TAVIN-EM

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TAVIN-EM (TAVIN-EM)

Composition:

Active substances: tenofovir disoproxil fumarate, emtricitabine;

One film-coated tablet contains: tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, pregelatinized starch, magnesium stearate, Opadry AMB white 80W68912 coating: polyvinyl alcohol, titanium dioxide (E 171), talc, lecithin, xanthan gum.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated tablets, white to almost white in color, with "EM" debossed on one side and "144" on the other.

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 is converted in vivo to tenofovir, a nucleotide analogue of adenosine monophosphate. Both emtricitabine and tenofovir exhibit specific activity against 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 used in combination within cells. Emtricitabine triphosphate and tenofovir diphosphate competitively inhibit HIV-1 reverse transcriptase, resulting in chain termination of viral DNA.

Both emtricitabine 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 was observed with the combination of emtricitabine and tenofovir in vitro. Additive effects were 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. Viruses resistant to emtricitabine with the M184V/I mutation were cross-resistant to lamivudine but remained sensitive to didanosine, stavudine, tenofovir, and zidovudine. The K65R mutation may also occur with abacavir or didanosine use and leads to reduced susceptibility to these agents, as well as to lamivudine, emtricitabine, and tenofovir. Patients with HIV-1 harboring the K65R mutation should avoid using tenofovir disoproxil. Additionally, the K70E substitution in HIV-1 reverse transcriptase is selected by tenofovir and leads to significant reduction in susceptibility to abacavir, emtricitabine, lamivudine, and tenofovir.

Patients with HIV-1 who have three or more thymidine analogue-associated mutations (TAMs), including either the M41L or L210W reverse transcriptase mutation, exhibited reduced susceptibility to tenofovir disoproxil fumarate.

In vivo. In an open-label randomized clinical trial (GS-01-934) 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, 144, or at the time of premature discontinuation of the investigational drug. At week 144:

• According to the analysis performed, the M184V/I mutation developed in 2 of 19 (10.5%) isolates from patients receiving emtricitabine/tenofovir disoproxil/efavirenz and in 10 of 29 (34.5%) isolates analyzed in patients receiving lamivudine/zidovudine/efavirenz (p < 0.05, Fisher's exact test comparison between patients receiving emtricitabine + tenofovir disoproxil and those receiving 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/efavirenz, compared to 21 of 29 (72%) patients in the comparator group.

Pediatric population.

The safety and efficacy of the drug in children under 12 years of age have not been established.

No clinical trials have been conducted in pediatric patients with HIV-1. The clinical efficacy and safety of the combination of tenofovir disoproxil fumarate and emtricitabine have been extrapolated from studies conducted with emtricitabine and tenofovir disoproxil fumarate as monotherapy.

Emtricitabine studies.

In studies using emtricitabine in infants and children aged 4 months and older, complete suppression of plasma HIV-1 RNA was achieved or maintained in the majority of cases by week 48 (89% achieved ≤ 400 copies/mL and 77% achieved ≤ 50 copies/mL).

Tenofovir disoproxil fumarate studies.

In study GS-US-104-0321, 87 HIV-1-infected patients aged 12 to 18 years received tenofovir disoproxil fumarate (n = 45) or placebo (n = 42) in combination with an optimized background regimen (OBR) for 48 weeks. Due to study limitations, the advantage 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 of adult data and comparative pharmacokinetic data (see section "Pharmacokinetics").

In patients receiving tenofovir disoproxil fumarate or placebo, mean Z-scores for lumbar spine bone mineral density (BMD) were -1.004 and -0.809, and mean Z-scores for whole-body BMD were -0.866 and -0.584 for tenofovir disoproxil fumarate or placebo, respectively. Mean changes at week 48 (end of 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 for tenofovir disoproxil fumarate or placebo, respectively. Mean BMD was lower with tenofovir disoproxil fumarate compared to placebo. At week 48, six adolescents receiving tenofovir disoproxil fumarate and one receiving placebo had significant lumbar spine BMD loss (defined as > 4%). Among 28 patients treated with tenofovir disoproxil fumarate for 96 weeks, BMD Z-scores decreased to -0.341 for lumbar spine and -0.458 for whole body.

In study GS-US-104-0352, 97 previously treated patients aged 2 to 12 years with stable virological suppression on regimens containing stavudine or zidovudine were randomized to either switch therapy: stavudine or zidovudine replaced by tenofovir disoproxil fumarate (n = 48) or continue their original 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 treatment group had HIV-1 RNA concentration < 400 copies/mL. The difference in the proportion of patients with levels < 400 copies/mL at week 48 was primarily influenced by a higher number of discontinuations in the tenofovir disoproxil fumarate group. When missing data were excluded, 91% of patients in the tenofovir disoproxil fumarate treatment group and 94% in the stavudine or zidovudine treatment group had HIV-1 RNA concentration < 400 copies/mL at week 48.

Reports of decreased BMD have been received 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 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 for tenofovir disoproxil fumarate and stavudine or zidovudine, respectively. Mean changes in lumbar spine BMD were similar between the tenofovir disoproxil fumarate and stavudine or zidovudine treatment groups. The overall rate of change in whole-body BMD in the tenofovir disoproxil fumarate treatment group was lower than in the stavudine or zidovudine treatment group. Treatment with tenofovir disoproxil fumarate alone without prior stavudine or zidovudine therapy led to significant (> 4%) lumbar spine BMD loss at week 48. BMD Z-scores decreased by -0.012 for lumbar spine and -0.338 for whole body in 64 individuals treated with tenofovir disoproxil fumarate for 96 weeks. BMD Z-scores were not corrected for growth and body size.

In study GS-US-104-0352, 4 of 89 pediatric patients exposed to tenofovir disoproxil fumarate discontinued treatment due to adverse reactions consistent with proximal renal tubulopathy (median duration of tenofovir disoproxil fumarate exposure was 104 weeks).

Pharmacokinetics.

Absorption. After oral administration of emtricitabine/tenofovir to healthy volunteers, emtricitabine and tenofovir disoproxil are rapidly absorbed, and tenofovir disoproxil is converted to tenofovir. Peak concentrations of emtricitabine and tenofovir in serum occur within 0.5 to 3.0 hours after dosing in the fasting state. Administration of emtricitabine/tenofovir with food delayed the time to peak concentration of tenofovir by approximately three-quarters of an hour and increased the AUC and Cmax of tenofovir by approximately 35% and 15%, respectively, when taken with a high-fat or light meal compared to fasting. To optimize absorption of tenofovir, 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, emtricitabine or tenofovir disoproxil is extensively distributed throughout the body. In vitro, binding of emtricitabine to human plasma proteins is < 4% and independent of concentration over the range of 0.02 to 200 mcg/mL. In vitro, binding of tenofovir to plasma or serum proteins was less than 0.7% and 7.2%, respectively, over the concentration range of tenofovir from 0.01 to 25 mcg/mL.

Biological transformation. Metabolism of emtricitabine is limited. Biotransformation of emtricitabine includes oxidation of the thiol moiety to form the 3'-sulfoxide diastereomer (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 nor tenofovir are substrates of CYP450 enzymes. Emtricitabine also does not inhibit uridine-5'-diphosphoglucuronosyltransferase, the enzyme responsible for glucuronidation.

Elimination. Emtricitabine is primarily eliminated by the kidneys (approximately 86%) and (approximately 14%) 13% of the emtricitabine dose was recovered 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.

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 mean clearance of tenofovir is approximately 307 mL/min. Renal clearance was estimated at approximately 210 mL/min, exceeding the glomerular filtration rate, indicating that tubular secretion is an important component of tenofovir elimination. After oral administration, the elimination half-life of tenofovir ranges from 12 to 18 hours.

Elderly patients. Pharmacokinetic studies of emtricitabine or tenofovir in elderly patients (over 65 years of age) have not been conducted.

Sex. Pharmacokinetics of emtricitabine and tenofovir are similar in male and female patients.

Ethnic origin. There is no clinically significant difference in emtricitabine pharmacokinetics related to ethnicity. Tenofovir pharmacokinetics has not been specifically studied in different ethnic groups.

Children. Pharmacokinetic studies of the combination of tenofovir disoproxil fumarate and emtricitabine have not been conducted in children and adolescents (under 18 years of age). Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1-infected adolescents (aged 12 to 18 years) with body weight > 35 kg and in 23 HIV-1-infected children aged 2 to 12 years. Exposure to tenofovir achieved in these patients receiving daily oral 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 exposure in adults receiving tenofovir disoproxil 245 mg (as fumarate) once daily. Pharmacokinetic studies of tenofovir disoproxil (as fumarate) have not been conducted in children under 2 years of age.

Overall, the pharmacokinetics of emtricitabine in infants, young children, and adolescents (aged 4 months to 18 years) are similar to those observed in adults.

Renal impairment. There are insufficient pharmacokinetic data on emtricitabine and tenofovir in patients with renal impairment after co-administration of these agents either separately or as a fixed-dose combination. Pharmacokinetic parameters were primarily determined after single doses of emtricitabine 200 mg or tenofovir disoproxil 245 mg administered to HIV-negative subjects with varying degrees of renal impairment. Degree of renal impairment was defined according to baseline creatinine clearance (CrCl) values (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 mcg•h/mL (25%) in patients with normal renal function to 20 mcg•h/mL (6%), 25 mcg•h/mL (23%), and 34 mcg•h/mL (6%) in subjects with mild, moderate, and severe renal impairment, respectively.

Mean (%CV) tenofovir exposure increased from 12 mcg•h/mL (25%) in patients with normal renal function to 20 mcg•h/mL (6%), 25 mcg•h/mL (23%), and 34 mcg•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 15,985 ng•h/mL (45%) in patients with mild, moderate, and severe renal impairment, respectively.

An increased dosing interval for emtricitabine/tenofovir in patients with moderate renal impairment is expected to result in higher Cmax and lower Cmin compared to patients with normal renal function.

In patients with end-stage renal disease requiring hemodialysis, emtricitabine exposure significantly increased over 72 hours to 53 mcg•h/mL (19%) and tenofovir over 48 hours to 42,857 ng•h/mL (29%).

A small clinical trial was conducted to evaluate the safety, antiviral activity, and pharmacokinetics of tenofovir disoproxil 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, daily dosing led to a 2- to 4-fold increase in tenofovir exposure and worsening renal function.

Pharmacokinetic studies of emtricitabine and tenofovir in children with renal impairment have not been conducted. There are no data available to provide dose recommendations (see sections "Special precautions", "Dosage and administration").

Hepatic impairment. The pharmacokinetics of emtricitabine/tenofovir disoproxil in patients with hepatic impairment have not been studied.

Emtricitabine pharmacokinetics has 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 was similar to that in healthy HBV-negative volunteers and HIV-infected patients.

A single 245 mg dose of tenofovir disoproxil was administered to HIV-negative patients with varying degrees of hepatic impairment classified according to the Child-Pugh-Turcotte (CPT) score. Pharmacokinetic parameters of tenofovir were not significantly altered in patients with hepatic impairment, indicating no need for dose adjustment in these patients. Mean (% CV) values of Cmax and AUC0-∞ 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.

Tavin-EM is indicated in combination antiretroviral therapy for the treatment of HIV-1 infected adults. The drug is also indicated for the treatment of HIV-1 infected adolescents aged 12 to 18 years who have resistance to nucleoside reverse transcriptase inhibitors or toxicity precluding the use of first-line agents (see section "Pharmacodynamics").

Contraindications.

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

Contraindicated in children under 12 years of age.

Interaction with other medicinal products and other forms of interactions.

Interaction studies have been conducted only in adults.

Since the product contains emtricitabine and tenofovir disoproxil, any interactions previously observed with these substances individually may also occur with Tavin-EM.

The steady-state pharmacokinetics of emtricitabine and tenofovir were not affected when emtricitabine and tenofovir disoproxil were administered together compared to administration of each medicinal product separately.

In vitro and clinical pharmacokinetic interaction studies showed a low potential for CYP450-mediated interactions of emtricitabine and tenofovir disoproxil with other medicinal products.

Concomitant use is not recommended.

Tavin-EM should not be taken concomitantly with other medicinal products containing emtricitabine, tenofovir disoproxil (as fumarate), tenofovir alafenamide, or other cytidine analogues such as lamivudine (see section "Special precautions for use"). Tavin-EM should not be taken concomitantly with adefovir dipivoxil.

Didanosine. Concomitant administration of Tavin-EM and didanosine is not recommended (see section "Special precautions for use" and Table 1).

Medicinal products eliminated via kidneys. Since emtricitabine and tenofovir are primarily eliminated by the kidneys, concomitant administration of Tavin-EM with other medicinal products eliminated via active tubular secretion (e.g., cidofovir) may lead to increased serum concentrations of emtricitabine and/or concomitantly administered medicinal products due to competition for this elimination pathway.

Concomitant or recent use of nephrotoxic medicinal products with Tavin-EM should be avoided, including aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2 (see section "Special precautions for use").

Other interactions.

Interactions between Tavin-EM or its components and other medicinal products are presented in Table 1 below (increases are indicated by "↑", decreases by "↓", no change by "↔", twice daily by "2 r/d", and once daily by "1 r/d"). Where possible, 90% confidence intervals are provided in parentheses.

Table 1. Interactions between the medicinal product Tavin-EM or its component(s) and other medicinal products

Table 1

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.

Special precautions.

HIV transmission. Since effective viral suppression with antiretroviral therapy using Tavin-EM has not been proven to substantially reduce the risk of sexual transmission of infection, residual risk cannot be excluded. Preventive measures to avoid transmission should be taken in accordance with national recommendations.

Patients with HIV-1 mutations.

Tavin-EM should be avoided in antiretroviral-experienced patients infected with HIV-1 strains carrying the K65R mutation (see section "Pharmacodynamics").

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 guidelines for HIV treatment when managing HIV infection in patients with concomitant hepatitis B (HBV) or C (HCV) virus infection.

When prescribing concomitant antiviral therapy for hepatitis B or C, reference should also be made to the appropriate product information for these medicinal products (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 demonstrated activity against hepatitis B virus in pharmacodynamic studies; however, the safety and efficacy of Tavin-EM for the treatment of patients with chronic HBV infection have not been established.

Discontinuation of Tavin-EM in patients with concomitant HIV and HBV infection may be associated with severe acute exacerbations of hepatitis. Patients co-infected with HIV and HBV who discontinue the drug must be closely monitored both clinically and through laboratory testing for several months after stopping treatment. Reinitiation of hepatitis B therapy may be warranted if necessary. Discontinuation of therapy is not recommended in patients with advanced liver disease or cirrhosis, as hepatitis flare after treatment may lead to hepatic decompensation.

Liver disease.

The safety and efficacy of Tavin-EM in patients with pre-existing severe 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 of Tavin-EM (see sections "Pharmacokinetics" and "Dosage and administration").

Patients with prior hepatic dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard clinical practice. If there is evidence of worsening liver disease, consideration should be given to interrupting or discontinuing therapy in such patients.

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. Renal failure, renal dysfunction, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy have been reported with the use of tenofovir disoproxil fumarate (see section "Adverse reactions").

Renal monitoring.

Prior to initiating HIV-1 infection treatment with Tavin-EM, creatinine clearance 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 initiation and every 3–6 months thereafter. Patients at risk for kidney disease require more frequent renal function monitoring.

See also "Concomitant use of other medicinal products" below.

Renal management in HIV-1-infected patients.

If serum phosphate is <1.5 mg/dL (0.48 mmol/L) or creatinine clearance decreases to <50 mL/min in any patient taking Tavin-EM, renal function should be re-evaluated within one week, including measurement of blood glucose and potassium concentrations and urine glucose (see section "Adverse reactions"). Treatment with Tavin-EM should be discontinued in patients with creatinine clearance <50 mL/min or serum phosphate concentration reduced to <1.0 mg/dL (0.32 mmol/L). Discontinuation of Tavin-EM should also be considered in cases of progressive renal function decline if no other cause is identified. The safety of Tavin-EM 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 creatinine clearance of 30–49 mL/min, dosage interval adjustment is recommended (see section "Dosage and administration"). Limited clinical trial data suggest that prolonged dosing intervals may not be optimal and could lead to increased toxicity and possibly unknown responses. Moreover, in a small clinical study of patients with CrCl 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, careful benefit-risk assessment and close monitoring of renal function are required when Tavin-EM is administered to patients with CrCl <60 mL/min. Additionally, clinical response to therapy should be closely monitored in patients receiving Tavin-EM with prolonged dosing intervals. Use of Tavin-EM is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min) or in patients requiring hemodialysis, as the fixed-dose combination tablet does not allow for the necessary dose reduction (see sections "Pharmacological properties" and "Dosage and administration").

Bone effects.

Bone abnormalities (rarely leading to fractures) may be associated with proximal renal tubulopathy. If bone abnormalities are suspected, appropriate consultations should be obtained.

Bone effects.

Bone abnormalities (sometimes leading to fractures) may be associated with proximal renal tubulopathy (see section "Adverse reactions"). If bone abnormalities are suspected, appropriate consultations should be obtained.

In both groups of patients in a controlled clinical trial at week 144 comparing tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, slight decreases in BMD of the hip and spine were observed. Reductions in spine BMD and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group over 144 weeks. Hip BMD reduction was significantly greater in this group up to week 96. However, after 144 weeks, no increased risk of fractures or clinically significant bone abnormalities was observed.

In other studies (prospective and cross-sectional), the most pronounced BMD reduction was 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.

Renal and bone effects in pediatric populations.

There is uncertainty regarding the long-term effects of tenofovir disoproxil fumarate on bones and renal toxicity. Additionally, the reversibility of renal toxicity cannot be fully determined. Therefore, a multidisciplinary approach is recommended for each individual case to assess the benefit-risk ratio of treatment, make decisions regarding appropriate monitoring during therapy (including decisions on discontinuation), and consider the need for supplementation.

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 clinical trial GS-US-104-0352 (see sections "Adverse reactions" and "Pharmacodynamics").

Renal monitoring.

Prior to initiating treatment, renal function (creatinine clearance and serum phosphate) should be assessed and monitored during treatment as in HIV-1-infected adults (see above).

Renal function monitoring.

If serum phosphate levels are <3.0 mg/dL (0.96 mmol/L) in any pediatric patient receiving tenofovir and emtricitabine, renal function should be re-evaluated within one week, including measurement of blood glucose and potassium concentrations and urine glucose. If renal abnormalities are suspected or detected, consultation with a nephrologist should be sought to consider discontinuation of treatment. Discontinuation of tenofovir and emtricitabine treatment should also be considered in cases of progressive renal function decline if no other cause is identified.

Concomitant use of other medicinal products and risk of nephrotoxicity.

The same recommendations apply as in adults (see section "Concomitant use of other medicinal products" below).

Renal impairment.

The use of tenofovir and emtricitabine is not recommended in pediatric patients with renal impairment. Treatment with the drug should not be initiated in pediatric patients with renal impairment, and it should be discontinued in pediatric patients who develop renal impairment during treatment with tenofovir and emtricitabine.

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 remain unknown (see section "Pharmacodynamics"). If bone abnormalities are detected or suspected in pediatric patients, consultation with an endocrinologist and/or nephrologist is necessary.

Body weight and metabolic parameters.

Weight gain and increases in serum lipid and glucose levels may occur during antiretroviral therapy. These changes may be partially related to disease control and lifestyle. In some cases, treatment may influence lipid levels, but there is no substantial evidence linking weight gain to any specific drug. Current HIV treatment guidelines recommend monitoring lipid and glucose levels. Lipid abnormalities should be managed as clinically indicated.

Mitochondrial dysfunction following in utero exposure.

Nucleoside and nucleotide analogues can significantly affect mitochondrial function, particularly stavudine, didanosine, and zidovudine. Reports of mitochondrial dysfunction have been received in HIV-negative infants and young children exposed to nucleoside analogues in utero and/or postnatally; this primarily concerns 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 these neurological disorders are transient or permanent. These findings should be considered in any child exposed to nucleoside or nucleotide analogues in utero who presents with a clinical diagnosis of unknown etiology, particularly neurological diagnoses. 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 severe immunodeficiency at the time of initiation of combination antiretroviral therapy (CART), a symptomatic inflammatory reaction to asymptomatic or residual opportunistic pathogens may occur, potentially causing serious clinical conditions or worsening of symptoms. Such reactions are typically observed within the first few weeks or months of starting CART. Typical examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treated appropriately if necessary.

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

Opportunistic infections.

HIV-1-infected patients receiving tenofovir and emtricitabine or any other antiretroviral agents may still develop opportunistic infections and other complications of HIV infection and should remain under ongoing clinical monitoring 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, stiffness, or difficulty moving.

Concomitant use of other medicinal products.

The use of Tavin-EM should be avoided when administering nephrotoxic medicinal products concomitantly or recently (see section "Interaction with other medicinal products and other forms of interaction"). If concomitant use of Tavin-EM 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 and with risk factors for renal dysfunction after initiating high doses or multiple nonsteroidal anti-inflammatory drugs (NSAIDs). If Tavin-EM is used concomitantly with NSAIDs, renal function should be closely monitored.

An increased 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"). Concomitant use of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated in HIV-1-infected patients with risk factors for renal impairment.

Tavin-EM 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 "Interaction with other medicinal products and other forms of interaction"). Tavin-EM should not be administered 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 has been shown to increase tenofovir plasma concentrations, particularly when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic booster (ritonavir or cobicistat).

The safety of tenofovir disoproxil fumarate when co-administered with ledipasvir/sofosbuvir or sofosbuvir/velpatasvir and a pharmacokinetic booster has not been established. The potential risks and benefits of concomitant administration should be carefully considered, especially 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 use is not recommended, as it increases systemic exposure to didanosine by 40–60%, potentially increasing the risk of didanosine-related adverse reactions (see section "Interaction with other medicinal products and other forms of interaction"). Rare cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported. Concomitant use of tenofovir disoproxil fumarate and didanosine 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to intracellular interaction increasing phosphorylated (i.e., active) didanosine. A reduced dose of 250 mg didanosine administered with tenofovir disoproxil fumarate has been associated with reports of high rates of virological failure in several studied combinations.

Triple nucleoside therapy.

Reports of high rates of virological failure and early emergence of resistance have been received in HIV-1-infected patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine once daily. There is close structural similarity between lamivudine and emtricitabine and similar pharmacokinetic and pharmacodynamic profiles of these two drugs. Therefore, similar problems may occur when Tavin-EM is used with a third nucleoside analogue.

Elderly patients.

The effect of Tavin-EM has not been studied in individuals aged 65 years or older. Individuals aged 65 years or older often have reduced renal function; therefore, caution should be exercised when administering Tavin-EM to these patients.

Use during pregnancy or breastfeeding.

Pregnancy.

Limited data from pregnant women (300–1000 completed pregnancies) indicate no teratogenic or embryotoxic effects associated with emtricitabine and tenofovir disoproxil fumarate. Animal studies of emtricitabine and tenofovir disoproxil fumarate did not show reproductive toxicity. Therefore, use of the drug during pregnancy is possible 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 newborns/infants; therefore, Tavin-EM 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 drug in humans. Animal studies do not indicate harmful effects of emtricitabine and tenofovir disoproxil fumarate on fertility.

Ability to drive and use machines.

Studies on the effect on the ability to drive or operate machinery have not been conducted; however, patients should be informed about the potential for dizziness during treatment with both emtricitabine and tenofovir disoproxil fumarate.

Method of Administration and Dosage

Tavin-EM 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.

Separate emtricitabine and tenofovir disoproxil fumarate products are available for the treatment of HIV-1 infection if there is a need to discontinue or adjust the dose of either component of Tavin-EM (see the "Summary of Product Characteristics" for these medicinal products).

If less than 12 hours have passed since the missed dose of Tavin-EM, 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 next scheduled dose is approaching, the missed dose should not be taken; instead, resume the regular dosing schedule.

If vomiting occurs within 1 hour after taking Tavin-EM, another tablet should be taken. If vomiting occurs more than 1 hour after taking Tavin-EM, an additional dose is not required.

Special patient populations.

Elderly patients. No dose adjustment is necessary (see section "Pharmacokinetics").

Renal impairment. Emtricitabine and tenofovir are eliminated via the kidneys. The exposure to emtricitabine and tenofovir increases in patients with impaired renal function (see sections "Pharmacokinetics" and "Special precautions for use").

Adults with renal impairment. Tavin-EM may be used in patients with creatinine clearance 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

Pediatric patients with renal impairment. Tavin-EM is not recommended for patients under 18 years of age with impaired renal function (see section "Special instructions").

Hepatic impairment. Dose adjustment is not required for patients with hepatic impairment (see sections "Pharmacokinetics" and "Special instructions").

Children. The safety and efficacy of Tavin-EM in children under 12 years of age have not been established (see section "Pharmacokinetics").

Administration.

Oral use. Tavin-EM tablets should be taken with food.

The tablets may be crushed and dissolved in approximately 100 mL of water, orange juice, or grape juice and taken immediately.

Children.

The safety and efficacy of Tavin-EM in children under 12 years of age have not been established (see section "Pharmacokin游戏副本").

Overdose.

In the event of overdose, patients should be monitored for signs of toxicity (see section "Adverse reactions"). If necessary, standard supportive treatment should be administered. Up to 30% of the emtricitabine dose and approximately 10% of the tenofovir dose may be removed by hemodialysis. It is not known whether emtricitabine or tenofovir is removed by peritoneal dialysis.

Adverse reactions.

Safety profile.

In an open-label randomized clinical study in adults (GS-01-934, see section "Pharmacodynamics"), the most common adverse reactions considered possibly 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 study was consistent with the previous experience of using each of these agents separately with other antiretroviral drugs.

Summary table of adverse reactions.

Adverse reactions that may have been related to the components of Tavin-EM and observed in clinical studies and post-marketing experience in HIV-1-infected patients are listed in Table 3 below by system organ class and frequency. Within each frequency grouping, adverse events are listed 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 Tavin-EM and its components, based on clinical study and post-marketing experience

Table 3

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 common, skin colour change (increased pigmentation) was very common when emtricitabine was used in paediatric patients.

3 This adverse reaction was identified during post-marketing surveillance, but was not observed in randomized controlled clinical trials in adults or clinical trials of emtricitabine treatment of HIV in children, or in randomized controlled clinical trials or the expanded access program of tenofovir disoproxil fumarate. The frequency category was established based on statistical calculations using the total number of patients who received emtricitabine in randomized controlled clinical trials and the expanded access program (n = 1563) or tenofovir disoproxil fumarate in randomized controlled clinical trials and the expanded access program (n = 7319).

Description of selected adverse reactions.

Renal impairment. Since Tavin-EM may lead to kidney dysfunction, monitoring of renal function is recommended. Proximal renal tubulopathy was generally resolved or improved after discontinuation of tenofovir disoproxil fumarate. However, in some HIV-infected patients, reduced creatinine clearance did not fully resolve despite discontinuation of tenofovir disoproxil fumarate. Patients at risk of renal function impairment (e.g., patients with baseline risk factors for kidney disorders, patients with progressive HIV disease, or patients receiving concomitant therapy with nephrotoxic agents) have an increased risk of incomplete recovery of renal function despite discontinuation of tenofovir disoproxil fumarate (see section "Special precautions").

Interaction with didanosine. Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended, as it leads to a 40–60% increase in the exposure to didanosine, which may increase the risk of didanosine-related adverse reactions (see section "Interaction with other medicinal products and other forms of interaction"). Cases of pancreatitis and lactic acidosis, sometimes fatal, have been rarely reported.

Metabolic parameters: During antiretroviral therapy, a patient's body weight, lipid levels in the blood, and glucose levels may increase (see section "Special precautions").

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) have also been reported; however, the reported time to onset of disease varied widely, and these events may occur many months after initiation of treatment (see section "Special precautions").

Osteonecrosis. Cases of osteonecrosis have been observed in patients with risk factors, advanced HIV disease, or with prolonged use of combination antiretroviral therapy. The frequency of this phenomenon is unknown (see section "Special precautions").

Elderly patients. 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 Tavin-EM to elderly patients (see section "Special precautions").

Paediatric patients.

The assessment of adverse reactions related to 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 agents: treatment-naïve patients (n = 123) and treatment-experienced patients (n = 46). In addition to adverse reactions reported in adults, anaemia (9.5%) and skin colour changes (31.8%) occurred more frequently in clinical trials in children than in adults (see section "Adverse reactions", summary table of adverse reactions).

The assessment of adverse reactions related to tenofovir disoproxil fumarate is based on two randomized studies (studies GS-US-104-0321 and GS-US-104-0352), 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 agents. 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 section "Pharmacodynamics", "Adverse reactions").

Decreased bone mineral density has been observed in paediatric patients. In HIV-1-infected adolescents (aged 12 to 18 years), bone mineral density Z-scores were lower with tenofovir disoproxil fumarate than with placebo. In HIV-1-infected children (aged 2 to 15 years), bone mineral density Z-scores in patients who switched to tenofovir disoproxil fumarate were lower than in those who continued treatment with regimens containing stavudine or zidovudine.

In study GS-US-104-0352, 89 paediatric patients with a median age of 7 years (aged 2 to 15 years) received tenofovir disoproxil fumarate for a median duration of 313 weeks. Four out of 89 patients discontinued treatment due to adverse reactions, specifically proximal renal tubulopathy. Seven patients had glomerular filtration rate (GFR) measured between 70 and 90 mL/min/1.73 m². Among them, two 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 Tavin-EM. Tavin-EM is not recommended for paediatric patients with renal impairment.

Patients with concomitant HIV/hepatitis B virus or hepatitis C virus infections. The adverse reaction profile of emtricitabine and tenofovir disoproxil fumarate in a limited number of HIV-infected patients co-infected with hepatitis B virus (n = 13) and hepatitis C virus (n = 26) in study GS-01-934 was similar to that observed in HIV-infected patients without concomitant infection. However, as expected in this patient population, elevations in liver enzymes were observed more frequently than in the general HIV-infected population.

Hepatitis flare after discontinuation of treatment. After discontinuation of treatment, clinical and laboratory signs of hepatitis flare have occurred in patients infected with hepatitis B virus (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

30 tablets in a plastic bottle containing a silica gel desiccant. One plastic bottle in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Emcure Pharmaceuticals Ltd.

Manufacturer's address and place of business.

Plot No. P-1 and P-2, ITVT Park, Phase II, MIDC, Hinjewadi, Pune - 411 057, Maharashtra, India.