INSTRUCTION for medical use of the medicinal product Talfatrax-E (Talfatrax-E)

Composition:

Active substances: emtricitabine, tenofovir alafenamide fumarate;

1 tablet of 200 mg/25 mg contains:

emtricitabine 200 mg; tenofovir alafenamide fumarate equivalent to tenofovir alafenamide 25 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, magnesium stearate,

coating Opadry White 03F580097: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: tablets from white to almost white, oval-shaped, film-coated, with "J 57" engraved on one side and smooth on the other side.

Pharmacotherapeutic group.

Antivirals for systemic use; antivirals for treatment of HIV infections, combinations. ATC code J05AR17.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Emtricitabine is a nucleoside reverse transcriptase inhibitor (NRTI) and a nucleoside analogue of 2'-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes to form emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication by incorporation into viral deoxyribonucleic acid (DNA) via HIV reverse transcriptase (RT), resulting in chain termination of viral DNA. Emtricitabine has activity against HIV-1, HIV-2, and hepatitis B virus (HBV).

Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor (NtRTI) and a phosphonamidate prodrug of tenofovir (a 2'-deoxyadenosine monophosphate analogue). Tenofovir alafenamide enters cells and, due to increased plasma stability and intracellular activation via cathepsin A hydrolysis, is more efficient than tenofovir disoproxil fumarate in delivering tenofovir concentrations into peripheral blood mononuclear cells (PBMCs). Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite, tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication by incorporation into viral DNA via HIV RT, leading to DNA chain termination.

Tenofovir is active against HIV-1, HIV-2, and HBV.

Pharmacokinetics

Absorption

Emtricitabine is rapidly absorbed after oral administration, with peak plasma concentrations observed within 1–2 hours after dosing. Following multiple oral doses of emtricitabine (mean ± SD), the steady-state peak plasma concentration (C_max) of emtricitabine was 1.8 ± 0.7 µg/mL, and the area under the plasma concentration-time curve over the 24-hour dosing interval (AUC) was 10.0 ± 3.1 µg•h/mL. The mean steady-state plasma concentration 24 hours after dosing was equal to or exceeded the mean in vitro IC₉₀ value for anti-HIV-1 activity. Systemic exposure to emtricitabine was not altered when emtricitabine was administered with food.

Following administration with food in healthy volunteers, peak plasma concentrations of tenofovir alafenamide occurred approximately 1 hour after dosing of F/TAF (25 mg) or E/C/F/TAF (10 mg). The mean C_max and AUC_last (mean ± SD) after a single 25 mg dose of tenofovir alafenamide co-formulated with emtricitabine administered with food were 0.21 ± 0.13 µg/mL and 0.25 ± 0.11 µg•h/mL, respectively. The mean C_max and AUC_last after a single 10 mg dose of tenofovir alafenamide administered in E/C/F/TAF were 0.21 ± 0.10 µg/mL and 0.25 ± 0.08 µg•h/mL, respectively.

Compared to administration of tenofovir alafenamide under fasting conditions, administration with a high-fat meal (~800 kcal, 50% fat) resulted in a 15–37% decrease in C_max and a 17–77% increase in AUC_last for tenofovir alafenamide.

Distribution

In vitro, emtricitabine protein binding in plasma was < 4% and was independent of concentration over the range of 0.02 to 200 µg/mL. The mean plasma-to-blood concentration ratio is approximately 1.0, and the mean semen-to-plasma concentration ratio is approximately 4.0. In vitro, tenofovir protein binding in plasma was < 0.7% and was independent of concentration over the range of 0.01 to 25 µg/mL. Ex vivo, protein binding of tenofovir alafenamide in human plasma samples collected during clinical studies was approximately 80%.

Metabolism

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

After administration of [14C]-emtricitabine, complete recovery of the emtricitabine dose was achieved in urine (~86%) and feces (~14%). Approximately 13% of the dose was excreted in urine as three identified metabolites. Biotransformation of emtricitabine includes oxidation of the thiol moiety to form 3’-sulfoxide diastereomers (~9% of dose) and glucuronic acid conjugation to form the 2’-O-glucuronide (~4% of dose). No other metabolites were identified.

Metabolism is the primary route of elimination of tenofovir alafenamide in humans, accounting for >80% of the oral dose. In vitro studies have shown that tenofovir alafenamide is metabolized to tenofovir (the major metabolite) by carboxylesterase-1 in hepatocytes and by cathepsin A in peripheral blood mononuclear cells (including lymphocytes and other HIV target cells) and macrophages. In vivo, tenofovir alafenamide is intracellularly hydrolyzed to tenofovir (the major metabolite), which is then phosphorylated to the active metabolite, tenofovir diphosphate. In human clinical studies, an oral 10 mg dose of tenofovir alafenamide (co-administered with emtricitabine, elvitegravir, and cobicistat) resulted in a 4-fold higher concentration of tenofovir diphosphate in peripheral blood mononuclear cells and lower plasma concentrations of tenofovir compared to a 300 mg dose of tenofovir disoproxil fumarate (co-administered with emtricitabine, elvitegravir, and cobicistat).

In vitro, tenofovir alafenamide is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolized by CYP3A4. When co-administered with the moderate CYP3A inducer efavirenz, exposure to tenofovir alafenamide was not substantially altered. After administration of tenofovir alafenamide, plasma [14C]-radioactivity showed a time-dependent profile, with tenofovir alafenamide being the predominant species in the first few hours and uric acid metabolites prevailing thereafter.

Elimination

Emtricitabine is primarily eliminated by the kidneys (~86%), with approximately 14% excreted in feces. About 13% of the emtricitabine dose was recovered in urine as three metabolites. The mean systemic clearance of emtricitabine is 307 mL/min. After oral administration, the elimination half-life of emtricitabine is approximately 10 hours.

Renal excretion of intact tenofovir alafenamide is minimal, with <1% of the dose recovered in urine. Tenofovir alafenamide is primarily eliminated following metabolism to tenofovir. The mean plasma elimination half-lives of tenofovir alafenamide and tenofovir are 0.51 and 32.37 hours, respectively. Tenofovir is eliminated by the kidneys through both glomerular filtration and active tubular secretion.

Pharmacokinetics in Special Populations

No clinically significant differences in pharmacokinetics were observed based on age, gender, or ethnicity.

Pediatric Population

Exposures to emtricitabine and tenofovir alafenamide (in combination with elvitegravir and cobicistat) achieved in 24 children aged 12 to <18 years receiving emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat were similar to those achieved in treatment-naïve adult patients.

Renal Impairment

No clinically significant differences in the pharmacokinetics of tenofovir alafenamide or tenofovir were observed between healthy individuals and patients with severe renal impairment (estimated CrCl ≥15 mL/min and <30 mL/min) in a Phase 1 tenofovir alafenamide study. In a separate Phase 1 study focusing solely on emtricitabine, mean systemic exposure to emtricitabine was higher in patients with severe renal impairment (estimated CrCl <30 mL/min) (33.7 µg•h/mL) compared to those with normal renal function (11.8 µg•h/mL). The safety of emtricitabine and tenofovir alafenamide in patients with severe renal impairment (estimated CrCl ≥15 mL/min and <30 mL/min) has not been established.

Exposure to emtricitabine and tenofovir in 12 patients with end-stage renal disease (estimated CrCl <15 mL/min) on chronic hemodialysis, who received emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet (F/TAF) in study GS-US-292-1825, was significantly higher than in patients with normal renal function. No clinically significant differences in the pharmacokinetics of tenofovir alafenamide in patients with end-stage renal disease on chronic hemodialysis compared to those with normal renal function were observed. No new safety concerns were identified in patients with end-stage renal disease on chronic hemodialysis receiving emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet.

Pharmacokinetic data for emtricitabine and tenofovir alafenamide in patients with end-stage renal disease (estimated CrCl <15 mL/min) not on chronic hemodialysis are lacking. The safety of emtricitabine and tenofovir alafenamide in these patients has not been established.

Hepatic Impairment

The pharmacokinetics of emtricitabine has not been studied in patients with hepatic impairment; however, emtricitabine undergoes minimal hepatic metabolism, so the impact of hepatic impairment is expected to be limited.

No clinically significant changes in the pharmacokinetics of tenofovir alafenamide or its metabolite tenofovir were observed in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, total plasma concentrations of tenofovir alafenamide and tenofovir are lower than in patients with normal hepatic function. However, when corrected for protein binding, unbound (free) plasma concentrations of tenofovir alafenamide are similar in severe hepatic impairment and normal hepatic function.

Hepatitis B and/or Hepatitis C Co-infection

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

Clinical characteristics.

Indications.

HIV-1 infection treatment

Talfratex-E should be administered as part of combination antiretroviral therapy for the treatment of HIV-1-infected adults and adolescents (aged 12 years and older with body weight at least 35 kg).

Pre-exposure prophylaxis

Talfratex-E 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).

Contraindications.

Hypersensitivity to the active substances or to any of the excipients.

Use for pre-exposure prophylaxis in individuals with unknown HIV-1 status.

Interaction with other medicinal products and other forms of interaction.

Drug interaction studies have been conducted only in adult patients.

The medicinal product should not be used concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine, or adefovir dipivoxil.

Emtricitabine

In vitro and clinical pharmacokinetic drug interaction studies have shown that the potential for CYP-mediated interactions involving emtricitabine with other medicinal products is low. Concomitant administration of emtricitabine with medicinal products eliminated via active tubular secretion may lead to increased concentrations of emtricitabine and/or the co-administered medicinal products. Medicinal products that reduce renal function may increase emtricitabine concentrations.

Tenofovir alafenamide

Tenofovir alafenamide is transported by P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Medicinal products that strongly affect the activity of P-gp and BCRP may lead to changes in the absorption of tenofovir alafenamide. P-gp inducers (e.g., rifampicin, rifabutin, carbamazepine, phenobarbital) are expected to reduce the absorption of tenofovir alafenamide, resulting in decreased plasma concentrations of tenofovir alafenamide, which may in turn lead to loss of therapeutic effect and development of resistance. Concomitant use of the medicinal product with other medicinal products that inhibit P-gp and BCRP activity (e.g., cobicistat, ritonavir, cyclosporine) is expected to increase absorption and plasma concentrations of tenofovir alafenamide. According to in vitro data, concomitant administration of tenofovir alafenamide with 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 neither an inhibitor nor an 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 influenced 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 unknown whether tenofovir alafenamide inhibits other UGT enzymes. Emtricitabine did not inhibit glucuronidation of a non-specific UGT substrate in vitro.

Interactions between components of the medicinal product and potential concomitant medicinal products are presented in Table 1 (increases indicated as "↑", decreases as "↓", no change as "↔"). The described drug interactions were observed during studies conducted with the medicinal product or its components as individual medicinal products and/or in combination, or are potential drug interactions that may occur with the medicinal product.

Interaction between components of the medicinal product and other medicinal products

Table 1

Medicinal products by therapeutic classes 1	Effect on drug concentration levels. Mean percentage change in AUC, Cmax, Cmin2	Recommendation for concomitant use with the medicinal product
ANTI-INFECTIOUS AGENTS
Antifungal agents
Ketoconazole Itraconazole	Interaction not studied with any component of the medicinal product. Concomitant use of ketoconazole and itraconazole, which are potent P-gp inhibitors, is expected to increase tenofovir alafenamide plasma concentrations.	The recommended dose of the medicinal product is 200/10 mg once daily.
Fluconazole Isavuconazole	Interaction not studied with any component of the medicinal product. Concomitant use of fluconazole or isavuconazole may increase tenofovir alafenamide plasma concentrations.	Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
Antimycobacterial agents
Rifabutin Rifampicin Rifapentine	Interaction not studied with any component of the medicinal product. Concomitant use of rifampicin, rifabutin, and rifapentine, which are P-gp inducers, may reduce tenofovir alafenamide plasma concentrations, potentially leading to loss of therapeutic effect and development of resistance.	Concomitant use of the medicinal product with rifabutin, rifampicin, or rifapentine is not recommended.
Antiviral agents for treatment of hepatitis C virus infection
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 % Metabolite of sofosbuvir GS-331007: AUC: ↑ 48 % Cmax: ↔ Cmin: ↑ 66 % Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir alafenamide: AUC: ↔ Cmax: ↔	No dose adjustment of ledipasvir or sofosbuvir is required. Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
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: ↔ Metabolite of sofosbuvir GS-331007: AUC: ↔ Cmax: ↔ Cmin: ↔ Emtricitabine: AUC: ↔ Cmax: ↔ Cmin: ↔ Tenofovir alafenamide: AUC: ↑ 32 % Cmax: ↔	No dose adjustment of ledipasvir or sofosbuvir is required. Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
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: ↔ Metabolite of sofosbuvir 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. Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
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 % Metabolite of sofosbuvir 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: ↔ Metabolite of sofosbuvir 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. Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
ANTIRETROVIRAL AGENTS
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: ↔	The recommended dose of the medicinal product 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: ↔	The recommended dose of the medicinal product 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: ↔	The recommended dose of the medicinal product 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: ↔	The recommended dose of the medicinal product 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: ↔	The recommended dose of the medicinal product is 200/10 mg once daily.
Tipranavir/ritonavir	Interaction with any component of the medicinal product has not been studied. Tipranavir/ritonavir induces P-gp. A decreased exposure of tenofovir alafenamide is expected when tipranavir/ritonavir is used concomitantly with the medicinal product.	Concomitant use is not recommended.
Other protease inhibitors	Effect unknown.	There are no data to provide dosing recommendations for concomitant use 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: ↔	The recommended dose of the medicinal product 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: ↔	The recommended dose of the medicinal product is 200/25 mg once daily.
Efavirenz (600 mg once daily), tenofovir alafenamide (40 mg once daily)4	Tenofovir alafenamide: AUC: ↓ 14 % Cmax: ↓ 22 %	The recommended dose of the medicinal product is 200/25 mg once daily.
Maraviroc Nevaripine Raltegravir	Interaction with any component of the medicinal product has not been studied. Maraviroc, nevirapine, or raltegravir are not expected to affect tenofovir alafenamide exposure, nor are they expected to affect metabolic and elimination pathways relevant to maraviroc, nevirapine, or raltegravir.	The recommended dose of the medicinal product is 200/25 mg once daily.
ANTICONVULSANTS
Oxcarbazepine Phenobarbital Phenytoin	Interaction with any component of the medicinal product has not been studied. Concomitant use of oxcarbazepine, phenobarbital, or phenytoin, which are P-gp inducers, may reduce tenofovir alafenamide plasma concentrations, potentially leading to loss of therapeutic effect and development of resistance.	Concomitant use of the medicinal product with oxcarbazepine, phenobarbital, or phenytoin is not recommended.
Carbamazepine (titrated from 100 mg to 300 mg twice daily), emtricitabine/tenofovir alafenamide (200 mg/25 mg once daily) 5,6	Tenofovir alafenamide: AUC: ↓ 55 % Cmax: ↓ 57 % Concomitant use of carbamazepine, a P-gp inducer, reduces tenofovir alafenamide plasma concentrations, potentially leading to loss of therapeutic effect and development of resistance.	Concomitant use 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. Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
HERBAL PRODUCTS
St. John's wort (Hypericum perforatum)	Interaction not studied with any component of the medicinal product. Concomitant use of St. John's wort, a P-gp inducer, may reduce tenofovir alafenamide plasma concentrations, potentially leading to loss of therapeutic effect and development of resistance.	Concomitant use of the medicinal product with St. John's wort is not recommended.
IMMUNOSUPPRESSANTS
Cyclosporine	Interaction not studied with any component of the medicinal product. Concomitant use of cyclosporine, a potent P-gp inhibitor, is expected to increase tenofovir alafenamide plasma concentrations.	The recommended dose of the medicinal product 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. Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
SEDATIVES/HYPNOTICS
Oral midazolam (2.5 mg single dose), tenofovir alafenamide (25 mg once daily)	Midazolam: AUC: ↔ Cmax: ↔	No dose adjustment of midazolam is required. Dose of the medicinal product should be administered according to concomitant antiretroviral therapy.
Intravenous midazolam (1 mg single dose), tenofovir alafenamide (25 mg once daily)	Midazolam: AUC: ↔ Cmax: ↔

1 If doses are indicated, these are the doses used in clinical drug interaction studies.

2 If there are data from drug interaction studies.

3 Study conducted with a fixed-dose combination tablet of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide.

4 Study conducted with the combination tablet emtricitabine/rilpivirine/tenofovir alafenamide.

5 Study conducted with emtricitabine/tenofovir alafenamide.

6 In this study, emtricitabine/tenofovir alafenamide was administered with food.

7 Study conducted using an additional dose of voxilaprevir 100 mg to achieve the expected effect of voxilaprevir in patients infected with HCV.

Special precautions for use.

General strategy for prevention of HIV-1 infection

The medicinal product is not always effective in preventing HIV-1 infection. The time to onset of protection after initiating the medicinal product is unknown.

Pre-exposure prophylaxis (PrEP) with this medicinal product to reduce the risk of sexually acquired HIV-1 infection should be used as part of a comprehensive prevention strategy. Individuals should be regularly counselled on the use of other preventive measures (e.g., consistent and correct use of condoms, knowledge of HIV-1 status of partner, regular testing for sexually transmitted infections that may increase the risk of HIV-1 transmission).

The efficacy of the medicinal product for pre-exposure prophylaxis of HIV infection in adults and adolescents who have receptive vaginal sex (or their partners) has not yet been established. There are limited data on the efficacy of the medicinal product for pre-exposure prophylaxis in transgender women.

Risk of resistance with undiagnosed HIV-1 infection:

The medicinal product should be used to reduce the risk of HIV-1 infection only in individuals with confirmed HIV-negative status. HIV-negative status should be periodically confirmed (e.g., at least every 3 months) using a combination antigen/antibody test during use of the medicinal product for pre-exposure prophylaxis.

Talftrex-E by itself is not a complete HIV-1 treatment regimen, and HIV-1 resistance mutations have occurred in individuals with undiagnosed HIV-1 infection who were taking only Talftrex-E.

If clinical symptoms consistent with acute HIV-1 infection are observed and there is suspicion of recent (within less than 1 month) HIV-1 infection, local clinical guidelines should be followed, and an approved or authorized test for diagnosis of acute or primary HIV-1 infection should be used.

Importance of adherence

The efficacy of the medicinal product in reducing the risk of HIV-1 infection is closely linked to adherence to the prescribed daily dosing schedule, as demonstrated by measurable drug levels in blood. HIV-negative individuals should be regularly counselled on strict adherence to the recommended daily dosing regimen.

HIV-infected patients with concomitant hepatitis B or C virus infection.

Patients with chronic hepatitis B or C undergoing antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse reactions.

The safety and efficacy of Talftrex-E in patients with HIV and concomitant hepatitis C virus infection have not been established.

Discontinuation of Talftrex-E in patients with HIV and concomitant hepatitis B virus (HBV) infection may be associated with severe acute exacerbation of hepatitis. Close monitoring, both clinically and through laboratory testing, should be maintained for several months after discontinuation of treatment in patients with concomitant HIV and hepatitis B (HBV) infection. Initiation of anti-hepatitis B therapy may be warranted, especially in individuals with progressive liver disease or cirrhosis, as hepatitis flare after treatment may lead to hepatic decompensation.

The safety and efficacy of the medicinal product for pre-exposure prophylaxis in individuals infected with hepatitis B (HBV) or C (HCV) have not been established.

Liver disease

The safety and efficacy of Talftrex-E have not been established in patients with severe underlying hepatic impairment.

Patients with prior hepatic dysfunction, including chronic active hepatitis, have an increased frequency of hepatic abnormalities during combination antiretroviral therapy (CART) and should be monitored according to standard practice. If there is evidence of worsening liver disease, consideration should be given to interruption or discontinuation of therapy.

Body weight and metabolic parameters

Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to control of the disease and lifestyle. Regarding lipids, there is some evidence of a treatment effect in certain cases, whereas for weight gain, there is no strong evidence linking it to any specific therapy. Monitoring of blood lipid and glucose levels should follow established HIV treatment guidelines. Metabolic disturbances of lipids should be managed as clinically indicated.

Mitochondrial dysfunction following in utero exposure

Nucleoside analogues cause varying degrees of mitochondrial injury, most pronounced with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally; these are primarily associated with regimens containing zidovudine. The main adverse events reported were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These adverse events were generally transient. Rarely, delayed neurological disorders (hypertonia, seizures, behavioral abnormalities) have been reported. It is currently unknown whether these neurological disorders are transient or permanent. Any child exposed in utero to nucleoside or nucleotide analogues should undergo clinical and laboratory evaluation for possible mitochondrial dysfunction if they present with relevant neurological symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women for prevention of vertical HIV transmission.

Immune reconstitution syndrome

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may occur, leading to serious clinical conditions or worsening of symptoms. These reactions typically occur within the first few weeks or months of starting CART. Examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treated as necessary.

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution; however, the time to onset has been variable, and these events may occur many months after initiation of treatment.

HIV-1 patients with pre-existing mutations

The medicinal product should be avoided in patients who have previously been treated with antiretroviral agents and who have HIV-1 strains with the K65R mutation.

Triple nucleoside therapy

Reports have indicated a high rate of early virological failure and emergence of resistance when tenofovir alafenamide is combined with lamivudine and abacavir, as well as with lamivudine and didanosine in a once-daily regimen. Therefore, similar problems may occur if Talftrex-E is used with a third nucleoside analogue.

Opportunistic infections

Opportunistic infections and other complications of HIV infection may continue to occur in patients receiving Talftrex-E or any other antiretroviral therapy; therefore, patients should remain under close clinical monitoring by physicians experienced in managing HIV-related diseases.

Osteonecrosis

Although the etiology is considered multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis have been observed, particularly in patients with advanced HIV disease and/or long-term CART. Patients should be advised to seek medical attention if they experience joint pain, stiffness, or difficulty moving.

Nephrotoxicity

Cases of renal failure, including acute renal failure and proximal renal tubulopathy, have been reported with medications containing tenofovir alafenamide.

The potential risk of nephrotoxicity due to chronic exposure to low levels of tenofovir from tenofovir alafenamide cannot be excluded.

Renal function should be assessed before or at the initiation of treatment with the medicinal product and monitored during therapy as clinically appropriate. In patients who develop clinically significant renal impairment or signs of proximal renal tubulopathy, discontinuation of the medicinal product should be considered.

Patients with end-stage renal disease on chronic haemodialysis

The medicinal product should generally be avoided; however, it may be used in adults with end-stage renal disease (estimated CrCl <15 ml/min) on chronic haemodialysis if the potential benefit outweighs the potential risks. 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 over 48 weeks, but exposure to emtricitabine was significantly higher than in patients with normal renal function. Although no new safety concerns were identified, the consequences of increased emtricitabine exposure remain uncertain.

Concomitant use with other medicinal products

Talftrex-E should not be used concomitantly with certain anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, and phenytoin), antimycobacterial agents (e.g., rifampicin, rifabutin, rifapentine), St. John’s wort, and HIV protease inhibitors other than atazanavir, lopinavir, and darunavir.

Talftrex-E should not be used concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine, or adefovir dipivoxil.

Warnings related to excipients.

The medicinal product contains 40 mg of sodium per tablet. This should be taken into account for patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate and well-controlled studies of Talftrex-E or its components in pregnant women. Data on the use of tenofovir alafenamide in pregnant women are absent or limited (fewer than 300 pregnancy outcomes). However, a large amount of data from pregnant women (over 1000 observed pregnancy outcomes) indicates no malformations or embryotoxicity/neonatal toxicity associated with emtricitabine.

Animal studies do not indicate direct or indirect harmful effects of emtricitabine on fertility, pregnancy, fetal development, delivery, or postnatal development. Animal studies with tenofovir alafenamide showed no evidence of harmful effects on fertility, pregnancy, or fetal development.

Talftrex-E may be used during pregnancy only if the potential benefit outweighs the risks.

Breastfeeding.

It is unknown whether tenofovir alafenamide passes into human breast milk. Animal studies have shown that tenofovir alafenamide is excreted in milk. Emtricitabine is excreted in human breast milk.

There is insufficient information on the effects of emtricitabine and tenofovir alafenamide on neonates/infants. Therefore, Talftrex-E should not be used during breastfeeding.

To prevent transmission of HIV to the infant, women living with HIV are advised not to breastfeed.

Fertility.

There are no data on the effect of the medicinal product on fertility in humans. Animal studies do not indicate harmful effects of emtricitabine and tenofovir alafenamide on fertility.

Ability to drive and use machines.

The medicinal product may have a minor influence on the ability to drive and use machines.

Patients should be informed that dizziness may occur during treatment with emtricitabine and tenofovir alafenamide.

Administration and Dosage

Treatment of HIV infection in adults and adolescents aged 12 years and older with body weight of at least 35 kg: Treatment should be prescribed by a physician experienced in the management of HIV infection.

Talfrateks–E should be administered as indicated in Table 2.

Dose of Talfrateks–E according to the third drug in the HIV treatment regimen.

Table 2

Dosage of the drug

Talfratrex-E

Third agent in the HIV treatment regimen

Emtricitabine +

Tenofovir alafenamide

200/25 mg once daily

Dolutegravir, efavirenz, maraviroc,

nevirapine, rilpivirine, raltegravir

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

One 200/25 mg tablet once daily.

Missed doses

If a patient misses a dose and less than 18 hours have passed since the time the dose was due, the patient should take the medication as soon as possible and continue with the usual dosing schedule. If a patient misses a dose and more than 18 hours have passed since the time the dose was due, meaning the next dose is nearly due, the patient should not take the missed dose but should resume the regular dosing schedule.

If vomiting occurs within 1 hour after taking the medication, the patient should take another tablet.

Geriatric patients

No dose adjustment is required for geriatric patients.

Renal impairment

No dose adjustment is required in adults and adolescents (aged 12 years and older with body weight at least 35 kg) with a calculated creatinine clearance (CrCl) ≥ 30 mL/min. The medication should be discontinued in patients whose estimated CrCl declines during treatment to below 30 mL/min.

Dose adjustment of Tafnatrex-E is not required in adults with end-stage renal disease (estimated CrCl <15 mL/min) on chronic hemodialysis; however, the use of the medication should generally be avoided, but may be considered in these patients if the potential benefit outweighs the potential risk. On hemodialysis days, the medication should be taken after completion of the hemodialysis treatment.

Tafnatrex-E is not recommended for patients with estimated CrCl ≥ 15 mL/min and <30 mL/min or <15 mL/min who are not on chronic hemodialysis, as the safety of the medication has not been established in these patient populations.

There are no data on the use of the medication in children under 18 years of age with end-stage renal disease.

Hepatic impairment

No dose adjustment is required in patients with hepatic impairment.

Women

The efficacy of the medication for pre-exposure prophylaxis in adult women and adolescent girls who have vaginal sex (or their partners) has not yet been established.

Administration method

The medication should be taken orally once daily, with or without food. The film-coated tablet should not be chewed or crushed due to its bitter taste.

For patients unable to swallow the tablet whole, the tablet may be split in half and both halves swallowed consecutively, ensuring the full dose is taken immediately.

Children.

The safety and efficacy of Tafnatrex-E in children under 12 years of age or weighing less than 35 kg have not been established. No data are available.

Overdose.

In case of overdose, the patient should be monitored for signs of toxicity. Management of overdose consists of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status.

Emtricitabine may be removed by hemodialysis, which removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting 1.5 hours after emtricitabine administration. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. It is not known whether emtricitabine or tenofovir is removed by peritoneal dialysis.

Adverse reactions.

Summary of safety profile.

HIV-1 infection treatment. The assessment of adverse reactions is based on safety data from all Phase 2 and 3 studies in which HIV-1-infected patients received emtricitabine and tenofovir alafenamide-containing regimens, as well as post-marketing experience. In clinical trials of treatment-naïve adult patients receiving emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat as a fixed-dose combination tablet (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg [E/C/F/TAF]) for 144 weeks, the most commonly reported adverse reactions were diarrhea (7%), nausea (11%), and headache (6%).

Pre-exposure prophylaxis (PrEP): In a double-blind, randomized, placebo-controlled study (GS-US-412-2055) of 96 weeks duration involving 5,387 HIV-1-negative cisgender men and transgender women who have sex with men, no new adverse reactions to emtricitabine/tenofovir alafenamide fumarate or emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) were identified when administered once daily for HIV-1 pre-exposure prophylaxis. The most common adverse reactions among participants receiving emtricitabine/tenofovir alafenamide fumarate were diarrhea (5%), nausea (4%), headache, and fatigue (2% each). The impact on biomarkers of kidney and bone disease was similar to that observed during HIV-1 treatment with emtricitabine/tenofovir alafenamide fumarate. No additional adverse reactions to emtricitabine/tenofovir alafenamide fumarate were identified from Week 96 to Week 144 in participants who continued open-label treatment.

Summary table of adverse reactions

Adverse reactions in the table are listed by system organ class and frequency.

Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1000 to < 1/100).

List of adverse reactions 1

Frequency	Adverse reaction
Blood and lymphatic system disorders
Uncommon:	anemia²
Psychiatric disorders
Common:	abnormal dreams
Nervous system disorders
Common:	headache, dizziness
Gastrointestinal disorders
Very common:	nausea
Common:	diarrhea, vomiting, abdominal pain, flatulence
Uncommon:	dyspepsia
Skin and subcutaneous tissue disorders
Common:	rash
Uncommon:	angioedema^3,4, pruritus, urticaria⁴
Musculoskeletal and connective tissue disorders
Uncommon:		arthralgia
General disorders and administration site conditions
Common:		fatigue

1 Except for angioedema3, anemia, and urticaria (see footnotes 2, 3, and 4), all adverse reactions were identified during clinical trials of drugs containing F/TAF. The pregnancy rate was obtained from Phase III clinical trials of E/C/F/TAF in 866 treatment-naïve adult patients over 144 weeks of treatment (GS-US-292-0104 and GS-US-292-0111).

2 This adverse reaction was not observed in clinical trials of F/TAF-containing drugs but was identified during clinical trials or post-marketing experience with emtricitabine when used in combination with other antiretroviral agents.

3 This adverse reaction was identified during post-marketing surveillance of emtricitabine-containing drugs.

4 This adverse reaction was identified during post-marketing surveillance of drugs containing tenofovir alafenamide.

Description of selected adverse reactions.

Immune Reconstitution Syndrome.

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

Osteonecrosis.

Cases of osteonecrosis have been reported in patients with risk factors, advanced HIV disease, or those who have received long-term combination antiretroviral therapy (CART). The frequency of this phenomenon is unknown.

Lipid laboratory test changes.

In studies involving treatment-naïve patients, increases from baseline in fasting lipid parameters—total cholesterol, direct low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides—were observed in both the tenofovir alafenamide fumarate and tenofovir disoproxil fumarate treatment groups at week 144. The mean increase from baseline in these parameters was higher in the E/C/F/TAF group compared to 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 between-group differences in fasting total cholesterol, direct LDL-C, HDL-C, and triglycerides). The median (Q1, Q3) change from baseline in the total cholesterol to HDL-C 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 between-group difference in treatment).

In a study of virologically suppressed patients who switched from emtricitabine/tenofovir disoproxil fumarate to emtricitabine/tenofovir alafenamide, maintaining the third antiretroviral agent (study GS-US-311-1089), increases from baseline in fasting lipid parameters—total cholesterol, direct LDL-C, and triglycerides—were observed in the emtricitabine/tenofovir alafenamide group compared to minimal changes in the emtricitabine/tenofovir disoproxil fumarate group (p ≤ 0.009 for between-group differences in changes from baseline). From baseline, mean values of HDL-C and fasting glucose, as well as the fasting total cholesterol to HDL-C ratio, changed minimally in both groups at week 96. None of these changes were considered clinically significant.

In a study of adult patients with virological suppression who switched from abacavir/lamivudine to emtricitabine/tenofovir alafenamide while maintaining the third antiretroviral agent (study GS-US-311-1717), minimal changes in lipid parameters were observed.

Metabolic disturbances.

Body weight, lipid levels, and blood glucose may increase during antiretroviral therapy.

Paediatric population.

The safety of emtricitabine and tenofovir alafenamide was evaluated over 48 weeks in an open-label clinical trial (GS-US-292-0106) in which HIV-1-infected 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 in combination with elvitegravir and cobicistat in 50 adolescent patients was consistent with the safety profile observed in adults.

Other special patient groups

Patients with renal impairment.

The safety of emtricitabine and tenofovir alafenamide was evaluated over 144 weeks in an open-label clinical trial (GS-US-292-0112) involving 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 [eGFR_CG]: 30–69 mL/min) receiving emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination. The safety profile in patients with mild to moderate renal impairment was similar to that in patients with normal renal function.

The safety of emtricitabine and tenofovir alafenamide was evaluated over 48 weeks in an open-label, single-arm clinical trial (GS-US-292-1825) involving 55 virologically suppressed HIV-1 patients with end-stage renal disease (eGFR_CG < 15 mL/min) on chronic hemodialysis receiving emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet. No new safety concerns were identified in patients with end-stage renal disease on chronic hemodialysis receiving emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as a fixed-dose combination tablet.

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 patients with concomitant HIV/HBV who received HIV treatment in an open-label clinical trial (GS-US-292-1249) over 48 weeks, during 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 concomitant HIV/HBV infection was similar to that in patients with HIV-1 monoinfection.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua and to Macleods Pharmaceuticals Limited, 7D Zdolbunivska St., Kyiv, 02081, Ukraine, Tel./Fax: (044) 574-42-94, E-mail: [email protected].

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

30 tablets in a bottle, 1 bottle in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

Macleods Pharmaceuticals Limited.

Manufacturer's address and location of its business operations.

Village Thedda, P.O. Lodhymaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.

Talftrex-e