4.1. Therapeutic indications

Treatment of HIV-1 infection:

Emtricitabine/Tenofovir Alafenamide Gilead is indicated in combination with other antiretroviral agents for the treatment of adults and adolescents (aged 12 years and older with body weight at least 35 kg) infected with human immunodeficiency virus type 1 (HIV-1) (see sections 4.2 and 5.1).

Pre-exposure prophylaxis (PrEP):

Emtricitabine/Tenofovir Alafenamide Gilead is indicated for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 infection in at-risk men who have sex with men, including adolescents (with body weight at least 35 kg) (see sections 4.2, 4.4 and 5.1).

4.2. Posology and method of administration

Posology

Treatment of HIV in adults and adolescents aged 12 years and older, weighing at least 35 kg:

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

Emtricitabine/Tenofovir Alafenamide Gilead should be administered as shown in Table 1.

Table 1: Dose of Emtricitabine/Tenofovir Alafenamide Gilead according to third agent in the HIV treatment regimen

Dose of Emtricitabine/Tenofovir Alafenamide Gilead

Third agent in HIV treatment regimen (see section 4.5)

Emtricitabine/Tenofovir Alafenamide Gilead 200/10 mg once daily

Atazanavir with ritonavir or cobicistat

Darunavir with ritonavir or cobicistat1

Lopinavir with ritonavir

Emtricitabine/Tenofovir Alafenamide Gilead 200/25 mg once daily

Dolutegravir, efavirenz, maraviroc, nevirapine, rilpivirine, raltegravir

1 Emtricitabine/Tenofovir Alafenamide Gilead 200/10 mg in combination with darunavir 800 mg and cobicistat 150 mg, administered as a fixed-dose combination tablet, was studied in treatment- naive subjects, see section 5.1.

Pre-exposure prophylaxis of HIV in men who have sex with men (MSM), including adolescents (weighing at least 35 kg):

One 200/25 mg tablet, once daily.

Missed doses

If a dose of Emtricitabine/Tenofovir Alafenamide Gilead is missed within 18 hours of the time it is usually taken, the individual should take Emtricitabine/Tenofovir Alafenamide Gilead as soon as possible and resume the normal dosing schedule. If a dose of Emtricitabine/Tenofovir Alafenamide Gilead is missed by more than 18 hours, the individual should not take the missed dose and simply resume the usual dosing schedule.

If the individual vomits within 1 hour of taking Emtricitabine/Tenofovir Alafenamide Gilead another tablet should be taken.

Elderly

No dose adjustment of Emtricitabine/Tenofovir Alafenamide Gilead is required (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment of Emtricitabine/Tenofovir Alafenamide Gilead is required in adults or adolescents (aged at least 12 years and of at least 35 kg body weight) with estimated creatinine clearance (CrCl) ≥ 30 mL/min. Emtricitabine/Tenofovir Alafenamide Gilead should be discontinued in individuals with estimated CrCl that declines below 30 mL/min during treatment (see section 5.2).

No dose adjustment of Emtricitabine/Tenofovir Alafenamide Gilead is required in adults with end stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however, Emtricitabine/Tenofovir Alafenamide Gilead should generally be avoided but may be used in these individuals if the potential benefits are considered to outweigh the potential risks (see sections 4.4 and 5.2). On days of haemodialysis, Emtricitabine/Tenofovir Alafenamide Gilead should be administered after completion of haemodialysis treatment.

Emtricitabine/Tenofovir Alafenamide Gilead should be avoided in individuals 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 Gilead has not been established in these populations.

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

Hepatic impairment

No dose adjustment of Emtricitabine/Tenofovir Alafenamide Gilead is required in individuals with hepatic impairment.

Paediatric population

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

Women

The efficacy of Emtricitabine/Tenofovir Alafenamide Gilead for PrEP in adult and adolescent women who have vaginal intercourse (or their partners) has not yet been established.

Method of administration

Oral use.

Emtricitabine/Tenofovir Alafenamide Gilead 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 due to the bitter taste.

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

4.3. Contraindications

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

Use for PrEP in individuals with unknown HIV-1 status.

4.4. Special warnings and precautions for use

Overall HIV-1 infection prevention strategy

Emtricitabine/Tenofovir Alafenamide Gilead is not always effective in preventing the acquisition of HIV-1. The time to onset of protection after commencing Emtricitabine/Tenofovir Alafenamide Gilead is unknown.

Emtricitabine/Tenofovir Alafenamide Gilead for PrEP to reduce the risk of HIV-1 infection should be used as part of a comprehensive prevention strategy to reduce the risk of sexually acquired infection. Individuals should be counselled at regular intervals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner HIV-1 status, regular testing for sexually transmitted infections that can facilitate HIV-1 transmission).

The efficacy of Emtricitabine/Tenofovir Alafenamide Gilead for PrEP in adult and adolescent women who have vaginal intercourse (or their partners) has not yet been established. There is limited data on the efficacy of Emtricitabine/Tenofovir Alafenamide Gilead for PrEP in transgender women (TGW, see section 5.1).

Risk of resistance with undetected HIV-1 infection:

Emtricitabine/Tenofovir Alafenamide Gilead should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV negative (see section 4.3). Individuals should be reconfirmed to be HIV negative at frequent intervals (e.g. at least every 3 months) using a combined antigen/antibody test while taking Emtricitabine/Tenofovir Alafenamide Gilead for PrEP.

Emtricitabine/Tenofovir Alafenamide Gilead alone does not constitute a complete regimen for the treatment of HIV-1, and HIV-1 resistance mutations have emerged in individuals with undetected HIV-1 infection who are only taking Emtricitabine/Tenofovir Alafenamide Gilead.

If clinical symptoms consistent with acute HIV-1 infection are present, and recent (<1 month) exposures to HIV-1 are suspected, follow local clinical guidelines and use an approved or cleared test to aid in the diagnosis of acute or primary HIV-1 infection.

Importance of adherence:

The effectiveness of Emtricitabine/Tenofovir Alafenamide Gilead in reducing the risk of acquiring HIV-1 is strongly correlated with adherence as demonstrated by measurable drug levels in blood (see section 5.1). HIV-1 uninfected individuals should be counselled at frequent intervals to strictly adhere to the recommended Emtricitabine/Tenofovir Alafenamide Gilead daily dosing schedule.

Individuals co-infected with hepatitis B (HBV) or C (HCV) virus

Individuals with chronic HBV or HCV treated with antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions.

The safety and efficacy of Emtricitabine/Tenofovir Alafenamide Gilead in patients co-infected with HIV-1 and HCV have not been established.

Discontinuation of Emtricitabine/Tenofovir Alafenamide Gilead in individuals infected with HBV may be associated with severe acute exacerbations of hepatitis. Individuals infected with HBV who discontinue Emtricitabine/Tenofovir Alafenamide Gilead should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

The safety and efficacy of Emtricitabine/Tenofovir Alafenamide Gilead for PrEP in individuals with HBV or HCV infection have not been established.

Liver disease

The safety and efficacy of Emtricitabine/Tenofovir Alafenamide Gilead in individuals with significant underlying liver disorders have not been established (see sections 4.2 and 5.2).

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

Weight and metabolic parameters

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 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 there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Mitochondrial dysfunction following exposure in utero

Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, who present with severe clinical findings of unknown aetiology, particularly neurologic findings. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome

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 and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples include cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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

Patients with HIV-1 harbouring mutations

Emtricitabine/Tenofovir Alafenamide Gilead should be avoided in antiretroviral-experienced patients 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 at an early stage in HIV-1 infected patients when tenofovir disoproxil was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen. Therefore, the same problems may be seen if Emtricitabine/Tenofovir Alafenamide Gilead is administered with a third nucleoside analogue.

Opportunistic infections

HIV-1 infected patient receiving Emtricitabine/Tenofovir Alafenamide Gilead or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and, therefore, should remain under close clinical observation by physicians experienced in the treatment of patients with HIV associated diseases.

Osteonecrosis

Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported 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, joint stiffness or difficulty in movement.

Nephrotoxicity

Post-marketing cases of renal impairment, including acute renal failure and proximal renal tubulopathy have been reported with tenofovir alafenamide-containing products. A potential risk of nephrotoxicity resulting from chronic exposure to low levels of tenofovir due to dosing 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 Gilead and that it is also monitored during therapy in all patients as clinically appropriate. In patients who develop clinically significant decreases in renal function, or evidence of proximal renal tubulopathy, discontinuation of Emtricitabine/Tenofovir Alafenamide Gilead should be considered.

Patients with end stage renal disease on chronic haemodialysis

Emtricitabine/Tenofovir Alafenamide Gilead 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 the potential risks (see section 4.2). In a study of emtricitabine + tenofovir alafenamide in combination with elvitegravir + cobicistat as a fixed-dose combination 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 48 weeks but emtricitabine exposure was significantly higher than in patients with normal renal function. Although there were no new safety issues identified, the implications of increased emtricitabine exposure remain uncertain (see sections 4.8 and 5.2).

Co-administration of other medicinal products

The co-administration of Emtricitabine/Tenofovir Alafenamide Gilead 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).

Emtricitabine/Tenofovir Alafenamide Gilead should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

Excipients

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

4.5. Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Emtricitabine/Tenofovir Alafenamide Gilead should not be administered concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine or adefovir dipivoxil.

Emtricitabine

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 tubular secretion 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

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 in tenofovir alafenamide absorption. Medicinal products that induce P-gp activity (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to decrease the absorption of tenofovir alafenamide, resulting in decreased plasma concentration of tenofovir alafenamide, which may lead to loss of therapeutic effect of Emtricitabine/Tenofovir Alafenamide Gilead and development of resistance. Co-administration of Emtricitabine/Tenofovir Alafenamide Gilead with 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 oxidase inhibitors (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 a substrate of OATP1B1 and OATP1B3 in vitro. The distribution of tenofovir alafenamide in the body may be affected by the activity of OATP1B1 and OATP1B3.

Other interactions

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 UGT substrate in vitro.

Interactions between the components of Emtricitabine/Tenofovir Alafenamide Gilead and potential co-administered medicinal products are listed in Table 2 (increase is indicated as “↑”, decrease as “↓”, no change as “↔”). The interactions described are based on studies conducted with Emtricitabine/Tenofovir Alafenamide Gilead, or the components of Emtricitabine/Tenofovir Alafenamide Gilead as individual agents and/or in combination, or are potential drug-drug interactions that may occur with Emtricitabine/Tenofovir Alafenamide Gilead.

Table 2: Interactions between the individual components of Emtricitabine/Tenofovir Alafenamide Gilead and other medicinal products

Medicinal product by therapeutic areas1

Effects on medicinal product levels.

Mean percent change in AUC, Cmax, Cmin2

Recommendation concerning co-administration with Emtricitabine/Tenofovir Alafenamide Gilead

ANTI-INFECTIVES

Antifungals

Ketoconazole

Itraconazole

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Co-administration of ketoconazole or itraconazole, which are potent P-gp inhibitors, is expected to increase plasma concentrations of tenofovir alafenamide.

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/10 mg once daily.

Fluconazole

Isavuconazole

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Co-administration of fluconazole or isavuconazole may increase plasma concentrations of tenofovir alafenamide.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

Antimycobacterials

Rifabutin

Rifampicin

Rifapentine

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Co-administration of rifampicin, rifabutin, and rifapentine, all of which are P-gp inducers, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Co-administration of Emtricitabine/Tenofovir Alafenamide Gilead and rifabutin rifampicin, or rifapentine is not recommended.

Anti-hepatitis C virus medicinal products

Ledipasvir (90 mg once daily)/ sofosbuvir (400 mg once daily), emtricitabine (200 mg once daily)/ tenofovir alafenamide (10 mg once daily)3

Ledipasvir:

AUC: ↑ 79%

Cmax: ↑ 65%

Cmin: ↑ 93%

Sofosbuvir:

AUC: ↑ 47%

Cmax: ↑ 29%

Sofosbuvir metabolite GS-331007:

AUC: ↑ 48%

Cmax: ↔

Cmin: ↑ 66%

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

No dose adjustment of ledipasvir or sofosbuvir is required.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

Ledipasvir (90 mg once daily)/ sofosbuvir (400 mg once daily), emtricitabine (200 mg once daily)/ tenofovir alafenamide (25 mg once daily)4

Ledipasvir:

AUC: ↔

Cmax: ↔

Cmin: ↔

Sofosbuvir:

AUC: ↔

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmax: ↔

Cmin: ↔

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir alafenamide:

AUC: ↑ 32%

Cmax: ↔

No dose adjustment of ledipasvir or sofosbuvir is required.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

Sofosbuvir (400 mg once daily)/velpatasvir (100 mg once daily), emtricitabine (200 mg once daily)/ tenofovir alafenamide

(10 mg once daily)3

Sofosbuvir:

AUC: ↑ 37%

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↑ 48%

Cmax: ↔

Cmin: ↑ 58%

Velpatasvir:

AUC: ↑ 50%

Cmax: ↑ 30%

Cmin: ↑ 60%

Emtricitabine:

AUC: ↔

Cmax: ↔

Cmin: ↔

Tenofovir alafenamide:

AUC: ↔

Cmax: ↓ 20%

No dose adjustment of sofosbuvir, velpatasvir or voxilaprevir is required.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg+100 mg once daily)7/emtricitabine (200 mg once daily)/ tenofovir alafenamide (10 mg once daily)3

Sofosbuvir:

AUC: ↔

Cmax: ↑ 27%

Sofosbuvir metabolite GS-331007:

AUC: ↑ 43%

Cmax: ↔

Velpatasvir:

AUC: ↔

Cmin: ↑ 46%

Cmax: ↔

Voxilaprevir:

AUC: ↑ 171%

Cmin: ↑ 350%

Cmax: ↑ 92%

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↔

Cmax: ↓ 21%

Sofosbuvir/velpatasvir/voxilaprevir (400 mg/100 mg/100 mg+100 mg once daily)7/emtricitabine (200 mg once daily)/ tenofovir alafenamide (25 mg once daily)4

Sofosbuvir:

AUC: ↔

Cmax: ↔

Sofosbuvir metabolite GS-331007:

AUC: ↔

Cmin: ↔

Velpatasvir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Voxilaprevir:

AUC: ↔

Cmin: ↔

Cmax: ↔

Emtricitabine:

AUC: ↔

Cmin: ↔

Cmax: ↔

Tenofovir alafenamide:

AUC: ↑ 52%

Cmax: ↑ 32%

No dose adjustment of sofosbuvir, velpatasvir or voxilaprevir is required.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

ANTIRETROVIRALS

HIV protease inhibitors

Atazanavir/cobicistat (300 mg/150 mg once daily), tenofovir alafenamide (10 mg)

Tenofovir alafenamide:

AUC: ↑ 75%

Cmax: ↑ 80%

Atazanavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/10 mg once daily.

Atazanavir/ritonavir (300/100 mg once daily), tenofovir alafenamide (10 mg)

Tenofovir alafenamide:

AUC: ↑ 91%

Cmax: ↑ 77%

Atazanavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/10 mg once daily.

Darunavir/cobicistat (800/150 mg once daily), tenofovir alafenamide (25 mg once daily)5

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↑ 224%

Cmax: ↑ 216%

Cmin: ↑ 221%

Darunavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/10 mg once daily.

Darunavir/ritonavir (800/100 mg once daily), tenofovir alafenamide (10 mg once daily)

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

Tenofovir:

AUC: ↑ 105%

Cmax: ↑ 142%

Darunavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/10 mg once daily.

Lopinavir/ritonavir (800/200 mg once daily), tenofovir alafenamide (10 mg once daily)

Tenofovir alafenamide:

AUC: ↑ 47%

Cmax: ↑ 119%

Lopinavir:

AUC: ↔

Cmax: ↔

Cmin: ↔

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/10 mg once daily.

Tipranavir/ritonavir

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Tipranavir/ritonavir results in P-gp induction. Tenofovir alafenamide exposure is expected to decrease when tipranavir/ritonavir is used in combination with Emtricitabine/Tenofovir Alafenamide Gilead.

Co-administration with Emtricitabine/Tenofovir Alafenamide Gilead is not recommended.

Other protease inhibitors

Effect is unknown.

There are no data available to make dosing recommendations for co-administration with other protease inhibitors.

Other HIV antiretrovirals

Dolutegravir (50 mg once daily), tenofovir alafenamide (10 mg once daily)3

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

Dolutegravir:

AUC: ↔

Cmax: ↔

Cmin: ↔

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/25 mg once daily.

Rilpivirine (25 mg once daily), tenofovir alafenamide (25 mg once daily)

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

Rilpivirine:

AUC: ↔

Cmax: ↔

Cmin: ↔

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/25 mg once daily.

Efavirenz (600 mg once daily), tenofovir alafenamide (40 mg once daily)4

Tenofovir alafenamide:

AUC: ↓ 14%

Cmax: ↓ 22%

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/25 mg once daily.

Maraviroc

Nevirapine

Raltegravir

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Tenofovir alafenamide exposure is not expected to be affected by maraviroc, nevirapine

or raltegravir, nor is it expected to affect the metabolic and excretion pathways relevant to maraviroc, nevirapine or raltegravir.

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/25 mg once daily.

ANTICONVULSANTS

Oxcarbazepine

Phenobarbital

Phenytoin

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Co-administration of oxcarbazepine, phenobarbital, or phenytoin, all of which are P-gp inducers, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Co-administration of Emtricitabine/Tenofovir Alafenamide Gilead and oxcarbazepine, phenobarbital or phenytoin is not recommended.

Carbamazepine (titrated from 100 mg to 300 mg twice a day), emtricitabine/tenofovir alafenamide (200 mg/25 mg once daily)5,6

Tenofovir alafenamide:

AUC: ↓ 55%

Cmax: ↓ 57%

Co-administration of carbamazepine, a P-gp inducer, decreases tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Co-administration of Emtricitabine/Tenofovir Alafenamide Gilead and carbamazepine is not recommended.

ANTIDEPRESSANTS

Sertraline (50 mg once daily), tenofovir alafenamide (10 mg once daily)3

Tenofovir alafenamide:

AUC: ↔

Cmax: ↔

Sertraline:

AUC: ↑ 9%

Cmax: ↑ 14%

No dose adjustment of sertraline is required.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

HERBAL PRODUCTS

St. John's wort (Hypericum perforatum)

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Co-administration of St. John's wort, a P-gp inducer, may decrease tenofovir alafenamide plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

Co-administration of Emtricitabine/Tenofovir Alafenamide Gilead with St. John's wort is not recommended.

IMMUNOSUPPRESSANTS

Ciclosporin

Interaction not studied with either of the components of Emtricitabine/Tenofovir Alafenamide Gilead.

Co-administration of ciclosporin, a potent P-gp inhibitor, is expected to increase plasma concentrations of tenofovir alafenamide.

HIV-1 treatment: The recommended dose of Emtricitabine/Tenofovir Alafenamide Gilead is 200/10 mg once daily.

ORAL CONTRACEPTIVES

Norgestimate (0.180/0.215/0.250 mg once daily), ethinylestradiol (0.025 mg once daily), emtricitabine/tenofovir alafenamide (200/25 mg once daily)5

Norelgestromin:

AUC: ↔

Cmin: ↔

Cmax: ↔

Norgestrel:

AUC: ↔

Cmin: ↔

Cmax: ↔

Ethinylestradiol:

AUC: ↔

Cmin: ↔

Cmax: ↔

No dose adjustment of norgestimate/ethinylestradiol is required.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

SEDATIVES/HYPNOTICS

Orally administered midazolam (2.5 mg single dose), tenofovir alafenamide (25 mg once daily)

Midazolam:

AUC: ↔

Cmax: ↔

No dose adjustment of midazolam is required.

HIV-1 treatment: Dose Emtricitabine/Tenofovir Alafenamide Gilead according to the concomitant antiretroviral (see section 4.2).

Intravenously administered midazolam (1 mg single dose), tenofovir alafenamide (25 mg once daily)

Midazolam:

AUC: ↔

Cmax: ↔

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 Gilead.

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

Emtricitabine/Tenofovir Alafenamide Gilead should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

It is not known whether tenofovir alafenamide is excreted in human milk. Emtricitabine is excreted in human 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, Emtricitabine/Tenofovir Alafenamide Gilead 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 do not breast-feed their infants.

Fertility

There are no data on fertility from the use of Emtricitabine/Tenofovir Alafenamide Gilead in humans. In animal studies there were no effects of emtricitabine and tenofovir alafenamide on mating or fertility parameters (see section 5.3).

4.7. Effects on ability to drive and use machines

Emtricitabine/Tenofovir Alafenamide Gilead may have minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with Emtricitabine/Tenofovir Alafenamide Gilead.

4.8. Undesirable effects

Summary of the safety profile

Treatment of HIV-1 infection: 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 tenofovir alafenamide and from post-marketing experience. In clinical studies of treatment-naïve adult patients receiving emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat as the fixed-dose combination 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 reactions were diarrhoea (7%), nausea (11%), and headache (6%).

PrEP: No new adverse reactions to Emtricitabine/Tenofovir Alafenamide Gilead were identified in the double-blind randomised placebo-controlled study (GS-US-412-2055) through 96 weeks in which 5,387 HIV-1 uninfected cisgender men and transgender women who have sex with men received Emtricitabine/Tenofovir Alafenamide Gilead or emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) once daily for HIV-1 PrEP. The most common adverse reaction in participants who received Emtricitabine/Tenofovir Alafenamide Gilead was diarrhoea (5%) followed by nausea (4%), headache and fatigue (2%, respectively). Effects on biomarkers of renal and bone disease were similar to those observed in the treatment of HIV-1 with Emtricitabine/Tenofovir Alafenamide Gilead. No additional adverse reactions to Emtricitabine/Tenofovir Alafenamide Gilead were identified from Week 96 through Week 144 in participants receiving open-label Emtricitabine/Tenofovir Alafenamide Gilead (see Section 5.1).

Tabulated summary of adverse reactions

The adverse reactions in Table 3 are listed by system organ class and frequency. Frequencies are 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

Blood and lymphatic system disorders

Uncommon:

anaemia2

Psychiatric disorders

Common:

abnormal dreams

Nervous system disorders

Common:

headache, dizziness

Gastrointestinal disorders

Very common:

nausea

Common:

diarrhoea, vomiting, abdominal pain, flatulence

Uncommon:

dyspepsia

Skin and subcutaneous tissue disorders

Common:

rash

Uncommon:

angioedema3,4, pruritus, urticaria4

Musculoskeletal and connective tissue disorders

Uncommon:

arthralgia

General disorders and administration site conditions

Common:

fatigue

1 With the exception of angioedema, anaemia and urticaria (see footnotes 2, 3 and 4), all adverse reactions were identified from clinical studies of F/TAF containing products. The frequencies were derived from Phase 3 E/C/F/TAF clinical studies 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 clinical studies 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.

Description of selected adverse reactions

Immune Reactivation Syndrome

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

Osteonecrosis

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

Changes in lipid laboratory tests

In studies in treatment- naïve patients, increases from baseline were observed in both the tenofovir alafenamide fumarate and tenofovir disoproxil fumarate containing treatment groups for the fasting lipid 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 those parameters was greater in the E/C/F/TAF group compared with the elvitegravir 150 mg/cobicistat 150 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 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/tenofovir disoproxil fumarate to Emtricitabine/Tenofovir Alafenamide Gilead while maintaining the third antiretroviral agent (Study GS-US-311-1089), increases from baseline were observed in the fasting lipid parameters total cholesterol, direct LDL cholesterol and triglycerides in the Emtricitabine/Tenofovir Alafenamide Gilead arm compared with little change in the emtricitabine/tenofovir disproxil fumarate arm (p ≤ 0.009 for the difference between groups in 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 in either 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 Gilead while maintaining the third antiretroviral agent (Study GS-US-311-1717), there were minimal changes in lipid parameters.

Metabolic parameters

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

Paediatric population

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 patients aged 12 to < 18 years received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile of emtricitabine and tenofovir alafenamide given with elvitegravir and cobicistat in 50 adolescent patients was similar to that in adults (see section 5.1).

Other special populations

Patients with renal impairment

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 either treatment-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) received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. The safety profile in patients with mild to moderate renal impairment was similar to 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 infected patients with end stage renal disease (eGFRCG < 15 mL/min) on chronic haemodialysis received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. There were no new safety issues identified in patients with end stage renal disease on chronic haemodialysis receiving emtricitabine and tenofovir alafenamide, in combination with elvitegravir and cobicistat as a fixed-dose combination tablet (see section 5.2).

Patients co-infected with HIV and HBV

The safety of emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as 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 an open-label clinical study (GS-US-292-1249), through Week 48, in which patients were switched from another antiretroviral regimen (which included tenofovir disoproxil 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 elvitegravir and 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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

If overdose occurs the individual must be monitored for evidence of toxicity (see section 4.8). Treatment of overdose with Emtricitabine/Tenofovir Alafenamide Gilead consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the individual.

Emtricitabine can be removed by haemodialysis, which removes approximately 30% of the emtricitabine 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 approximately 54%. It is not known whether emtricitabine or tenofovir can be removed by peritoneal dialysis.