DESCOVY 200mg / 25mg film-coated tablets medication leaflet

Descovy 200 mg/25 mg film-coated tablets

Each tablet contains 200 mg of emtricitabine and tenofovir alafenamide fumarate equivalent to 25 mgof tenofovir alafenamide.

Film-coated tablet.

Blue, rectangular-shaped, film-coated tablet of dimensions 12.5 mm x 6.4 mm debossed with “GSI”on one side and “225” on the other side of the tablet.

Descovy is indicated in combination with other antiretroviral agents for the treatment of adults andadolescents (aged 12 years and older with body weight at least 35 kg) infected with humanimmunodeficiency virus type 1 (HIV-1) (see sections 4.2 and 5.1).

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

Descovy should be administered as shown in Table 1.

Table 1: Dose of Descovy according to third agent in the HIV treatment regimen

Dose of Descovy Third agent in HIV treatment regimen(see section 4.5)

Descovy 200/10 mg once Atazanavir with ritonavir or cobicistatdaily Darunavir with ritonavir or cobicistat1

Lopinavir with ritonavir

Descovy 200/25 mg once Dolutegravir, efavirenz, maraviroc,daily nevirapine, rilpivirine, raltegravir1 Descovy 200/10 mg in combination with darunavir 800 mg and cobicistat 150 mg, administered as a fixed-dosecombination tablet, was studied in treatment- naive subjects, see section 5.1.

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

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

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

No dose adjustment of Descovy 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. Descovy should bediscontinued in patients with estimated CrCl that declines below 30 mL/min during treatment (seesection 5.2).

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

CrCl < 15 mL/min) on chronic haemodialysis; however, Descovy 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, Descovy should be administered aftercompletion of haemodialysis treatment.

Descovy 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 Descovy has not been establishedin these populations.

No data are available to make dose recommendations in children less than 18 years with end stagerenal disease.

No dose adjustment of Descovy is required in patients with hepatic impairment.

The safety and efficacy of Descovy in children younger than 12 years of age, or weighing < 35 kg,have not yet been established. No data are available.

Oral use.

Descovy should be taken once daily with or without food (see section 5.2). It is recommended that thefilm-coated tablet is not chewed or crushed due to the bitter taste.

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

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

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 Descovy 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 Descovy 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 Descovy should be closelymonitored with both clinical and laboratory follow-up for at least several months after stoppingtreatment.

The safety and efficacy of Descovy in patients with significant underlying liver disorders have notbeen established (see sections 4.2 and 5.2).

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(hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurologicaldisorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether suchneurological disorders are transient or permanent is currently unknown. These findings should beconsidered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinicalfindings of unknown aetiology, particularly neurologic findings. These findings do not affect currentnational recommendations to use antiretroviral therapy in pregnant women to prevent verticaltransmission of HIV.

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

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

Patients with HIV-1 harbouring mutations

Descovy should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65Rmutation (see section 5.1).

Triple nucleoside therapy

There have been reports of a high rate of virological failure and of emergence of resistance at an earlystage when tenofovir disoproxil was combined with lamivudine and abacavir as well as withlamivudine and didanosine as a once daily regimen. Therefore, the same problems may be seen if

Descovy is administered with a third nucleoside analogue.

Patients receiving Descovy 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 Descovy 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 Descovy should be considered.

Descovy should generally be avoided, but may be used in adults with end stage renal disease(estimated CrCl < 15 mL/min) on chronic haemodialysis if the potential benefits outweigh thepotential risks (see section 4.2). In a study of emtricitabine + tenofovir alafenamide in combinationwith elvitegravir + cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in HIV-1 infected adultswith end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy wasmaintained through 48 weeks but emtricitabine exposure was significantly higher than in patients withnormal renal function. Although there were no new safety issues identified, the implications ofincreased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

The co-administration of Descovy is not recommended with certain anticonvulsants (e.g.,carbamazepine, oxcarbazepine, phenobarbital and phenytoin), antimycobacterials (e.g., rifampicin,rifabutin, rifapentine), St. John’s wort and HIV protease inhibitors (PIs) other than atazanavir,lopinavir and darunavir (see section 4.5).

Descovy should not be administered concomitantly with medicinal products containing tenofoviralafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

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

Interaction studies have only been performed in adults.

Descovy should not be administered concomitantly with medicinal products containing tenofoviralafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

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

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

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

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

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein(BCRP). Medicinal products that strongly affect P-gp and BCRP activity may lead to changes intenofovir alafenamide absorption. Medicinal products that induce P-gp activity (e.g., rifampicin,rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofoviralafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead toloss of therapeutic effect of Descovy and development of resistance. Co-administration of Descovywith other medicinal products that inhibit P-gp and BCRP activity (e.g., cobicistat, ritonavir,ciclosporin) is expected to increase the absorption and plasma concentration of tenofovir alafenamide.

Based on data from an in vitro study, co-administration of tenofovir alafenamide and xanthine oxidaseinhibitors (e.g., febuxostat) is not expected to increase systemic exposure to tenofovir in vivo.

Tenofovir alafenamide is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or

CYP2D6 in vitro. It is not an inhibitor or inducer of CYP3A in vivo. Tenofovir alafenamide is asubstrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the bodymay be affected by the activity of OATP1B1 and OATP1B3.

Tenofovir alafenamide is not an inhibitor of human uridine diphosphate glucuronosyltransferase(UGT) 1A1 in vitro. It is not known whether tenofovir alafenamide is an inhibitor of other

UGT enzymes. Emtricitabine did not inhibit the glucuronidation reaction of a non-specific UGTsubstrate in vitro.

Interactions between the components of Descovy and potential co-administered medicinal products arelisted in Table 2 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). The interactionsdescribed are based on studies conducted with Descovy, or the components of Descovy as individualagents and/or in combination, or are potential drug-drug interactions that may occur with Descovy.

Table 2: Interactions between the individual components of Descovy and other medicinalproducts

Medicinal product by Effects on medicinal product levels. Recommendation concerningtherapeutic areas1 Mean percent change in AUC, co-administration with Descovy

C 2max, Cmin

ANTI-INFECTIVES

Antifungals

Ketoconazole Interaction not studied with either of The recommended dose of Descovy

Itraconazole the components of Descovy. is 200/10 mg once daily.

Co-administration of ketoconazole oritraconazole, which are potent P-gpinhibitors, is expected to increaseplasma concentrations of tenofoviralafenamide.

Fluconazole Interaction not studied with either of Dose Descovy according to the

Isavuconazole the components of Descovy. concomitant antiretroviral (seesection 4.2).

Co-administration of fluconazole orisavuconazole may increase plasmaconcentrations of tenofoviralafenamide.

Antimycobacterials

Rifabutin Interaction not studied with either of Co-administration of Descovy and

Rifampicin the components of Descovy. rifabutin rifampicin, or rifapentine

Rifapentine is not recommended.

Co-administration of rifampicin,rifabutin, and rifapentine, all of whichare P-gp inducers, may decreasetenofovir alafenamide plasmaconcentrations, which may result inloss of therapeutic effect anddevelopment of resistance.

Anti-hepatitis C virus medicinal products

Ledipasvir (90 mg once daily)/ Ledipasvir: No dose adjustment of ledipasvir orsofosbuvir (400 mg once daily), AUC: ↑ 79% sofosbuvir is required. Doseemtricitabine (200 mg once Cmax: ↑ 65% Descovy according to thedaily)/ tenofovir alafenamide Cmin: ↑ 93% concomitant antiretroviral (see(10 mg once daily)3 section 4.2).

AUC: ↑ 47%

Cmax: ↑ 29%

Sofosbuvir metabolite GS-331007:

AUC: ↑ 48%

Cmax: ↔

Cmin: ↑ 66%

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Medicinal product by Effects on medicinal product levels. Recommendation concerningtherapeutic areas1 Mean percent change in AUC, co-administration with Descovy

Cmax, C 2min

Ledipasvir (90 mg once daily)/ Ledipasvir: No dose adjustment of ledipasvir orsofosbuvir (400 mg once daily), AUC: ↔ sofosbuvir is required. Doseemtricitabine (200 mg once Cmax: ↔ Descovy according to thedaily)/ tenofovir alafenamide Cmin: ↔ concomitant antiretroviral (see(25 mg once daily)4 section 4.2).

AUC: ↔

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↑ 32%

Cmax: ↔

Sofosbuvir (400 mg once daily)/ Sofosbuvir: No dose adjustment of sofosbuvir,velpatasvir (100 mg once daily), AUC: ↑ 37% velpatasvir or voxilaprevir isemtricitabine (200 mg once Cmax: ↔ required. Dose Descovy accordingdaily)/ tenofovir alafenamide to the concomitant antiretroviral(10 mg once daily)3 Sofosbuvir metabolite GS-331007: (see section 4.2).

AUC: ↑ 48%

Cmax: ↔

Cmin: ↑ 58%

AUC: ↑ 50%

Cmax: ↑ 30%

Cmin: ↑ 60%

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↓ 20%

Medicinal product by Effects on medicinal product levels. Recommendation concerningtherapeutic areas1 Mean percent change in AUC, co-administration with Descovy

Cmax, C 2min

Sofosbuvir/velpatasvir/ Sofosbuvir:

voxilaprevir AUC: ↔(400 mg/100 mg/100 mg+100 mg Cmax: ↑ 27%once daily)7/emtricitabine (200 mg once Sofosbuvir metabolite GS-331007:

daily)/ tenofovir alafenamide AUC: ↑ 43%(10 mg once daily)3 Cmax: ↔

AUC: ↔

Cmin: ↑ 46%

Cmax: ↔

AUC: ↑ 171%

Cmin: ↑ 350%

Cmax: ↑ 92%

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmax: ↓ 21%

Sofosbuvir/velpatasvir/ Sofosbuvir: No dose adjustment of sofosbuvir,voxilaprevir AUC: ↔ velpatasvir or voxilaprevir is(400 mg/100 mg/100 mg+100 mg Cmax: ↔ required. Dose Descovy accordingonce daily)7/ to the concomitant antiretroviralemtricitabine (200 mg once Sofosbuvir metabolite GS-331007: (see section 4.2).

daily)/ tenofovir alafenamide AUC: ↔(25 mg once daily)4 Cmin: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↑ 52%

Cmax: ↑ 32%

Medicinal product by Effects on medicinal product levels. Recommendation concerningtherapeutic areas1 Mean percent change in AUC, co-administration with Descovy

C 2max, Cmin

ANTIRETROVIRALS

HIV protease inhibitors

Atazanavir/cobicistat Tenofovir alafenamide: The recommended dose of Descovy(300 mg/150 mg once daily), AUC: ↑ 75% is 200/10 mg once daily.

tenofovir alafenamide (10 mg) Cmax: ↑ 80%

AUC: ↔

Cmax: ↔

Cmin: ↔

Atazanavir/ritonavir (300/100 mg Tenofovir alafenamide: The recommended dose of Descovyonce daily), tenofovir AUC: ↑ 91% is 200/10 mg once daily.

alafenamide (10 mg) Cmax: ↑ 77%

AUC: ↔

Cmax: ↔

Cmin: ↔

Darunavir/cobicistat (800/150 mg Tenofovir alafenamide: The recommended dose of Descovyonce daily), tenofovir AUC: ↔ is 200/10 mg once daily.

alafenamide (25 mg once daily)5 Cmax: ↔

Tenofovir:

AUC: ↑ 224%

Cmax: ↑ 216%

Cmin: ↑ 221%

AUC: ↔

Cmax: ↔

Cmin: ↔

Darunavir/ritonavir (800/100 mg Tenofovir alafenamide: The recommended dose of Descovyonce daily), tenofovir AUC: ↔ is 200/10 mg once daily.

alafenamide (10 mg once daily) Cmax: ↔

Tenofovir:

AUC: ↑ 105%

Cmax: ↑ 142%

AUC: ↔

Cmax: ↔

Cmin: ↔

Lopinavir/ritonavir (800/200 mg Tenofovir alafenamide: The recommended dose of Descovyonce daily), tenofovir AUC: ↑ 47% is 200/10 mg once daily.

alafenamide (10 mg once daily) Cmax: ↑ 119%

Lopinavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tipranavir/ritonavir Interaction not studied with either of Co-administration with Descovy isthe components of Descovy. not recommended.

Tipranavir/ritonavir results in P-gpinduction. Tenofovir alafenamideexposure is expected to decreasewhen tipranavir/ritonavir is used incombination with Descovy.

Medicinal product by Effects on medicinal product levels. Recommendation concerningtherapeutic areas1 Mean percent change in AUC, co-administration with Descovy

C , C 2max min

Other protease inhibitors Effect is unknown. There are no data available to makedosing recommendations forco-administration with otherprotease inhibitors.

Other HIV antiretrovirals

Dolutegravir (50 mg once daily), Tenofovir alafenamide: The recommended dose of Descovytenofovir alafenamide (10 mg AUC: ↔ is 200/25 mg once daily.

once daily)3 Cmax: ↔

Dolutegravir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine (25 mg once daily), Tenofovir alafenamide: The recommended dose of Descovytenofovir alafenamide (25 mg AUC: ↔ is 200/25 mg once daily.

once daily) Cmax: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Efavirenz (600 mg once daily), Tenofovir alafenamide: The recommended dose of Descovytenofovir alafenamide (40 mg AUC: ↓ 14% is 200/25 mg once daily.

once daily)4 Cmax: ↓ 22%

Maraviroc Interaction not studied with either of The recommended dose of Descovy

Nevirapine the components of Descovy. is 200/25 mg once daily.

Raltegravir

Tenofovir alafenamide exposure isnot expected to be affected bymaraviroc, nevirapineor raltegravir, nor is it expected toaffect the metabolic and excretionpathways relevant to maraviroc,nevirapine or raltegravir.

ANTICONVULSANTS

Oxcarbazepine Interaction not studied with either of Co-administration of Descovy and

Phenobarbital the components of Descovy. oxcarbazepine, phenobarbital or

Phenytoin phenytoin is not recommended.

Co-administration of oxcarbazepine,phenobarbital, or phenytoin, all ofwhich are P-gp inducers, maydecrease tenofovir alafenamideplasma concentrations, which mayresult in loss of therapeutic effect anddevelopment of resistance.

Carbamazepine (titrated from Tenofovir alafenamide: Co-administration of Descovy and100 mg to 300 mg twice a day), AUC: ↓ 55% carbamazepine is notemtricitabine/tenofovir Cmax: ↓ 57% recommended.

alafenamide (200 mg/25 mg oncedaily)5,6 Co-administration of carbamazepine,a P-gp inducer, decreases tenofoviralafenamide plasma concentrations,which may result in loss oftherapeutic effect and development ofresistance.

Medicinal product by Effects on medicinal product levels. Recommendation concerningtherapeutic areas1 Mean percent change in AUC, co-administration with Descovy

Cmax, C 2min

ANTIDEPRESSANTS

Sertraline (50 mg once daily), Tenofovir alafenamide: No dose adjustment of sertraline istenofovir alafenamide (10 mg AUC: ↔ required. Dose Descovy accordingonce daily)3 Cmax: ↔ to the concomitant antiretroviral(see section 4.2).

Sertraline:

AUC: ↑ 9%

Cmax: ↑ 14%

HERBAL PRODUCTS

St. John’s wort (Hypericum Interaction not studied with either of Co-administration of Descovy withperforatum) the components of Descovy. St. John’s wort is notrecommended.

Co-administration of St. John’s wort,a P-gp inducer, may decreasetenofovir alafenamide plasmaconcentrations, which may result inloss of therapeutic effect anddevelopment of resistance.

IMMUNOSUPPRESSANTS

Ciclosporin Interaction not studied with either of The recommended dose of Descovythe components of Descovy. is 200/10 mg once daily.

Co-administration of ciclosporin, apotent P-gp inhibitor, is expected toincrease plasma concentrations oftenofovir alafenamide.

ORAL CONTRACEPTIVES

Norgestimate Norelgestromin: No dose adjustment of(0.180/0.215/0.250 mg once AUC: ↔ norgestimate/ethinylestradiol isdaily), ethinylestradiol (0.025 mg Cmin: ↔ required. Dose Descovy accordingonce daily), Cmax: ↔ to the concomitant antiretroviralemtricitabine/tenofovir (see section 4.2).

alafenamide (200/25 mg once Norgestrel:

daily)5 AUC: ↔

Cmin: ↔

Cmax: ↔

Ethinylestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

SEDATIVES/HYPNOTICS

Orally administered midazolam Midazolam: No dose adjustment of midazolam(2.5 mg single dose), tenofovir AUC: ↔ is required. Dose Descovyalafenamide (25 mg once daily) Cmax: ↔ according to the concomitant

Intravenously administered Midazolam: antiretroviral (see section 4.2).

midazolam (1 mg single dose), AUC: ↔tenofovir alafenamide (25 mg Cmax: ↔once daily)1 When doses are provided, they are the doses used in clinical drug-drug interaction studies.2 When data are available from drug-drug interaction studies.3 Study conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose combination tablet.4 Study conducted with emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose combination tablet.5 Study conducted with Descovy.6 Emtricitabine/tenofovir alafenamide was taken with food in this study.7 Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposurers expected in HCV-infectedpatients.

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

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

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

Descovy should be used during pregnancy only if the potential benefit justifies the potential risk tothe foetus.

It is not known whether tenofovir alafenamide is excreted in human milk. Emtricitabine is excreted inhuman milk. In animal studies it has been shown that tenofovir is excreted in milk.

There is insufficient information on the effects of emtricitabine and tenofovir in newborns/infants.

Therefore, Descovy 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 Descovy in humans. In animal studies there were noeffects of emtricitabine and tenofovir alafenamide on mating or fertility parameters (see section 5.3).

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

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

HIV-1 infected patients received medicinal products containing emtricitabine and tenofoviralafenamide and from post-marketing experience. In clinical studies of treatment-naïve adult patientsreceiving emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat as the fixed-dosecombination tablet elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide(as fumarate) 10 mg (E/C/F/TAF) through 144 weeks, the most frequently reported adverse reactionswere diarrhoea (7%), nausea (11%), and headache (6%).

The adverse reactions in Table 3 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 3: Tabulated list of adverse reactions1

Frequency Adverse reaction

Uncommon: anaemia2

Common: abnormal dreams

Common: headache, dizziness

Very common: nausea

Common: diarrhoea, vomiting, abdominal pain, flatulence

Uncommon: dyspepsia

Common: rash

Uncommon: angioedema3,4, pruritus, urticaria4

Uncommon: arthralgia

Common: fatigue1 With the exception of angioedema, anaemia and urticaria (see footnotes 2, 3 and 4), all adverse reactions were identifiedfrom clinical studies of F/TAF containing products. The frequencies were derived from Phase 3 E/C/F/TAF clinicalstudies in 866 treatment-naïve adult patients through 144 weeks of treatment (GS-US-292-0104 and GS-US-292-0111).2 This adverse reaction was not observed in the clinical studies of F/TAF-containing products but identified from clinicalstudies or post-marketing experience for emtricitabine 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.

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).

In studies in treatment- naïve patients, increases from baseline were observed in both the tenofoviralafenamide fumarate and tenofovir disoproxil fumarate containing treatment groups for the fastinglipid parameters total cholesterol, direct low-density lipoprotein (LDL)- and high-density lipoprotein(HDL)-cholesterol, and triglycerides at Week 144. The median increase from baseline for thoseparameters was greater in the E/C/F/TAF group compared with the elvitegravir 150 mg/cobicistat150 mg/emtricitabine 200 mg/tenofovir disoproxil (as fumarate) 245 mg (E/C/F/TDF) group at

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 E/C/F/TAF group and 0.1(-0.4, 0.6) in the E/C/F/TDF group (p = 0.006 for the difference between treatment groups).

In a study of virologically suppressed patients switching from emtricitabine/tenofovir disoproxilfumarate to Descovy while maintaining the third antiretroviral agent (Study GS-US-311-1089),increases from baseline were observed in the fasting lipid parameters total cholesterol, direct LDLcholesterol and triglycerides in the Descovy arm compared with little change in theemtricitabine/tenofovir disproxil fumarate arm (p ≤ 0.009 for the difference between groups inchanges from baseline). There was little change from baseline in median fasting values for HDLcholesterol and glucose, or in the fasting total cholesterol to HDL cholesterol ratio in either treatmentarm at Week 96. None of the changes was considered clinically relevant.

In a study of virologically suppressed adult patients switching from abacavir/lamivudine to Descovywhile maintaining the third antiretroviral agent (Study GS-US-311-1717), there were minimal changesin lipid parameters.

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

The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in an open-label clinical study (GS-US-292-0106) in which HIV-1 infected, treatment-naïve paediatric patientsaged 12 to < 18 years received emtricitabine and tenofovir alafenamide in combination withelvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile of emtricitabine andtenofovir alafenamide given with elvitegravir and cobicistat in 50 adolescent patients was similar tothat in adults (see section 5.1).

The safety of emtricitabine and tenofovir alafenamide was evaluated through 144 weeks in an open-label clinical study (GS-US-292-0112) in which 248 HIV-1 infected patients who were eithertreatment-naïve (n = 6) or virologically suppressed (n = 242) with mild to moderate renal impairment(estimated glomerular filtration rate by Cockcroft-Gault method [eGFRCG]: 30-69 mL/min) receivedemtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dosecombination tablet. The safety profile in patients with mild to moderate renal impairment was similarto that in patients with normal renal function (see section 5.1).

The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in a single arm,open-label clinical study (GS-US-292-1825) in which 55 virologically suppressed HIV-1 infectedpatients with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis receivedemtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dosecombination tablet. There were no new safety issues identified in patients with end stage renal diseaseon chronic haemodialysis receiving emtricitabine and tenofovir alafenamide, in combination withelvitegravir and cobicistat as a fixed-dose combination tablet (see section 5.2).

The safety of emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistatas a fixed-dose combination tablet (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide[E/C/F/TAF]) was evaluated in 72 HIV/HBV co-infected patients receiving treatment for HIV in anopen-label clinical study (GS-US-292-1249), through Week 48, in which patients were switched fromanother antiretroviral regimen (which included tenofovir disoproxil fumarate [TDF] in 69 of 72patients) to E/C/F/TAF. Based on these limited data, the safety profile of emtricitabine and tenofoviralafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet, inpatients with HIV/HBV co-infection, was similar to that in patients with HIV-1 monoinfection (seesection 4.4).

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 Descovy consists of general supportive measures including monitoring of vital signsas well as observation of the clinical status of the patient.

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

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

Pharmacotherapeutic group: Antiviral for systemic use; antivirals for treatment of HIV infections,combinations. ATC code: J05AR17.

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 viraldeoxyribonucleic acid (DNA) by the HIV reverse transcriptase (RT), which results in DNA chain-termination. Emtricitabine has activity against HIV-1, HIV-2, and HBV.

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and phosphonamidateprodrug of tenofovir (2’-deoxyadenosine monophosphate analogue). Tenofovir alafenamide ispermeable into cells and due to increased plasma stability and intracellular activation throughhydrolysis by cathepsin A, tenofovir alafenamide is more efficient than tenofovir disoproxil fumaratein concentrating tenofovir in peripheral blood mononuclear cells (PBMCs) or HIV target cellsincluding lymphocytes 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 DNA chain-termination.

Tenofovir has activity against HIV-1, HIV-2, and HBV.

Emtricitabine and tenofovir alafenamide demonstrated synergistic antiviral activity in cell culture.

No antagonism was observed with emtricitabine or tenofovir alafenamide when combined with otherantiretroviral agents.

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 50% effective concentration(EC50) values for emtricitabine were in the range of 0.0013 to 0.64 μM. Emtricitabine displayedantiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from0.007 to 0.075 μM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007to 1.5 μM).

The antiviral activity of tenofovir alafenamide against laboratory and clinical isolates of

HIV-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primary monocyte/macrophagecells and CD4+-T lymphocytes. The EC50 values for tenofovir alafenamide were in the range of 2.0 to14.7 nM. Tenofovir alafenamide displayed antiviral activity in cell culture against all HIV-1 groups(M, N, 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 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.

In a pooled analysis of antiretroviral-naïve patients receiving emtricitabine and tenofovir alafenamide(10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet in Phase 3 studies

GS-US-292-0104 and GS-US-292-0111, genotyping was performed on plasma HIV-1 isolates from allpatients with HIV-1 RNA ≥ 400 copies/mL at confirmed virological failure, at Week 144, or at thetime of early study drug discontinuation. Through Week 144, the development of one or moreprimary emtricitabine, tenofovir alafenamide, or elvitegravir resistance-associated mutations wasobserved in HIV-1 isolates from 12 of 22 patients with evaluable genotypic data from paired baselineand E/C/F/TAF treatment-failure isolates (12 of 866 patients [1.4%]) compared with 12 of20 treatment-failure isolates from patients with evaluable genotypic data in the E/C/F/TDF group (12of 867 patients [1.4%]). In the E/C/F/TAF group, the mutations that emerged 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 with resistance 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 developed resistance mutations toelvitegravir in integrase also developed resistance mutations to emtricitabine in RT.

In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis B, whoreceived emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as afixed-dose combination tablet (E/C/F/TAF), for 48 weeks (GS-US-292-1249, n = 72), 2 patientsqualified for resistance analysis. In these 2 patients, no amino acid substitutions associated withresistance to any of the components of E/C/F/TAF were identified in HIV-1 or HBV.

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

The K65R and K70E mutations result in reduced susceptibility to abacavir, didanosine, lamivudine,emtricitabine, and tenofovir, but retain sensitivity to zidovudine.

Multinucleoside-resistant HIV-1 with a T69S double insertion mutation or with a Q151M mutationcomplex including K65R showed reduced susceptibility to tenofovir alafenamide.

There are no efficacy and safety studies conducted in treatment-naïve patients with Descovy.

Clinical efficacy of Descovy was established from studies conducted with emtricitabine and tenofoviralafenamide when given with elvitegravir and cobicistat as the fixed-dose combination tablet

E/C/F/TAF.

In studies GS-US-292-0104 and GS-US-292-0111, patients were randomised in a 1:1 ratio to receiveeither emtricitabine 200 mg and tenofovir alafenamide 10 mg (n = 866) once daily or emtricitabine200 mg + tenofovir disoproxil (as fumarate) 245 mg (n = 867) once daily, both given with elvitegravir150 mg + cobicistat 150 mg as a fixed-dose combination tablet. The mean age was 36 years (range:

18-76), 85% were male, 57% were White, 25% were Black, and 10% were Asian. Nineteen percent ofpatients were identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was4.5 log10 copies/mL (range: 1.3-7.0) and 23% had baseline viral loads > 100,000 copies/mL. Themean baseline CD4+ cell count was 427 cells/mm3 (range: 0-1,360) and 13% had a CD4+ cell count< 200 cells/mm3.

E/C/F/TAF 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 4.

Table 4: Pooled virological outcomes of Studies GS-US-292-0104 and GS-US-292-0111 at

Weeks 48 and 144a,b

Week 48 Week 144

E/C/F/TAF E/C/F/TDFe E/C/F/TAF 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 4% 6% 11% 16%

Week 48 or 144 window

Discontinued study drug 1% 2% 1% 3%due to AE or deathd

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

HIV-1 RNA< 50 copies/mLe

Missing data during 1% < 1% 1% 1%window but on studydrug

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

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/TAF = elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide

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 1049(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 patients receiving

E/C/F/TAF and 211 cells/mm3 in patients receiving E/C/F/TDF (p = 0.024) at Week 48, and 326cells/mm3 in E/C/F/TAF-treated patients and 305 cells/mm3 in E/C/F/TDF-treated patients (p = 0.06)at Week 144.

Clinical efficacy of Descovy in treatment-naïve patients was also established from a study conductedwith emtricitabine and tenofovir alafenamide (10 mg) when given with darunavir (800 mg) andcobicistat as a fixed-dose combination tablet (D/C/F/TAF). In Study GS-US-299-0102, patients wererandomised in a 2:1 ratio to receive either fixed-dose combination D/C/F/TAF once daily (n = 103) ordarunavir and cobicistat and emtricitabine/tenofovir disoproxil fumarate once daily (n = 50). Theproportions of patients with plasma HIV-1 RNA < 50 copies/mL and < 20 copies/mL are shown in

Table 5.

Table 5: Virological outcomes of Study GS-US-299-0102 at Week 24 and 48a

Week 24 Week 48

D/C/F/TAF Darunavir, D/C/F/TAF Darunavir,(n = 103) cobicistat and (n = 103) cobicistat andemtricitabine/tenofovir emtricitabine/tenofovirdisoproxil fumarate disoproxil fumarate(n = 50) (n = 50)

HIV-1 RNA 75% 74% 77% 84%< 50 copies/mL

Treatment difference 3.3% (95% CI: -11.4% to 18.1%) -6.2% (95% CI: -19.9% to 7.4%)

HIV-1 RNA 20% 24% 16% 12%≥ 50 copies/mLb

No virologic data at 5% 2% 8% 4%

Week 48 window

Discontinued study 1% 0 1% 2%drug due to AE ordeathc

Discontinued studydrug due to otherreasons and last 4% 2% 7% 2%available HIV-1 RNA< 50 copies/mLd

Missing data during 0 0 0 0window but on studydrug

HIV-1 RNA 55% 62% 63% 76%< 20 copies/mL

Treatment difference -3.5% (95% CI: -19.8% to 12.7%) -10.7% (95% CI: -26.3% to 4.8%)

D/C/F/TAF = darunavir/cobicistat/emtricitabine/tenofovir alafenamidea Week 48 window was between Day 294 and 377 (inclusive).

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

c 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.

d 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-311-1089, the efficacy and safety of switching from emtricitabine/tenofovirdisoproxil fumarate to Descovy while maintaining the third antiretroviral agent were evaluated in arandomised, double-blind study of virologically suppressed HIV-1 infected adults (n = 663). Patientsmust have been stably suppressed (HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least6 months and had HIV-1 with no resistance mutations to emtricitabine or tenofovir alafenamide priorto study entry. Patients were randomised in a 1:1 ratio to either switch to Descovy (n = 333), or stayon their baseline emtricitabine/tenofovir disoproxil fumarate containing regimen (n = 330). Patientswere stratified by the class of the third agent in their prior treatment regimen. At baseline, 46% ofpatients were receiving emtricitabine/tenofovir disoproxil fumarate in combination with a boosted PIand 54% of patients were receiving emtricitabine/tenofovir disoproxil fumarate in combination with anunboosted third agent.

Treatment outcomes of Study GS-US-311-1089 through 48 and 96 weeks are presented in Table 6.

Table 6: Virological outcomes of Study GS-US-311-1089 at Weeks 48a and 96b

Week 48 Week 96

Descovy containing Emtricitabine/tenofov Descovy containing Emtricitabine/tenofovregimen ir disoproxil fumarate regimen ir disoproxil fumarate(n = 333) containing regimen (n = 333) containing regimen(n = 330) (n = 330)

HIV-1 RNA 94% 93% 89% 89%< 50 copies/mL

Treatment 1.3% (95% CI: -2.5% to 5.1%) -0.5% (95% CI: -5.3% to 4.4%)difference

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

No virologic data at 5% 5% 9% 10%

Week 48 or 96window

Discontinued 2% 1% 2% 2%study drug dueto AE or deathd

Discontinued 7% 9%study drug dueto other reasonsand last 3% 5%available

HIV-1 RNA< 50 copies/mLe

Missing data < 1% 0 0 <1%during windowbut on studydrug

Proportion (%) ofpatients with

HIV-1 RNA< 50 copies/mL byprior treatmentregimen

Boosted PIs 142/155 (92%) 140/151 (93%) 133/155 (86%) 133/151 (88%)

Other third 172/178 (97%) 167/179 (93%) 162/178 (91%) 161/179 (90%)agents

PI = protease inhibitora Week 48 window was between Day 294 and 377 (inclusive).

b Week 96 window was between Day 630 and 713 (inclusive).

c 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.

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.

In Study GS-US-311-1717, patients who were virologically suppressed (HIV-1 RNA <50 copies/mL)on their abacavir/lamivudine containing regimen for at least 6 months were randomised in a 1:1 ratioto either switch to Descovy (N=280) while maintaining their third agent at baseline or stay on theirbaseline abacavir/lamivudine -containing regimen (N=276).

Patients were stratified by the class of the third agent in their prior treatment regimen. At baseline,30% of patients were receiving abacavir/lamivudine in combination with a boosted protease inhibitorand 70% of patients were receiving abacavir/lamivudine in combination with an unboosted third agent.

Virologic success rates at Week 48 were: Descovy Containing Regimen: 89.7% (227 of 253 subjects);

Abacavir/lamivudine Containing Regimen: 92.7%% (230 of 248 subjects). At Week 48, switching to a

Descovy-containing regimen was non-inferior to staying on a baseline abacavir/lamivudine-containingregimen in maintaining HIV-1 RNA < 50 copies/mL

In Study GS-US-292-0112, the efficacy and safety of emtricitabine and tenofovir alafenamide wereevaluated in an open-label clinical study in which 242 HIV-1 infected patients with mild to moderaterenal impairment (eGFRCG: 30-69 mL/min) were switched to emtricitabine and tenofovir alafenamide(10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tablet. Patients werevirologically suppressed (HIV-1 RNA < 50 copies/mL) for at least 6 months before switching.

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. Thirteenpercent of patients were identified as Hispanic/Latino. At baseline, median eGFR was 56 mL/min,and 33% of patients had an eGFR from 30 to 49 mL/min. The mean baseline CD4+ cell count was664 cells/mm3 (range: 126-1,813).

At Week 144, 83.1% (197/237 patients) maintained HIV-1 RNA < 50 copies/mL after switching toemtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat as a fixed-dosecombination tablet.

In Study GS-US-292-1825, the efficacy and safety of emtricitabine and tenofovir alafenamide, givenwith elvitegravir and cobicistat as a fixed-dose combination tablet 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 toemtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dosecombination tablet. Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) for at least6 months before switching.

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 emtricitabine and tenofovir alafenamide, given withelvitegravir and cobicistat as a fixed-dose combination tablet. There were no clinically significantchanges in fasting lipid laboratory tests in patients who switched.

In open-label Study GS-US-292-1249, the efficacy and safety of emtricitabine and tenofoviralafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet (E/C/F/TAF),were evaluated in adult patients co-infected with HIV-1 and chronic hepatitis B. Sixty-nine of the72 patients were on prior TDF-containing antiretroviral therapy. At the start of treatment with

E/C/F/TAF, the 72 patients had been HIV-suppressed (HIV-1 RNA < 50 copies/mL) for at least6 months with or without suppression of HBV DNA and had compensated liver function. The meanage was 50 years (range 28-67), 92% of patients were male, 69% were White, 18% were Black, and10% were Asian. The mean baseline CD4+ cell count was 636 cells/mm3 (range 263-1498).

Eighty-six percent of patients (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 Week 48.

At Week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after switching toemtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dosecombination tablet. 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 E/C/F/TAF in HIV/HBV co-infected patients who aretreatment-naïve.

In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with elvitegravirand cobicistat as a fixed-dose combination tablet was associated with smaller reductions in bonemineral density (BMD) compared to E/C/F/TDF through 144 weeks of treatment as measured by dualenergy X ray absorptiometry (DXA) analysis of hip (mean change: −0.8% vs −3.4%, p < 0.001) andlumbar spine (mean change: −0.9% vs −3.0%, p < 0.001). In a separate study, emtricitabine andtenofovir alafenamide given with darunavir and cobicistat as a fixed-dose combination tablet was alsoassociated with smaller reductions in BMD (as measured by hip and lumbar spine DXA analysis)through 48 weeks of treatment compared to darunavir, cobicistat, emtricitabine and tenofovirdisoproxil fumarate.

In a study in virologically suppressed adult patients, improvements in BMD were noted through96 weeks after switching to Descovy from a TDF containing regimen compared to minimal changeswith maintaining the TDF containing regimen as measured by DXA analysis of hip (mean changefrom baseline of 1.9% vs -0.3%, p < 0.001) and lumbar spine (mean change from baseline of 2.2% vs

- 0.2%, p < 0.001).

In a study in virologically suppressed adult patients, BMD did not change significantly through 48weeks after switching to Descovy from an abacavir/lamivudine containing regimen compared tomaintaining the abacavir/lamivudine containing regimen as measured by DXA analysis of hip (meanchange from baseline of 0.3% vs 0.2%, p = 0.55) and lumbar spine (mean change from baseline of0.1% vs < 0.1%, p = 0.78).

In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given with elvitegravirand cobicistat as a fixed-dose combination tablet through 144 weeks was associated with a lowerimpact on renal safety parameters (as measured after 144 weeks treatment by eGFRCG and urineprotein to creatinine ratio and after 96 weeks treatment by urine albumin to creatinine ratio) comparedto E/C/F/TDF. Through 144 weeks of treatment, no subject discontinued E/C/F/TAF due to atreatment-emergent renal adverse event compared with 12 subjects who discontinued E/C/F/TDF(p < 0.001).

In a separate study in treatment-naïve patients, emtricitabine and tenofovir alafenamide given withdarunavir and cobicistat as a fixed-dose combination tablet was associated with a lower impact onrenal safety parameters through 48 weeks of treatment compared to darunavir and cobicistat givenwith emtricitabine/tenofovir disoproxil fumarate (see also section 4.4).

In a study in virologically suppressed adult patients measures of tubular proteinuria were similar inpatients switching to a regimen containing Descovy compared to patients who stayed on anabacavir/lamivudine containing regimen at baseline. At Week 48, the median percentage change inurine retinol binding protein to creatinine ratio was 4% in the Descovy group and 16% in thoseremaining on an abacavir/lamivudine containing regimen; and in urine beta-2 microglobulin tocreatinine ratio it was 4% vs. 5%.

In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine and tenofoviralafenamide were evaluated in an open-label study in which 50 HIV-1 infected, treatment-naïveadolescents received emtricitabine and tenofovir alafenamide (10 mg) given with elvitegravir andcobicistat as a fixed-dose combination tablet. Patients had a mean age of 15 years (range: 12-17), and56% were female, 12% were Asian, and 88% were Black. At baseline, median plasma HIV-1 RNAwas 4.7 log10 copies/mL, median CD4+ cell count was 456 cells/mm3 (range: 95-1,110), and median

CD4+% was 23% (range: 7-45%). Overall, 22% had baseline plasma HIV-1 RNA> 100,000 copies/mL. At 48 weeks, 92% (46/50) achieved HIV-1 RNA < 50 copies/mL, similar toresponse rates in studies of treatment-naïve HIV-1 infected adults. The mean increase from baselinein CD4+ cell count at Week 48 was 224 cells/mm3. No emergent resistance to E/C/F/TAF wasdetected through Week 48.

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

Descovy in one or more subsets of the paediatric population in the treatment of HIV-1 infection (seesection 4.2 for information on paediatric use).

Emtricitabine is rapidly and extensively absorbed following oral administration with peak plasmaconcentrations occurring at 1 to 2 hours post-dose. Following multiple dose oral administration ofemtricitabine to 20 HIV-1 infected subjects, the (mean ± SD) steady state plasma emtricitabine peakconcentrations (Cmax) were 1.8 ± 0.7 μg/mL and the area-under the plasma concentration-time curveover a 24-hour dosing interval (AUC) was 10.0 ± 3.1 μg*h/mL. The mean steady state plasma troughconcentration at 24 hours post-dose was equal to or greater than the mean in vitro IC90 value foranti-HIV-1 activity.

Emtricitabine systemic exposure was unaffected when emtricitabine was administered with food.

Following administration of food in healthy subjects, peak plasma concentrations were observedapproximately 1 hour post-dose for tenofovir alafenamide administered as F/TAF (25 mg) or

E/C/F/TAF (10 mg). The mean Cmax and AUClast, (mean ± SD) under fed conditions following asingle 25 mg dose of tenofovir alafenamide administered in Descovy were 0.21 ± 0.13 μg/mL and0.25 ± 0.11 μg*h/mL, respectively. The mean Cmax and AUClast following a single 10 mg dose oftenofovir alafenamide administered in E/C/F/TAF were 0.21 ± 0.10 μg/mL and 0.25 ± 0.08 μg*h/mL,respectively.

Relative to fasting conditions, the administration of tenofovir alafenamide with a high fat meal(~800 kcal, 50% fat) resulted in a decrease in tenofovir alafenamide Cmax (15-37%) and an increase in

AUClast (17-77%).

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%.

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 (given with emtricitabine and elvitegravir and cobicistat) resulted in tenofovirdiphosphate concentrations > 4-fold higher in PBMCs and > 90% lower concentrations of tenofovir inplasma as compared to a 245 mg oral dose of tenofovir disoproxil (as fumarate) (given withemtricitabine and elvitegravir and cobicistat).

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.

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 renally eliminated by both glomerular filtration and active tubular secretion.

No clinically relevant pharmacokinetic differences due to age, gender or ethnicity have been identifiedfor emtricitabine, or tenofovir alafenamide.

Exposures of emtricitabine and tenofovir alafenamide (given with elvitegravir and cobicistat) achievedin 24 paediatric patients aged 12 to < 18 years who received emtricitabine and tenofovir alafenamidegiven with elvitegravir and cobicistat in Study GS-US-292-0106 were similar to exposures achieved intreatment-naïve adults (Table 7).

Table 7: Pharmacokinetics of emtricitabine and tenofovir alafenamide in antiretroviral-naïveadolescents and adults

Adolescents Adults

FTCa TAFb TFVb FTCa TAFc TFVc

AUCtau 14,424.4 242.8 275.8 11,714.1 206.4 292.6(ng*h/mL) (23.9) (57.8) (18.4) (16.6) (71.8) (27.4)

Cmax 2,265.0 121.7 14.6 (20.0) 2,056.3 162.2 15.2(ng/mL) (22.5) (46.2) (20.2) (51.1) (26.1)

Ctau 10.0 (19.6) 10.6102.4 (38.9)b N/A 95.2 (46.7) N/A(ng/mL) (28.5)

E/C/F/TAF = elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate

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

N/A = not applicable

Data are presented as mean (%CV).

a n = 24 adolescents (GS-US-292-0106); n = 19 adults (GS-US-292-0102)b n = 23 adolescents (GS-US-292-0106, population PK analysis)c n = 539 (TAF) or 841 (TFV) adults (GS-US-292-0111 and GS-US-292-0104, population PK analysis)

No clinically relevant differences in tenofovir alafenamide, or tenofovir pharmacokinetics wereobserved between healthy subjects and patients with severe renal impairment (estimated CrCl > 15mL/min and < 30 mL/min) in a Phase 1 study of tenofovir alafenamide. In a separate Phase 1 study ofemtricitabine alone, mean systemic emtricitabine exposure was higher in patients with severe renalimpairment (estimated CrCl < 30 mL/min) (33.7 μg*h/mL) than in subjects with normal renal function(11.8 μg*h/mL). The safety of emtricitabine and tenofovir alafenamide has not been established inpatients 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 emtricitabine and tenofovir alafenamide incombination with elvitegravir and cobicistat as a fixed-dose combination tablet (E/C/F/TAF) in Study

GS-US-292-1825 were significantly higher than in patients with normal renal function. No clinicallyrelevant differences in 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 in patients with end stage renal disease on chronic haemodialysisreceiving emtricitabine and tenofovir alafenamide, in combination with elvitegravir and cobicistat as afixed-dose combination tablet (see section 4.8).

There are no pharmacokinetic data on emtricitabine or tenofovir alafenamide in patients with end stagerenal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis. The safety of emtricitabineand tenofovir alafenamide has not been established in these patients.

The pharmacokinetics of emtricitabine have not been studied in subjects 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 HBV and/or HCV.

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

Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney as the primarytarget organs of toxicity. Bone toxicity was observed as reduced BMD in rats and dogs at tenofovirexposures at least four times greater than those expected after administration of Descovy. A minimalinfiltration of histiocytes was present in the eye in dogs at tenofovir alafenamide and tenofovirexposures of approximately 4 and 17 times greater, respectively, than those expected afteradministration of Descovy.

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 fumarate, carcinogenicity studies and a rat peri-postnatal study were conducted only with tenofovir disoproxil fumarate. No special hazard forhumans was revealed in conventional studies of carcinogenic potential and toxicity to reproductionand development. Reproductive toxicity studies in rats and rabbits showed no effects on mating,fertility, pregnancy or foetal parameters. However, tenofovir disoproxil fumarate reduced the viabilityindex and weight of pups in a peri-postnatal toxicity study at maternally toxic doses.

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

Polyvinyl alcohol

Titanium dioxide

Macrogol 3350

Talc

Indigo carmine aluminium lake (E132)

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 60 (2 bottles of 30) and 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/1/16/1099/003

EU/1/16/1099/004

EU/1/16/1099/006

Date of first authorisation: 21 April 2016

Date of latest renewal: 11 February 2021

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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.