-infected with HIV and HBV who discontinue Genvoya should be closelymonitored with both clinical and laboratory follow-up for at least several months after stoppingtreatment.

The safety and efficacy of Genvoya 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 life-style. 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(hyperlactataemia, hyperlipasaemia). These events have often been transitory. Late onsetneurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).

Whether such neurological disorders are transient or permanent is currently unknown. These findingsshould be considered for any child exposed in utero to nucleos(t)ide analogues, who present withsevere clinical findings of unknown aetiology, particularly neurologic findings. These findings do notaffect current national recommendations to use antiretroviral therapy in pregnant women to preventvertical transmission 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 receiving Genvoya or any other antiretroviral therapy may continue to develop opportunisticinfections and other complications of HIV infection, and therefore should remain under close clinicalobservation by physicians experienced 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 Genvoya 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 Genvoya should be considered.

Genvoya 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 Genvoya in HIV-1 infected adults with end stage renaldisease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy was maintained through48 weeks but emtricitabine exposure was significantly higher than in patients with normal renalfunction. Although there were no new safety issues identified, the implications of increasedemtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Some medicinal products should not be co-administered with Genvoya (see sections 4.3 and 4.5).

Genvoya should not be co-administered with other antiretroviral medicinal products (see section 4.5).

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

HBV infection (see section 4.5).

Female patients of childbearing potential should use either a hormonal contraceptive containing atleast 30 µg ethinyloestradiol and containing drospirenone or norgestimate as the progestogen or shoulduse an alternative reliable method of contraception (see sections 4.5 and 4.6). The use of Genvoyawith oral contraceptives containing other progestogens should be avoided (see section 4.5). Plasmaconcentrations of drospirenone are expected to be increased following co-administration with

Genvoya and clinical monitoring is recommended due to the potential for hyperkalaemia (seesection 4.5).

Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy hasbeen shown to result in lower elvitegravir exposures (see section 5.2). Cobicistat levels decrease andmay not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result invirological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore,therapy with Genvoya should not be initiated during pregnancy, and women who become pregnantduring therapy with Genvoya should be switched to an alternative regimen (see section 4.6).

Reductions in BMD (≥ 4%) of the spine and total-body-less-head (TBLH) have been reported inpatients aged between 3 to < 12 years receiving Genvoya for 48 weeks in study GS-US-292-0106 (seesections 4.8 and 5.1). The long-term effects of changes in BMD on the growing bone, including therisk of fracture, are uncertain. A multidisciplinary approach is recommended to decide the appropriatemonitoring during treatment.

Genvoya contains lactose monohydrate. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

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

Genvoya should not be co-administered with other antiretroviral medicinal products. Therefore,information regarding drug-drug interactions with other antiretroviral products (including proteaseinhibitors [PIs] and non-nucleoside reverse transcriptase inhibitors [NNRTIs]) is not provided (seesection 4.4). Interaction studies have only been performed in adults.

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

HBV infection.

Elvitegravir is primarily metabolised by CYP3A, and medicinal products that induce or inhibit

CYP3A may affect the exposure of elvitegravir. Co-administration of Genvoya with medicinalproducts that induce CYP3A may result in decreased plasma concentrations of elvitegravir andreduced therapeutic effect of Genvoya (see “Concomitant use contraindicated” and section 4.3).

Elvitegravir may have the potential to induce CYP2C9 and/or inducible uridine diphosphateglucuronosyltransferase (UGT) enzymes; as such it may decrease the plasma concentration ofsubstrates of these enzymes.

Cobicistat is a strong mechanism-based inhibitor of CYP3A and is also a CYP3A substrate. Cobicistatis also a weak CYP2D6 inhibitor and is metabolised, to a minor extent, by CYP2D6. Medicinalproducts that inhibit CYP3A may decrease the clearance of cobicistat, resulting in increased plasmaconcentrations of cobicistat. Medicinal products that have active metabolite(s) formed by CYP3Amay result in reduced plasma concentrations of these active metabolite(s).

Medicinal products that are highly dependent on CYP3A metabolism and have high first passmetabolism are the most susceptible to large increases in exposure when co-administered withcobicistat (see “Concomitant use contraindicated” and section 4.3).

Cobicistat is an inhibitor of the following transporters: P-gp, breast cancer resistance protein (BCRP),organic anion transporting polypeptide (OATP) 1B1 and OATP1B3. Co-administration withmedicinal products that are substrates of P-gp, BCRP, OATP1B1 and OATP1B3 may result inincreased plasma concentrations of these products.

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-gp and BCRP. Medicinal products that strongly affect P-gpand BCRP activity may lead to changes in tenofovir alafenamide absorption. However, uponco-administration with cobicistat in Genvoya, near maximal inhibition of P-gp by cobicistat isachieved leading to increased availability of tenofovir alafenamide with resulting exposurescomparable to tenofovir alafenamide 25 mg administered alone. As such, tenofovir alafenamideexposures following administration of Genvoya are not expected to be further increased when used incombination with another P-gp and/or BCRP inhibitor (e.g., ketoconazole). Based on data from anin vitro study, co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g.,febuxostat) is not expected to increase systemic exposure to tenofovir in vivo. In vitro and clinicalpharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediatedinteractions involving tenofovir alafenamide with other medicinal products is low. Tenofoviralafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

Tenofovir alafenamide is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is asubstrate of OATP in vitro. Inhibitors of OATP and BCRP include ciclosporin.

Co-administration of Genvoya and some medicinal products that are primarily metabolised by CYP3Amay result in increased plasma concentrations of these products, which are associated with thepotential for serious or life-threatening adverse reactions such as peripheral vasospasm or ischaemia(e.g., dihydroergotamine, ergotamine, ergometrine), or myopathy, including rhabdomyolysis (e.g.,simvastatin, lovastatin), or prolonged or increased sedation or respiratory depression (e.g., orallyadministered midazolam or triazolam). Co-administration of Genvoya and other medicinal productsprimarily metabolised by CYP3A such as amiodarone, lomitapide, quinidine, cisapride, pimozide,lurasidone, alfuzosin and sildenafil for pulmonary arterial hypertension is contraindicated (seesection 4.3).

Co-administration of Genvoya and some medicinal products that induce CYP3A such as St. John’swort (Hypericum perforatum), rifampicin, carbamazepine, phenobarbital, and phenytoin may result insignificantly decreased cobicistat and elvitegravir plasma concentrations, which may result in loss oftherapeutic effect and development of resistance (see section 4.3).

Cobicistat and tenofovir alafenamide are not inhibitors of human UGT1A1 in vitro. It is not knownwhether cobicistat, emtricitabine, or tenofovir alafenamide are inhibitors of other UGT enzymes.

Interactions between the components of Genvoya and potential co-administered medicinal productsare listed in Table 1 below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). Theinteractions described are based on studies conducted with Genvoya, or the components of Genvoya(elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide), as individual agents and/or incombination, or are potential drug-drug interactions that may occur with Genvoya.

Table 1: Interactions between the individual components of Genvoya and other medicinalproducts

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

ANTI-INFECTIVES

Antifungals

Ketoconazole (200 mg twice Elvitegravir: When administering with Genvoya,daily)/ Elvitegravir (150 mg once AUC: ↑ 48% the maximum daily dose ofdaily)2 Cmin: ↑ 67% ketoconazole should not exceed

Cmax: ↔ 200 mg per day. Caution iswarranted and clinical monitoring is

Concentrations of ketoconazole recommended during theand/or cobicistat may increase with co-administration.co-administration of Genvoya.

Itraconazole3 Interaction not studied with any of Clinical monitoring should be made

Voriconazole3 the components of Genvoya. upon co-administration with

Posaconazole3 Genvoya. When administering with

Fluconazole Concentrations of itraconazole, Genvoya, the maximum daily dosefluconazole and posaconazole may of itraconazole should not exceedbe increased when co-administered 200 mg per day.with cobicistat.

An assessment of benefit/risk ratio

Concentrations of voriconazole is recommended to justify use ofmay increase or decrease when voriconazole with Genvoya.co-administered with Genvoya.

Antimycobacterials

Rifabutin (150 mg every other Co-administration of rifabutin, a Co-administration of Genvoya andday)/ Elvitegravir (150 mg once potent CYP3A inducer, may rifabutin is not recommended.daily)/ Cobicistat (150 mg once significantly decrease cobicistatdaily) and elvitegravir plasma If the combination is needed, theconcentrations, which may result in recommended dose of rifabutin isloss of therapeutic effect and 150 mg 3 times per week on setdevelopment of resistance. days (for example Monday-

Wednesday-Friday).

Rifabutin: Increased monitoring for

AUC: ↔ rifabutin-associated adverse

Cmin: ↔ reactions including neutropenia and

Cmax: ↔ uveitis is warranted due to anexpected increase in exposure to25-O-desacetyl-rifabutin desacetyl-rifabutin. Further dose

AUC: ↑ 525% reduction of rifabutin has not been

Cmin: ↑ 394% studied. It should be kept in mind

Cmax: ↑ 384% that a twice weekly dose of 150 mgmay not provide an optimal

Elvitegravir: exposure to rifabutin thus leading to

AUC: ↓ 21% a risk of rifamycin resistance and a

Cmin: ↓ 67% treatment failure.

Cmax: ↔

AUC: ↔

Cmin: ↓ 66%

Cmax: ↔

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

Anti-hepatitis C virus medicinal products

Ledipasvir (90 mg once daily)/ Ledipasvir: No dose adjustment of

Sofosbuvir (400 mg once daily)/ AUC: ↑ 79% ledipasvir/sofosbuvir and Genvoya

Elvitegravir (150 mg once daily)/ Cmin: ↑ 93% is warranted upon co-administration.

Cobicistat (150 mg once daily)/ Cmax: ↑ 65%

Emtricitabine (200 mg once daily)/

Tenofovir alafenamide (10 mg Sofosbuvir:once daily)5 AUC: ↑ 47%

Cmin: N/A

Cmax: ↑ 28%

Sofosbuvir metabolite GS-566500:

AUC: ↔

Cmin: ↔

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↑ 48%

Cmin: ↑ 66%

Cmax: ↔

AUC: ↔

Cmin: ↑ 46%

Cmax: ↔

AUC: ↑ 53%

Cmin: ↑ 225%

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: N/A

Cmax: ↔

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

Sofosbuvir (400 mg once daily)/ Sofosbuvir: No dose adjustment of

Velpatasvir (100 mg once daily)/ AUC: ↑ 37% sofosbuvir/velpatasvir and Genvoya

Elvitegravir (150 mg once daily)/ Cmin: N/A is warranted upon co-administration.

Cobicistat (150 mg once daily)/ Cmax: ↔

Emtricitabine (200 mg once daily)/

Tenofovir alafenamide (10 mg Sofosbuvir metabolite GS-331007:once daily)5 AUC: ↑ 48%

Cmin: ↑ 58%

Cmax: ↔

AUC: ↑ 50%

Cmin: ↑ 60%

Cmax: ↑ 30%

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↑ 103%

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: N/A

Cmax: ↓ 20%

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

Sofosbuvir/Velpatasvir/ Sofosbuvir: No dose adjustment of

Voxilaprevir AUC: ↔ sofosbuvir/velpatasvir/voxilaprevir(400 mg/100 mg/100 mg+100 mg Cmin: N/A and Genvoya is warranted upononce daily)7/ Cmax: ↑ 27% co-administration.

Elvitegravir (150 mg once daily)/

Cobicistat (150 mg once daily)/ Sofosbuvir metabolite GS-331007:

Emtricitabine (200 mg once daily)/ AUC: ↑ 43%

Tenofovir alafenamide (10 mg Cmin: N/Aonce daily)5 Cmax: ↔

AUC: ↔

Cmin: ↑ 46%

Cmax: ↔

AUC: ↑ 171%

Cmin: ↑ 350%

Cmax: ↑ 92%

AUC: ↔

Cmin: ↑ 32%

Cmax: ↔

AUC: ↑ 50%

Cmin: ↑ 250%

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: N/A

Cmax: ↓ 21%

Clarithromycin Interaction not studied with any of Clarithromycin dosing should bethe components of Genvoya. based on the patient’s CrCl, takinginto consideration the effect of

Concentrations of clarithromycin cobicistat on CrCl and serumand/or cobicistat may be altered creatinine (see section 4.8).with co-administration of Genvoya.

Patients with CrCl greater than orequal to 60 mL/min:

No dose adjustment ofclarithromycin is required.

Patients with CrCl between30 mL/min and 60 mL/min:

The dose of clarithromycin shouldbe reduced by 50%.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

Telithromycin Interaction not studied with any of Clinical monitoring is recommendedthe components of Genvoya. upon co-administration of Genvoya.

Concentrations of telithromycinand/or cobicistat may be alteredwith co-administration of Genvoya.

ANTICONVULSANTS

Carbamazepine (200 mg twice Co-administration of Carbamazepine decreases plasmadaily)/ Elvitegravir (150 mg once carbamazepine, a potent CYP3A concentrations of elvitegravir anddaily)/ Cobicistat (150 mg once inducer, may significantly decrease cobicistat, which may result in lossdaily) cobicistat plasma concentrations. of therapeutic effect anddevelopment of resistance.

Elvitegravir: Co-administration of Genvoya with

AUC: ↓ 69% carbamazepine is contraindicated

Cmin: ↓ 97% (see section 4.3).

Cmax: ↓ 45%

AUC: ↓ 84%

Cmin: ↓ 90%

Cmax: ↓ 72%

Carbamazepine:

AUC: ↑ 43%

Cmin: ↑ 51%

Cmax: ↑ 40%

Carbamazepine-10,11-epoxide:

AUC: ↓ 35%

Cmin: ↓ 41%

Cmax: ↓ 27%

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

GLUCOCORTICOIDS

Corticosteroids primarily Interaction not studied with any of Concomitant use of Genvoya andmetabolised by CYP3A (including the components of Genvoya. corticosteroids that are metabolisedbetamethasone, budesonide, by CYP3A (e.g. fluticasonefluticasone, mometasone, Plasma concentrations of these propionate or other inhaled or nasalprednisone, triamcinolone). medicinal products may be corticosteroids) may increase theincreased when co-administered risk of development of systemicwith Genvoya, resulting in reduced corticosteroid effects, includingserum cortisol concentrations. Cushing’s syndrome and adrenalsuppression.

Co-administration with

CYP3A-metabolised corticosteroidsis not recommended unless thepotential benefit to the patientoutweighs the risk, in which casepatients should be monitored forsystemic corticosteroid effects.

Alternative corticosteroids whichare less dependent on CYP3Ametabolism e.g. beclomethasone forintranasal or inhalational use shouldbe considered, particularly forlong-term use.

For coadministration ofcutaneously-administeredcorticosteroids sensitive to CYP3Ainhibition, refer to the prescribinginformation of the corticosteroid forconditions or uses that augment itssystemic absorption.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

MEDICINAL PRODUCTS or ORAL SUPPLEMENTS CONTAINING POLYVALENT CATIONS (e.g. Mg,

Al, Ca, Fe, Zn)

Magnesium/aluminium-containing Elvitegravir (antacid suspension It is recommended to separateantacid suspension (20 mL single after ± 2 hours): Genvoya and administration ofdose)/ Elvitegravir (50 mg single AUC: ↔ antacids, medicinal products or oraldose)/ Ritonavir (100 mg single Cmin: ↔ supplements containing polyvalentdose) Cmax: ↔ cations by at least 4 hours.

Elvitegravir (simultaneous For information on other acidadministration): reducing agents (e.g., H2-receptor

AUC: ↓ 45% antagonists and proton pump

Cmin: ↓ 41% inhibitors), see “Studies conducted

Cmax: ↓ 47% with other medicinal products”.

Elvitegravir plasma concentrationsare lower with antacids due to localcomplexation in the gastrointestinaltract and not to changes in gastricpH.

Calcium or iron supplements Interaction not studied with any of(including multivitamins) the components of Genvoya.

Other cation-containing antacids

Cation-containing laxatives Elvitegravir plasma concentrations

Sucralfate are expected to be lower with

Buffered medicinal products antacids, medicinal products or oralsupplements containing polyvalentcations, due to local complexationin the gastrointestinal tract and notto changes in gastric pH.

ORAL ANTI-DIABETICS

Metformin Interaction not studied with any of Careful patient monitoring and dosethe components of Genvoya. adjustment of metformin isrecommended in patients who are

Cobicistat reversibly inhibits taking Genvoya.

MATE1, and concentrations ofmetformin may be increased whenco-administered with Genvoya.

NARCOTIC ANALGESICS

Methadone (80-120 mg)/ Methadone: No dose adjustment of methadone is

Elvitegravir (150 mg once daily)/ AUC: ↔ required.

Cobicistat (150 mg once daily) Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

Buprenorphine/Naloxone (16/4 to Buprenorphine: No dose adjustment of24/6 mg)/ Elvitegravir (150 mg AUC: ↑ 35% buprenorphine/naloxone is required.once daily)/ Cobicistat (150 mg Cmin: ↑ 66%once daily) Cmax: ↔

Naloxone:

AUC: ↓ 28%

Cmax: ↓ 28%

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

ORAL CONTRACEPTIVES

Drospirenone/Ethinyloestradiol Interaction not studied with Plasma concentrations of(3 mg/0.02 mg single dose)/ Genvoya. drospirenone may be increased

Cobicistat (150 mg once daily) when co-administered with

Expected cobicistat-containing products.

Drospirenone: Clinical monitoring is recommended

AUC: ↑ due to the potential forhyperkalaemia.

Norgestimate Norelgestromin:(0.180/0.215/0.250 mg once daily)/ AUC: ↔ Caution should be exercised when

Ethinyloestradiol (0.025 mg once Cmin: ↔ co-administering Genvoya and adaily)/ Emtricitabine/Tenofovir Cmax: ↔ hormonal contraceptive. Thealafenamide (200/25 mg once hormonal contraceptive shoulddaily)6 Norgestrel: contain at least 30 µg

AUC: ↔ ethinyloestradiol and contain

Cmin: ↔ drospirenone or norgestimate as the

Cmax: ↔ progestogen or patients should usean alternative reliable method of

Ethinyloestradiol: contraception (see sections 4.4 and

AUC: ↔ 4.6).

Cmin: ↔

Cmax: ↔ The long-term effects of substantialincreases in progestogen exposureare unknown.

Norgestimate (0.180/0.215 mg Norgestimate:once daily)/ Ethinyloestradiol AUC: ↑ 126%(0.025 mg once daily)/ Elvitegravir Cmin: ↑ 167%(150 mg once daily)/ Cobicistat Cmax: ↑ 108%(150 mg once daily)4

Ethinyloestradiol:

AUC: ↓ 25%

Cmin: ↓ 44%

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

ANTIARRHYTHMICS

Digoxin (0.5 mg single dose)/ Digoxin: It is recommended that digoxin

Cobicistat (150 mg multiple doses) AUC: ↔ levels be monitored when digoxin is

Cmax: ↑ 41% combined with Genvoya.

Disopyramide Interaction not studied with any of Caution is warranted and clinical

Flecainide the components of Genvoya. monitoring is recommended upon

Systemic lidocaine co-administration with Genvoya.

Mexiletine Concentrations of these

Propafenone antiarrhythmic drugs may beincreased when co-administeredwith cobicistat.

ANTI-HYPERTENSIVES

Metoprolol Interaction not studied with any of Clinical monitoring is recommended

Timolol the components of Genvoya. and a dose decrease may benecessary when these agents are

Concentrations of beta-blockers co-administered with Genvoya.may be increased whenco-administered with cobicistat.

Amlodipine Interaction not studied with any of Clinical monitoring of therapeutic

Diltiazem the components of Genvoya. effects and adverse reactions is

Felodipine recommended when these medicinal

Nicardipine Concentrations of calcium channel products are concomitantly

Nifedipine blockers may be increased when administered with Genvoya.

Verapamil co-administered with cobicistat.

ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan Interaction not studied with any of Alternative endothelin receptorthe components of Genvoya. antagonists may be considered.

Co-administration with Genvoyamay lead to decreased elvitegravirand/or cobicistat exposures andloss of therapeutic effect anddevelopment of resistance.

ANTICOAGULANTS

Dabigatran Interaction not studied with any of Co-administration of Genvoya withthe components of Genvoya. dabigatran is contraindicated.

Co-administration with Genvoyamay increase dabigatran plasmaconcentrations with similar effectsas seen with other strong P-gpinhibitors.

Apixaban Interaction not studied with any of Co-administration of apixaban,

Rivaroxaban the components of Genvoya. rivaroxaban or edoxaban is not

Edoxaban recommended with Genvoya.

Co-administration with Genvoyamay result in increased plasmaconcentrations of the DOAC,which may lead to an increasedbleeding risk.

Warfarin Interaction not studied with any of It is recommended that thethe components of Genvoya. international normalised ratio (INR)be monitored upon

Concentrations of warfarin may be co-administration of Genvoya. INRaffected upon co-administration should continue to be monitoredwith Genvoya. during the first weeks followingceasing treatment with Genvoya.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

ANTIPLATELETS

Clopidogrel Interaction not studied with any of Co-administration of Genvoya withthe components of Genvoya. clopidogrel is not recommended.

Co-administration of clopidogrelwith cobicistat is expected todecrease clopidogrel activemetabolite plasma concentrations,which may reduce the antiplateletactivity of clopidogrel.

Prasugrel Interaction not studied with any of No dose adjustment of prasugrel isthe components of Genvoya. required.

Genvoya is not expected to have aclinically relevant effect on plasmaconcentrations of the activemetabolite of prasugrel.

INHALED BETA AGONIST

Salmeterol Interaction not studied with any of Concurrent administration ofthe components of Genvoya. salmeterol and Genvoya is notrecommended.

Co-administration with Genvoyamay result in increased plasmaconcentrations of salmeterol, whichis associated with the potential forserious or life-threatening adversereactions.

HMG CO-A REDUCTASE INHIBITORS

Rosuvastatin (10 mg single dose)/ Elvitegravir: Concentrations of rosuvastatin are

Elvitegravir (150 mg once daily)/ AUC: ↔ transiently increased when

Cobicistat (150 mg once daily) Cmin: ↔ administered with elvitegravir and

Cmax: ↔ cobicistat. Dose modifications arenot necessary when rosuvastatin is

Rosuvastatin: administered in combination with

AUC: ↑ 38% Genvoya.

Cmin: N/A

Cmax: ↑ 89%

Atorvastatin (10 mg single Atorvastatin: Concentrations of atorvastatin aredose)/Elvitegravir (150 mg once AUC: ↑ 160% increased when co-administereddaily)/Cobicistat (150 mg once Cmin: N/A with elvitegravir and cobicistat.daily)/Emtricitabine (200 mg once Cmax: ↑ 132% Start with the lowest possible dosedaily)/Tenofovir alafenamide of atorvastatin with careful(10 mg once daily) Elvitegravir: monitoring upon co-administration

AUC: ↔ with Genvoya.

Cmin: ↔

Cmax: ↔

Pitavastatin Interaction not studied with any of Caution should be exercised whenthe components of Genvoya. co-administering Genvoya withpitavastatin.

Concentrations of pitavastatin maybe increased when administeredwith elvitegravir and cobicistat.

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

Pravastatin Interaction not studied with any of Dose modifications are not

Fluvastatin the components of Genvoya. necessary when administered incombination with Genvoya.

Concentrations of these

HMG Co-A reductase inhibitorsare expected to transiently increasewhen administered withelvitegravir and cobicistat.

Lovastatin Interaction not studied with any of Co-administration of Genvoya and

Simvastatin the components of Genvoya. lovastatin and simvastatin iscontraindicated (see section 4.3).

LIPID-MODIFYING AGENTS

Lomitapide Interaction not studied with any of Coadministration with lomitapide isthe components of Genvoya. contraindicated (see section 4.3).

Lomitapide is highly dependent on

CYP3A for its metabolism and co-administration with Genvoya mayresult in increased concentrationsof lomitapide and potential formarkedly increased transaminases.

PHOSPHODIESTERASE TYPE 5 (PDE-5) INHIBITORS

Sildenafil Interaction not studied with any of Co-administration of Genvoya and

Tadalafil the components of Genvoya. sildenafil for the treatment of

Vardenafil pulmonary arterial hypertension is

PDE-5 inhibitors are primarily contraindicated.metabolised by CYP3A.

Co-administration with Genvoya Caution should be exercised,may result in increased plasma including consideration of doseconcentrations of sildenafil and reduction, when co-administeringtadalafil, which may result in Genvoya with tadalafil for the

PDE-5 inhibitor-associated adverse treatment of pulmonary arterialreactions. hypertension.

For the treatment of erectiledysfunction, it is recommended thata single dose of sildenafil no morethan 25 mg in 48 hours, vardenafilno more than 2.5 mg in 72 hours, ortadalafil no more than 10 mg in72 hours be co-administered with

Genvoya.

ANTIDEPRESSANTS

Sertraline (50 mg single dose)/ Elvitegravir: Concentrations of sertraline are not

Elvitegravir (150 mg once daily)/ AUC: ↔ affected upon co-administration

Cobicistat (150 mg once daily)/ Cmin: ↔ with Genvoya. No dose adjustment

Emtricitabine (200 mg once daily)/ Cmax: ↔ is required upon co-administration.

Tenofovir alafenamide (10 mgonce daily)5 Tenofovir alafenamide:

AUC: ↔

Cmin: ↔

Cmax: ↔

Sertraline:

AUC: ↔

Cmin: ↔

Cmax: ↔

Medicinal product by Effects on medicinal product Recommendation concerningtherapeutic areas levels. co-administration with Genvoya

Mean percent change in AUC,

Cmax, Cmin1

Tricyclic antidepressants (TCAs) Interaction not studied with any of Careful dose titration of the

Trazodone the components of Genvoya. antidepressant and monitoring for

Selective serotonin reuptake antidepressant response isinhibitors (SSRIs) Concentrations of antidepressant recommended.

Escitalopram agents may be increased whenco-administered with cobicistat.

IMMUNOSUPPRESSANTS

Ciclosporin Interaction not studied with any of Therapeutic monitoring is

Sirolimus the components of Genvoya. recommended upon

Tacrolimus co-administration with Genvoya.

Concentrations of theseimmunosuppressant agents may beincreased when administered withcobicistat.

SEDATIVES/HYPNOTICS

Buspirone Interaction not studied with any of Co-administration of Genvoya and

Clorazepate the components of Genvoya. triazolam is contraindicated (see

Diazepam section 4.3). With other

Estazolam Triazolam is primarily metabolised sedatives/hypnotics, dose reduction

Flurazepam by CYP3A. Co-administration may be necessary and concentration

Lorazepam with Genvoya may result in monitoring is recommended.

Triazolam increased plasma concentrations of

Zolpidem this medicinal product, which isassociated with the potential forserious or life-threatening adversereactions.

Concentrations of otherbenzodiazepines, includingdiazepam, may be increased whenadministered with Genvoya.

Based on non-CYP-mediatedelimination pathways forlorazepam, no effect on plasmaconcentrations is expected uponco-administration with Genvoya.

Orally administered midazolam Midazolam: Co-administration of Genvoya and(2.5 mg single dose)/ Tenofovir AUC: ↔ orally administered midazolam isalafenamide (25 mg once daily) Cmax: ↔ contraindicated (see section 4.3).

Intravenously administered Midazolam is primarilymidazolam (1 mg single dose)/ metabolised by CYP3A. Due to

Tenofovir alafenamide (25 mg the presence of cobicistat,once daily) co-administration with Genvoyamay result in increased plasmaconcentrations of this medicinalproduct, which is associated withthe potential for serious orlife-threatening adverse reactions.

ANTI-GOUT

Colchicine Interaction not studied with any of Dose reductions of colchicine maythe components of Genvoya. be required. Genvoya should not beco-administered with colchicine to

Co-administration with Genvoya patients with renal or hepaticmay result in increased plasma impairment.concentrations of this medicinalproduct.

N/A = not applicable

DOAC = direct oral anticoagulant1 When data available from drug-drug interaction studies.2 These studies were performed with ritonavir boosted elvitegravir.3 These are medicinal products within class where similar interactions could be predicted.4 This study was conducted using elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate.5 This study was conducted using Genvoya.6 This study was conducted using emtricitabine/tenofovir alafenamide.7 This study was conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in

HCV infected patients.

Based on drug-drug interaction studies conducted with Genvoya or the components of Genvoya, noclinically significant drug-drug interactions have been either observed or are expected between thecomponents of Genvoya and the following medicinal products: entecavir, famciclovir, ribavirin,famotidine, and omeprazole.

Women of childbearing potential/contraception in males and females

The use of Genvoya should be accompanied by the use of effective contraception (see sections 4.4and 4.5).

There are no adequate and well-controlled studies of Genvoya or its components in pregnant women.

There are no or limited data (less than 300 pregnancy outcomes) from the use of Genvoya in pregnantwomen. However, a large amount of data on pregnant women (more than 1,000 exposed outcomes)indicate no malformative nor foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of elvitegravir, cobicistat, oremtricitabine, administered separately, with respect to fertility parameters, pregnancy, foetaldevelopment, parturition or postnatal development. Studies of tenofovir alafenamide in animals haveshown no evidence of harmful effects of tenofovir alafenamide on fertility parameters, pregnancy, orfoetal development (see section 5.3).

Treatment with cobicistat and elvitegravir during the second and third trimesters of pregnancy hasbeen shown to result in lower elvitegravir exposures (see section 5.2). Cobicistat levels decrease andmay not provide sufficient boosting. The substantial reduction in elvitegravir exposure may result invirological failure and an increased risk of mother-to-child transmission of HIV infection. Therefore,therapy with Genvoya should not be initiated during pregnancy, and women who become pregnantduring therapy with Genvoya should be switched to an alternative regimen (see section 4.4).

It is not known whether elvitegravir, cobicistat, or tenofovir alafenamide are excreted in human milk.

Emtricitabine is excreted in human milk. In animal studies it has been shown that elvitegravir,cobicistat, and tenofovir are excreted in milk.

There is insufficient information on the effects of elvitegravir, cobicistat, emtricitabine and tenofovirin newborns/infants. Therefore, Genvoya 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.

There are no data on fertility from the use of Genvoya in humans. In animal studies there were noeffects of elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide on mating or fertilityparameters (see section 5.3).

Genvoya may have minor influence on the ability to drive and use machines. Patients should beinformed that dizziness has been reported during treatment with Genvoya.

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

Genvoya and from post-marketing experience. The most frequently reported adverse reactions inclinical studies through 144 weeks were nausea (11%), diarrhoea (7%), and headache (6%).

The adverse reactions in Table 2 are listed by system organ class and frequency. Frequencies aredefined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to< 1/100).

Table 2: Tabulated list of adverse reactions

Frequency Adverse reaction

Uncommon: anaemia1

Common: abnormal dreams

Uncommon: suicidal ideation and suicide attempt (in patients with a pre-existing history ofdepression or psychiatric illness), depression2

Common: headache, dizziness

Very common: nausea

Common: diarrhoea, vomiting, abdominal pain, flatulence

Uncommon: dyspepsia

Common: rash

Uncommon: angioedema3,4, pruritus, urticaria4

Common: fatigue1 This adverse reaction was not observed in the Phase 3 clinical studies for Genvoya but identified from clinical studies orpost-marketing experience for emtricitabine when used with other antiretrovirals.2 This adverse reaction was not observed in the Phase 3 clinical studies for Genvoya but identified from clinical studies forelvitegravir when used with other antiretrovirals.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.

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).

Cobicistat increases serum creatinine due to inhibition of tubular secretion of creatinine withoutaffecting renal glomerular function. In clinical studies of Genvoya, increases in serum creatinineoccurred by Week 2 of treatment and remained stable through 144 weeks. In treatment-naïve patients,a mean change from baseline of 0.04 ± 0.12 mg/dL (3.5 ± 10.6 µmol/L) was observed after 144 weeksof treatment. Mean increases from baseline in the Genvoya group were smaller than in the elvitegravir150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg(E/C/F/TDF) group at Week 144 (difference -0.04, p < 0.001).

In studies in treatment-naïve patients, increases from baseline were observed in both treatment groupsfor the fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)- andhigh-density lipoprotein (HDL)-cholesterol, and triglycerides at Week 144. The median increase frombaseline for those parameters was greater in the Genvoya group compared with the E/C/F/TDF groupat Week 144 (p < 0.001 for the difference between treatment groups for fasting total cholesterol, direct

LDL- and HDL-cholesterol, and triglycerides). The median (Q1, Q3) change from baseline in totalcholesterol to HDL-cholesterol ratio at Week 144 was 0.2 (-0.3, 0.7) in the Genvoya group and 0.1(-0.4, 0.6) in the E/C/F/TDF group (p = 0.006 for the difference between treatment groups).

The safety of Genvoya was evaluated through 48 weeks in HIV-1 infected adolescent patients aged 12to < 18 years weighing ≥ 35 kg (n = 100), in children aged 7 to < 12 years weighing > 25 kg (n = 52),and in children aged 3 to 9 years and weighing ≥ 14 to < 25 kg (n = 27). The safety profile inpaediatric patients who received treatment with Genvoya was similar to that in adults. After 48 weeksof treatment with Genvoya, reductions in BMD of the spine and of the TBLH ≥ 4% have beenreported in 2.1% (1/47) and 0.0% of adolescents, in 12.2% (6/49) and 3.9% (2/51) of children aged 7to < 12 years weighing at least 25 kg, and in 3.7% (1/27) and 0.0% of children aged at least 3 yearsand weighing at least 14 kg to < 25 kg respectively.

The safety of Genvoya in 248 HIV-1 infected patients who were either treatment-naïve (n = 6) orvirologically suppressed (n = 242) with mild to moderate renal impairment (estimated glomerularfiltration rate by Cockcroft-Gault method [eGFRCG]: 30-69 mL/min) was evaluated through 144 weeksin an open-label clinical study (GS-US-292-0112). The safety profile of Genvoya in patients withmild to moderate renal impairment was similar to that in patients with normal renal function (seesection 5.1).

The safety of Genvoya in 55 virologically suppressed HIV-1 infected patients with end stage renaldisease (eGFRCG < 15 mL/min) on chronic haemodialysis was evaluated through 48 weeks in a singlearm, open-label clinical study (GS-US-292-1825). There were no new safety issues identified inpatients with end stage renal disease on chronic haemodialysis receiving Genvoya (see section 5.2).

The safety of Genvoya was evaluated in 72 HIV/HBV co-infected patients receiving treatment for

HIV in an open-label clinical study (GS-US-292-1249), through Week 48, in which patients wereswitched from another antiretroviral regimen (which included tenofovir disoproxil in 69 of72 patients) to Genvoya. Based on these limited data, the safety profile of Genvoya in patients with

HIV/HBV co-infection was similar to that in patients with HIV-1 monoinfection.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows 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 Genvoya consists of general supportive measures including monitoring of vital signsas well as observation of the clinical status of the patient.

As elvitegravir and cobicistat are highly bound to plasma proteins, it is unlikely that they would besignificantly removed by haemodialysis or peritoneal dialysis. Emtricitabine can be removed byhaemodialysis, which removes approximately 30% of the emtricitabine dose over a 3 hour dialysisperiod starting within 1.5 hours of emtricitabine dosing. Tenofovir is efficiently removed byhaemodialysis with an extraction coefficient of approximately 54%. It is not known whetheremtricitabine or tenofovir can be removed by peritoneal dialysis.

Pharmacotherapeutic group: Antivirals for systemic use; antivirals for treatment of HIV infections,combinations. ATC code: J05AR18.

Elvitegravir is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encodedenzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1deoxyribonucleic acid (DNA) into host genomic DNA, blocking the formation of the HIV-1 provirusand propagation of the viral infection.

Cobicistat is a selective, mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the

CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemicexposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life isshortened by CYP3A-dependent metabolism.

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogue of2’-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabinetriphosphate. Emtricitabine triphosphate inhibits HIV replication through incorporation into viral

DNA by the HIV reverse transcriptase (RT), which results in DNA chain-termination. Emtricitabinehas 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 inconcentrating tenofovir in peripheral blood mononuclear cells (PBMCs) (including lymphocytes andother HIV target cells) and macrophages. Intracellular tenofovir is subsequently phosphorylated to thepharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits

HIV replication through incorporation into viral DNA by the HIV RT, which results in DNAchain-termination. Tenofovir has activity against HIV-1, HIV-2, and HBV.

Elvitegravir, emtricitabine, and tenofovir alafenamide demonstrated synergistic antiviral activity incell culture. Antiviral synergy was maintained for elvitegravir, emtricitabine, and tenofoviralafenamide when tested in the presence of cobicistat.

The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed inlymphoblastoid cells, monocyte/macrophage cells, and peripheral blood lymphocytes and the50% effective concentration (EC50) values were in the range of 0.02 to 1.7 nM. Elvitegravir displayedantiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values rangedfrom 0.1 to 1.3 nM) and activity against HIV-2 (EC50 of 0.53 nM).

Cobicistat has no detectable antiviral activity against HIV-1 and does not antagonise the antiviraleffects of elvitegravir, emtricitabine, or tenofovir.

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 strain specific 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 cellsand 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, and O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nM)and showed strain specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nM).

In vitro

Reduced susceptibility to elvitegravir is most commonly associated with the primary integrasemutations T66I, E92Q, and Q148R. Additional integrase mutations observed in cell culture selectionincluded H51Y, F121Y, S147G, S153Y, E157Q, and R263K. HIV-1 with the raltegravir-selectedsubstitutions T66A/K, Q148H/K, and N155H showed cross-resistance to elvitegravir.

No in vitro resistance can be demonstrated with cobicistat due to its lack of antiviral activity.

Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 RT.

HIV-1 isolates with reduced susceptibility to tenofovir alafenamide express a K65R mutation in

HIV-1 RT; in addition, a K70E mutation in HIV-1 RT has been transiently observed. HIV-1 isolateswith the K65R mutation have low-level reduced susceptibility to abacavir, emtricitabine, tenofovir,and lamivudine.

In a pooled analysis, genotyping was performed on plasma HIV-1 isolates from antiretroviral-naïvepatients receiving Genvoya in Phase 3 studies GS-US-292-0104 and GS-US-292-0111 with

HIV-1 RNA ≥ 400 copies/mL at confirmed virologic failure, Week 144, or time of early study drugdiscontinuation. Up to Week 144, the development of one or more primary elvitegravir, emtricitabine,or tenofovir alafenamide resistance-associated mutations was observed in HIV-1 isolates from 12 of22 patients with evaluable genotypic data from paired baseline and Genvoya treatment-failure isolates(12 of 866 patients [1.4%]) compared with 12 of 20 treatment-failure isolates from patients withevaluable genotypic data in the E/C/F/TDF treatment group (12 of 867 patients [1.4%]). Of the

HIV-1 isolates from 12 patients with resistance development in the Genvoya group, the mutations thatemerged were M184V/I (n = 11) and K65R/N (n = 2) in RT and T66T/A/I/V (n = 2), E92Q (n = 4),

Q148Q/R (n = 1) and N155H (n = 2) in integrase. Of the HIV-1 isolates from 12 patients withresistance development in the E/C/F/TDF group, the mutations that emerged were M184V/I (n = 9),

K65R/N (n = 4), and L210W (n = 1) in RT and E92Q/V (n = 4), and Q148R (n = 2), and N155H/S(n = 3) in integrase. Most HIV-1 isolates from patients in both treatment groups who developedresistance mutations to elvitegravir developed resistance mutations to both emtricitabine andelvitegravir.

In phenotypic analyses of patients in the final resistance analysis population, 7 of 22 patients (32%)had HIV-1 isolates with reduced susceptibility to elvitegravir in the Genvoya group compared with

HIV-1 isolates from 7 of 20 patients (35%) in the E/C/F/TDF group, HIV-1 isolates from 8 patients(36%) had reduced susceptibility to emtricitabine in the Genvoya group compared with HIV-1 isolatesfrom 7 patients (35%) in the E/C/F/TDF group. One patient in the Genvoya group (1 of 22 [4.5%])and 2 patients in the E/C/F/TDF group (2 of 20 [10%]) had reduced susceptibility to tenofovir.

Three patients with emergent HIV-1 resistance to Genvoya were identified (M184M/I; M184I+E92G;

M184V+E92Q) up to Week 96 in a clinical study of virologically suppressed patients who switchedfrom a regimen containing emtricitabine/tenofovir disoproxil and a third agent (GS-US-292-0109,n = 959).

In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis B, whoreceived Genvoya for 48 weeks (GS-US-292-1249, n = 72), 2 patients qualified for resistance analysis.

In these 2 patients, no amino acid substitutions associated with resistance to any of the components of

Genvoya were identified in HIV-1 or HBV.

Elvitegravir-resistant viruses show varying degrees of cross-resistance to the INSTI raltegravirdepending on the type and number of mutations. Viruses expressing the T66I/A mutations maintainsusceptibility to raltegravir, while most other patterns showed reduced susceptibility to raltegravir.

Viruses expressing elvitegravir or raltegravir resistance mutations maintain susceptibility todolutegravir.

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.

In studies GS-US-292-0104 and GS-US-292-0111, patients were randomised in a 1:1 ratio to receiveeither Genvoya (n = 866) once daily or elvitegravir 150 mg/cobicistat 150 mg/emtricitabine200 mg/tenofovir disoproxil (as fumarate) 245 mg (E/C/F/TDF) (n = 867) once daily. The mean agewas 36 years (range 18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian.

Nineteen percent of patients were identified as Hispanic/Latino. The mean baseline plasma

HIV-1 RNA was 4.5 log10 copies/mL (range 1.3-7.0) and 23% had baseline viral loads> 100,000 copies/mL. The mean baseline CD4+ cell count was 427 cells/mm3 (range 0-1,360) and13% had a CD4+ cell count < 200 cells/mm3.

Genvoya demonstrated statistical superiority in achieving HIV-1 RNA < 50 copies/mL whencompared to E/C/F/TDF at Week 144. The difference in percentage was 4.2% (95% CI: 0.6% to7.8%). Pooled treatment outcomes at 48 and 144 weeks are shown in Table 3.

Table 3: Pooled virologic outcomes of studies GS-US-292-0104 and GS-US-292-0111 at

Weeks 48 and 144a,b

Week 48 Week 144

Genvoya E/C/F/TDF Genvoya E/C/F/TDF(n = 866) (n = 867) (n = 866) (n = 867)

HIV-1 RNA < 50 copies/mL 92% 90% 84% 80%

Treatment difference 2.0% (95% CI: -0.7% to 4.7%) 4.2% (95% CI: 0.6% to 7.8%)

HIV-1 RNA ≥ 50 copies/mLc 4% 4% 5% 4%

No virologic data at Week 48 4% 6% 11% 16%or 144 window

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

AE or deathd

Discontinued study drug due to 2% 4% 9% 11%other reasons and last available

HIV-1 RNA < 50 copies/mLe

Missing data during window 1% < 1% 1% 1%but on study drug

Proportion (%) of patients with

HIV-1 RNA < 50 copies/mL bysubgroup

Age< 50 years 716/777 (92%) 680/753 (90%) 647/777 (83%) 602/753 (80%)≥ 50 years 84/89 (94%) 104/114 (91%) 82/89 (92%) 92/114 (81%)

Sex

Male 674/733 (92%) 673/740 (91%) 616/733 (84%) 603/740 (81%)

Female 126/133 (95%) 111/127 (87%) 113/133 (85%) 91/127 (72%)

Black 197/223 (88%) 177/213 (83%) 168/223 (75%) 152/213 (71%)

Non-black 603/643 (94%) 607/654 (93%) 561/643 (87%) 542/654 (83%)

Baseline viral load≤ 100,000 copies/mL 629/670 (94%) 610/672 (91%) 567/670 (85%) 537/672 (80%)> 100,000 copies/mL 171/196 (87%) 174/195 (89%) 162/196 (83%) 157/195 (81%)

Baseline CD4+ cell count< 200 cells/mm3 96/112 (86%) 104/117 (89%) 93/112 (83%) 94/117 (80%)≥ 200 cells/mm3 703/753 (93%) 680/750 (91%) 635/753 (84%) 600/750 (80%)

HIV-1 RNA < 20 copies/mL 84.4% 84.0% 81.1% 75.8%

Treatment difference 0.4% (95% CI: -3.0% to 3.8%) 5.4% (95% CI: 1.5% to 9.2%)

E/C/F/TDF = elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumaratea Week 48 window was between Day 294 and 377 (inclusive); Week 144 window was between Day 966 and 1,049(inclusive).b In both studies, patients were stratified by baseline HIV-1 RNA (≤ 100,000 copies/mL, > 100,000 copies/mL to≤ 400,000 copies/mL, or > 400,000 copies/mL), by CD4+ cell count (< 50 cells/µL, 50-199 cells/µL, or ≥ 200 cells/µL),and by region (US or ex-US).

c Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack orloss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacyand at the time of discontinuation had a viral value of ≥ 50 copies/mL.

d 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.

e 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.

The mean increase from baseline in CD4+ cell count was 230 cells/mm3 in Genvoya-treated patientsand 211 cells/mm3 in E/C/F/TDF-treated patients (p = 0.024) at Week 48, and 326 cells/mm3 in

Genvoya-treated patients and 305 cells/mm3 in E/C/F/TDF-treated patients (p = 0.06) at Week 144.

In Study GS-US-292-0109, the efficacy and safety of switching from either efavirenz(EFV)/emtricitabine (FTC)/tenofovir disoproxil, FTC/tenofovir disoproxil plus atazanavir (boosted byeither cobicistat or ritonavir), or E/C/F/TDF to Genvoya were evaluated in a randomised, open-labelstudy of virologically suppressed (HIV-1 RNA < 50 copies/mL) HIV-1 infected adults (n = 1,436).

Patients must have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen forat least 6 months and had HIV-1 with no resistance mutations to any of the components of Genvoyaprior to study entry. Patients were randomised in a 2:1 ratio to either switch to Genvoya at baseline(n = 959), or stay on their baseline antiretroviral regimen (n = 477). Patients had a mean age of41 years (range 21-77), 89% were male, 67% were White, and 19% were Black. The mean baseline

CD4+ cell count was 697 cells/mm3 (range 79-1,951). Patients were stratified by prior treatmentregimen. At screening, 42% of patients were receiving FTC/tenofovir disoproxil plus atazanavir(boosted by either cobicistat or ritonavir), 32% of patients were receiving E/C/F/TDF, and 26% ofpatients were receiving EFV/FTC/tenofovir disoproxil.

Switching from a tenofovir disoproxil-based regimen to Genvoya was superior in maintaining

HIV-1 RNA < 50 copies/mL compared to staying on the baseline regimen (Table 4).

Table 4: Virologic outcomes of Study GS-US-292-0109 at Weeks 48a and 96b

Week 48 Week 96

Genvoya Baseline Baseline(n = 959) regimen Genvoya regimen(n = 477) (n = 959) (n = 477)

HIV-1 RNA < 50 copies/mL 97% 93% 93% 89%

Treatment difference 4.1% (95% CI: 1.6% to 6.7%, 3.7% (95% CI: 0.4% to 7.0%,p < 0.001c) p < 0.017c)

HIV-1 RNA ≥ 50 copies/mLd 1% 1% 2% 2%

No virologic data at

Week 48/ Week 96 window 2% 6% 5% 9%

Discontinued study drugdue to AE or deathe 1% 1% 1% 3%

Discontinued study drugdue to other reasons andlast available HIV-1 RNA 1% 4% 3% 6%< 50 copies/mLf

Missing data duringwindow but on study drug 0% < 1% 1% < 1%

Proportion (%) of patientswith HIV-1 RNA< 50 copies/mL by priortreatment regimen

EFV/FTC/tenofovirdisoproxil 96% 90% 90% 86%

FTC/tenofovir disoproxilplus boosted atazanavir 97% 92% 92% 88%

E/C/F/TDF 98% 97% 96% 93%

EFV = efavirenz; FTC = emtricitabine; E/C/F/TDF = elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumaratea Week 48 window was between Day 294 and 377 (inclusive).b Week 96 window was between Day 630 and 713 (inclusive).c P-value for the superiority test comparing the percentages of virologic success was from the CMH test stratified by theprior treatment regimen (EFV/FTC/tenofovir disoproxil, FTC/tenofovir disoproxil plus boosted atazanavir, or

E/C/F/TDF).

d Includes patients who had ≥ 50 copies/mL in the Week 48 or Week 96 window; patients who discontinued early due tolack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss ofefficacy and at the time of discontinuation had a viral value of ≥ 50 copies/mL.

e 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.

f 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.

In Study GS-US-292-0112, the efficacy and safety of Genvoya were evaluated in an open-labelclinical study of 242 HIV-1 infected patients with mild to moderate renal impairment (eGFRCG:30-69 mL/min). Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least6 months before switching to Genvoya. The mean age was 58 years (range 24-82), with 63 patients(26%) who were ≥ 65 years of age. Seventy-nine percent were male, 63% were White, 18% were

Black, and 14% were Asian. Thirteen percent of patients were identified as Hispanic/Latino. Atbaseline, 80 patients (33%) had eGFRCG < 50 mL/min and 162 patients had eGFRCG ≥ 50 mL/min. Atbaseline, median eGFR was 56 mL/min. The mean baseline CD4+ cell count was 664 cells/mm3(range 126-1,813).

At Week 144, 83.1% (197/237 patients) maintained HIV-1 RNA < 50 copies/mL after switching to

Genvoya.

In Study GS-US-292-1825, the efficacy and safety of Genvoya were evaluated in a single-arm,open-label clinical study in which 55 HIV-1 infected adults with end stage renal disease(eGFRCG < 15 mL/min) on chronic haemodialysis for at least 6 months before switching to Genvoya.

Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months beforeswitching to Genvoya.

The mean age was 48 years (range 23-64). Seventy-six percent were male, 82% were Black and 18%were White. Fifteen percent of patients identified as Hispanic/Latino. The mean baseline CD4+ cellcount was 545 cells/mm3 (range 205-1473). At Week 48, 81.8% (45/55 patients) maintained HIV-1

RNA < 50 copies/mL after switching to Genvoya. There were no clinically significant changes infasting lipid laboratory tests in patients who switched to Genvoya.

In open-label Study GS-US-292-1249, the efficacy and safety of Genvoya were evaluated in adultpatients co-infected with HIV-1 and chronic hepatitis B. Sixty-nine of the 72 patients were on priortenofovir disoproxil-containing antiretroviral therapy. At the start of treatment with Genvoya, the72 patients had been HIV suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months with orwithout suppression of HBV DNA and had compensated liver function. The mean age was 50 years(range 28-67), 92% of patients were male, 69% were White, 18% were Black, and 10% were Asian.

The mean baseline CD4+ cell count was 636 cells/mm3 (range 263-1,498). Eighty-six percent ofpatients (62/72) were HBV suppressed (HBV DNA < 29 IU/mL) and 42% (30/72) were

HBeAg positive at baseline.

Of the patients who were HBeAg positive at baseline, 1/30 (3.3%) achieved seroconversion toanti-HBe at Week 48. Of the patients who were HBsAg positive at baseline, 3/70 (4.3%) achievedseroconversion to anti-HBs at Week 48.

At Week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after switching to

Genvoya. The mean change from baseline in CD4+ cell count at Week 48 was -2 cells/mm3.

Ninety-two percent (66/72 patients) had HBV DNA < 29 IU/mL using missing = failure analysis at

Week 48. Of the 62 patients who were HBV suppressed at baseline, 59 remained suppressed and3 had missing data. Of the 10 patients who were not HBV suppressed at baseline(HBV DNA ≥ 29 IU/mL), 7 became suppressed, 2 remained detectable, and 1 had missing data.

There are limited clinical data on the use of Genvoya in HIV/HBV co-infected patients who aretreatment-naïve.

In studies in treatment-naïve patients, Genvoya was associated with smaller reductions in bone mineraldensity (BMD) compared to E/C/F/TDF as measured by DXA analysis of hip (mean change: -0.8%versus -3.4%, p < 0.001) and lumbar spine (mean change: -0.9% versus -3.0%, p < 0.001) after144 weeks of treatment.

Improvements in BMD were noted at 96 weeks after switching to Genvoya from a tenofovirdisoproxil-containing regimen compared to maintaining the tenofovir disoproxil-containing regimen.

In studies in treatment-naïve patients, Genvoya was associated with a lower impact on renal safetyparameters (as measured after 144 weeks treatment by estimated glomerular filtration rate by

Cockcroft-Gault method, and urine protein to creatinine ratio and after 96 weeks treatment by urinealbumin to creatinine ratio) compared to E/C/F/TDF (see also section 4.4). Through 144 weeks oftreatment, no subject discontinued Genvoya due to a treatment-emergent renal adverse eventcompared with 12 subjects who discontinued E/C/F/TDF (p < 0.001).

An improved renal safety profile was maintained through Week 96 in patients who switched to

Genvoya compared with those who stayed on a tenofovir disoproxil-containing regimen.

In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of Genvoya were evaluated inan open-label study in HIV-1 infected, treatment-naïve adolescents between the ages of 12 to< 18 years, weighing ≥ 35 kg (n = 50) in Cohort 1, in virologically suppressed children between theages of 7 to < 12 years, weighing > 25 kg (n = 52) in Cohort 2, and in virologically suppressedchildren between the ages of 3 to 9 years, weighing ≥ 14 to < 25 kg (n = 27) in Cohort 3.

Patients in Cohort 1 had a mean age of 15 years (range 12 to 17), were 44% male, 12% Asian, and88% Black. At baseline, mean plasma HIV-1 RNA was 4.6 log10 copies/mL, median CD4+ cell countwas 456 cells/mm3 (range: 95 to 1,110), and median CD4+% was 23% (range: 7 to 45%). Overall,22% had baseline plasma HIV-1 RNA > 100,000 copies/mL.

At Week 48, the virologic response rate to Genvoya in treatment-naïve HIV-1 infected adolescentswas similar to response rates in studies of treatment-naïve HIV-1 infected adults. In patients treatedwith Genvoya, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL. The mean increase from baselinein CD4+ cell count at Week 48 was 224 cells/mm3. Three patients had virologic failure at Week 48;there was no virologic resistance detected to Genvoya.

Patients in Cohort 2 had a mean age of 10 years (range: 7 to 11), a mean baseline weight of 32 kg(range: 26 to 58), were 42% male, 25% Asian, and 71% Black. At baseline, median CD4+ cell countwas 926 cells/mm3 (range: 336 to 1,611), and median CD4+% was 38% (range: 23 to 51%).

After switching to Genvoya, 98% (51/52) 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 and percentage at

Week 48 was -66 cells/mm3 and -0.6%, respectively. One of 52 patients met the criteria for inclusionin the resistance analysis population through Week 48; no emergent resistance to Genvoya wasdetected through Week 48.

Patients in Cohort 3 had a mean age of 6 years (range: 3 to 9), a mean baseline weight of 19 kg (range:15 to 24), were 37% male, 11% Asian, and 89% Black. At baseline, median CD4+ cell count was1061 cells/mm3 (range: 383 to 2401), and median CD4+% was 37% (range: 24 to 53%).

After switching to Genvoya, 96% (26/27) of patients in Cohort 3 remained suppressed (HIV-1 RNA< 50 copies/mL) at Week 48. The mean change from baseline in CD4+ cell count and percentage at

Week 48 was -179 cells/mm3 and 0.2% respectively. One patient had virologic failure at Week 48; noemergent resistance to Genvoya was detected through Week 48.

In Study GS-US-292-1515, the efficacy and safety of Genvoya were evaluated in an open-label studyin HIV-1 infected, virologically suppressed adolescents between the ages of 12 and 18 years, weighing≥ 35 kg (n = 50).

Patients in the study had a median age of 15 years (range: 12 to 17 years), 64% were female and 98%were Black. At baseline, median CD4+ cell count was 742 cells/mm3 (range: 255 to 1,246) andmedian CD4+% was 34% (range: 21 to 53%).

After switching to Genvoya, 90% (45/50) of patients remained suppressed (HIV-1 RNA< 50 copies/mL) at Week 48. The mean change from baseline in CD4+ cell count and percentage at

Week 48 was -43 cells/mm3 and -0.1%, respectively. Five subjects had virologic failure through theend of the study; no phenotypic or genotypic resistance to Genvoya was detected.

Following oral administration with food in HIV-1 infected patients, peak plasma concentrations wereobserved approximately 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hourspost-dose for emtricitabine, and 1 hour post-dose for tenofovir alafenamide. The steady-state mean

Cmax, AUCtau, and Ctrough (mean ± SD) in HIV-1 infected patients, respectively, were 1.7 ± 0.39 µg/mL,23 ± 7.5 µg*h/mL, and 0.45 ± 0.26 µg/mL for elvitegravir, which provides inhibitory quotient of ~10(ratio of Ctrough: protein binding-adjusted IC95 for wild-type HIV-1 virus). Corresponding steady-statemean Cmax, AUCtau, and Ctrough (mean ± SD) were 1.1 ± 0.40 µg/mL, 8.3 ± 3.8 µg*h/mL, and0.05 ± 0.13 µg/mL for cobicistat; 1.9 ± 0.5 µg/mL, 13 ± 4.5 µg*h/mL, and 0.14 ± 0.25 µg/mL foremtricitabine. Steady-state mean Cmax and AUCtau for tenofovir alafenamide were 0.16 ± 0.08 µg/mLand 0.21 ± 0.15 µg*h/mL, respectively.

For elvitegravir, Cmax and AUC increased 22% and 36% with a light meal, and 56% and 91% with ahigh-fat meal, relative to fasting conditions. Cobicistat exposures were unaffected by a light meal andalthough there was a modest decrease of 24% and 18% in Cmax and AUC respectively with a high-fatmeal, no difference was observed in its pharmacoenhancing effect on elvitegravir. Emtricitabineexposures were unaffected by a light or high-fat meal. Relative to fasting conditions, theadministration of Genvoya with a light meal (~400 kcal, 20% fat) or high-fat meal (~800 kcal, 50%fat) did not affect overall exposures of tenofovir alafenamide to a clinically meaningful extent(approximately 15% and 18% higher AUC with a light or high-fat meal, respectively, versus fasted).

Elvitegravir is 98-99% bound to human plasma proteins and binding is independent of drugconcentration over the range of 1 ng/mL to 1.6 µg/mL. The mean plasma to blood drug concentrationratio was 1.37.

Cobicistat is 97-98% bound to human plasma proteins and the mean plasma to blood drugconcentration ratio was 2.

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

Elvitegravir undergoes primarily oxidative metabolism via CYP3A, and is secondarily glucuronidatedvia UGT1A1/3 enzymes. Following oral administration of boosted [14C]-elvitegravir, elvitegravir wasthe predominant species in plasma, representing ~94% of the circulating radioactivity. Aromatic andaliphatic hydroxylation or glucuronidation metabolites are present in very low levels, displayingconsiderably lower antiviral activity against HIV-1 and do not contribute to the overall antiviralactivity of elvitegravir.

Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation and does notundergo glucuronidation. Following oral administration of [14C]-cobicistat, 99% of circulatingradioactivity in plasma was unchanged cobicistat.

In vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes. Followingadministration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved inurine (~86%) and faeces (~14%). Thirteen percent of the dose was recovered in the urine as threeputative metabolites. The biotransformation of emtricitabine includes oxidation of the thiol moiety toform the 3’-sulfoxide diastereomers (~9% of dose) and conjugation with glucuronic acid to form2’-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 10 mg oral dose of tenofoviralafenamide in Genvoya resulted in tenofovir diphosphate concentrations > 4-fold higher in PBMCsand > 90% lower concentrations of tenofovir in plasma as compared to a 245 mg oral dose of tenofovirdisoproxil (as fumarate) in E/C/F/TDF.

In vitro, tenofovir alafenamide is not metabolised by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6. Tenofovir alafenamide is minimally metabolised by CYP3A4. Upon co-administrationwith the moderate CYP3A inducer probe efavirenz, tenofovir alafenamide exposure was notsignificantly affected. Following administration of tenofovir alafenamide, plasma [14C]-radioactivityshowed a time-dependent profile with tenofovir alafenamide as the most abundant species in the initialfew hours and uric acid in the remaining period.

Following oral administration of [14C]-elvitegravir/ritonavir, 94.8% of the dose was recovered infaeces, consistent with the hepatobiliary excretion of elvitegravir; 6.7% of the administered dose wasrecovered in urine. The median terminal plasma half-life of elvitegravir following administration of

E/C/F/TDF is approximately 12.9 hours.

Following oral administration of [14C]-cobicistat, 86% and 8.2% of the dose were recovered in faecesand urine, respectively. The median terminal plasma half-life of cobicistat following administration of

E/C/F/TDF is approximately 3.5 hours and the associated cobicistat exposures provide elvitegravir

Ctrough approximately 10-fold above the protein-binding adjusted IC95 for wild-type HIV-1 virus.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the dose achieved inurine (approximately 86%) and faeces (approximately 14%). Thirteen percent of the emtricitabinedose was recovered in urine as three metabolites. The systemic clearance of emtricitabine averaged307 mL/min. Following oral administration, the elimination half-life of emtricitabine is approximately10 hours.

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the dose eliminatedin urine. Tenofovir alafenamide is mainly eliminated following metabolism to tenofovir. Tenofoviralafenamide and tenofovir have a median plasma half-life of 0.51 and 32.37 hours, respectively.

Tenofovir is eliminated from the body by the kidneys by both glomerular filtration and active tubularsecretion.

No clinically relevant pharmacokinetic differences due to gender or ethnicity have been identified forcobicistat-boosted elvitegravir, cobicistat, emtricitabine, or tenofovir alafenamide.

Exposures of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir alafenamide achieved in24 adolescent patients aged 12 to < 18 years who received Genvoya in Study GS-US-292-0106 weresimilar to exposures achieved in treatment-naïve adults following administration of Genvoya(Table 5).

Table 5: Pharmacokinetics of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofoviralafenamide in antiretroviral-naïve adolescents and adults

Adolescents aged 12 to < 18 years, ≥ 35 kg Adults

Genvoya Genvoya

EVGa COBIa FTCa TAFb TFVb EVGe COBIe FTCe TAFf TFVf

AUCtau 23,840.1 8,240.8 14,424.4 242.8c 275.8 22,797.0 9,459.1 11,714.1 206.4 292.6(ng*h/mL) (25.5) (36.1)b (23.9) (57.8) (18.4) (34.7) (33.9) (16.6) (71.8) (27.4)

Cmax 2,229.6 1,202.4 2,265.0 121.7 14.6 2,113.1 1,450.3 2,056.3 162.2 15.2(ng/mL) (19.2) (35.0) (22.5) (46.2) (20.0) (33.7) (28.4) (20.2) (51.1) (26.1)

Ctau 300.8 25.0 102.4 N/A 10.0 287.3 20.6 95.2 10.6(ng/mL) (81.0) (180.0)d (38.9)b (19.6) (61.7) (85.2) (46.7) N/A (28.5)

EVG = elvitegravir; COBI = cobicistat; FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TFV = tenofovir

N/A = not applicable

Data are presented as mean (%CV).a n = 24 adolescents.b n = 23 adolescents.c AUClast.d n = 15 adolescents.e n = 19 adults.f n = 539 (TAF) or 841 (TFV) adults.

Mean exposures of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir alafenamideachieved in children aged 8 to < 12 years (> 25 kg; n = 23) who received Genvoya150 mg/150 mg/200 mg/10 mg in study GS-US-292-0106 were higher (20 to 80%) than the meanexposures achieved in adults (Table 6).

Table 6: Pharmacokinetics of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofoviralafenamide in virologically suppressed children (aged 8 to < 12 years, > 25 kg) and adults

Children aged 8 to < 12 years, > 25 kg Adults

Genvoya Genvoya

EVGa COBIa FTCa TAFa TFVa EVGe COBIe FTCe TAFf TFVf

AUC dtau 33,813.9 15,890.7 20,629.2 332.9 440.2 22,797.0 9,459.1 11,714.1 206.4 292.6(ng*h/mL) (57.8)b (51.7)c (18.9)b (44.8) (20.9) (34.7) (33.9) (16.6) (71.8) (27.4)

Cmax 3,055.2 2,079.4 3,397.4 313.3 26.1 2,113.1 1,450.3 2,056.3 162.2 15.2(ng/mL) (38.7) (46.7) (27.0) (61.2) (20.8) (33.7) (28.4) (20.2) (51.1) (26.1)

Ctau 370.0 96.0 114.9 15.1 287.3 20.6 95.2 10.6(ng/mL) (118.5) (168.7) (24.1) N/A (24.9) (61.7) (85.2) (46.7) N/A (28.5)

EVG = elvitegravir; COBI = cobicistat; FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TFV = tenofovir

N/A = not applicable

Data are presented as mean (%CV).a n = 23 children.b n = 22 children.c n = 20 children.d AUClast.e n = 19 adults.f n = 539 (TAF) or 841 (TFV) adults.

Mean exposures of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofovir alafenamideachieved in children aged ≥ 2 years (≥ 14 to < 25 kg; n = 27) who received Genvoya90 mg/90 mg/120 mg/6 mg in study GS-US-292-0106 were generally higher (less than 2-fold) than themean exposures achieved in adults receiving the 150 mg/150 mg/200 mg/10 mg dose of Genvoya(Table 7).

Table 7: Pharmacokinetics of elvitegravir, cobicistat, emtricitabine, tenofovir, and tenofoviralafenamide in virologically suppressed children (aged ≥ 2 years, ≥ 14 to < 25 kg) and adults

Children aged ≥ 2 years, ≥ 14 to < 25 kg Adults

Genvoya Genvoya

EVGa COBIa FTCa TAFa TFVa EVGg COBIg FTCg TAFh TFVh

AUCtau 33,245.6 14,485.2 19,468.1 327.8f 334.9 22,797.0 9,459.1 11,714.1 206.4 292.6(ng*h/mL) (46.6)b (49.5)d (28.9) (59.5) (22.9) (34.7) (33.9) (16.6) (71.8) (27.4)

Cmax 3,297.2 1,525.5 3,007.4 286.6 19.6 2,113.1 1,450.3 2,056.3 162.2 15.2(ng/mL) (52.2) (51.7) (37.8) (72.2) (24.1) (33.7) (28.4) (20.2) (51.1) (26.1)

Ctau 277.5 23.0 82.5 11.4 287.3 20.6 95.2 10.6(ng/mL) (80.5)c (100.2)e (32.1) N/A (23.2) (61.7) (85.2) (46.7) N/A (28.5)

EVG = elvitegravir; COBI = cobicistat; FTC = emtricitabine; TAF = tenofovir alafenamide fumarate; TFV = tenofovir

N/A = not applicable

Data are presented as mean (%CV).a n = 27 children.b n = 24 children.c n = 22 children.d n = 21 children.e n = 18 children.f AUClast.g n = 19 adults.h n = 539 (TAF) or 841 (TFV) adults.

No clinically relevant differences in elvitegravir, cobicistat, tenofovir alafenamide, or tenofovirpharmacokinetics were observed between healthy subjects and patients with severe renal impairment(estimated CrCl ≥ 15 mL/min and < 30 mL/min) in Phase 1 studies of cobicistat-boosted elvitegraviror of tenofovir alafenamide, respectively. In a separate Phase 1 study of emtricitabine alone, meansystemic emtricitabine exposure was higher in patients with severe renal impairment (estimated

CrCl < 30 mL/min) (33.7 µg*h/mL) than in subjects with normal renal function (11.8 µg*h/mL). Thesafety of Genvoya has not been established in patients with severe renal impairment (estimated

CrCl ≥ 15 mL/min and < 30 mL/min).

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

CrCl < 15 mL/min) on chronic haemodialysis who received Genvoya in Study GS-US-292-1825 weresignificantly higher than in patients with normal renal function. No clinically relevant differences inelvitegravir, cobicistat, or tenofovir alafenamide pharmacokinetics were observed in patients withend stage renal disease on chronic haemodialysis as compared to those with normal renal function.

There were no new safety issues identified in patients with end stage renal disease on chronichaemodialysis receiving Genvoya (see section 4.8).

There are no pharmacokinetic data on elvitegravir, cobicistat, emtricitabine or tenofovir alafenamidein patients with end stage renal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis.

The safety of elvitegravir, cobicistat, emtricitabine or tenofovir alafenamide has not been establishedin these patients.

Both elvitegravir and cobicistat are primarily metabolised and eliminated by the liver. A study of thepharmacokinetics of cobicistat-boosted elvitegravir was performed in non-HIV-1 infected patientswith moderate hepatic impairment (Child-Pugh Class B). No clinically relevant differences inelvitegravir or cobicistat pharmacokinetics were observed between patients with moderate hepaticimpairment and subjects with normal hepatic function. The effect of severe hepatic impairment(Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied.

The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment;however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liverimpairment should be limited.

Clinically relevant changes in the pharmacokinetics of tenofovir alafenamide or its metabolitetenofovir were not observed in patients with mild or moderate hepatic impairment. In patients withsevere hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir arelower than those seen in subjects with normal hepatic function. When corrected for protein binding,unbound (free) plasma concentrations of tenofovir alafenamide in severe hepatic impairment andnormal hepatic function are similar.

The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated inpatients co-infected with hepatitis B and/or C virus. Limited data from population pharmacokineticanalysis (n = 24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect onthe exposure of boosted elvitegravir.

The results reported from a prospective study (IMPAACT P1026s) showed that treatment withcobicistat and elvitegravir-containing regimens during pregnancy results in lower elvitegravir andcobicistat exposures (Table 8).

Table 8: Changes in pharmacokinetic parameters from the IMPAACT P1026s study forelvitegravir and cobicistat in women receiving cobicistat and elvitegravir-containing regimensduring the second and third trimesters of pregnancy compared to paired postpartum data

Comparison to paired Mean % change of elvitegravir Mean % change of cobicistatpostpartum data, n pharmacokinetic parametersa pharmacokinetic parametersa

AUC24 Cmax C24 AUC24 Cmax C242T/PP, n = 14 ↓ 24%b ↓ 8% ↓ 81%b ↓ 44%b ↓ 28%b ↓ 60%b3T/PP, n = 24 ↓ 44%b ↓ 28%b ↓ 89%b ↓ 59%b ↓ 38%b ↓ 76%b2T = second trimester; 3T = third trimester; PP =postpartuma paired comparisonsb P<0.10 compared with postpartum

Elvitegravir was negative in an in vitro bacterial mutagenicity test (Ames test) and negative in anin vivo rat micronucleus assay at doses up to 2,000 mg/kg. In an in vitro chromosomal aberration test,elvitegravir was negative with metabolic activation; however, an equivocal response was observedwithout activation.

Cobicistat was not mutagenic or clastogenic in conventional genotoxicity assays. Ex vivo rabbitstudies and in vivo dog studies suggest that cobicistat has a low potential for QT prolongation, andmay slightly prolong the PR interval and decrease left ventricular function at concentrations at least11-fold higher than the human exposure at the recommended 150 mg daily dose. In a human clinicalstudy of 35 healthy subjects, echocardiograms performed at baseline and after receiving 150 mgcobicistat once daily for at least 15 days indicated no clinically significant change in left ventricularfunction.

Reproductive toxicity studies in rats and rabbits with cobicistat showed no effects on mating, fertility,pregnancy or foetal parameters. However increased post-implantation loss and decreased foetalweights were observed in rats associated with significant decreases in maternal body weights at125 mg/kg/day.

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.

Elvitegravir, cobicistat, and emtricitabine have all 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 4 times greater than those expected after administration of Genvoya. Aminimal infiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide andtenofovir exposures of approximately 4 and 17 times greater, respectively, than those expected afteradministration of Genvoya.

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.

Lactose (as monohydrate)

Microcrystalline cellulose (E460)

Croscarmellose sodium

Hydroxypropyl cellulose (E463)

Silicon dioxide (E551)

Sodium lauryl sulfate

Magnesium stearate

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Polyethylene glycol (E1521)

Talc (E553b)

Iron oxide yellow (E172)

Indigo carmine aluminium lake (E132) (Genvoya 150 mg/150 mg/200 mg/10 mg tablets only)

Iron oxide black (E172) (Genvoya 90 mg/90 mg/120 mg/6 mg tablets only)

Not applicable.

3 years.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

High density polyethylene (HDPE) bottle with a polypropylene continuous-thread, child-resistant cap,lined with an induction activated aluminium foil liner containing 30 film-coated tablets. Each bottlecontains silica gel desiccant and polyester coil.

The following pack sizes are available: outer cartons containing 1 bottle of 30 film-coated tablets andouter cartons containing 90 (3 bottles 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/1/15/1061/001

EU/1/15/1061/002

EU/1/15/1061/003

EU/1/15/1061/004

Date of first authorisation: 19 November 2015

Date of latest renewal: 17 September 2020

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

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