Emtricitabine tenofovir
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EMTRICITABINE TENOFOVIR
Composition:
Active substances: emtricitabine, tenofovir disoproxil fumarate;
One film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil);
Excipients: pregelatinized starch, lactose (monohydrate), microcrystalline cellulose, sodium croscarmellose, magnesium stearate, Opadry II Blue 32K505037 (indigo carmine (E 132), triacetin, lactose (monohydrate), hypromellose).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties: blue, capsule-shaped film-coated tablets, engraved with «Н» on one side and «124» on the other side.
Pharmacotherapeutic group. Direct-acting antiviral agents for systemic use. Antiviral agents for the treatment of HIV infection in combination. ATC code J05AR03.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Emtricitabine is a nucleoside analogue of cytidine. Tenofovir disoproxil fumarate is converted in vivo to tenofovir, a nucleoside monophosphate (nucleotide) analogue of adenosine monophosphate. Both emtricitabine and tenofovir exhibit antiviral activity specific to human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.
Emtricitabine and tenofovir are phosphorylated by cellular enzymes to form emtricitabine triphosphate and tenofovir diphosphate, respectively. In vitro studies have shown that both emtricitabine and tenofovir can be fully phosphorylated when combined together in cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in chain termination of viral DNA.
Emtricitabine triphosphate and tenofovir diphosphate are weak inhibitors of mammalian DNA polymerases; there is no evidence of mitochondrial toxicity in vitro or in vivo.
Antiviral activity in vitro
Synergistic antiviral activity has been observed with the combination of emtricitabine and tenofovir in vitro. Additive effects have also been observed in combination studies with protease inhibitors and with nucleoside and non-nucleoside reverse transcriptase inhibitors of HIV.
Resistance
In vitro. Resistance has been observed in vitro and in some HIV-1-infected patients due to the development of M184V/I mutations with emtricitabine or the K65R mutation with tenofovir. Emtricitabine-resistant viruses with the M184V/I mutation were cross-resistant to lamivudine but remained sensitive to didanosine, stavudine, tenofovir, and zidovudine. The K65R mutation may also be selected by abacavir or didanosine and leads to reduced susceptibility to these agents as well as to lamivudine, emtricitabine, and tenofovir. HIV-1-infected patients with the K65R mutation should avoid the use of tenofovir disoproxil fumarate. Additionally, the K70E substitution in HIV-1 reverse transcriptase is selected by tenofovir and results in significantly reduced susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.
HIV-1-infected patients who had 3 or more thymidine analogue-associated mutations (TAMs), including either the M41L or L210W reverse transcriptase mutation, showed reduced susceptibility to tenofovir disoproxil fumarate.
In vivo – HIV-1 treatment. In an open-label randomized clinical trial in antiretroviral-naïve patients, genotyping was performed on HIV-1 isolates from plasma of all patients with confirmed HIV RNA > 400 copies/mL at week 48, 96, or 144, or at the time of premature discontinuation of the investigational drug. At week 144:
– According to the analysis, the M184V/I mutation developed in 2 of 19 (10.5%) isolates from patients receiving emtricitabine/tenofovir disoproxil fumarate/efavirenz, and in 10 of 29 (34.5%) isolates analyzed in patients receiving lamivudine/zidovudine/efavirenz (p < 0.05, Fisher’s exact test comparing patients receiving emtricitabine + tenofovir disoproxil fumarate versus lamivudine/zidovudine);
– None of the analyzed viruses contained the K65R or K70E mutation;
– Genotypic resistance to efavirenz, primarily the K103N viral mutation, developed in 13 of 19 (68%) patients receiving emtricitabine/tenofovir disoproxil fumarate/efavirenz compared to 21 of 29 (72%) patients in the control group.
In vivo – Pre-exposure prophylaxis. Plasma samples from two clinical trials in HIV-1-uninfected subjects were analyzed for four HIV-1 variants expressing amino acid substitutions (i.e., K65R, K70E, M184V, and M184I) potentially conferring resistance to tenofovir or emtricitabine. In one of these clinical trials, no HIV-1 variants expressing K65R, K70E, M184V, or M184I were detected at seroconversion among subjects who became infected with HIV-1 after enrollment. Among 3 of 10 subjects who had acute HIV infection at study entry, M184I and M184V mutations were detected in HIV in 2 of 2 subjects in the emtricitabine/tenofovir disoproxil fumarate group and in 1 of 8 subjects in the placebo group.
In another clinical trial, no HIV-1 variants expressing K65R, K70E, M184V, or M184I were detected at seroconversion among subjects who became infected with HIV-1 during the study. Among 2 of 14 subjects who had acute HIV infection at study entry, the K65R mutation was detected in HIV in 1 of 5 subjects in the tenofovir disoproxil 245 mg group, and the M184V mutation (associated with resistance to emtricitabine) was detected in HIV in 1 of 3 subjects in the emtricitabine/tenofovir disoproxil fumarate group.
Pediatric population
The safety and efficacy of the fixed-dose combination of emtricitabine/tenofovir disoproxil fumarate in children under 12 years of age have not been established.
HIV-1 treatment in the pediatric population
Clinical trials of the fixed-dose combination emtricitabine/tenofovir disoproxil fumarate have not been conducted in pediatric patients with HIV-1. The clinical efficacy and safety of this combination have been established in studies using emtricitabine and tenofovir disoproxil fumarate as monotherapy.
Emtricitabine studies
In infants and children aged 4 months and older, the majority of patients receiving emtricitabine achieved or maintained complete suppression of plasma HIV-1 RNA by week 48 (89% achieved ≤ 400 copies/mL and 77% achieved ≤ 50 copies/mL).
Tenofovir disoproxil fumarate studies
In Study 87, 87 HIV-1-infected patients aged 12 to 18 years were randomized to receive tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with an optimized background regimen (OBR) for 48 weeks. Due to study limitations, a benefit of tenofovir disoproxil fumarate over placebo based on plasma HIV RNA levels at week 24 was not demonstrated. However, benefit in adolescent patients is expected based on extrapolation from adult data and comparative pharmacokinetic data (see section "Pharmacological properties").
In patients receiving tenofovir disoproxil fumarate or placebo, mean Z-scores for bone mineral density (BMD) of the lumbar spine were -1.004 and -0.809, and mean Z-scores for whole-body BMD were -0.866 and -0.584 for tenofovir disoproxil fumarate and placebo, respectively. Mean changes at week 48 (end of the double-blind phase) were -0.215 and -0.165 for lumbar spine BMD Z-scores and -0.254 and -0.179 for whole-body BMD Z-scores with tenofovir disoproxil fumarate or placebo, respectively. Mean BMD was lower with tenofovir disoproxil fumarate compared to placebo. At week 48, 6 adolescents receiving tenofovir disoproxil fumarate and 1 receiving placebo had significant loss of lumbar spine BMD (defined as > 4%). In 28 patients treated with tenofovir disoproxil fumarate for 96 weeks, BMD Z-scores declined to -0.341 for the lumbar spine and -0.458 for whole body.
In another study, 97 previously treated patients aged 2 to 12 years with stable viral suppression on a regimen containing stavudine or zidovudine were randomized to replace stavudine or zidovudine with tenofovir disoproxil fumarate (n = 48) or continue their initial regimen (n = 49) for 48 weeks. At week 48, 83% of patients in the tenofovir disoproxil fumarate treatment group and 92% in the stavudine or zidovudine group had HIV-1 RNA concentration < 400 copies/mL. The difference in the proportion of patients with HIV-1 RNA < 400 copies/mL at week 48 was mainly influenced by a higher number of treatment discontinuations in the tenofovir disoproxil fumarate group. When missing data were excluded, 91% of patients in the tenofovir disoproxil fumarate group and 94% in the stavudine or zidovudine group had HIV-1 RNA concentration < 400 copies/mL at week 48.
Cases of decreased BMD have been reported in pediatric patients. In patients receiving tenofovir disoproxil fumarate or stavudine or zidovudine, mean Z-scores for lumbar spine BMD were -1.034 and -0.498, and mean Z-scores for whole-body BMD were -0.471 and -0.386, respectively. Mean changes at week 48 (end of the randomized phase) were 0.032 and 0.087 for lumbar spine BMD Z-scores and -0.184 and -0.027 for whole-body BMD Z-scores with tenofovir disoproxil fumarate and stavudine or zidovudine, respectively. Mean changes at week 48 in the lumbar spine were similar between the tenofovir disoproxil fumarate and stavudine or zidovudine treatment groups. The overall rate of change in whole-body BMD was lower in the tenofovir disoproxil fumarate group compared to the stavudine or zidovudine group. Treatment with tenofovir disoproxil fumarate alone, without stavudine or zidovudine, resulted in significant (> 4%) loss of lumbar spine BMD at week 48. BMD Z-scores decreased by -0.012 for the lumbar spine and -0.338 for whole body in 64 individuals treated with tenofovir disoproxil fumarate for 96 weeks. BMD Z-scores were not adjusted for patient height and body weight.
In one study, 8 of 89 pediatric patients (9.0%) exposed to tenofovir disoproxil fumarate discontinued clinical trials due to urinary system disorders. Clinical laboratory assessments for proximal renal tubulopathy were conducted in five patients (5.6%), four of whom discontinued tenofovir disoproxil fumarate treatment (median exposure to tenofovir disoproxil fumarate was 331 weeks).
Pre-exposure prophylaxis in the pediatric population
The efficacy and safety of the fixed-dose combination emtricitabine/tenofovir disoproxil fumarate for pre-exposure prophylaxis in adolescents adhering to daily dosing are expected to be similar to those in adults with comparable adherence. The potential effects on kidneys and bones with long-term use of this fixed-dose combination for pre-exposure prophylaxis in adolescents are unknown (see section "Special precautions for use").
Pharmacokinetics
Absorption
Bioequivalence of one tablet of the fixed-dose combination emtricitabine/tenofovir disoproxil fumarate and one 200 mg capsule of emtricitabine plus one 300 mg tablet of tenofovir disoproxil fumarate was established after single-dose administration in the fasting state to healthy volunteers. After oral administration of the fixed-dose combination to healthy volunteers, emtricitabine and tenofovir disoproxil fumarate were rapidly absorbed, and tenofovir disoproxil fumarate was converted to tenofovir. Maximum concentrations (Cmax) of emtricitabine and tenofovir in plasma were reached within 0.5–3.0 hours after administration in the fasting state. Administration of the fixed-dose combination with food delayed the time to maximum tenofovir concentration by approximately 45 minutes. The area under the plasma concentration-time curve (AUC) and Cmax of tenofovir increased by approximately 35% and 15%, respectively, when administered with a high-fat or light meal compared to fasting. To optimize tenofovir absorption, administration with food is recommended.
Distribution
After intravenous administration, the volume of distribution of emtricitabine and tenofovir was approximately 1.4 L/kg and 800 mL/kg, respectively. After oral administration of emtricitabine or tenofovir disoproxil fumarate, emtricitabine and tenofovir are extensively distributed throughout the body. In vitro, emtricitabine binding to human plasma proteins was < 4% and independent of concentration over the range of 0.02 to 200 µg/mL. In vitro, tenofovir binding to plasma or serum proteins was less than 0.7% and 7.2%, respectively, over the concentration range of 0.01 to 25 µg/mL.
Biotransformation
Metabolism of emtricitabine is limited. Biotransformation of emtricitabine includes oxidation of the thiol moiety to form 3'-sulfoxide diastereomers (approximately 9% of dose) and conjugation with glucuronic acid to form the 2'-O-glucuronide (approximately 4% of dose). In vitro studies showed that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Neither emtricitabine nor tenofovir inhibited in vitro drug metabolism mediated by any of the major human CYP450 isoenzymes involved in drug biotransformation. Emtricitabine also did not inhibit uridine-5'-diphosphoglucuronosyl transferase, the enzyme responsible for glucuronidation.
Elimination
Emtricitabine is primarily eliminated by the kidneys, with approximately 86% of the dose recovered in urine and 14% in feces. Thirteen percent of the emtricitabine dose is excreted in urine as metabolites. Systemic clearance of emtricitabine averages 307 mL/min. After oral administration, the elimination half-life of emtricitabine is approximately 10 hours.
Tenofovir is primarily eliminated by the kidneys via both glomerular filtration and active tubular transport, with approximately 70–80% of the dose excreted unchanged in urine after intravenous administration. Apparent clearance of tenofovir is approximately 307 mL/min. Renal clearance is approximately 210 mL/min, exceeding the glomerular filtration rate, indicating that tubular secretion plays an important role in tenofovir elimination. After oral administration, the elimination half-life of tenofovir is approximately 12 to 18 hours.
Elderly patients
Pharmacokinetic studies of emtricitabine or tenofovir in elderly patients (aged 65 years and older) have not been conducted.
Gender
Pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients.
Ethnic origin
There is no clinically significant pharmacokinetic difference for emtricitabine based on patient ethnicity. Tenofovir pharmacokinetics has not been specifically studied in different ethnic groups.
Children
Pharmacokinetic studies of the fixed-dose combination have not been conducted in children and adolescents (under 18 years of age). Steady-state pharmacokinetics of tenofovir were determined in 8 HIV-1-infected adolescent patients (12–18 years) with body weight ≥ 35 kg and in 23 HIV-1-infected children (aged 2 to 12 years). Exposure to tenofovir in pediatric patients receiving an oral dose of tenofovir disoproxil 245 mg (as fumarate) or 6.5 mg/kg body weight of tenofovir disoproxil (as fumarate) up to a maximum dose of 245 mg was similar to that in adults receiving daily doses of tenofovir disoproxil 245 mg (as fumarate). Pharmacokinetic studies have not been conducted with tenofovir disoproxil (as fumarate) in children under 2 years of age. Emtricitabine pharmacokinetics in infants, young children, and adolescents (aged 4 months to 18 years) is similar to that observed in adults.
Emtricitabine and tenofovir (as tenofovir disoproxil fumarate) pharmacokinetics are expected to be similar in HIV-1-infected and uninfected adolescents based on comparable emtricitabine and tenofovir exposure in HIV-1-infected adolescents and adults, as well as similar emtricitabine and tenofovir exposure in HIV-1-infected and uninfected adults.
Renal impairment
There are insufficient pharmacokinetic data for emtricitabine and tenofovir in patients with renal impairment following co-administration of these drugs either separately or as a fixed-dose combination. Pharmacokinetic parameters were mainly determined after single doses of emtricitabine 200 mg or tenofovir disoproxil 245 mg in HIV-uninfected patients with varying degrees of renal impairment. Renal impairment was categorized based on baseline creatinine clearance (CrCl) (normal renal function: CrCl > 80 mL/min; mild impairment: CrCl = 50–79 mL/min; moderate impairment: CrCl = 30–49 mL/min; severe impairment: CrCl = 10–29 mL/min). Mean (% CV – coefficient of variation) emtricitabine exposure increased from 12 µg•h/mL (25%) in patients with normal renal function to 20 µg•h/mL (6%), 25 µg•h/mL (23%), and 34 µg•h/mL (6%) in patients with mild, moderate, and severe renal impairment, respectively.
Mean (% CV) tenofovir exposure increased from 2185 ng•h/mL (12%) in patients with normal renal function to 3064 ng•h/mL (30%), 6009 ng•h/mL (42%), and 15985 ng•h/mL (45%) in patients with mild, moderate, and severe renal impairment, respectively.
An increased dosing interval in HIV-infected patients with moderate renal impairment is expected to result in higher Cmax and lower minimum plasma concentration (Cmin) compared to patients with normal renal function.
In patients with end-stage renal disease (ESRD) requiring hemodialysis, drug AUC was significantly increased: over 72 hours, emtricitabine AUC reached 53 µg•h/mL (19%), and over 48 hours, tenofovir AUC reached 42,857 ng•h/mL (29%).
A small clinical study evaluated the safety, antiviral activity, and pharmacokinetics of tenofovir disoproxil fumarate in combination with emtricitabine in HIV-infected patients with renal impairment. In a subgroup of patients with baseline creatinine clearance of 50–60 mL/min, once-daily dosing resulted in a 2- to 4-fold increase in tenofovir AUC and worsening of renal function.
Pharmacokinetics of emtricitabine and tenofovir in pediatric patients with renal impairment have not been studied. There are no data to provide dosing recommendations (see sections "Special precautions for use", "Dosage and administration").
Hepatic impairment
The pharmacokinetics of the fixed-dose combination in patients with hepatic impairment have not been studied.
Emtricitabine pharmacokinetics have not been studied in patients without hepatitis B virus (HBV) infection and with varying degrees of hepatic impairment. Overall, emtricitabine pharmacokinetics in HBV-infected patients were similar to those in non-HBV-infected and HIV-infected patients.
A single 245 mg dose of tenofovir disoproxil was administered to HIV-uninfected patients with varying degrees of hepatic impairment classified according to the Child-Pugh-Turcotte (CPT) score. Tenofovir pharmacokinetic parameters were not significantly altered in patients with hepatic impairment, indicating no need for dose adjustment in these patients. Mean (% CV) Cmax and AUC0-∞ values for tenofovir were 223 ng/mL (34.8%) and 2050 ng•h/mL (50.8%), respectively, in patients without hepatic impairment, compared to 289 ng/mL (46%) and 2310 ng•h/mL (43.5%) in patients with moderate hepatic impairment, and 305 ng/mL (24.8%) and 2740 ng•h/mL (44%) in patients with severe hepatic impairment.
Clinical Characteristics
Indications
The medicinal product is indicated in combination antiretroviral therapy for the treatment of HIV-1 infected adults. The medicinal product is also indicated for the treatment of HIV-1 infected adolescents with resistance to or toxicity precluding the use of first-line nucleoside reverse transcriptase inhibitors (see sections "Pharmacological Properties", "Special Warnings and Precautions for Use", "Dosage and Administration").
The medicinal product is indicated in combination with safe sex practices for pre-exposure prophylaxis to reduce the risk of sexually acquired HIV-1 infection in adults and adolescents at high risk (see sections "Pharmacological Properties", "Special Warnings and Precautions for Use", "Dosage and Administration").
Contraindications
Hypersensitivity to the active substances or to any of the excipients of the medicinal product.
Use for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status.
Interaction with Other Medicinal Products and Other Forms of Interaction
Interaction studies have been conducted only in adults.
Since the medicinal product contains emtricitabine and tenofovir disoproxil fumarate, any interactions observed when these substances are used individually may also occur with the medicinal product. The steady-state pharmacokinetics of emtricitabine and tenofovir are not altered when emtricitabine and tenofovir disoproxil fumarate are administered together compared to administration of each medicinal product separately.
In vitro and clinical pharmacokinetic interaction studies have shown that the potential for CYP450-mediated interactions of emtricitabine and tenofovir disoproxil fumarate with other medicinal products is low.
Concomitant use not recommended
The medicinal product should not be co-administered with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate), tenofovir alafenamide, or other cytidine analogues such as lamivudine (see section "Special Warnings and Precautions for Use"). The medicinal product should not be co-administered with adefovir dipivoxil.
Didanosine. Concomitant administration of the medicinal product and didanosine is not recommended (see section "Special Warnings and Precautions for Use" and Table 1).
Medicinal products eliminated via the kidneys. Since emtricitabine and tenofovir are primarily eliminated by the kidneys, concomitant administration of the medicinal product with other medicinal products that are eliminated by active tubular secretion (e.g., cidofovir) may lead to increased serum concentrations of emtricitabine and/or the co-administered medicinal product due to competition for this elimination pathway.
Concomitant use of the medicinal product with nephrotoxic medicinal products should be avoided. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2 (see section "Special Warnings and Precautions for Use").
Other interactions
Interactions between components of the medicinal product and other medicinal products are presented in Table 1 below (increase is denoted by "↑", decrease by "↓", no change by "↔", twice daily by "b.i.d.", and once daily by "q.d."). If available, 90% confidence intervals are provided in parentheses.
Table 1
Interactions between components of the medicinal product and other medicinal products
| Medicinal products by therapeutic area |
Effect on drug concentration levels. Mean percentage change in AUC, Cmax, Cmin with 90% confidence intervals if available (mechanism) |
Recommendations for concomitant use with the medicinal product (emtricitabine 200 mg, tenofovir disoproxil fumarate 300 mg) |
| ANTIMICROBIAL AGENTS |
||
| Antiretrovirals |
||
| Protease inhibitors |
||
| Atazanavir/ritonavir/ tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./ 300 mg q.d.) |
Atazanavir: AUC: ↓ 25 % (↓ 42 to ↓ 3) Cmax: ↓ 28 % (↓ 50 to ↑ 5) Cmin: ↓ 26 % (↓ 46 to ↑ 10) Tenofovir: AUC: ↑ 37 % Cmax: ↑ 34 % Cmin: ↑ 29 % |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-associated adverse events, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Atazanavir/ritonavir/ emtricitabine |
Interaction not studied |
|
| Darunavir/ritonavir/ tenofovir disoproxil fumarate (300 mg q.d./100 mg q.d./ 300 mg q.d.) |
Darunavir: AUC: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 22 % Cmin: ↑ 37 % |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-associated adverse events, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Darunavir/ritonavir/ emtricitabine |
Interaction not studied |
|
| Lopinavir/ritonavir/ tenofovir disoproxil fumarate (400 mg b.i.d./100 mg b.i.d./ 300 mg q.d.) |
Lopinavir/ritonavir: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 32 % (↑ 25 to ↑ 38) Сmax: ↔ Cmin: ↑ 51 % (↑ 37 to ↑ 66) |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance tenofovir-associated adverse events, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Lopinavir/ritonavir/ emtricitabine |
Interaction not studied |
|
| Nucleoside reverse transcriptase inhibitors (NRTIs) |
||
| Didanosine/tenofovir disoproxil fumarate |
Concomitant administration of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60% increase in systemic exposure to didanosine. |
Concomitant use of the medicinal product and didanosine is not recommended (see section “Special precautions for use”). Increased systemic exposure to didanosine may increase the risk of didanosine-related adverse reactions. Rare, sometimes fatal cases of pancreatitis and lactic acidosis have been reported. Concomitant use of tenofovir disoproxil and didanosine at a dose of 400 mg per day has been associated with significant decreases in CD4 lymphocyte count, possibly due to increased intracellular interaction of phosphorylated (i.e. active) didanosine. A reduced dose of didanosine 250 mg, administered concomitantly with tenofovir disoproxil therapy, has been associated with high rates of virological failure during multiple controlled combination therapies for the treatment of HIV-1 infection. |
| Didanosine/emtricitabine |
Interaction not studied |
|
| Lamivudine/tenofovir disoproxil fumarate |
Lamivudine: AUC: ↓ 3 % (↓ 8 to ↑ 15) Сmax: ↓ 24 % (↓ 44 to ↓ 12) Cmin: NC Tenofovir: AUC: ↓ 4 % (↓ 15 to ↑ 8) Сmax: ↓ 102 % (↓ 96 to ↑ 108) Cmin: NC |
Lamivudine and the medicinal product should not be administered concomitantly (see section “Special precautions for use”) |
| Efavirenz/tenofovir disoproxil fumarate |
Efavirenz: AUC: ↓ 4 % (↓ 7 to ↓ 1) Сmax: ↓ 4 % (↓ 9 to ↑ 2) Cmin: NC Tenofovir: AUC: ↓ 1 % (↓ 8 to ↑ 6) Сmax: ↑ 7 % (↓ 6 to ↑ 22) Cmin: NC |
No dose adjustment of efavirenz is required |
| ANTIMICROBIAL AGENTS |
||
| Antiviral agents for hepatitis B virus (HBV) |
||
| Adefovir dipivoxil/ tenofovir disoproxil fumarate |
Adefovir dipivoxil: AUC: ↓ 11 % (↓ 14 to ↓ 7) Сmax: ↓ 7 % (↓ 13 to ↓ 0) Cmin: NC Tenofovir: AUC: ↓ 2 % (↓ 5 to ↑ 0) Сmax: ↓ 1 % (↓ 7 to ↑ 6) Cmin: NC |
Adefovir dipivoxil and the medicinal product should not be administered concomitantly (see section “Special precautions for use”) |
| Antiviral agents for hepatitis C virus (HCV) |
||
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + atazanavir/ritonavir (300 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Ledipasvir: AUC: ↑ 96 % (↑ 74 to ↑ 121) Сmax: ↑ 68 % (↑ 54 to ↑ 84) Cmin: ↑ 118 % (↑ 91 to ↑ 150) Sofosbuvir: AUC: ↔; Сmax: ↔ GS-3310072: AUC: ↔; Сmax: ↔ Cmin: ↑ 42 % (↑ 34 to ↑ 49) Atazanavir: AUC: ↔; Сmax: ↔ Cmin: ↑ 63 % (↑ 45 to ↑ 84) Ritonavir: AUC: ↔; Сmax: ↔ Cmin: ↑ 45 % (↑ 27 to ↑ 64) Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↔ Сmax: ↑ 47 % (↑ 37 to ↑ 58) Cmin: ↑ 47 % (↑ 38 to ↑ 57) |
Elevated plasma tenofovir concentrations resulting from concomitant use of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir, and atazanavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function and in the absence of alternative therapy (see section “Special precautions for use”). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + darunavir/ritonavir (800 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.)1 |
Ledipasvir: AUC: ↔; Сmax: ↔; Cmin: ↔ Sofosbuvir: AUC: ↓ 27 % (↓ 35 to ↓ 18) Сmax: ↓ 37 % (↓ 48 to ↓ 25) GS-33100722: AUC: ↔; Сmax: ↔; Cmin: ↔ Darunavir: AUC: ↔; Сmax: ↔; Cmin: ↔ Ritonavir: AUC: ↔; Сmax: ↔ Cmin: ↑ 48 % (↑ 34 to ↑ 63) Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 50 % (↑ 42 to ↑ 59) Сmax: ↑ 64 % (↑ 54 to ↑ 74) Cmin: ↑ 59 % (↑ 49 to ↑ 70) |
Elevated plasma tenofovir concentrations resulting from concomitant use of tenofovir disoproxil fumarate, ledipasvir/sofosbuvir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with ledipasvir/sofosbuvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function and in the absence of alternative therapy (see section “Special precautions for use”). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + efavirenz/emtricitabine/ tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Ledipasvir: AUC: ↓ 34 % (↓ 41 to ↓ 25) Сmax: ↓ 34 % (↓ 41 to ↑ 25) Cmin: ↓ 34 % (↓ 43 to ↑ 24) Sofosbuvir: AUC: ↔; Сmax: ↔ GS-3310072: AUC: ↔; Сmax: ↔; Cmin: ↔ Efavirenz: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 98 % (↑ 77 to ↑ 123) Сmax: ↑ 79 % (↑ 56 to ↑ 104) Cmin: ↑ 163 % (↑ 137 to ↑ 197) |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + emtricitabine/rilpivirine/ tenofovir disoproxil fumarate (200 mg/25 mg/300 mg q.d.) |
Ledipasvir: AUC: ↔; Сmax: ↔; Cmin: ↔ Sofosbuvir: AUC: ↔; Сmax: ↔ GS-3310072: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Rilpivirine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 40 % (↑ 31 to ↑ 50) Сmax: ↔ Cmin: ↑ 91 % (↑ 74 to ↑ 110) |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Ledipasvir/sofosbuvir (90 mg/400 mg q.d.) + dolutegravir (50 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔; Сmax: ↔ GS-3310072 AUC: ↔; Сmax: ↔; Cmin: ↔ Ledipasvir: AUC: ↔; Сmax: ↔; Cmin: ↔ Dolutegravir: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 65 % (↑ 59 to ↑ 71) Сmax: ↑ 61 % (↑ 51 to ↑ 72) Cmin: ↑ 115 % (↑ 105 to ↑ 126) |
No dose adjustment required. Increased tenofovir exposure may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + atazanavir/ritonavir (300 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔; Сmax: ↔ GS-3310072: AUC: ↔; Сmax: ↔ Cmin: ↑ 42 % (↑ 37 to ↑ 49) Velpatasvir: AUC: ↑ 142 % (↑ 123 to ↑ 164) Сmax: ↑ 55 % (↑ 41 to ↑ 71) Cmin: ↑ 301 % (↑ 257 to ↑ 350) Atazanavir: AUC: ↔; Сmax: ↔ Cmin: ↑ 39 % (↑ 20 to ↑ 61) Ritonavir: AUC: ↔; Сmax: ↔ Cmin: ↑ 29 % (↑ 15 to ↑ 44) Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↔ Сmax: ↑ 55 % (↑ 43 to ↑ 68) Cmin: ↑ 39 % (↑ 31 to ↑ 48) |
Elevated plasma tenofovir concentrations resulting from concomitant use of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and atazanavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section “Special precautions for use”). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + darunavir/ritonavir (800 mg q.d./100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↓ 28 % (↓ 34 to ↓ 20) Сmax: ↓ 38 % (↓ 46 to ↓ 29) GS-3310072: AUC: ↔; Сmax: ↔; Cmin: ↔ Velpatasvir: AUC: ↔ Сmax: ↓ 24 % (↓ 35 to ↓ 11) Cmin: ↔) Darunavir: AUC: ↔; Сmax: ↔; Cmin: ↔ Ritonavir: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 39 % (↑ 33 to ↑ 44) Сmax: ↑ 55 % (↑ 45 to ↑ 66) Cmin: ↑ 52 % (↑ 45 to ↑ 59) |
Elevated plasma tenofovir concentrations resulting from concomitant use of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section “Special precautions for use”). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + lopinavir/ritonavir (800 mg q.d./200 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↓ 29 % (↓ 36 to ↓ 22) Сmax: ↓ 41 % (↓ 51 to ↓ 29) GS-3310072: AUC: ↔; Сmax: ↔; Cmin: ↔ Velpatasvir: AUC: ↔ Сmax: ↓ 30 % (↓ 41 to ↓ 17) Cmin: ↑ 63 % (↑ 43 to ↑ 85) Lopinavir: AUC: ↔; Сmax: ↔; Cmin: ↔ Ritonavir: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↔ Сmax: ↑ 42 % (↑ 27 to ↑ 57) Cmin: ↔ |
Elevated plasma tenofovir concentrations resulting from concomitant use of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir, and lopinavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section “Special precautions for use”). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + raltegravir (400 mg b.i.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔; Сmax: ↔ GS-3310072: AUC: ↔; Сmax: ↔; Cmin: ↔ Velpatasvir: AUC: ↔; Сmax: ↔; Cmin: ↔ Raltegravir: AUC: ↔; Сmax: ↔ Cmin: ↓ 21 % (↓ 58 to ↑ 48) Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 40 % (↑ 34 to ↑ 45) Сmax: ↑ 46 % (↑ 39 to ↑ 54) Cmin: ↑ 70 % (↑ 61 to ↑ 79) |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + efavirenz/emtricitabine/ tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Сmax: ↑ 38 % (↑ 14 to ↑ 67) GS-3310072: AUC: ↔; Сmax: ↔; Cmin: ↔ Velpatasvir: AUC: ↓ 53 % (↓ 61 to ↓ 43) Сmax: ↓ 47 % (↓ 57 to ↓ 36) Cmin: ↓ 57 % (↓ 64 to ↓ 48) Efavirenz: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 81 % (↑ 68 to ↑ 94) Сmax: ↑ 77 % (↑ 53 to ↑ 104) Cmin: ↑ 121 % (↑ 100 to ↑ 143) |
Concomitant administration of sofosbuvir/velpatasvir and efavirenz reduces plasma concentrations of velpatasvir. Concomitant use of sofosbuvir/velpatasvir in treatment regimens containing efavirenz is not recommended. |
| Sofosbuvir/velpatasvir/ voxilaprevir (400 mg/100 mg/100 mg + 100 mg q.d.)3 + darunavir (800 mg q.d.) + ritonavir (100 mg q.d.) + emtricitabine/tenofovir disoproxil fumarate (200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Сmax: ↓ 30 % Cmin: N/A GS-3310072: AUC: ↔ Сmax: ↔ Cmin: N/A Velpatasvir: AUC: ↔; Сmax: ↔; Cmin: ↔ Voxilaprevir: AUC: ↑ 143 % Сmax: ↑ 72 % Cmin: ↑ 300 % Darunavir: AUC: ↔; Сmax: ↔ Cmin: ↓ 34 % Ritonavir: AUC: ↑ 45 % Сmax: ↑ 60 % Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 39 % Сmax: ↑ 48 % Cmin: ↑ 47 % |
Elevated plasma tenofovir concentrations resulting from concomitant use of tenofovir disoproxil fumarate, sofosbuvir/velpatasvir/voxilaprevir, and darunavir/ritonavir may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal disorders. The safety of tenofovir disoproxil fumarate when used with sofosbuvir/velpatasvir/ voxilaprevir and a pharmacokinetic enhancer (e.g., ritonavir or cobicistat) has not been established. This combination should be prescribed only with frequent monitoring of renal function (see section “Special precautions for use”). |
| Sofosbuvir/velpatasvir (400 mg/100 mg q.d.) + emtricitabine/rilpivirine/ tenofovir disoproxil fumarate (200 mg/25 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔; Сmax: ↔ GS-3310072: AUC: ↔; Сmax: ↔; Cmin: ↔ Velpatasvir: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Rilpivirine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↑ 40 % (↑ 34 to ↑ 46) Сmax: ↑ 44 % (↑ 33 to ↑ 55) Cmin: ↑ 84 % (↑ 76 to ↑ 92) |
Dose adjustment is not recommended. Increased tenofovir exposure may enhance adverse reactions associated with tenofovir disoproxil fumarate, including renal impairment. Renal function should be closely monitored (see section “Special precautions for use”). |
| Sofosbuvir (400 mg q.d.) + efavirenz/ emtricitabine/ tenofovir disoproxil fumarate (600 mg/200 mg/300 mg q.d.) |
Sofosbuvir: AUC: ↔ Сmax: ↓ 19 % (↓ 40 to ↑ 10) GS-3310072: AUC: ↔ Сmax: ↓ 23 % (↓ 30 to ↑ 16) Efavirenz: AUC: ↔; Сmax: ↔; Cmin: ↔ Emtricitabine: AUC: ↔; Сmax: ↔; Cmin: ↔ Tenofovir: AUC: ↔ Сmax: ↑ 25 % (↑ 8 to ↑ 45) Cmin: ↔ |
No dose adjustment required. |
| Ribavirin/tenofovir disoproxil fumarate |
Ribavirin: AUC: ↑ 26 % (↑ 20 to ↑ 32) Сmax: ↓ 5 % (↓ 11 to ↑ 1) Cmin: NC |
No dose adjustment of ribavirin is required. |
| Antiviral agents for herpes virus |
||
| Famciclovir/emtricitabine |
Famciclovir: AUC: ↓ 9 % (↓ 16 to ↓ 1) Сmax: ↓ 7 % (↓ 22 to ↑ 11) Cmin: NC Emtricitabine AUC: ↓ 7 % (↓ 13 to ↓ 1) Сmax: ↓ 11 % (↓ 20 to ↑ 1) Cmin: NC |
No dose adjustment of famciclovir is required. |
| Antimycobacterial agents |
||
| Rifampicin/tenofovir disoproxil fumarate |
Tenofovir: AUC: ↓ 12 % (↓ 16 to ↓ 8) Сmax: ↓ 16 % (↓ 22 to ↓ 10) Cmin: ↓ 15 % (↓ 12 to ↓ 9) |
No dose adjustment required. |
| ORAL CONTRACEPTIVES |
||
| Norgestimate/ ethinylestradiol/tenofovir disoproxil fumarate |
Norgestimate: AUC: ↓ 4 % (↓ 32 to ↑ 34) Сmax: ↓ 5 % (↓ 27 to ↑ 24) Cmin: NC Ethinylestradiol: AUC: ↓ 4 % (↓ 9 to ↑ 0) Сmax: ↓ 6 % (↓ 13 to ↑ 0) Cmin: ↓ 2 % (↓ 9 to ↑ 6) |
No dose adjustment of norgestimate/ ethinylestradiol is required. |
| IMMUNOSUPPRESSANTS |
||
| Tacrolimus/tenofovir disoproxil fumarate/ emtricitabine |
Tacrolimus: AUC: ↑ 4 % (↓ 3 to ↑ 11) Сmax: ↑ 3 % (↓ 3 to ↑ 9) Cmin: NC Emtricitabine: AUC: ↓ 5% (↓ 9 to ↓ 1) Сmax: ↓ 11 % (↓ 17 to ↓ 5) Cmin: NC Tenofovir: AUC: ↑ 6 % (↓ 1 to ↑ 13) Сmax: ↑ 13 % (↑ 1 to ↑ 27) Cmin: NC |
No dose adjustment of tacrolimus is required. |
| NARCOTIC ANALGESICS |
||
| Methadone/tenofovir disoproxil fumarate |
Methadone: AUC: ↑ 5 % (↓ 2 to ↑ 13) Сmax: ↑ 5 % (↓ 3 to ↑ 14) Cmin: NC |
No dose adjustment of methadone is required. |
NC – not calculated
1 Data obtained with concomitant administration with ledipasvir/sofosbuvir. Sequential dosing (12 hours apart) yielded similar results.
2 Predominant circulating metabolite of sofosbuvir.
3 Study conducted with an additional dose of voxilaprevir 100 mg to achieve voxilaprevir exposure expected in patients infected with hepatitis C virus.
Special precautions for use
HIV-1 patients with viral mutations
Emtricitabine Tenofovir should be avoided in antiretroviral-experienced patients with HIV-1 strains harboring the K65R mutation (see section "Pharmacological properties").
General strategy for prevention of HIV-1 infection
Emtricitabine Tenofovir is not always effective in preventing HIV-1 infection. The time to onset of protection after initiating the medication is unknown.
The medication should only be used for pre-exposure prophylaxis as part of a comprehensive strategy to prevent HIV-1 infection, including other preventive measures (e.g., consistent and correct condom use, knowledge of HIV-1 status, regular testing for other sexually transmitted infections).
Risk of resistance with undiagnosed HIV-1 infection
Emtricitabine Tenofovir should only be used to reduce the risk of acquiring HIV-1 in individuals confirmed to be HIV-negative (see section "Contraindications"). HIV-negative status should be periodically reconfirmed (e.g., at least every 3 months) using a combination antigen/antibody test during pre-exposure prophylaxis.
Emtricitabine Tenofovir alone is not a complete antiretroviral regimen, and HIV-1 resistance mutations have developed in individuals with undiagnosed HIV infection who received only Emtricitabine Tenofovir.
If clinical symptoms suggestive of acute viral infection are present and recent (<1 month) HIV-1 infection is suspected, initiation of the medication should be deferred for at least one month, and HIV-1 status should be reconfirmed before starting pre-exposure prophylaxis.
Importance of adherence
The efficacy of the fixed-dose combination in reducing the risk of acquiring HIV-1 is closely linked to adherence, as demonstrated by measurable drug levels in blood (see section "Pharmacological properties"). HIV-negative individuals should be counselled at regular intervals regarding strict adherence to the recommended daily dosing regimen.
HIV patients with concomitant hepatitis B or C virus infection
HIV-infected patients with chronic hepatitis B or C undergoing antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse reactions. Physicians should refer to current HIV treatment guidelines for managing HIV infection in patients with concomitant hepatitis B (HBV) or C (HCV) virus infection.
The safety and efficacy of the fixed-dose combination for pre-exposure prophylaxis in patients with HBV or HCV infection have not been established.
When prescribing concomitant antiviral therapy for hepatitis B or C, refer to the relevant product information for these medications (see section "Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir").
Tenofovir disoproxil fumarate is indicated for the treatment of hepatitis B virus, and emtricitabine has shown anti-hepatitis B activity in pharmacodynamic studies; however, the safety and efficacy of the fixed-dose combination for treating patients with chronic HBV infection have not been established.
Discontinuation of the medication in patients with concomitant HIV and HBV infection may be associated with severe acute exacerbation of hepatitis. Close monitoring (both clinically and with laboratory tests) is required for at least several months after stopping treatment in patients with concomitant HIV and HBV infection. Resumption of hepatitis B treatment may be warranted if necessary. Discontinuation is not recommended in patients with advanced liver disease or cirrhosis, as post-treatment hepatitis flare may lead to hepatic decompensation.
Liver disease
The safety and efficacy of the fixed-dose combination in patients with pre-existing significant hepatic impairment have not been established. The pharmacokinetics of tenofovir have been studied in patients with hepatic impairment, and dose adjustment is not required in these patients. The pharmacokinetics of emtricitabine in patients with hepatic insufficiency have not been studied. Given the minimal hepatic metabolism and renal elimination pathway of emtricitabine, it is unlikely that patients with hepatic impairment will require dose adjustment (see sections "Pharmacological properties", "Dosage and administration").
HIV-infected patients with pre-existing hepatic dysfunction, including chronic active hepatitis, have an increased frequency of hepatic adverse events 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 interrupting or discontinuing therapy.
Renal and bone effects in adults
Renal effects
Emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion. Reports of renal failure, renal impairment, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil fumarate (see section "Adverse reactions").
Renal monitoring
Before initiating treatment with the medication for HIV-1 infection or for pre-exposure prophylaxis, creatinine clearance (CrCl) should be determined in all patients. In patients without risk factors for kidney disease, renal function (creatinine clearance and serum phosphate) should be monitored 2–4 weeks after starting treatment and every 3–6 months thereafter. Patients at risk of kidney disease require more frequent monitoring.
See also "Concomitant use of other medicinal products" below.
Renal treatment in HIV-1-infected patients
If serum phosphate levels are <1.5 mg/dL (0.48 mmol/L) or CrCl decreases to <50 mL/min in any patient taking the medication, renal function should be re-evaluated within one week, including measurement of blood glucose and potassium and urine glucose (see section "Adverse reactions"). Treatment should be discontinued in patients with CrCl <50 mL/min or serum phosphate concentration <1.0 mg/dL (0.32 mmol/L). Discontinuation of the medication should also be considered in cases of progressive renal function decline if no other cause is identified.
The safety of treatment without renal impact has been partially studied in HIV-1-infected patients with renal impairment (CrCl <80 mL/min). For HIV-1-infected patients with CrCl of 30–49 mL/min, dose interval adjustment is recommended (see section "Dosage and administration").
Limited clinical trial data suggest that extended dosing intervals may not be optimal and could lead to increased toxicity and possibly unknown outcomes. Furthermore, in a small clinical trial in patients with CrCl of 50–60 mL/min receiving tenofovir disoproxil fumarate in combination with emtricitabine every 24 hours, tenofovir levels were 2–4 times higher and renal function worsened (see section "Pharmacological properties"). Therefore, the benefit-risk ratio should be carefully assessed and renal function closely monitored if the medication is used in patients with CrCl <60 mL/min. Additionally, clinical response should be carefully monitored in patients receiving the medication with extended dosing intervals. The medication is not recommended for patients with significant renal impairment (CrCl <30 mL/min) or those requiring hemodialysis, as the fixed-dose tablet does not allow for the necessary dose reduction (see sections "Pharmacological properties", "Dosage and administration").
Renal treatment for pre-exposure prophylaxis
The fixed-dose combination of emtricitabine/tenofovir disoproxil has not been studied in HIV-negative individuals with creatinine clearance <60 mL/min; therefore, the medication is not recommended for this population. If serum phosphate levels are <1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to <60 mL/min in any individual receiving the medication for pre-exposure prophylaxis, renal function should be re-evaluated within one week, including measurement of blood glucose, blood potassium, and urine glucose (see section "Adverse reactions", "Proximal tubulopathy"). Discontinuation of the medication should be considered in individuals with creatinine clearance <60 mL/min or serum phosphate levels <1.0 mg/dL (0.32 mmol/L). Interruption of the medication should also be considered in cases of progressive decline in renal function if no other cause is identified.
Bone effects
Bone abnormalities (sometimes leading to fractures) may be associated with proximal renal tubulopathy (see section "Adverse reactions").
If bone abnormalities are suspected or identified, appropriate specialist consultations should be obtained.
HIV-1 infection treatment
Decreases in bone mineral density (BMD) have been observed with tenofovir disoproxil in randomized, controlled clinical trials of up to 144 weeks in HIV- or HBV-infected patients. These BMD decreases generally improved after discontinuation of treatment.
In other studies, the most pronounced BMD decreases were observed in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Alternative treatment regimens should be considered for patients with osteoporosis who are at high risk of fractures.
Pre-exposure prophylaxis
In clinical trials of HIV-negative individuals, small decreases in BMD were observed. In a study of 498 men, mean changes in BMD from baseline to week 24 were between -0.4% and -1.0% at the hip, spine, femoral neck, and trochanter in men receiving daily pre-exposure prophylaxis with the fixed-dose combination (n = 247) compared to placebo (n = 251).
Renal and bone effects in pediatric populations
There are uncertainties regarding the long-term effects of tenofovir disoproxil on the kidneys and bones during treatment of HIV-1 infection in pediatric populations, and the long-term effects of emtricitabine and tenofovir disoproxil on the kidneys and bones when used for pre-exposure prophylaxis in HIV-negative adolescents (see section "Pharmacological properties"). Additionally, the reversibility of renal toxicity after discontinuation of tenofovir disoproxil for HIV-1 treatment or after stopping the fixed-dose combination for pre-exposure prophylaxis cannot be fully established.
Therefore, a multidisciplinary approach is recommended for each individual case to determine the benefit-risk ratio of using the medication for HIV-1 treatment or pre-exposure prophylaxis, to make decisions regarding appropriate monitoring during treatment (including discontinuation), and to consider the need for additional measures.
When using the medication for pre-exposure prophylaxis, patients should be re-evaluated at each visit to ensure they remain in a high-risk group for HIV-1 infection. The risk of HIV-1 infection should be balanced against the potential for renal and bone effects with long-term use of the medication.
Renal effects
Cases of adverse reactions in the form of proximal renal tubulopathy have been reported in HIV-1-infected pediatric patients aged 2 to 12 years in a clinical trial (see sections "Pharmacological properties", "Adverse reactions").
Renal monitoring
Before initiating the medication for HIV-1 treatment or pre-exposure prophylaxis, renal function (creatinine clearance and serum phosphate level) should be assessed and monitored during treatment as in adults (see above).
Renal function monitoring
If serum phosphate levels are <3.0 mg/dL (0.96 mmol/L) in any pediatric patient receiving the medication, renal function should be re-evaluated within one week, including measurement of blood glucose, blood potassium, and urine glucose (see section "Adverse reactions", "Proximal tubulopathy"). If renal abnormality is suspected or identified, consultation with a nephrologist should be obtained to consider discontinuation of treatment. Discontinuation of the medication should also be considered in cases of progressive decline in renal function if no other cause is identified.
Concomitant use of other medicinal products and risk of nephrotoxicity
The same recommendations apply as for adults (see section "Concomitant use of other medicinal products" below).
Renal impairment
Treatment with the medication is not recommended in patients under 18 years of age with renal impairment (see section "Dosage and administration"). Treatment with the medication should not be initiated in pediatric patients with renal impairment, and should be discontinued in pediatric patients who develop renal impairment during treatment.
Bone effects
Tenofovir disoproxil fumarate may cause a decrease in BMD. The long-term consequences of BMD changes associated with tenofovir disoproxil fumarate on bone health and fracture risk are not yet known (see section "Pharmacological properties"). If pediatric patients have bone function abnormalities or suspected abnormalities, consultation with an endocrinologist and/or nephrologist is required.
Body weight and metabolic parameters
Weight gain and increases in serum lipid and glucose levels may occur during antiretroviral therapy. These changes may be partly related to treatment and lifestyle. In some cases, treatment may affect lipid levels, but there is no substantial evidence linking weight gain to any specific medication. Current HIV treatment guidelines recommend monitoring of blood lipid and glucose levels. Lipid abnormalities should be treated as clinically indicated.
Mitochondrial dysfunction due to in utero exposure
Nucleoside and nucleotide analogues can significantly affect mitochondrial function, particularly stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside analogues in utero and/or postnatally, primarily in regimens containing zidovudine. The main adverse events reported were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Rarely, delayed-onset 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 in any child exposed in utero to nucleoside or nucleotide analogues who presents with a clinical condition of unknown etiology, particularly neurological findings. These findings 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 advanced immune deficiency at the time of initiation of cART, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur, potentially causing serious clinical conditions or worsening of symptoms. Such reactions typically occur within the first few weeks or months of cART. Examples include cytomegalovirus retinitis, generalized and/or focal 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 varied widely, and these events may occur many months after starting treatment.
Opportunistic infections
HIV-1-infected patients receiving the medication or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection and should remain under ongoing clinical supervision by physicians experienced in managing HIV-1-infected patients.
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, joint stiffness, or difficulty moving.
Concomitant use of other medicinal products
The medication should be avoided if used concomitantly or recently with a nephrotoxic medicinal product (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant use of the medication and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.
Cases of acute renal failure have been reported in HIV-1-infected patients receiving tenofovir disoproxil fumarate who have risk factors for renal impairment and who initiated high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs). If the medication is used with NSAIDs, renal function should be closely monitored.
A higher risk of worsening renal function has been observed in HIV-1-infected patients receiving tenofovir disoproxil fumarate in combination with a ritonavir- or cobicistat-boosted protease inhibitor. These patients require careful monitoring of renal function (see section "Interaction with other medicinal products and other forms of interaction"). The concomitant use of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated in HIV-1-infected patients with risk factors for kidney disease.
The medication should not be prescribed concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate), tenofovir alafenamide, or other cytidine analogues such as lamivudine (see section "Interaction with other medicinal products and other forms of interaction"). The medication should not be used concomitantly with adefovir dipivoxil.
Use with ledipasvir and sofosbuvir or sofosbuvir and velpatasvir
Concomitant use of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir increases plasma tenofovir concentrations, particularly when used with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat).
The safety of tenofovir disoproxil fumarate when used concomitantly with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir and a pharmacokinetic booster has not been established. The potential risks and benefits of concomitant use should be carefully considered, particularly in patients at increased risk of renal dysfunction. In patients receiving ledipasvir/sofosbuvir or sofosbuvir/velpatasvir concomitantly with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor, adverse reactions associated with tenofovir disoproxil fumarate should be monitored.
Concomitant use of tenofovir disoproxil fumarate and didanosine
Concomitant administration of tenofovir disoproxil and didanosine is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Nucleoside triple therapy
Reports of high rates of virological failure and early emergence of resistance have been reported in HIV-1-infected patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, or with lamivudine and didanosine once daily. There is close structural similarity between lamivudine and emtricitabine and similar pharmacokinetic and pharmacodynamic profiles of these two agents. Therefore, similar problems may occur if the medication is taken with a third nucleoside analogue.
Elderly patients
The effect of the fixed-dose combination has not been studied in individuals aged 65 years or older. Elderly individuals often have reduced renal function; therefore, caution should be exercised when administering the medication to these patients.
The medication contains lactose monohydrate. Therefore, patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
The medication contains less than 1 mmol of sodium (23 mg) per tablet. Therefore, it is essentially sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
A large amount of data from pregnant women (over 1,000 completed pregnancies) indicates no malformations or embryo/fetal toxicity associated with emtricitabine and tenofovir disoproxil fumarate. Animal studies with emtricitabine and tenofovir disoproxil fumarate did not show reproductive toxicity. Therefore, the medication can be used during pregnancy if necessary.
Breastfeeding
Emtricitabine and tenofovir have been detected in human breast milk. There is insufficient information on the effects of emtricitabine and tenofovir on neonates/infants. Therefore, the medication should not be used during breastfeeding.
HIV-infected women are generally advised not to breastfeed under any circumstances to avoid transmission of HIV to the infant.
Fertility
There are no data on the effect of the fixed-dose combination on human fertility. Animal studies do not indicate harmful effects of emtricitabine and tenofovir disoproxil fumarate on fertility.
Ability to affect reaction speed when driving or operating machinery
Studies on the effect on the ability to drive or operate machinery have not been conducted. However, patients should be informed that dizziness may occur during treatment with both emtricitabine and tenofovir disoproxil fumarate.
Dosage and Administration
The medication should be prescribed by a physician experienced in the management of HIV infection.
Dosage
Treatment of HIV infection in adults and adolescents aged 12 years and older with body weight ≥ 35 kg: 1 tablet once daily.
Prevention of HIV in adults and adolescents aged 12 years and older with body weight ≥ 35 kg: 1 tablet once daily.
For the treatment of HIV-1 infection, individual emtricitabine and tenofovir disoproxil fumarate medications are available if there is a need to discontinue or adjust the dose of one of the components of the medicinal product (see the package leaflets for these medicinal products).
If less than 12 hours have passed since the missed dose, the dose should be taken as soon as possible, and the regular dosing schedule should be resumed. If more than 12 hours have passed since the last dose and the time for the next dose is approaching, the missed dose should not be taken; instead, resume the regular dosing schedule.
If vomiting occurs within 1 hour after taking the tablet, another tablet should be taken. If vomiting occurs more than 1 hour after taking the tablet, an additional dose is not required.
Special patient populations
Elderly patients. Dose adjustment is not required (see section "Pharmacological Properties").
Patients with renal impairment. Emtricitabine and tenofovir are eliminated via the kidneys, and exposure to emtricitabine and tenofovir increases in patients with impaired renal function (see sections "Pharmacological Properties" and "Special Warnings and Precautions for Use").
Adults with renal impairment. The medicinal product can be used in patients with CrCl < 80 mL/min only if the potential benefit is considered to outweigh the risks (see Table 2).
Table 2
Dosage recommendations for adults with renal impairment
| Treatment of HIV-1 infection |
Pre-exposure prophylaxis |
|
| Mild renal impairment (CrCl 50–80 mL/min) |
Limited clinical trial data support once-daily dosing (see section "Dosage and administration") |
Limited clinical trial data support once-daily dosing in HIV-1 uninfected individuals with creatinine clearance of 60–80 mL/min. Use is not recommended in HIV-1 uninfected individuals with creatinine clearance <60 mL/min, as studies in this population have not been conducted (see sections "Dosage and administration" and "Pharmacological properties") |
| Moderate renal impairment (CrCl 30–49 mL/min) |
Dosing every 48 hours is recommended based on pharmacokinetic modeling of single-dose emtricitabine and tenofovir disoproxil fumarate in HIV-uninfected individuals with varying degrees of renal impairment (see section "Dosage and administration") |
Not recommended for use in this patient category |
| Acute renal failure (CrCl < 30 mL/min) and patients on hemodialysis |
Use of the medicinal product is not recommended, as appropriate dose reduction cannot be achieved with combination drugs |
Not recommended for use in this patient category |
Pediatric patients with renal impairment. The use of the drug is not recommended for patients under 18 years of age with impaired renal function (see section "Special precautions").
Hepatic impairment. Dose adjustment is not required for patients with hepatic impairment (see sections "Pharmacological properties", "Special precautions").
Children. Safety and efficacy of the drug in children under 12 years of age have not been established (see section "Pharmacological properties").
Method of administration
Administer orally. Tablets should be taken with food.
Tablets may be crushed and dissolved in approximately 100 mL of water, orange juice, or grape juice, and taken immediately.
Children
Safety and efficacy of the drug in children under 12 years of age have not been established (see section "Pharmacological properties").
Overdose
In case of overdose, patients should be monitored for signs of toxicity (see section "Adverse reactions"); if necessary, standard supportive treatment should be administered.
Approximately 30% of the emtricitabine dose and about 10% of the tenofovir dose may be removed by hemodialysis. It is not known whether emtricitabine or tenofovir is eliminated by peritoneal dialysis.
Adverse Reactions
Safety profile
Treatment of HIV-1 infection. In a clinical trial involving adults, the most common adverse reactions considered probably related to emtricitabine and/or tenofovir disoproxil fumarate were nausea (12%) and diarrhea (7%). The safety profile of emtricitabine and tenofovir disoproxil fumarate in this trial was consistent with the previous experience with each of these agents administered separately with other antiretroviral agents.
Pre-exposure prophylaxis (PrEP). In two clinical trials in which 2830 HIV-1-uninfected adults received emtricitabine/tenofovir once daily for pre-exposure prophylaxis, no new adverse reactions to emtricitabine/tenofovir were identified. Patients were followed for a median of 71 and 87 weeks, respectively. The most common adverse reaction reported in the emtricitabine/tenofovir group in one of the trials was headache (1%).
Summary table of adverse reactions
Adverse reactions that may have been related to the components of the medicinal product and observed in clinical trials and post-marketing experience in HIV-1-infected patients are listed in Table 3 below by system organ class and frequency. Within each frequency group, adverse events are presented in order of decreasing severity. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), or rare (≥ 1/10000 to < 1/1000).
Table 3
Adverse reactions associated with individual components of the medicinal product based on clinical trial and post-marketing experience
| Frequency |
Emtricitabine |
Tenofovir disoproxil fumarate |
| Blood and lymphatic system disorders |
||
| common |
neutropenia |
|
| uncommon |
anemia2 |
|
| Immune system disorders |
||
| common |
allergic reactions |
|
| Metabolism and nutrition disorders |
||
| very common |
hypophosphatemia1 |
|
| common |
hyperglycemia, hypertriglyceridemia |
|
| uncommon |
hypokalemia1 |
|
| rare |
lactic acidosis |
|
| Psychiatric disorders |
||
| common |
insomnia, abnormal dreams |
|
| Nervous system disorders |
||
| very common |
headache |
dizziness |
| common |
dizziness |
headache |
| Gastrointestinal disorders |
||
| very common |
diarrhea, nausea |
diarrhea, vomiting, nausea |
| common |
increased amylase levels, including increased pancreatic amylase levels, increased serum lipase levels, vomiting, abdominal pain, dyspepsia |
abdominal pain, abdominal distension, flatulence |
| uncommon |
pancreatitis |
|
| Hepatobiliary disorders |
||
| common |
increased serum aspartate aminotransferase (AST) and/or increased serum alanine aminotransferase (ALT) levels, hyperbilirubinemia |
increased transaminase levels |
| rare |
fatty liver degeneration, hepatitis |
|
| Skin and subcutaneous tissue disorders |
||
| very common |
rash |
|
| common |
vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin color changes (increased pigmentation)2 |
|
| uncommon |
angioedema3 |
|
| rare |
angioedema |
|
| Musculoskeletal and connective tissue disorders |
||
| very common |
increased creatine kinase levels |
|
| common |
decreased bone mineral density |
|
| uncommon |
acute skeletal muscle necrosis1, muscle weakness1 |
|
| rare |
osteomalacia (manifested as bone pain and infrequently contributing to fractures)1,3, myopathy1 |
|
| Renal and urinary disorders |
||
| uncommon |
increased creatinine levels, proteinuria, proximal renal tubulopathy, including Fanconi syndrome |
|
| rare |
renal failure (acute and chronic), acute tubular necrosis, nephritis (including acute interstitial nephritis)3, nephrogenic diabetes insipidus |
|
| General disorders and administration site conditions |
||
| very common |
asthenia |
|
| common |
pain, asthenia |
|
1 A side effect may occur as a result of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition.
2 Anaemia was frequent, skin discoloration (increased pigmentation) was very common when emtricitabine was administered to paediatric patients.
3 This adverse reaction was identified during post-marketing surveillance, but was not observed in clinical trials in adults or clinical trials of emtricitabine for HIV treatment in children, or in clinical trials or expanded access programmes with tenofovir disoproxil fumarate. The frequency category was established based on statistical calculations using the total number of patients who received emtricitabine in clinical trials and expanded access programmes (n = 1563) or tenofovir disoproxil fumarate in clinical trials and expanded access programmes (n = 7319).
Description of selected adverse reactions
Renal failure. Since the medicinal product may lead to kidney impairment, monitoring of renal function is recommended (see section "Special warnings and precautions for use"). Proximal renal tubulopathy was generally reversible or improved after discontinuation of tenofovir disoproxil fumarate. However, in some HIV-infected patients, reduced creatinine clearance did not completely resolve despite discontinuation of tenofovir disoproxil fumarate. Patients at risk of renal function impairment (e.g., patients with baseline risk factors for renal disorders, patients with progressive HIV disease, or patients receiving concomitant therapy with nephrotoxic medicinal products) have an increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil fumarate (see section "Special warnings and precautions for use").
Lactic acidosis. Cases of lactic acidosis have been reported during treatment with tenofovir disoproxil alone or in combination with other antiretroviral medicinal products. Patients with predisposing conditions, specifically those with decompensated liver disease or those taking concomitant medications that may cause lactic acidosis, have an increased risk of developing severe lactic acidosis during treatment with tenofovir disoproxil, sometimes with fatal outcome.
Metabolic parameters. During antiretroviral therapy, a patient's body weight as well as blood lipid and glucose levels may increase (see section "Special warnings and precautions for use").
Immune reconstitution syndrome. In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic pathogens may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset of disease was highly 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 observed in patients with risk factors, advanced HIV disease, or with long-term use of combination antiretroviral therapy. The frequency of this event is unknown (see section "Special warnings and precautions for use").
Elderly patients. The use of the medicinal product in patients aged 65 years and older has not been studied. Elderly patients are more likely to have decreased renal function; therefore, caution should be exercised when administering the medicinal product to elderly patients (see section "Special warnings and precautions for use").
Paediatric patients
The assessment of adverse reactions for emtricitabine is based on three paediatric studies (n = 169), in which HIV-infected patients aged from 4 months to 18 years received emtricitabine in combination with other antiretroviral medicinal products: treatment-naïve patients (n = 123) and treatment-experienced patients (n = 46). In addition to adverse reactions reported in adults, anaemia (9.5%) and skin discoloration (31.8%) occurred more frequently in paediatric clinical trials than in adults (see section "Adverse reactions", Summary table of adverse reactions).
The assessment of adverse reactions for tenofovir disoproxil fumarate is based on two studies in which 184 HIV-1-infected paediatric patients (aged 2 to 18 years) received tenofovir disoproxil fumarate (n = 93) or placebo/active comparator (n = 91) in combination with other antiretroviral medicinal products. Treatment lasted for 48 weeks (see section "Pharmacological properties"). Adverse reactions in paediatric patients receiving tenofovir disoproxil fumarate were consistent with those observed in clinical trials of tenofovir disoproxil fumarate in adults (see sections "Pharmacological properties" and "Adverse reactions", Summary table of adverse reactions).
Decreased BMD was observed in paediatric patients. In HIV-1-infected adolescents (aged 12 to 18 years), BMD Z-scores were lower with tenofovir disoproxil fumarate compared to placebo. In HIV-1-infected children (aged 2 to 15 years), BMD Z-scores after switching to tenofovir disoproxil fumarate were lower than with continuation of a regimen containing stavudine or zidovudine (see sections "Pharmacological properties", "Special warnings and precautions for use").
In a study, 89 paediatric patients with a mean age of 7 years (range 2 to 15 years) received tenofovir disoproxil fumarate for a mean duration of 331 weeks. Eight out of 89 patients (9.0%) discontinued the clinical trial due to renal adverse events. Clinical laboratory assessments for proximal renal tubulopathy were conducted in five patients (5.6%), four of whom discontinued tenofovir disoproxil fumarate treatment. Glomerular filtration rate (GFR) was measured in seven patients and ranged from 70 to 90 mL/min/1.73 m². Three of these patients experienced clinically significant decreases in GFR during therapy, which improved after discontinuation of tenofovir disoproxil fumarate.
Other special patient groups
Patients with renal impairment. Since tenofovir disoproxil fumarate may lead to nephrotoxicity, careful monitoring of renal function is recommended in all adults with renal impairment receiving the medicinal product (see sections "Pharmacological properties", "Special warnings and precautions for use", "Dosage and administration"). The medicinal product is not recommended for paediatric patients with renal impairment (see sections "Special warnings and precautions for use", "Dosage and administration").
Patients with concomitant HIV/hepatitis B or C virus infections. The adverse reaction profile of emtricitabine and tenofovir disoproxil fumarate in a limited number of HIV-infected patients who were also co-infected with hepatitis B virus (n = 13) and hepatitis C virus (n = 26) during the study was similar to that observed in HIV-infected patients without concomitant infection. However, as expected in this patient population, elevations in AST and ALT levels were observed more frequently than in the general HIV-infected population.
Hepatitis exacerbation after discontinuation of treatment. After discontinuation of treatment, clinical and laboratory signs of hepatitis exacerbation occurred in patients infected with hepatitis B virus (see section "Special warnings and precautions for use").
Reporting of adverse reactions
Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of this medicinal product. Healthcare professionals and patients, or their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.
Packaging. 30 tablets in a container; 1 container in a cardboard box.
Prescription status. Prescription only.
Manufacturer. HETERO LABS LIMITED / Hetero Labs Limited.
Manufacturer's address and location of its operations
Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India / Unit ІІІ, Formulation Plot Nо 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.