EMTRICITABINA/TENOFOVIR ALAFENAMIDA VIATRIS 200mg / 10mg film-coated tablets medication leaflet

Emtricitabine/Tenofovir alafenamide Viatris 200 mg/10 mg film-coated tablets

Emtricitabine/Tenofovir alafenamide Viatris 200 mg/25 mg film-coated tablets

200 mg/10 mg film-coated tablets

Each tablet contains 200 mg of emtricitabine and tenofovir alafenamide monofumarateequivalent to 10 mg of tenofovir alafenamide.

200 mg/25 mg film-coated tablets

Each tablet contains 200 mg of emtricitabine and tenofovir alafenamide monofumarateequivalent to 25 mg of tenofovir alafenamide.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

200 mg/10 mg film-coated tablets

Grey, film-coated, rectangle shaped, beveled edge, biconvex tablet (approximately 15 mm x7 mm), debossed with ‘ET 1’on one side of the tablet and V on the other side.

200 mg/25 mg film-coated tablets

Blue, film-coated, rectangle shaped, beveled edge, biconvex tablet of dimensions(approximately 15 mm x 7 mm) debossed with ‘ET 2’ on one side of the tablet and V on theother side.

Emtricitabine/Tenofovir alafenamide Viatris is indicated in combination with otherantiretroviral agents for the treatment of adults and adolescents (aged 12 years and older withbody weight at least 35 kg) infected with human immunodeficiency virus type 1 (HIV-1) (seesections 4.2 and 5.1).

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

Emtricitabine/Tenofovir alafenamide Viatris should be administered as shown in Table 1.

Table 1: Dose of Emtricitabine/Tenofovir alafenamide Viatris according to third agentin the HIV treatment regimen

Dose of Emtricitabine/Tenofovir Third agent in HIV treatment regimen (see section 4.5)alafenamide Viatris

Emtricitabine/Tenofovir alafenamide Atazanavir with ritonavir or cobicistat

Viatris 200/10 mg once daily Darunavir with ritonavir or cobicistat1

Lopinavir with ritonavir

Emtricitabine/Tenofovir alafenamide Dolutegravir, efavirenz, maraviroc, nevirapine, rilpivirine,

Viatris 200/25 mg once daily raltegravir1 Emtricitabine/Tenofovir alafenamide Viatris 200/10 mg in combination with darunavir 800 mg and cobicistat150 mg, administered as a fixed-dose combination tablet, was studied in treatment-naive subjects, seesection 5.1.

If the patient misses a dose of Emtricitabine/Tenofovir alafenamide Viatris within 18 hours ofthe time it is usually taken, the patient should take Emtricitabine/Tenofovir alafenamide

Viatris as soon as possible and resume the normal dosing schedule. If a patient misses a doseof Emtricitabine/Tenofovir alafenamide Viatris by more than 18 hours, the patient should nottake the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Emtricitabine/Tenofovir alafenamide Viatrisanother tablet should be taken.

No dose adjustment of Emtricitabine/Tenofovir alafenamide Viatris is required in elderlypatients (see sections 5.1 and 5.2).

No dose adjustment of Emtricitabine/Tenofovir alafenamide Viatris is required in adults oradolescents (aged at least 12 years and of at least 35 kg body weight) with estimatedcreatinine clearance (CrCl) ≥ 30 mL/min. Emtricitabine/Tenofovir alafenamide Viatris shouldbe discontinued in patients with estimated CrCl that declines below 30 mL/min duringtreatment (see section 5.2).

No dose adjustment of Emtricitabine/Tenofovir alafenamide Viatris is required in adults withend stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however,

Emtricitabine/Tenofovir alafenamide Viatris should generally be avoided but may be used inthese patients if the potential benefits are considered to outweigh the potential risks (seesections 4.4 and 5.2). On days of haemodialysis, Emtricitabine/Tenofovir alafenamide Viatrisshould be administered after completion of haemodialysis treatment.

Emtricitabine/Tenofovir alafenamide Viatris 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 Emtricitabine/Tenofovir alafenamide Viatris has not been established in thesepopulations.

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

No dose adjustment of Emtricitabine/Tenofovir alafenamide Viatris is required in patientswith hepatic impairment.

The safety and efficacy of Emtricitabine/Tenofovir alafenamide in children younger than12 years of age, or weighing < 35 kg, have not yet been established. No data are available.

Oral use.

Emtricitabine/Tenofovir alafenamide Viatris should be taken once daily with or without food(see section 5.2). It is recommended that the film-coated tablet is not chewed or crushed dueto the bitter taste.

For patients who are unable to swallow the tablet whole, the tablet may be split in half andboth 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.

Patients with chronic hepatitis B or C treated with antiretroviral therapy are at an increasedrisk for severe and potentially fatal hepatic adverse reactions.

The safety and efficacy of Emtricitabine/Tenofovir alafenamide Viatris in patients co-infectedwith HIV-1 and hepatitis C virus (HCV) have not been established.

Tenofovir alafenamide is active against hepatitis B virus (HBV). Discontinuation of

Emtricitabine/Tenofovir alafenamide Viatris therapy in patients co-infected with HIV and

HBV may be associated with severe acute exacerbations of hepatitis. Patients co-infectedwith HIV and HBV who discontinue Emtricitabine/Tenofovir alafenamide Viatris should beclosely monitored with both clinical and laboratory follow-up for at least several months afterstopping treatment.

The safety and efficacy of Emtricitabine/Tenofovir alafenamide Viatris in patients withsignificant underlying liver disorders have not been established (see sections 4.2 and 5.2).

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have anincreased frequency of liver function abnormalities during combination antiretroviral therapy(CART) and should be monitored according to standard practice. If there is evidence ofworsening liver disease in such patients, interruption or discontinuation of treatment must beconsidered.

An increase in weight and in levels of blood lipids and glucose may occur duringantiretroviral therapy. Such changes may in part be linked to disease control and life style.

For lipids, there is in some cases evidence for a treatment effect, while for weight gain thereis no strong evidence relating this to any particular treatment. For monitoring of blood lipidsand glucose reference is made to established HIV treatment guidelines. Lipid disordersshould be managed as clinically appropriate.

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which ismost pronounced with stavudine, didanosine and zidovudine. There have been reports ofmitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally tonucleoside analogues; these have predominantly concerned treatment with regimenscontaining zidovudine. The main adverse reactions reported are haematological disorders(anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). Theseevents have often been transitory. Late onset neurological disorders have been reported rarely(hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders aretransient or permanent is currently unknown. These findings should be considered for anychild exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings ofunknown 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,an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise andcause serious clinical conditions, or aggravation of symptoms. Typically, such reactions havebeen observed within the first few weeks or months of initiation of CART. Relevantexamples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections,and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated andtreatment instituted when necessary.

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

Patients with HIV-1 harbouring mutations

Emtricitabine/Tenofovir alafenamide Viatris should be avoided in antiretroviral-experiencedpatients with HIV-1 harbouring the K65R mutation (see section 5.1).

Triple nucleoside therapy

There have been reports of a high rate of virological failure and of emergence of resistance atan early stage when tenofovir disoproxil was combined with lamivudine and abacavir as wellas with lamivudine and didanosine as a once daily regimen. Therefore, the same problemsmay be seen if Emtricitabine/Tenofovir alafenamide Viatris is administered with a thirdnucleoside analogue.

Patients receiving Emtricitabine/Tenofovir alafenamide Viatris or any other antiretroviraltherapy may continue to develop opportunistic infections and other complications of HIVinfection, and, therefore, should remain under close clinical observation by physiciansexperienced in the treatment of patients with HIV associated diseases.

Although the aetiology is considered to be multifactorial (including corticosteroid use,alcohol consumption, severe immunosuppression, higher body mass index), cases ofosteonecrosis have been reported particularly in patients with advanced HIV disease and/orlong-term exposure to CART. Patients should be advised to seek medical advice if theyexperience joint aches and pain, joint stiffness 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 potentialrisk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due todosing with tenofovir alafenamide cannot be excluded (see section 5.3).

It is recommended that renal function is assessed in all patients prior to, or when initiating,therapy with Emtricitabine/Tenofovir alafenamide Viatris and that it is also monitored duringtherapy in all patients as clinically appropriate. In patients who develop clinically significantdecreases in renal function, or evidence of proximal renal tubulopathy, discontinuation of

Emtricitabine/Tenofovir alafenamide Viatris should be considered.

Emtricitabine/Tenofovir alafenamide Viatris should generally be avoided, but may be used inadults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis ifthe potential benefits outweigh the potential risks (see section 4.2). In a study of emtricitabine+ tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dosecombination tablet (E/C/F/TAF) in HIV-1 infected adults with end stage renal disease(estimated CrCl < 15 mL/min) on chronic haemodialysis, efficacy was maintained through 48weeks 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).

The co-administration of Emtricitabine/Tenofovir alafenamide Viatris is not recommendedwith certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital andphenytoin), 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).

Emtricitabine/Tenofovir alafenamide Viatris should not be administered concomitantly withmedicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine,lamivudine or adefovir dipivoxil.

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

Interaction studies have only been performed in adults.

Emtricitabine/Tenofovir alafenamide Viatris should not be administered concomitantly withmedicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine,lamivudine or adefovir dipivoxil.

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that thepotential for CYP-mediated interactions involving emtricitabine with other medicinalproducts is low. Co-administration of emtricitabine with medicinal products that areeliminated by active tubular secretion may increase concentrations of emtricitabine, and/orthe co-administered medicinal product. Medicinal products that decrease renal function mayincrease concentrations of emtricitabine.

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistanceprotein (BCRP). Medicinal products that strongly affect P-gp and BCRP activity may lead tochanges in tenofovir alafenamide absorption. Medicinal products that induce P-gp activity(e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to decrease theabsorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofoviralafenamide, which may lead to loss of therapeutic effect of Emtricitabine/Tenofoviralafenamide and development of resistance. Co-administration of Emtricitabine/Tenofoviralafenamide with other medicinal products that inhibit P-gp and BCRP activity (e.g.,cobicistat, ritonavir, ciclosporin) is expected to increase the absorption and plasmaconcentration of tenofovir alafenamide. Based on data from an in vitro study, co-administration of tenofovir alafenamide and xanthine oxidase inhibitors (e.g., febuxostat) isnot 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. Tenofoviralafenamide is a substrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofoviralafenamide in the body may be affected by the activity of OATP1B1 and OATP1B3.

Tenofovir alafenamide is not an inhibitor of human uridine diphosphateglucuronosyltransferase (UGT) 1A1 in vitro. It is not known whether tenofovir alafenamide isan inhibitor of other UGT enzymes. Emtricitabine did not inhibit the glucuronidation reactionof a non-specific UGT substrate in vitro.

Interactions between the components of Emtricitabine/Tenofovir alafenamide and potentialco-administered medicinal products are listed in Table 2 (increase is indicated as ‘↑’, decreaseas ‘↓’, no change as ‘↔’). The interactions described are based on studies conducted with

Emtricitabine/Tenofovir alafenamide, or the components of Emtricitabine/Tenofoviralafenamide as individual agents and/or in combination, or are potential drug-druginteractions that may occur with Emtricitabine/Tenofovir alafenamide.

Table 2: Interactions between the individual components of Emtricitabine/Tenofoviralafenamide Viatris and other medicinal products

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

C 2min Emtricitabine/Tenofoviralafenamide Viatris

ANTI-INFECTIVES

Antifungals

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

Itraconazole components of Emtricitabine/Tenofovir Emtricitabine/Tenofoviralafenamide Viatris. alafenamide Viatris is200/10 mg once daily.

Co-administration of ketoconazole oritraconazole, which are potent P-gpinhibitors, is expected to increase plasmaconcentrations of tenofovir alafenamide.

Fluconazole Interaction not studied with either of the Dose Emtricitabine/Tenofovir

Isavuconazole components of Emtricitabine/Tenofovir alafenamide Viatris according toalafenamide Viatris. the concomitant antiretroviral(see section 4.2).

Co-administration of fluconazole orisavuconazole may increase plasmaconcentrations of tenofovir alafenamide.

Antimycobacterials

Rifabutin Interaction not studied with either of the Co-administration of

Rifampicin components of Emtricitabine/Tenofovir Emtricitabine/Tenofovir

Rifapentine alafenamide Viatris. alafenamide Viatris andrifabutin rifampicin, or

Co-administration of rifampicin, rifabutin, rifapentine is not recommended.and rifapentine, all of which are P-gpinducers, may decrease tenofoviralafenamide plasma concentrations, whichmay result in loss of therapeutic effect anddevelopment of resistance.

Anti-hepatitis C virus medicinal products

Ledipasvir (90 mg once Ledipasvir: No dose adjustment ofdaily)/ sofosbuvir AUC: ↑ 79% ledipasvir or sofosbuvir is(400 mg once daily), Cmax: ↑ 65% required. Doseemtricitabine (200 mg Cmin: ↑ 93% Emtricitabine/Tenofovironce daily)/ tenofovir alafenamide Viatris according toalafenamide (10 mg once Sofosbuvir: the concomitant antiretroviraldaily) 3 AUC: ↑ 47% (see section 4.2).

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, Cmax, co-administration with

C 2min Emtricitabine/Tenofoviralafenamide Viatris

Ledipasvir (90 mg once Ledipasvir: No dose adjustment ofdaily)/ sofosbuvir AUC: ↔ ledipasvir or sofosbuvir is(400 mg once daily), Cmax: ↔ required. Doseemtricitabine (200 mg Cmin: ↔ Emtricitabine/Tenofovironce daily)/ tenofovir alafenamide Viatris according toalafenamide (25 mg once Sofosbuvir: the concomitant antiretroviraldaily) 4 AUC: ↔ (see section 4.2).

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↔

Cmax: ↔

Cmin: ↔

AUC: ↑ 32%

Cmax: ↔

Sofosbuvir (400 mg once Sofosbuvir: No dose adjustment ofdaily)/ AUC: ↑ 37% sofosbuvir, velpatasvir orvelpatasvir (100 mg once Cmax: ↔ voxilaprevir is required. Dosedaily), emtricitabine Emtricitabine/Tenofovir(200 mg once daily)/ Sofosbuvir metabolite GS-331007: alafenamide Viatris according totenofovir alafenamide AUC: ↑ 48% the concomitant antiretroviral(10 mg once daily)3 Cmax: ↔ (see section 4.2).

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, Cmax, co-administration with

C 2min Emtricitabine/Tenofoviralafenamide Viatris

Sofosbuvir/velpatasvir/ Sofosbuvir:voxilaprevir AUC: ↔(400 mg/100 mg/100 mg Cmax: ↑ 27%+100 mg once daily)7/emtricitabine (200 mg Sofosbuvir metabolite GS-331007:once daily)/ tenofovir AUC: ↑ 43%alafenamide (10 mg once Cmax: ↔daily)3

AUC: ↔

Cmin: ↑ 46%

Cmax: ↔

AUC: ↑ 171%

Cmin: ↑ 350%

Cmax: ↑ 92%

AUC: ↔

Cmin: ↔

Cmax: ↔

AUC: ↔

Cmax: ↓ 21%

Sofosbuvir/velpatasvir/ Sofosbuvir: No dose adjustment ofvoxilaprevir AUC: ↔ sofosbuvir, velpatasvir or(400 mg/100 mg/100 mg Cmax: ↔ voxilaprevir is required. Dose+100 mg once daily)7/ Emtricitabine/Tenofoviremtricitabine (200 mg Sofosbuvir metabolite GS-331007: alafenamide Viatris according toonce daily)/ tenofovir AUC: ↔ the concomitant antiretroviralalafenamide (25 mg once Cmin: ↔ (see section 4.2).daily)4

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, Cmax, co-administration with

C 2min Emtricitabine/Tenofoviralafenamide Viatris

ANTIRETROVIRALS

HIV protease inhibitors

Atazanavir/cobicistat Tenofovir alafenamide: The recommended dose of(300 mg/150 mg once AUC: ↑ 75% Emtricitabine/Tenofovirdaily), tenofovir Cmax: ↑ 80% alafenamide Viatris isalafenamide (10 mg) 200/10 mg once daily.

AUC: ↔

Cmax: ↔

Cmin: ↔

Atazanavir/ritonavir Tenofovir alafenamide: The recommended dose of(300/100 mg once daily), AUC: ↑ 91% Emtricitabine/Tenofovirtenofovir alafenamide Cmax: ↑ 77% alafenamide Viatris is(10 mg) 200/10 mg once daily.

AUC: ↔

Cmax: ↔

Cmin: ↔

Darunavir/cobicistat Tenofovir alafenamide: The recommended dose of(800/150 mg once daily), AUC: ↔ Emtricitabine/Tenofovirtenofovir alafenamide Cmax: ↔ alafenamide Viatris is(25 mg once daily)5 200/10 mg once daily.

Tenofovir:

AUC: ↑ 224%

Cmax: ↑ 216%

Cmin: ↑ 221%

AUC: ↔

Cmax: ↔

Cmin: ↔

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

Tenofovir:

AUC: ↑ 105%

Cmax: ↑ 142%

AUC: ↔

Cmax: ↔

Cmin: ↔

Lopinavir/ritonavir Tenofovir alafenamide: The recommended dose of(800/200 mg once daily), AUC: ↑ 47% Emtricitabine/Tenofovirtenofovir alafenamide Cmax: ↑ 119% alafenamide Viatris is(10 mg once daily) 200/10 mg once daily.

Lopinavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

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

C 2min Emtricitabine/Tenofoviralafenamide Viatris

Tipranavir/ritonavir Interaction not studied with either of the Co-administration withcomponents of Emtricitabine/Tenofovir Emtricitabine/Tenofoviralafenamide. alafenamide Viatris is not

Tipranavir/ritonavir results in P-gp recommended.induction. Tenofovir alafenamide exposureis expected to decrease whentipranavir/ritonavir is used in combinationwith Emtricitabine/Tenofovir alafenamide.

Other protease inhibitors Effect is unknown. There are no data available tomake dosing recommendationsfor co-administration with otherprotease inhibitors.

Other HIV antiretrovirals

Dolutegravir (50 mg Tenofovir alafenamide: The recommended dose ofonce daily), tenofovir AUC: ↔ Emtricitabine/Tenofoviralafenamide (10 mg once Cmax: ↔ alafenamide Viatris isdaily)3 200/25 mg once daily.

Dolutegravir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Rilpivirine (25 mg once Tenofovir alafenamide: The recommended dose ofdaily), tenofovir AUC: ↔ Emtricitabine/Tenofoviralafenamide (25 mg once Cmax: ↔ alafenamide Viatris isdaily) 200/25 mg once daily.

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Efavirenz (600 mg once Tenofovir alafenamide: The recommended dose ofdaily), tenofovir AUC: ↓ 14% Emtricitabine/Tenofoviralafenamide (40 mg once Cmax: ↓ 22% alafenamide Viatris isdaily)4 200/25 mg once daily.

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

Nevirapine components of Emtricitabine/Tenofovir Emtricitabine/Tenofovir

Raltegravir alafenamide. alafenamide Viatris is

Tenofovir alafenamide exposure is not 200/25 mg once daily.expected to be affected by maraviroc,nevirapineor raltegravir, nor is it expected to affectthe metabolic and excretion pathwaysrelevant to maraviroc, nevirapine orraltegravir.

ANTICONVULSANTS

Oxcarbazepine Interaction not studied with either of the Co-administration of

Phenobarbital components of Emtricitabine/Tenofovir Emtricitabine/Tenofovir

Phenytoin alafenamide. alafenamide Viatris and

Co-administration of oxcarbazepine, oxcarbazepine, phenobarbital orphenobarbital, or phenytoin, all of which phenytoin is not recommended.are P-gp inducers, may decrease tenofoviralafenamide plasma concentrations, whichmay result in loss of therapeutic effect anddevelopment of resistance.

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

C 2min Emtricitabine/Tenofoviralafenamide Viatris

Carbamazepine (titrated Tenofovir alafenamide: Co-administration offrom 100 mg to 300 mg AUC: ↓ 55% Emtricitabine/Tenofovirtwice a day), Cmax: ↓ 57% alafenamide Viatris andemtricitabine/tenofovir carbamazepine is notalafenamide Co-administration of carbamazepine, a P- recommended.(200 mg/25 mg once gp inducer, decreases tenofovirdaily) 5,6 alafenamide plasma concentrations, whichmay result in loss of therapeutic effect anddevelopment of resistance.

ANTIDEPRESSANTS

Sertraline (50 mg once Tenofovir alafenamide: No dose adjustment of sertralinedaily), tenofovir AUC: ↔ is required. Dosealafenamide (10 mg once Cmax: ↔ Emtricitabine/Tenofovirdaily)3 alafenamide Viatris according to

Sertraline: the concomitant antiretroviral

AUC: ↑ 9% (see section 4.2).

Cmax: ↑ 14%

HERBAL PRODUCTS

St. John’s wort Interaction not studied with either of the Co-administration of(Hypericum perforatum) components of Emtricitabine/Tenofovir Emtricitabine/Tenofoviralafenamide Viatris. alafenamide Viatris with St.

John’s wort is not

Co-administration of St. John’s wort, a recommended.

P-gp inducer, may decrease tenofoviralafenamide plasma concentrations, whichmay result in loss of therapeutic effect anddevelopment of resistance.

IMMUNOSUPPRESSANTS

Ciclosporin Interaction not studied with either of the The recommended dose ofcomponents of Emtricitabine/Tenofovir Emtricitabine/Tenofoviralafenamide Viatris. alafenamide Viatris is200/10 mg once daily.

Co-administration of ciclosporin, a potent

P-gp inhibitor, is expected to increaseplasma concentrations of tenofoviralafenamide.

ORAL CONTRACEPTIVES

Norgestimate Norelgestromin: No dose adjustment of(0.180/0.215/0.250 mg AUC: ↔ norgestimate/ethinylestradiol isonce daily), Cmin: ↔ required. Doseethinylestradiol Cmax: ↔ Emtricitabine/Tenofovir(0.025 mg once daily), alafenamide Viatris according toemtricitabine/tenofovir Norgestrel: the concomitant antiretroviralalafenamide (200/25 mg AUC: ↔ (see section 4.2).once daily)5 Cmin: ↔

Cmax: ↔

Ethinylestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

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

C 2min Emtricitabine/Tenofoviralafenamide Viatris

SEDATIVES/HYPNOTICS

Orally administered Midazolam: No dose adjustment ofmidazolam (2.5 mg AUC: ↔ midazolam is required. Dosesingle dose), tenofovir Cmax: ↔ Emtricitabine/Tenofoviralafenamide (25 mg once alafenamide Viatris according todaily) the concomitant antiretroviral(see section 4.2).

Intravenously Midazolam:

administered midazolam AUC: ↔(1 mg single dose), Cmax: ↔tenofovir alafenamide(25 mg 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 Emtricitabine/Tenofovir alafenamide.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-infected patients.

There are no adequate and well-controlled studies of Emtricitabine/Tenofovir alafenamide orits components in pregnant women. There are no or limited data (less than 300 pregnancyoutcomes) from the use of tenofovir alafenamide in pregnant women. However, a largeamount of data on pregnant women (more than 1 000 exposed outcomes) indicate nomalformative nor foetal/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of emtricitabine with respectto fertility parameters, pregnancy, foetal development, parturition or postnatal development.

Studies of tenofovir alafenamide in animals have shown no evidence of harmful effects onfertility parameters, pregnancy, or foetal development (see section 5.3).

Emtricitabine/Tenofovir alafenamide Viatris should be used during pregnancy only if thepotential benefit justifies the potential risk to the foetus.

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

There is insufficient information on the effects of emtricitabine and tenofovir innewborns/infants. Therefore, Emtricitabine/Tenofovir alafenamide Viatris should not be usedduring breast-feeding.

In order to avoid transmission of HIV to the infant it is recommended that women living with

HIV do not breast-feed their infants.

There are no data on fertility from the use of Emtricitabine/Tenofovir alafenamide in humans.

In animal studies there were no effects of emtricitabine and tenofovir alafenamide on matingor fertility parameters (see section 5.3).

Emtricitabine/Tenofovir alafenamide Viatris may have minor influence on the ability to driveand use machines. Patients should be informed that dizziness has been reported duringtreatment with Emtricitabine/Tenofovir alafenamide.

Assessment of adverse reactions is based on safety data from across all Phase 2 and 3 studiesin which HIV-1 infected patients received medicinal products containing emtricitabine andtenofovir alafenamide and from post-marketing experience. In clinical studies of treatment-naïve adult patients receiving emtricitabine and tenofovir alafenamide with elvitegravir andcobicistat as the fixed-dose combination tablet elvitegravir 150 mg/cobicistat150 mg/emtricitabine 200 mg/tenofovir alafenamide (as fumarate) 10 mg (E/C/F/TAF)through 144 weeks, the most frequently reported adverse reactions were diarrhoea (7%),nausea (11%), and headache (6%).

The adverse reactions in Table 3 are listed by system organ class and frequency. Frequenciesare defined 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 clinical studiesin 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.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also beenreported; however, the reported time to onset is more variable, and these events can occurmany months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generallyacknowledged risk factors, advanced HIV disease or long-term exposure to CART. Thefrequency of this is unknown (see section 4.4).

In studies in treatment-naïve patients, increases from baseline were observed in both thetenofovir alafenamide fumarate and tenofovir disoproxil fumarate containing treatmentgroups for the fasting lipid parameters total cholesterol, direct low-density lipoprotein (LDL)-and high-density lipoprotein (HDL)-cholesterol, and triglycerides at Week 144. The medianincrease from baseline for those parameters was greater in the E/C/F/TAF group comparedwith the elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil (asfumarate) 245 mg (E/C/F/TDF) group at Week 144 (p < 0.001 for the difference betweentreatment groups for fasting total cholesterol, direct LDL- and HDL-cholesterol, andtriglycerides). The median (Q1, Q3) change from baseline in total cholesterol 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/tenofovirdisoproxil fumarate to Emtricitabine/Tenofovir alafenamide while maintaining the thirdantiretroviral agent (Study GS-US-311-1089), increases from baseline were observed in thefasting lipid parameters total cholesterol, direct LDL cholesterol and triglycerides in the

Emtricitabine/Tenofovir alafenamide arm compared with little change in theemtricitabine/tenofovir disproxil fumarate arm (p ≤ 0.009 for the difference between groupsin changes from baseline). There was little change from baseline in median fasting values for

HDL cholesterol and glucose, or in the fasting total cholesterol to HDL cholesterol ratio ineither treatment arm at Week 96. None of the changes was considered clinically relevant.

In a study of virologically suppressed adult patients switching from abacavir/lamivudine to

Emtricitabine/Tenofovir alafenamide while maintaining the third antiretroviral agent (Study

GS-US-311-1717), there were minimal changes in 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 anopen-label clinical study (GS-US-292-0106) in which HIV-1 infected, treatment-naïvepaediatric patients aged 12 to < 18 years received emtricitabine and tenofovir alafenamide incombination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safetyprofile of emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat in 50adolescent patients was similar to that in adults (see section 5.1).

The safety of emtricitabine and tenofovir alafenamide was evaluated through 144 weeks in anopen-label clinical study (GS-US-292-0112) in which 248 HIV-1 infected patients who wereeither treatment-naïve (n = 6) or virologically suppressed (n = 242) with mild to moderaterenal impairment (estimated glomerular filtration rate by Cockcroft-Gault method [eGFRCG]:30-69 mL/min) received emtricitabine and tenofovir alafenamide in combination withelvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile in patientswith mild to moderate renal impairment was similar to that in patients with normal renalfunction (see section 5.1).

The safety of emtricitabine and tenofovir alafenamide was evaluated through 48 weeks in asingle arm, open-label clinical study (GS-US-292-1825) in which 55 virologically suppressed

HIV-1 infected patients with end stage renal disease (eGFRCG < 15 mL/min) on chronichaemodialysis received emtricitabine and tenofovir alafenamide in combination withelvitegravir and cobicistat as a fixed-dose combination tablet. There were no new safetyissues identified in patients with end stage renal disease on chronic haemodialysis receivingemtricitabine and tenofovir alafenamide, in combination with elvitegravir and cobicistat as afixed-dose combination tablet (see section 5.2).

The safety of emtricitabine and tenofovir alafenamide in combination with elvitegravir andcobicistat as a fixed-dose combination tablet (elvitegravir/cobicistat/emtricitabine/tenofoviralafenamide [E/C/F/TAF]) was evaluated in 72 HIV/HBV co-infected patients receivingtreatment for HIV in an open-label clinical study (GS-US-292-1249), through Week 48, inwhich patients were switched from another antiretroviral regimen (which included tenofovirdisoproxil fumarate [TDF] in 69 of 72 patients) to E/C/F/TAF. Based on these limited data,the safety profile of emtricitabine and tenofovir alafenamide in combination with elvitegravirand cobicistat as a fixed-dose combination tablet, in patients with HIV/HBV co-infection,was similar to that in patients with HIV-1 monoinfection (see section 4.4).

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

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8).

Treatment of overdose with Emtricitabine/Tenofovir alafenamide Viatris consists of generalsupportive measures including monitoring of vital signs as well as observation of the clinicalstatus 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 emtricitabinedosing. Tenofovir is efficiently removed by haemodialysis with an extraction coefficient ofapproximately 54%. It is not known whether emtricitabine or tenofovir can be removed byperitoneal dialysis.

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

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and nucleoside analogueof 2’-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to formemtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication throughincorporation into viral deoxyribonucleic 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) andphosphonamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate analogue).

Tenofovir alafenamide is permeable into cells and due to increased plasma stability andintracellular activation through hydrolysis by cathepsin A, tenofovir alafenamide is moreefficient than tenofovir disoproxil fumarate in concentrating tenofovir in peripheral bloodmononuclear cells (PBMCs) or HIV target cells including lymphocytes and macrophages.

Intracellular tenofovir is subsequently phosphorylated to the pharmacologically activemetabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication throughincorporation 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 cellculture. No antagonism was observed with emtricitabine or tenofovir alafenamide whencombined with other antiretroviral agents.

The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 wasassessed in lymphoblastoid cell lines, the MAGI CCR5 cell line, and PBMCs. The 50%effective concentration (EC50) values for emtricitabine were in the range of 0.0013 to0.64 μM. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B,

C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 μM) and showed strain specificactivity 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-1 subtype B was assessed in lymphoblastoid cell lines, PBMCs, primarymonocyte/macrophage cells and CD4+-T lymphocytes. The EC50 values for tenofoviralafenamide were in the range of 2.0 to 14.7 nM. Tenofovir alafenamide displayed antiviralactivity 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 activityagainst 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 mutationin 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 tenofoviralafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dose combination tabletin Phase 3 studies GS-US-292-0104 and GS-US-292-0111, genotyping was performed onplasma HIV-1 isolates from all patients with HIV-1 RNA ≥ 400 copies/mL at confirmedvirological failure, at Week 144, or at the time of early study drug discontinuation. Through

Week 144, the development of one or more primary emtricitabine, tenofovir alafenamide, orelvitegravir resistance-associated mutations was observed in HIV-1 isolates from 12 of22 patients with evaluable genotypic data from paired baseline and E/C/F/TAF treatment-failure isolates (12 of 866 patients [1.4%]) compared with 12 of 20 treatment-failure isolatesfrom patients with evaluable genotypic data in the E/C/F/TDF group (12 of 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 inthe 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) inintegrase. Most HIV-1 isolates from patients in both treatment groups who developedresistance mutations to elvitegravir in integrase also developed resistance mutations toemtricitabine in RT.

In a clinical study of HIV virologically suppressed patients co-infected with chronic hepatitis

B, who received emtricitabine and tenofovir alafenamide, given with elvitegravir andcobicistat as a fixed-dose combination tablet (E/C/F/TAF), for 48 weeks (GS-US-292-1249,n = 72), 2 patients qualified for resistance analysis. In these 2 patients, no amino acidsubstitutions associated with resistance to any of the components of E/C/F/TAF wereidentified in HIV-1 or HBV.

Emtricitabine-resistant viruses with the M184V/I substitution were cross-resistant tolamivudine, but retained 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 Q151Mmutation complex including K65R showed reduced susceptibility to tenofovir alafenamide.

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

Emtricitabine/Tenofovir alafenamide.

Clinical efficacy of Emtricitabine/Tenofovir alafenamide was established from studiesconducted with emtricitabine and tenofovir alafenamide when given with elvitegravir andcobicistat 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 toreceive either emtricitabine 200 mg and tenofovir alafenamide 10 mg (n = 866) once daily oremtricitabine 200 mg + tenofovir disoproxil (as fumarate) 245 mg (n = 867) once daily, bothgiven with elvitegravir 150 mg + cobicistat 150 mg as a fixed-dose combination tablet. Themean age was 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. Themean baseline plasma HIV-1 RNA was 4.5 log10 copies/mL (range: 1.3-7.0) and 23% hadbaseline viral loads > 100 000 copies/mL. The mean baseline CD4+ cell count was427 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/mLwhen compared to E/C/F/TDF at Week 144. The difference in percentage was 4.2% (95% CI:0.6% to 7.8%). 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-292-0111at 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 Week 48 or 4% 6% 11% 16%144 window

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

Discontinued study drug due to other 2% 4% 9% 11%reasons and last available HIV-1 RNA< 50 copies/mLe

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

Proportion (%) of patients with HIV-1

RNA < 50 copies/mL by subgroup

Proportion (%) of patients with 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 000copies/mL, or > 400 000 copies/mL), by CD4+ cell count (< 50 cells/μL, 50-199 cells/μL, or ≥ 200 cells/μL), and by region (USor ex-US).c Includes patients who had ≥ 50 copies/mL in the Week 48 or 144 window; patients who discontinued early due to lack or lossof efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lack or loss of efficacy and at thetime 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 this resulted inno 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, lossto 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, and326 cells/mm3 in E/C/F/TAF-treated patients and 305 cells/mm3 in E/C/F/TDF-treatedpatients (p = 0.06) at Week 144.

Clinical efficacy of Emtricitabine/Tenofovir alafenamide in treatment-naïve patients was alsoestablished from a study conducted with emtricitabine and tenofovir alafenamide (10 mg)when given with darunavir (800 mg) and cobicistat as a fixed-dose combination tablet(D/C/F/TAF). In Study GS-US-299-0102, patients were randomised in a 2:1 ratio to receiveeither fixed-dose combination D/C/F/TAF once daily (n = 103) or darunavir and cobicistatand emtricitabine/tenofovir disoproxil fumarate once daily (n = 50). The proportions ofpatients 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/tenof emtricitabine/tenofovir disoproxil ovir disoproxilfumarate (n = 50) fumarate (n = 50)

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

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

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

No virologic data at Week 48 window 5% 2% 8% 4%

Discontinued study drug due to AE or 1% 0 1% 2%deathc

Discontinued study drug due to other 4% 2% 7% 2%reasons and last available HIV-1 RNA< 50 copies/mLd

Missing data during window but on 0 0 0 0study drug

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

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 tolack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE), death or lackor loss of efficacy and at the 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 windowif this resulted 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 Emtricitabine/Tenofovir alafenamide while maintaining the thirdantiretroviral agent were evaluated in a randomised, double-blind study of virologicallysuppressed HIV-1 infected adults (n = 663). Patients must have been stably suppressed(HIV-1 RNA < 50 copies/mL) on their baseline regimen for at least 6 months and had HIV-1with no resistance mutations to emtricitabine or tenofovir alafenamide prior to study entry.

Patients were randomised in a 1:1 ratio to either switch to Emtricitabine/Tenofoviralafenamide (n = 333), or stay on their baseline emtricitabine/tenofovir disoproxil fumaratecontaining regimen (n = 330). Patients were stratified by the class of the third agent in theirprior treatment regimen. At baseline, 46% of patients were receiving emtricitabine/tenofovirdisoproxil fumarate in combination with a boosted PI and 54% of patients were receivingemtricitabine/tenofovir disoproxil fumarate in combination with an unboosted 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

Emtricitabine/ Emtricitabine/ Emtricitabine/ Emtricitabine/

Tenofovir tenofovir Tenofovir tenofoviralafenamide disoproxil alafenamide disoproxilcontaining regimen fumarate containing regimen fumarate(n = 333) containing regimen (n = 333) containing regimen(n = 330) (n = 330)

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

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

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

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

Week 48 or 96 window

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

Discontinued study drug 3% 5% 7% 9%due to other reasons andlast available HIV-1

RNA < 50 copies/mLe

Missing data during < 1% 0 0 <1%window but on studydrug

Proportion (%) of patients with HIV-1 RNA < 50 copies/mL by prior treatment regimen

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

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

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 discontinuedearly due to lack or loss of efficacy; patients who discontinued for reasons other than an adverse event (AE),death or lack or loss of efficacy 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 windowif this resulted 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 wererandomised in a 1:1 ratio to either switch to Emtricitabine/Tenofovir alafenamide (N=280)while maintaining their third agent at baseline or stay on their baseline abacavir/lamivudine -containing regimen (N=276).

Patients were stratified by the class of the third agent in their prior treatment regimen. Atbaseline, 30% of patients were receiving abacavir/lamivudine in combination with a boostedprotease inhibitor and 70% of patients were receiving abacavir/lamivudine in combinationwith an unboosted third agent. Virologic success rates at Week 48 were:

Emtricitabine/Tenofovir alafenamide Containing Regimen: 89.7% (227 of 253 subjects);

Abacavir/lamivudine Containing Regimen: 92.7%% (230 of 248 subjects). At Week 48,switching to a Emtricitabine/Tenofovir alafenamide-containing regimen was non-inferior tostaying on a baseline abacavir/lamivudine-containing regimen in maintaining HIV-1 RNA <50 copies/mL.

In Study GS-US-292-0112, the efficacy and safety of emtricitabine and tenofovir alafenamidewere evaluated in an open-label clinical study in which 242 HIV-1 infected patients with mildto moderate renal impairment (eGFRCG: 30-69 mL/min) were switched to emtricitabine andtenofovir alafenamide (10 mg) given with elvitegravir and cobicistat as a fixed-dosecombination tablet. Patients were virologically suppressed (HIV-1 RNA < 50 copies/mL) forat least 6 months before switching.

The mean age was 58 years (range: 24-82), with 63 patients (26%) who were ≥ 65 years ofage. Seventy-nine percent were male, 63% were White, 18% were Black, and 14% were

Asian. Thirteen percent of patients were identified as Hispanic/Latino. At baseline, medianeGFR was 56 mL/min, and 33% of patients had an eGFR from 30 to 49 mL/min. The meanbaseline 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 afterswitching to emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat asa fixed-dose combination tablet.

In Study GS-US-292-1825, the efficacy and safety of emtricitabine and tenofoviralafenamide, given with elvitegravir and cobicistat as a fixed-dose combination tablet wereevaluated in a single arm, open-label clinical study in which 55 HIV-1 infected adults withend stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis for at least6 months before switching to emtricitabine and tenofovir alafenamide, given with elvitegravirand cobicistat as a fixed-dose combination tablet. Patients were virologically suppressed(HIV-1 RNA < 50 copies/mL) for at least 6 months before switching.

The mean age was 48 years (range 23-64). Seventy-six percent were male, 82% were Blackand 18% were White. Fifteen percent of patients identified as Hispanic/Latino. The meanbaseline CD4+ cell count was 545 cells/mm3 (range 205-1473). At Week 48, 81.8% (45/55patients) maintained HIV-1 RNA < 50 copies/mL after switching to emtricitabine andtenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combinationtablet. There were no clinically significant changes in fasting lipid laboratory tests in patientswho 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 the 72 patients were on prior TDF-containing antiretroviral therapy. At thestart of treatment with E/C/F/TAF, the 72 patients had been HIV-suppressed (HIV-1 RNA< 50 copies/mL) for at least 6 months with or without suppression of HBV DNA and hadcompensated liver function. The mean age was 50 years (range 28-67), 92% of patients weremale, 69% were White, 18% were Black, and 10% were Asian. The mean baseline CD4+ cellcount was 636 cells/mm3 (range 263-1498). Eighty-six percent of patients (62/72) were HBVsuppressed (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 seroconversionto anti-HBe at Week 48. Of the patients who were HBsAg positive at baseline, 3/70 (4.3%)achieved seroconversion to anti-HBs Week 48.

At Week 48, 92% of patients (66/72) maintained HIV-1 RNA < 50 copies/mL after switchingto emtricitabine and tenofovir alafenamide, given with elvitegravir and cobicistat as a fixed-dose combination 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 and 3 had missing data. Of the 10 patients who were not HBVsuppressed at baseline (HBV DNA ≥ 29 IU/mL), 7 became suppressed, 2 remaineddetectable, and 1 had missing data.

There are limited clinical data on the use of E/C/F/TAF in HIV/HBV co-infected patientswho are treatment-naïve.

In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given withelvitegravir and cobicistat as a fixed-dose combination tablet was associated with smallerreductions in bone mineral density (BMD) compared to E/C/F/TDF through 144 weeks oftreatment as measured by dual energy X ray absorptiometry (DXA) analysis of hip (meanchange: −0.8% vs −3.4%, p < 0.001) and lumbar spine (mean change: −0.9% vs −3.0%,p < 0.001). In a separate study, emtricitabine and tenofovir alafenamide given with darunavirand cobicistat as a fixed-dose combination tablet was also associated with smaller reductionsin BMD (as measured by hip and lumbar spine DXA analysis) through 48 weeks of treatmentcompared to darunavir, cobicistat, emtricitabine and tenofovir disoproxil fumarate.

In a study in virologically suppressed adult patients, improvements in BMD were notedthrough 96 weeks after switching to Emtricitabine/Tenofovir alafenamide from a TDFcontaining regimen compared to minimal changes with maintaining the TDF containingregimen as measured by DXA analysis of hip (mean change from 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 significantlythrough 48 weeks after switching to Emtricitabine/Tenofovir alafenamide from anabacavir/lamivudine containing regimen compared to maintaining the abacavir/lamivudinecontaining regimen as measured by DXA analysis of hip (mean change from baseline of 0.3%vs 0.2%, p = 0.55) and lumbar spine (mean change from baseline of 0.1% vs < 0.1%,p = 0.78).

In studies in treatment-naïve patients, emtricitabine and tenofovir alafenamide given withelvitegravir and cobicistat as a fixed-dose combination tablet through 144 weeks wasassociated with a lower impact on renal safety parameters (as measured after 144 weekstreatment by eGFRCG and urine protein to creatinine ratio and after 96 weeks treatment byurine albumin to creatinine ratio) compared to E/C/F/TDF. Through 144 weeks of treatment,no subject discontinued E/C/F/TAF due to a treatment-emergent renal adverse eventcompared with 12 subjects who discontinued E/C/F/TDF (p < 0.001).

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

In a study in virologically suppressed adult patients measures of tubular proteinuria weresimilar in patients switching to a regimen containing Emtricitabine/Tenofovir alafenamidecompared to patients who stayed on an abacavir/lamivudine containing regimen at baseline.

At Week 48, the median percentage change in urine retinol binding protein to creatinine ratiowas 4% in the Emtricitabine/Tenofovir alafenamide group and 16% in those remaining on anabacavir/lamivudine containing regimen; and in urine beta-2 microglobulin to creatinine ratioit was 4% vs. 5%.

In Study GS-US-292-0106, the efficacy, safety, and pharmacokinetics of emtricitabine andtenofovir alafenamide were evaluated in an open-label study in which 50 HIV-1 infected,treatment-naïve adolescents received emtricitabine and tenofovir alafenamide (10 mg) givenwith elvitegravir and cobicistat as a fixed-dose combination tablet. Patients had a mean age of15 years (range: 12-17), and 56% were female, 12% were Asian, and 88% were Black. Atbaseline, median plasma HIV-1 RNA was 4.7 log10 copies/mL, median CD4+ cell count was456 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 to response rates in studies of treatment-naïve

HIV-1 infected adults. The mean increase from baseline in CD4+ cell count at Week 48 was224 cells/mm3. No emergent resistance to E/C/F/TAF was detected through Week 48.

The European Medicines Agency has deferred the obligation to submit the results of studieswith the reference medicinal product containing Emtricitabine/Tenofovir alafenamide in oneor 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 peakplasma concentrations occurring at 1 to 2 hours post-dose. Following multiple dose oraladministration of emtricitabine to 20 HIV-1 infected subjects, the (mean ± SD) steady stateplasma emtricitabine peak concentrations (Cmax) were 1.8 ± 0.7 μg/mL and the area-under theplasma concentration-time curve over a 24-hour dosing interval (AUC) was10.0 ± 3.1 μg*h/mL. The mean steady state plasma trough concentration at 24 hours post-dosewas equal to or greater than the mean in vitro IC90 value for anti-HIV-1 activity.

Emtricitabine systemic exposure was unaffected when emtricitabine was administered withfood.

Following administration of food in healthy subjects, peak plasma concentrations wereobserved approximately 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 fedconditions following a single 25 mg dose of tenofovir alafenamide administered in

Emtricitabine/Tenofovir alafenamide were 0.21 ± 0.13 μg/mL and 0.25 ± 0.11 μg*h/mL,respectively. The mean Cmax and AUClast following a single 10 mg dose of tenofoviralafenamide 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 fatmeal (~800 kcal, 50% fat) resulted in a decrease in tenofovir alafenamide Cmax (15-37%) andan 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 meanplasma to blood drug concentration ratio was ~1.0 and the mean semen to plasma drugconcentration ratio was ~4.0.

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

In vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes.

Following administration of [14C]-emtricitabine, complete recovery of the emtricitabine dosewas achieved in urine (~86%) and faeces (~14%). Thirteen percent of the dose was recoveredin the urine as three putative metabolites. The biotransformation of emtricitabine includesoxidation of the thiol moiety to form the 3’-sulfoxide diastereomers (~9% of dose) andconjugation with glucuronic acid to form 2’-O-glucuronide (~4% of dose). No othermetabolites were identifiable.

Metabolism is a major elimination pathway for tenofovir alafenamide in humans, accountingfor > 80% of an oral dose. In vitro studies have shown that tenofovir alafenamide ismetabolised to tenofovir (major metabolite) by cathepsin A in PBMCs (includinglymphocytes and other HIV target cells) and macrophages; and by carboxylesterase-1 inhepatocytes. In vivo, tenofovir alafenamide is hydrolysed within cells to form tenofovir(major metabolite), which is phosphorylated to the active metabolite tenofovir diphosphate.

In human clinical studies, a 10 mg oral dose of tenofovir alafenamide (given withemtricitabine and elvitegravir and cobicistat) resulted in tenofovir diphosphateconcentrations > 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. Uponco-administration with the moderate CYP3A inducer probe efavirenz, tenofovir alafenamideexposure was not significantly affected. Following administration of tenofovir alafenamide,plasma [14C]-radioactivity showed a time-dependent profile with tenofovir alafenamide asthe most abundant species in the initial few hours and uric acid in the remaining period.

Emtricitabine is primarily excreted by the kidneys with complete recovery of the doseachieved in urine (approximately 86%) and faeces (approximately 14%). Thirteen percent ofthe emtricitabine dose was recovered in urine as three metabolites. The systemic clearance ofemtricitabine averaged 307 mL/min. Following oral administration, the elimination half-lifeof emtricitabine is approximately 10 hours.

Renal excretion of intact tenofovir alafenamide is a minor pathway with < 1% of the doseeliminated in urine. Tenofovir alafenamide is mainly eliminated following metabolism totenofovir. Tenofovir alafenamide and tenofovir have a median plasma half-life of 0.51 and32.37 hours, respectively. Tenofovir is renally eliminated by both glomerular filtration andactive tubular secretion.

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

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

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

Adolescents Adults

FTCa TAFb TFVb FTCa TAFc TFVc

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

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

Ctau (ng/mL) 102.4 (38.9)b N/A 10.0 (19.6) 95.2 (46.7) N/A 10.6 (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 pharmacokineticswere observed between healthy subjects and patients with severe renal impairment (estimated

CrCl ≥ 15 mL/min and < 30 mL/min) in a Phase 1 study of tenofovir alafenamide. In aseparate Phase 1 study of emtricitabine alone, mean systemic emtricitabine exposure washigher 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). The safety ofemtricitabine and tenofovir alafenamide has not been established in patients with severe renalimpairment (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 andtenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dosecombination tablet (E/C/F/TAF) in Study GS-US-292-1825 were significantly higher than inpatients with normal renal function. No clinically relevant differences in tenofoviralafenamide pharmacokinetics were observed in patients with end stage renal disease onchronic haemodialysis as compared to those with normal renal function. There were no newsafety issues identified in patients with end stage renal disease on chronic haemodialysisreceiving emtricitabine and tenofovir alafenamide, in combination with elvitegravir andcobicistat as a fixed-dose combination tablet (see section 4.8).

There are no pharmacokinetic data on emtricitabine or tenofovir alafenamide in patients withend stage renal disease (estimated CrCl < 15 mL/min) not on chronic haemodialysis. Thesafety of emtricitabine and tenofovir alafenamide has not been established in these patients.

The pharmacokinetics of emtricitabine have not been studied in subjects with hepaticimpairment; however, emtricitabine is not significantly metabolised by liver enzymes, so theimpact of liver impairment 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 patientswith severe hepatic impairment, total plasma concentrations of tenofovir alafenamide andtenofovir are lower than those seen in subjects with normal hepatic function. When correctedfor protein binding, unbound (free) plasma concentrations of tenofovir alafenamide in severehepatic impairment and normal hepatic function are similar.

The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fullyevaluated in patients co-infected with HBV and/or HCV.

Non-clinical data on emtricitabine reveal no special hazard for humans based on conventionalstudies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential,toxicity to reproduction and development. Emtricitabine has demonstrated low carcinogenicpotential in mice and rats.

Non-clinical studies of tenofovir alafenamide in rats and dogs revealed bone and kidney asthe primary target organs of toxicity. Bone toxicity was observed as reduced BMD in rats anddogs at tenofovir exposures at least four times greater than those expected afteradministration of Emtricitabine/Tenofovir alafenamide. A minimal infiltration of histiocyteswas present in the eye in dogs at tenofovir alafenamide and tenofovir exposures ofapproximately 4 and 17 times greater, respectively, than those expected after administrationof Emtricitabine/Tenofovir alafenamide.

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 oftenofovir alafenamide compared to tenofovir disoproxil fumarate, carcinogenicity studies anda rat peri-postnatal study were conducted only with tenofovir disoproxil fumarate. No specialhazard for humans was revealed in conventional studies of carcinogenic potential and toxicityto reproduction and development. Reproductive toxicity studies in rats and rabbits showed noeffects on mating, fertility, pregnancy or foetal parameters. However, tenofovir disoproxilfumarate reduced the viability index and weight of pups in a peri-postnatal toxicity study atmaternally toxic doses.

200 mg/10 mg film-coated tablets

Cellulose, microcrystalline

Croscarmellose sodium

Magnesium stearate

Poly (vinyl alcohol) partially hydrolyzed

Titanium dioxide (E171)

Macrogol

Talc

Black Iron Oxide (E172)200 mg/25 mg film-coated tablets

Cellulose, microcrystalline

Croscarmellose sodium

Magnesium stearate

Poly (vinyl alcohol) partially hydrolyzed

Titanium dioxide (E171)

Macrogol

Talc

Indigo carmine Aluminum lake (E132)

Not applicable.

Blisters2 years

HDPE Bottle2 years.

Do not store above 30°C.

HDPE bottle

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

200 mg/10 mg film-coated tablets

High density polyethylene (HDPE) bottle with white opaque polypropylene (PP)child-resistant closure along with a desiccant containing 30 and 90 film-coated tablets.

200 mg/25 mg film-coated tablets

Blister (OPA/alu/PE/desiccant/HDPE-alu/PE) containing 30 and 90 film-coated tablets.

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Any unused medicinal product or waste material should be disposed of in accordance withlocal requirements.

Viatris Limited

Damastown Industrial Park,

Mulhuddart, Dublin 15,

DUBLIN

Ireland

200 mg/10 mg film-coated tablets

EU/1/25/1952/001

EU/1/25/1952/002200 mg/25 mg film-coated tablets

EU/1/25/1952/003

EU/1/25/1952/004

EU/1/25/1952/005

EU/1/25/1952/006

EU/1/25/1952/007

EU/1/25/1952/008

Date of first authorisation: 18 July 2025

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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