Tafnext - em
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAFNEXT - EM (TAFNEXT - EM)
Composition:
Active substances: emtricitabine, tenofovir alafenamide;
1 tablet contains emtricitabine 200 mg, tenofovir alafenamide hemifumarate equivalent to tenofovir alafenamide 25 mg;
Excipients: microcrystalline cellulose; sodium croscarmellose; magnesium stearate; Opadry II pink 85F94172 (polyvinyl alcohol (E 1203), titanium dioxide (E 171), polyethylene glycol (E 1521), talc (E 553b), red iron oxide (E 172), black iron oxide (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: film-coated tablets, pink-colored, oval-shaped, biconvex, with the imprint «V» on one side and «21» on the other.
Pharmacotherapeutic group. Antiviral agent for systemic use. Antiviral agents for the treatment of HIV infection, combinations. ATC code J05A R17.
Pharmacological Properties.
Pharmacodynamics.
Mechanism of Action
Emtricitabine is a nucleoside reverse transcriptase inhibitor and a nucleoside analogue of 2'-deoxycytidine. Emtricitabine is phosphorylated by cellular enzymes, resulting in the formation of emtricitabine triphosphate. Emtricitabine triphosphate inhibits HIV replication by incorporation into viral DNA by HIV reverse transcriptase, leading to DNA chain termination. Emtricitabine is active against HIV-1, HIV-2, and hepatitis B virus.
Tenofovir alafenamide is a nucleotide reverse transcriptase inhibitor and a phosphonoamidate prodrug of tenofovir (an analogue of 2'-deoxyadenosine monophosphate). Tenofovir alafenamide can enter cells, and due to its enhanced stability in plasma and intracellular activation via hydrolysis by cathepsin A, it is more efficient than tenofovir disoproxil, resulting in higher concentrations of tenofovir in peripheral blood mononuclear cells (including lymphocytes and other HIV target cells) and macrophages. Intracellular tenofovir is further phosphorylated to form the pharmacologically active metabolite—tenofovir diphosphate. Tenofovir diphosphate inhibits HIV replication by incorporation into viral DNA by HIV reverse transcriptase, leading to DNA chain termination. Tenofovir is active against HIV-1, HIV-2, and hepatitis B virus.
In vitro Antiviral Activity
Emtricitabine and tenofovir alafenamide demonstrated synergistic antiviral activity in cell cultures. No antagonism was observed with emtricitabine or tenofovir alafenamide in combination with other antiretroviral agents.
The antiviral activity of emtricitabine against laboratory and clinical strains of HIV-1 was evaluated in lymphoblastoid cell lines, the MAGI CCR5 cell line, and peripheral blood mononuclear cells. The EC50 values of emtricitabine ranged from 0.0013 to 0.64 μmol. Emtricitabine demonstrated antiviral activity in cell culture against HIV-1 subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.007 to 0.075 μmol) and showed specific activity against HIV-2 (EC50 values ranged from 0.007 to 1.5 μmol).
The antiviral activity of tenofovir alafenamide against laboratory and clinical strains of HIV-1 subtype B was evaluated in lymphoblastoid cell lines, peripheral blood mononuclear cells, primary monocytes/macrophages, and CD4+ T-lymphocytes. The EC50 values of tenofovir alafenamide ranged from 2.0 to 14.7 nmol. Tenofovir alafenamide demonstrated antiviral activity in cell culture against all monophyletic groups of HIV-1 (M, N, and O), including subtypes A, B, C, D, E, F, and G (EC50 values ranged from 0.10 to 12.0 nmol), and also showed strain-specific activity against HIV-2 (EC50 values ranged from 0.91 to 2.63 nmol).
Resistance
In vitro
Reduced susceptibility to emtricitabine is associated with M184V/I mutations in HIV-1 reverse transcriptase.
HIV-1 strains with reduced susceptibility to tenofovir alafenamide exhibit the K65R mutation in HIV-1 reverse transcriptase. Additionally, the K70E mutation in HIV-1 reverse transcriptase was transiently observed.
Cross-resistance in HIV-1-infected patients without prior treatment or with inadequate virological response
Viruses resistant to emtricitabine with M184V/I substitution exhibit cross-resistance to lamivudine but remain susceptible to didanosine, stavudine, tenofovir, and zidovudine.
The K65R and K70E mutations lead to reduced susceptibility to abacavir, didanosine, lamivudine, emtricitabine, and tenofovir, while maintaining susceptibility to zidovudine.
Multinucleoside-resistant HIV-1 with the T69S double insertion mutation or the Q151M mutation complex, including K65R, demonstrated reduced susceptibility to tenofovir alafenamide.
In vivo – Pre-Exposure Prophylaxis (PrEP)
In a study involving HIV-1-uninfected cisgender men and transgender women who have sex with men and are at risk of HIV-1 infection, who received fixed-dose emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate for HIV-1 pre-exposure prophylaxis, genotyping was performed in participants who were diagnosed with HIV during the study and had HIV-1 RNA ≥ 400 copies/mL (7 out of 8 participants received the fixed-dose combination of emtricitabine/tenofovir alafenamide during the blinded phase, and 3 participants received emtricitabine/tenofovir alafenamide during the open-label phase, including 2 who switched from emtricitabine/tenofovir disoproxil fumarate to emtricitabine/tenofovir alafenamide at week 96). The development of emtricitabine resistance-associated substitutions was not observed in patients who used emtricitabine/tenofovir alafenamide under standard resistance testing.
Pharmacokinetics.
Absorption
Emtricitabine is rapidly and extensively absorbed after oral administration, with maximum plasma concentration (Cmax) observed 1–2 hours after dosing. After repeated oral dosing of emtricitabine 200 mg in 20 HIV-infected patients (mean ± standard deviation), the steady-state Cmax of emtricitabine in plasma was 1.8 ± 0.7 μg/mL, and the area under the plasma concentration-time curve (AUC) over the 24-hour dosing interval was 10.0 ± 3.1 μg•h/mL. The mean steady-state minimum concentration (Cmin) in plasma 24 hours after administration was equal to or exceeded the mean in vitro IC90 value for anti-HIV-1 activity.
The systemic exposure of emtricitabine was not altered when emtricitabine was administered with food.
After administration with food in healthy volunteers, peak plasma concentration of tenofovir alafenamide was observed approximately 1 hour after dosing when administered as F/TAF (25 mg) or E/C/F/TAF (10 mg). Mean Cmax and AUClast (mean ± standard deviation) under fed conditions after a single 25 mg dose of tenofovir alafenamide in F/TAF were 0.21 ± 0.13 μg/mL and 0.25 ± 0.11 μg•h/mL, respectively. Mean Cmax and AUClast 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 fasting conditions, administration of tenofovir alafenamide with a high-fat meal (~800 kcal, 50% fat) resulted in a decrease in Cmax of tenofovir alafenamide (15–37%) and an increase in AUClast (17–77%).
Distribution
In vitro protein binding of emtricitabine to human plasma proteins was < 4% and independent of drug concentration in the range of 0.02–200 μg/mL. At maximum plasma concentration, the ratio of mean drug concentration in plasma to mean drug concentration in blood was ~1.0, and the ratio of mean drug concentration in semen to mean drug concentration in plasma was ~4.0.
In vitro protein binding of tenofovir to human plasma proteins was < 0.7% and independent of drug concentration in the range of 0.0125 μg/mL. Ex vivo protein binding of tenofovir alafenamide to human plasma proteins in samples collected during clinical trials was approximately 80%.
Biotransformation
In vitro studies indicate that emtricitabine is not an inhibitor of human CYP enzymes. After oral administration of [14C]-emtricitabine, complete elimination of the dose occurred via urine (~86%) and feces (~14%). 13% of the dose was excreted in urine as three hypothetical metabolites. Biotransformation of emtricitabine involves oxidation of the thiol group, leading to the formation of diastereoisomers of 3-sulfoxide (~9% of dose), and conjugation with glucuronic acid, leading to the formation of 2-O-glucuronide (~4% of dose). No other identifiable metabolites were detected.
Metabolism is the primary route of elimination of tenofovir alafenamide in humans—>80% of the oral dose. In vitro studies demonstrated that tenofovir alafenamide is metabolized to tenofovir (the major metabolite) by cathepsin A in peripheral blood mononuclear cells (including lymphocytes and other HIV target cells) and macrophages, and by carboxylesterase-1 in hepatocytes. In vivo, tenofovir alafenamide is hydrolyzed intracellularly, resulting in the formation of tenofovir (the major metabolite), which is then phosphorylated to form the active metabolite—tenofovir diphosphate.
In vitro, tenofovir alafenamide is not metabolized by CYP1A2, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Tenofovir alafenamide is minimally metabolized by CYP3A4. After co-administration with the moderate CYP3A inducer efavirenz, the effect of tenofovir alafenamide was not significantly altered. After administration of tenofovir alafenamide, radioactivity in plasma due to [14C] showed a time-dependent profile in which tenofovir alafenamide was the predominant component during the first few hours, and tenofovir for the remainder of the time.
Elimination
Emtricitabine is primarily eliminated by the kidneys, with complete excretion of the dose in urine (~86%) and feces (~14%). 13% of the emtricitabine dose was excreted in urine as three metabolites. Systemic clearance of emtricitabine averaged 307 mL/min. After oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
Renal excretion of unchanged tenofovir alafenamide is a minor pathway, accounting for less than 1% of the dose excreted in urine. Tenofovir alafenamide is primarily eliminated after metabolic conversion to tenofovir. Tenofovir alafenamide and tenofovir have mean plasma elimination half-lives of 0.51 and 32.37 hours, respectively. Tenofovir is eliminated from the body by the kidneys via glomerular filtration and active tubular secretion.
Pharmacokinetics in Special Populations
Age, Sex, and Ethnicity
No clinically significant pharmacokinetic differences for emtricitabine or tenofovir alafenamide were observed due to age, sex, or ethnicity.
Renal Impairment
No clinically significant differences in the pharmacokinetics of tenofovir alafenamide or tenofovir were observed between healthy volunteers and patients with severe renal impairment (estimated creatinine clearance (CrCl) > 15 mL/min and < 30 mL/min) in a phase 1 study of tenofovir alafenamide. In a separate study using emtricitabine alone, the mean systemic exposure of emtricitabine was higher in patients with severe renal impairment (estimated CrCl < 30 mL/min) (33.7 μg•h/mL) compared to participants with normal renal function (11.8 μg•h/mL). The safety of emtricitabine and tenofovir alafenamide has not been established in patients with severe renal impairment (estimated CrCl ≥ 15 mL/min and < 30 mL/min).
Concentrations of 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 (E/C/F/TAF) in a study, were significantly higher than in patients with normal renal function. No clinically significant differences in the pharmacokinetics of tenofovir alafenamide were observed in patients with end-stage renal disease on chronic hemodialysis compared to patients with normal renal function. No new safety concerns were identified in patients with end-stage renal disease on chronic hemodialysis receiving the fixed-dose tablet (E/C/F/TAF) (see section "Adverse Reactions").
Data on the pharmacokinetic properties of emtricitabine or tenofovir alafenamide in patients with end-stage renal disease (estimated CrCl < 15 mL/min) not on chronic hemodialysis are lacking. The safety of emtricitabine or tenofovir alafenamide in such patients has not been established.
Hepatic Impairment
The pharmacokinetics of emtricitabine have not been studied in patients with hepatic impairment; however, hepatic enzymes play a minimal role in emtricitabine metabolism, so the impact of hepatic impairment is expected to be limited.
Clinically significant changes in pharmacokinetic parameters of tenofovir alafenamide or its metabolite tenofovir were not observed in patients with mild to 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. After correction for protein binding, the concentration of unbound (free) tenofovir alafenamide in plasma in severe hepatic impairment is similar to that in normal hepatic function.
Concurrent Infection of HIV Patients with Hepatitis B and/or Hepatitis C
The pharmacokinetics of emtricitabine and tenofovir alafenamide have not been fully evaluated in patients also infected with hepatitis B virus and/or hepatitis C virus.
Clinical characteristics.
Indications.
HIV-1 infection treatment
Indicated in combination with other antiretroviral medicinal products 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).
Pre-exposure prophylaxis (PrEP)
Indicated for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 infection in at-risk men, including adolescents (with body weight at least 35 kg).
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Use for PrEP in individuals with unknown HIV-1 status.
Interaction with other medicinal products and other forms of interaction.
Studies on interaction have been conducted only in adult patients.
The medicinal product Taftnekst-EM should not be taken concurrently with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine, or adefovir dipivoxil.
Emtricitabine
Results from laboratory and clinical pharmacokinetic drug interaction studies have demonstrated that the potential for CYP-mediated interaction between emtricitabine and other medicinal products is low. Concomitant administration of emtricitabine with medicinal products that are eliminated via active tubular secretion may increase the concentrations of emtricitabine and/or the co-administered medicinal product. Medicinal products that impair 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 significantly affect the activity of P-gp and BCRP may alter the absorption of tenofovir alafenamide. Medicinal products that induce P-gp activity (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 lead to loss of therapeutic effect of Taftnekst-EM and development of resistance. Concomitant use of Taftnekst-EM with other medicinal products that inhibit P-gp and BCRP activity (e.g., cobicistat, ritonavir, cyclosporine) is expected to increase the absorption and concentration of tenofovir alafenamide. According to in vitro data, concomitant use 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 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 UGT1A1 enzymes under in vitro conditions. 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 fixed-dose combination and potentially co-administered medicinal products are presented in the table (increases are indicated as “↑”, decreases as “↓”, and no change as “↔”). The described interactions are based on studies conducted with the fixed-dose combination or its components as individual agents and/or in combination, or are potential drug interactions that may occur.
| Medicinal products by therapeutic areas1 |
Effect on drug levels. Mean percentage change AUC, Cmax, Cmin2 |
Recommendations for co-administration with fixed-dose combination |
|
| ANTIMICROBIAL AGENTS |
|||
| Antifungal agents |
|||
| Ketoconazole Itraconazole |
Interaction not studied with any component of the fixed-dose combination. Co-administration of ketoconazole or itraconazole, which are strong P-gp inhibitors, is expected to increase tenofovir alafenamide plasma concentrations. |
HIV-1 treatment: recommended dose of the fixed-dose combination is 200/10 mg once daily. |
|
| Fluconazole Isavuconazole |
Interaction not studied with any component of the fixed-dose combination. Co-administration of fluconazole or isavuconazole may increase tenofovir alafenamide plasma concentrations. |
HIV-1 treatment: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| Antimycobacterial agents |
|||
| Rifabutin Rifampicin Rifapentine |
Interaction not studied with any component of the fixed-dose combination. Co-administration of rifampicin, rifabutin, or rifapentine, which are P-gp inducers, may reduce tenofovir alafenamide plasma concentrations, potentially leading to loss of therapeutic effect and development of resistance. |
Co-administration of the fixed-dose combination with rifabutin, rifampicin, or rifapentine is not recommended. |
|
| Medicinal products for hepatitis C treatment |
|||
| 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: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| 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: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| 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: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| 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: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| 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: ↔ |
HIV-1 treatment: recommended dose of the fixed-dose combination 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: recommended dose of the fixed-dose combination 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: recommended dose of the fixed-dose combination 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: recommended dose of the fixed-dose combination 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: recommended dose of the fixed-dose combination is 200/10 mg once daily. |
|
| Tipranavir/ritonavir |
Interaction not studied with any component of the fixed-dose combination. Tipranavir/ritonavir induces P-gp. Decreased exposure of tenofovir alafenamide is expected when tipranavir/ritonavir is co-administered with the fixed-dose combination. |
Co-administration with the fixed-dose combination is not recommended. |
|
| Other protease inhibitors |
Effect unknown. |
No data available to recommend dosing for co-administration with other protease inhibitors. |
|
| Other antiretroviral agents for HIV |
|||
| Dolutegravir (50 mg once daily), tenofovir alafenamide (10 mg once daily)3 |
Tenofovir alafenamide: AUC: ↔ Cmax: ↔ Dolutegravir: AUC: ↔ Cmax: ↔ Cmin: ↔ |
HIV-1 treatment: recommended dose of the fixed-dose combination 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: recommended dose of the fixed-dose combination 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: recommended dose of the fixed-dose combination is 200/25 mg once daily. |
|
| Maraviroc Nevirapine Raltegravir |
Interaction not studied with any component of the fixed-dose combination. No effect of tenofovir alafenamide is expected with maraviroc, nevirapine, or raltegravir, and no effect on metabolic and elimination pathways typical for maraviroc, nevirapine, or raltegravir is expected. |
HIV-1 treatment: recommended dose of the fixed-dose combination is 200/25 mg once daily. |
|
| ANTICONVULSANTS |
|||
| Oxcarbazepine Phenobarbital Phenytoin |
Interaction not studied with any component of the fixed-dose combination. Co-administration 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. |
Co-administration of the fixed-dose combination 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 % Co-administration of carbamazepine, a P-gp inducer, reduces tenofovir alafenamide plasma concentrations, potentially leading to loss of therapeutic effect and development of resistance. |
Co-administration of the fixed-dose combination with 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: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| HERBAL PRODUCTS |
|||
| St. John's wort (Hypericum perforatum) |
Interaction not studied with any component of the fixed-dose combination. Co-administration 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. |
Co-administration of the fixed-dose combination with St. John's wort is not recommended. |
|
| IMMUNOSUPPRESSANTS |
|||
| Cyclosporine |
Interaction not studied with any component of the fixed-dose combination. Co-administration of cyclosporine, a strong P-gp inhibitor, is expected to increase tenofovir alafenamide plasma concentrations. |
HIV-1 treatment: recommended dose of the fixed-dose combination 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: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| SEDATIVES / HYPNOTICS |
|||
| Midazolam oral (2.5 mg single dose), tenofovir alafenamide (25 mg once daily) |
Midazolam: AUC: ↔ Cmax: ↔ |
No dose adjustment of midazolam is required. HIV-1 treatment: dosing according to concomitant antiretroviral agent (see section “Posology and method of administration”). |
|
| Midazolam intravenous (1 mg single dose), tenofovir alafenamide (25 mg once daily) |
Midazolam: AUC: ↔ Cmax: ↔ |
||
1 When doses are provided, these are the doses used in clinical drug interaction studies.
2 When data from drug interaction studies are available.
3 The study was conducted with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fixed-dose combination tablets.
4 The study was conducted with emtricitabine/rilpivirine/tenofovir alafenamide fixed-dose combination tablets.
5 The study was conducted with emtricitabine/tenofovir alafenamide fixed-dose combination tablets.
6 In this study, emtricitabine/tenofovir alafenamide was administered with food.
7 Study conducted with an additional dose of voxilaprevir 100 mg to achieve expected voxilaprevir exposure in patients infected with hepatitis C virus.
Special precautions for use.
HIV transmission
Although effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to avoid HIV transmission should be followed according to national guidelines.
General strategy for prevention of HIV-1 infection
The medicinal product Taftnecst-EM is not always effective in preventing HIV-1 infection. The time to onset of protection after initiation of Taftnecst-EM is unknown.
Taftnecst-EM for PrEP should be used as part of a comprehensive prevention strategy to reduce the risk of sexually acquired HIV-1 infection. Individuals should be counselled regularly regarding 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 fixed-dose combination tablet emtricitabine/tenofovir alafenamide for PrEP 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 fixed-dose combination tablet emtricitabine/tenofovir alafenamide for PrEP in transgender women (see section "Pharmacodynamics").
Risk of resistance with undiagnosed HIV-1 infection
Taftnecst-EM should only be used to reduce the risk of HIV-1 infection in individuals who have tested HIV-negative (see section "Contraindications"). HIV-negative status should be periodically confirmed (e.g., at least every 3 months) using a combination antigen/antibody test during treatment with Taftnecst-EM for PrEP.
Taftnecst-EM alone is not a complete HIV-1 treatment regimen; HIV-1 resistance mutations have occurred in individuals with undiagnosed HIV infection who received only the fixed-dose combination tablet emtricitabine/tenofovir alafenamide.
If clinical symptoms consistent with acute HIV-1 infection are present and recent (within the past month) HIV-1 infection is suspected, follow local clinical guidelines and use an approved or authorized test to assist in diagnosing acute or primary HIV-1 infection.
Importance of adherence
The effectiveness of Taftnecst-EM in reducing the risk of HIV-1 infection is closely linked to adherence, as confirmed by measurable drug levels in blood (see section "Pharmacodynamics"). Individuals who are not infected with HIV-1 should be counselled regularly regarding strict adherence to the recommended daily dosing regimen of Taftnecst-EM.
Individuals co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV)
Individuals with chronic hepatitis B or hepatitis C receiving antiretroviral therapy have an increased risk of serious and potentially fatal hepatic adverse reactions.
The safety and efficacy of the fixed-dose combination tablet emtricitabine/tenofovir alafenamide in patients co-infected with HIV-1 and hepatitis C have not been established.
Discontinuation of Taftnecst-EM in patients infected with hepatitis B virus may be associated with severe acute exacerbations of hepatitis. Patients infected with hepatitis B who discontinue Taftnecst-EM should be closely monitored both clinically and laboratory-wise for at least several months after stopping treatment. Initiation of anti-hepatitis B therapy may be justified, particularly in individuals with progressive liver disease or cirrhosis, as hepatitis flare after treatment may lead to hepatic decompensation.
The safety and efficacy of the fixed-dose combination tablet emtricitabine/tenofovir alafenamide for PrEP in patients with HBV or HCV infection have not been established.
Liver disease
The safety and efficacy of the fixed-dose combination tablet emtricitabine/tenofovir alafenamide in patients with severe hepatic impairment have not been established (see sections "Pharmacokinetics" and "Dosage and administration").
In individuals with pre-existing liver dysfunction, including chronic active hepatitis, increased frequency of liver function abnormalities may occur during combination antiretroviral therapy (cART), and they should be monitored according to standard practice. If signs of worsening liver disease occur in such individuals, interruption or discontinuation of treatment should be considered.
Body weight and metabolic parameters
During antiretroviral therapy, increases in body weight and levels of blood lipids and glucose may occur. These changes may be partly related to disease control and lifestyle. Regarding lipids, there is some evidence of a treatment effect, whereas for weight gain, there is no strong evidence linking it to any specific treatment. Monitoring of blood lipids and glucose should follow established guidelines for HIV treatment. Lipid disorders should be managed according to clinical circumstances.
Mitochondrial dysfunction following in utero exposure
Nucleoside and nucleotide analogues may affect mitochondrial function to varying degrees, most notably with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogues. These cases primarily involved treatment regimens containing zidovudine. The main adverse reactions reported were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events were often transient. Rarely, delayed neurological disorders (hypertension, seizures, abnormal behavior) have been reported. It is currently unknown whether such neurological disorders are transient or permanent. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues who presents with serious clinical symptoms of unknown etiology, particularly neurological symptoms. These conclusions do not affect current national recommendations for the use of antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Immune reconstitution syndrome
In HIV-infected patients with severe immunodeficiency at the time of initiation of cART, inflammatory reactions to asymptomatic or residual opportunistic pathogens may frequently occur and may cause serious clinical conditions or symptom exacerbation. These reactions are mainly observed during the first weeks or months of cART. Important examples include cytomegalovirus retinitis, generalized and/or localized mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated as necessary and appropriate treatment initiated.
Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution; however, the time to onset of these disorders varied, and such reactions may occur many months after starting treatment.
HIV-1 patients with mutations
Use of Taftnecst-EM should be avoided in HIV-1 patients with the K65R mutation who have previously received antiretroviral therapy (see section "Pharmacodynamics").
Triple nucleoside therapy
There have been reports of high rates of virological failure and early emergence of resistance in HIV-infected patients when tenofovir disoproxil was combined with lamivudine and abacavir, as well as with lamivudine and didanosine in a once-daily regimen. Therefore, similar problems may arise if Taftnecst-EM is administered with a third nucleoside analogue.
Opportunistic infections
Opportunistic infections and other complications of HIV infection may continue to develop in HIV-infected patients receiving Taftnecst-EM or any other antiretroviral therapy; therefore, patients should remain under close clinical supervision by physicians experienced in managing HIV-associated diseases.
Osteonecrosis
Although the etiology is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, high body mass index), cases of osteonecrosis have been observed predominantly 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 joints.
Nephrotoxicity
A potential risk of nephrotoxicity due to chronic low-level exposure to tenofovir from tenofovir alafenamide dosing cannot be excluded.
Renal function should be assessed in all patients before or at the start of treatment with Taftnecst-EM and monitored during treatment in all patients according to clinical circumstances. In patients who develop clinically significant decline in renal function or signs of proximal renal tubulopathy, discontinuation of Taftnecst-EM should be considered.
Patients with end-stage renal disease on chronic hemodialysis
Generally, use of Taftnecst-EM should be avoided; however, it may be used in adults with end-stage renal disease (estimated CrCl < 15 ml/min) on chronic hemodialysis if the expected benefit outweighs the potential risk (see section "Dosage and administration"). 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 (calculated CrCl < 15 ml/min) on chronic hemodialysis, efficacy was maintained over 48 weeks, but emtricitabine exposure 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 (see sections "Pharmacokinetics" and "Adverse reactions").
Concomitant use with other medicinal products
Concomitant use of Taftnecst-EM 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 (PIs), except atazanavir, lopinavir, and darunavir, is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Taftnecst-EM should not be used concomitantly with medicinal products containing tenofovir alafenamide, tenofovir disoproxil, emtricitabine, lamivudine, or adefovir dipivoxil.
Excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate and well-controlled studies of the fixed-dose combination tablet emtricitabine/tenofovir alafenamide 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 exposure outcomes) indicates no malformations and no fetal/neonatal toxicity associated with emtricitabine.
Animal studies do not indicate direct or indirect harmful effects of emtricitabine on fertility, pregnancy, fetal development, parturition, or postnatal development. Animal studies of tenofovir alafenamide showed no evidence of harmful effects on fertility, pregnancy, or fetal development.
The medicinal product should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.
Breastfeeding
It is unknown whether tenofovir alafenamide is excreted in breast milk. Emtricitabine passes into breast milk. Animal studies have shown that tenofovir is excreted in breast milk.
There is insufficient information on the effects of emtricitabine and tenofovir on newborns/infants. Therefore, the medicinal product Taftnecst-EM should not be used during breastfeeding.
To prevent transmission of HIV to infants, HIV-infected women should under no circumstances breastfeed their infants.
Fertility
There are no data on fertility with the use of the fixed-dose combination tablet emtricitabine/tenofovir alafenamide in humans. Animal studies showed no effect of emtricitabine and tenofovir alafenamide on mating or fertility parameters.
Ability to affect the speed of reaction when driving or operating machinery
Taftnecst-EM may have a negligible influence on the ability to drive vehicles or operate machinery. Patients should be informed about possible dizziness during treatment.
Dosage and method of administration.
Treatment of HIV in adults and adolescents aged 12 years and older with body weight of at least 35 kg:
Treatment should be initiated by a physician experienced in managing HIV infection.
The medicinal product Tafnext-EM should be used as indicated in the table below.
Dose of the medicinal product Tafnext-EM according to the third agent in the HIV treatment regimen
| Dosage |
Third agent in HIV treatment regimen (see section "Interaction with other medicinal products and other forms of interaction") |
| 200/10 mg once daily |
Atazanavir with ritonavir or cobicistat Darunavir with ritonavir or cobicistat1 Lopinavir with ritonavir |
| 200/25 mg once daily |
Dolutegravir, efavirenz, maraviroc, nevirapine, rilpivirine, raltegravir |
1 Tablet 200/10 mg in combination with darunavir 800 mg and cobicistat 150 mg, administered as a fixed-dose combination tablet, was studied in treatment-naïve patients; see section "Pharmacodynamics".
HIV pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM), including adolescents (with body weight at least 35 kg):
One tablet 200/25 mg once daily.
Missed doses
If a dose of the medicinal product is missed within 18 hours of the usual dosing time, the patient should take the dose as soon as possible and continue on the usual dosing schedule. If a dose of the medicinal product is missed for more than 18 hours, the patient should not take the missed dose but simply continue with the regular dosing schedule.
If vomiting occurs within 1 hour after taking the medicinal product, another tablet should be taken.
Elderly patients
Dose adjustment of the medicinal product is not required.
Renal impairment
No dose adjustment of the medicinal product Taftnecst-EM is required in adults or adolescents (aged 12 years and older with body weight at least 35 kg) with estimated CrCl ≥ 30 mL/min. Treatment with Taftnecst-EM should be discontinued in individuals whose estimated creatinine clearance declines below 30 mL/min during treatment (see section "Pharmacokinetics").
No dose adjustment of the medicinal product Taftnecst-EM is required in adults with end-stage renal disease (estimated CrCl < 15 mL/min) on chronic haemodialysis; however, use of Taftnecst-EM should be avoided, but may be considered if the anticipated benefit outweighs the potential risk (see sections "Pharmacokinetics" and "Special warnings and precautions for use"). On haemodialysis days, Taftnecst-EM should be administered after completion of haemodialysis treatment.
Use of Taftnecst-EM 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 safety of the medicinal product has not been established in these populations.
There are no data to recommend dosing in children under 18 years of age with end-stage renal disease.
Hepatic impairment
Dose adjustment of the medicinal product Taftnecst-EM is not required in patients with hepatic impairment.
Children
Safety and efficacy of the medicinal product in children under 12 years of age or with body weight < 35 kg have not been established. No data available.
Women
The efficacy of the medicinal product for PrEP in adults and adolescents who have vaginal sex (or their partners) has not yet been established.
Method of administration
Oral use.
The medicinal product Taftnecst-EM should be taken once daily, independent of food intake. Film-coated tablets should not be chewed or crushed due to their bitter taste.
For individuals who cannot 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.
Children
Safety and efficacy of the medicinal product in children under 12 years of age or with body weight < 35 kg have not been established. No data available.
Overdose.
In case of overdose, the patient should be monitored for signs of toxicity (see section "Adverse reactions"). Management of overdose consists of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status.
Emtricitabine can be removed by haemodialysis, which removes approximately 30% of the emtricitabine dose during a 3-hour dialysis period initiated 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.
Adverse reactions
HIV-1 infection treatment. The assessment of adverse reactions is based on safety data obtained from all phase 2 and 3 studies in which HIV-infected patients received medicinal products containing emtricitabine and tenofovir alafenamide, as well as on post-marketing experience. In clinical studies of treatment-naïve adult patients who received emtricitabine and tenofovir alafenamide with elvitegravir and cobicistat as a single-tablet regimen of elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide (as fumarate) 10 mg (E/C/F/TAF) for 144 weeks, the most commonly reported adverse reactions were diarrhea (7%), nausea (11%), and headache (6%).
PrEP. In a 96-week study, no new adverse reactions to the fixed-dose combination of emtricitabine/tenofovir alafenamide were identified, during which 5387 HIV-1 uninfected cisgender men and transgender women who have sex with men received either the fixed-dose combination of emtricitabine/tenofovir alafenamide or emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) once daily for HIV-1 PrEP. The most common adverse reaction among participants receiving the fixed-dose combination of emtricitabine/tenofovir alafenamide was diarrhea (5%), followed by 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 the fixed-dose combination of emtricitabine/tenofovir alafenamide. No additional adverse reactions to the fixed-dose combination of emtricitabine/tenofovir alafenamide were identified between weeks 96 and 144 in participants who continued open-label treatment with emtricitabine/tenofovir alafenamide (see section "Pharmacodynamics").
Adverse reactions* are listed below 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).
| Frequency |
Adverse reactions |
| From the blood and lymphatic system |
|
| Uncommon: |
anemia2 |
| Psychiatric disorders |
|
| Common: |
abnormal dreams |
| From the nervous system |
|
| Common: |
headache, dizziness |
| From the gastrointestinal system |
|
| Very common: |
nausea |
| Common: |
diarrhea, vomiting, abdominal pain, flatulence |
| Uncommon: |
dyspepsia |
| From the skin and subcutaneous tissue |
|
| Common: |
rash |
| Uncommon: |
angioneurotic edema3,4, pruritus, urticaria4 |
| From the musculoskeletal and connective tissue |
|
| Uncommon: |
arthralgia |
| General disorders |
|
| Common: |
fatigue |
1 Except for angioedema, anemia, and urticaria (see notes 2, 3, and 4), all adverse reactions were identified during clinical trials of medicinal products containing F/TAF. The frequency was obtained from phase 3 clinical trials of E/C/F/TAF involving 866 treatment-naïve adult patients over 144 weeks of treatment.
2 This adverse reaction was not observed during clinical trials of medicinal products containing F/TAF but was identified during clinical trials or post-marketing experience with emtricitabine when used in combination with other antiretroviral medicinal products.
3 This adverse reaction was identified during post-marketing surveillance of medicinal products containing emtricitabine.
4 This adverse reaction was identified during post-marketing surveillance of medicinal products containing tenofovir alafenamide.
Description of selected adverse reactions
Immune Reconstitution Syndrome
In HIV-infected patients with severe immunodeficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory response to asymptomatic or residual opportunistic infections may occur. 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 may occur many months after initiation of treatment (see section "Special Warnings and Precautions for Use").
Osteonecrosis
Cases of osteonecrosis have been reported, particularly in patients with generally recognized risk factors, advanced HIV infection, or long-term exposure to CART. The frequency is unknown (see section "Special Warnings and Precautions for Use").
Changes in lipid laboratory parameters
In studies involving treatment-naïve patients, fasting lipid parameters, including total cholesterol, direct low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL) cholesterol, and triglycerides, increased from baseline in treatment groups containing tenofovir alafenamide fumarate and tenofovir disoproxil fumarate by week 144. Mean increases in these parameters from baseline were greater 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 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 a study of patients with virological suppression who switched from emtricitabine/tenofovir disoproxil fumarate to emtricitabine/tenofovir alafenamide while maintaining a third antiretroviral agent, increases in lipid parameters (total cholesterol, direct LDL-C, and triglycerides) from baseline 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). Mean values for HDL-C cholesterol and fasting glucose or the total cholesterol to HDL-C and LDL-C to HDL-C ratios in either treatment group at week 96 showed minimal changes. None of these changes were considered clinically significant.
In a study involving adult patients with virological suppression who switched from abacavir/lamivudine to emtricitabine/tenofovir alafenamide while maintaining a third antiretroviral agent, minimal changes in lipid parameters were observed.
Metabolic parameters
Weight gain and increases in blood lipid and glucose levels may occur during antiretroviral therapy (see section "Special Warnings and Precautions for Use").
Pediatric population
The safety of emtricitabine and tenofovir alafenamide was evaluated over 48 weeks in an open-label clinical trial in which HIV-1-infected, treatment-naïve children 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 when used with elvitegravir and cobicistat in 50 adolescent patients was similar to that in adults (see section "Pharmacodynamics").
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 or moderate renal impairment (calculated creatinine clearance by Cockcroft-Gault method [eGFRCG]: 30–69 mL/min), receiving 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 "Pharmacodynamics").
The safety of emtricitabine and tenofovir alafenamide was also evaluated over 48 weeks in a study involving 55 HIV-1 patients with virological suppression and end-stage renal disease (eGFRCG < 15 mL/min) on chronic hemodialysis, who received 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 fixed-dose combination tablets.
Patients with HIV/HBV co-infection
The safety of emtricitabine and tenofovir alafenamide in combination with elvitegravir and cobicistat as fixed-dose combination tablets (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide [E/C/F/TAF]) was evaluated in 72 HIV/HBV co-infected patients receiving treatment for HIV in a study up to week 48, during which patients were switched from another antiretroviral therapy regimen (which included tenofovir disoproxil fumarate [TDF] in 69 out 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 mono-infection (see section "Special Warnings and Precautions for Use").
Reporting of adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua
Shelf life. 2 years.
Storage conditions. Store in the original tightly closed packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.
Packaging. 30 tablets in a container; 1 container in a cardboard box.
Prescription category. Prescription only.
Manufacturer. Annora Pharma Private Limited / Annora Pharma Private Limited.
Manufacturer's address and location of its business operations.
Sy. No. 261, Annaram Village, Gummadidala Mandal, Sangareddy District, Telangana State - 502313, India / Sy. No. 261, Annaram Village, Gummadidala Mandal, Sangareddy District, Telangana State - 502313, India.
Marketing Authorization Holder.
Hetero Labs Limited / Hetero Labs Limited.