Virfoten pills 300mg, 30pcs

Composition

Active ingredient:

Tenofovir disoproxil fumarate 300 mg

Auxiliary substances:

Each film-coated tablet contains:

The core:  sodium carboxymethyl starch (primogel) – 33.0 mg, sodium stearyl fumarate-11.8 mg, croscarmellose sodium-42.0 mg, lactose monohydrate-72.0 mg, hypromellose E-15-9.6 mg, microcrystalline cellulose-131.6 mg.

Ready-made water-soluble film shell – 18.0 mg.

(Shell composition: hypromellose-74.2%, macrogol 6000-14.3%, titanium dioxide-3.5%, talc – 2.3%, iron oxide red dye-1.4%, iron oxide yellow dye-4.3%).

Pharmacological action

Pharmacotherapy group: Antiviral agentath: J. 05. A. F. 07 Tenofovir Pharmacodynamics :

Mechanism of action

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug of tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the Active ingredient tenofovir, which is an analog of nucleoside monophosphate (nucleotide). Tenofovir is then converted to the active metabolite, tenofovir diphosphate, which is an obligate chain terminator, by constructively expressed cellular enzymes.

Tenofovir diphosphate has an intracellular half-life of 10 hours in activated peripheral blood mononuclear cells and 50 hours at rest.

Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and hepatitis B virus (HBV) polymerase by competing for direct binding to the active site of the enzyme with a natural deoxyribonucleotide substrate and breaking the DNA chain after incorporation into it.

Tenofovir diphosphate is a weak inhibitor of cell polymerases α, β and γ.

In vitro analyses of tenofovir at concentrations up to 300 mmol / L also showed no effect on mitochondrial DNA synthesis or lactic acid production.

Anti-HIV activism

Anti-HIV activity in vitro

The concentration of tenofovir required for 50% inhibition (EC50 – 50% effective concentration) of the laboratory strain of wild-type HIV – 1IIIB is 1-6 mmol/l in the lymphoid cell line and 1.1 mmol/l against primary isolates of HIV-1 subtype B in peripheral blood mononuclear cells.

Tenofovir is also active against HIV-1 subtypes A, C, D, E, F, G and O, as well as against HIVVal in primary monocytes/macrophages.

Tenofovir is also active in vitro against HIV-2 with a 50% effective EC50 concentration of 4.9 mmol / L in MT-4 cells.

Activity against HBV

Activity against HBV in vitro

The antiviral activity of tenofovir against HBV in vitro was evaluated on the HepG2 2.2.15 cell line. EC50 values for tenofovir ranged from 0.14 to 1.5 mmol/l, and CC50 values (50% cytotoxic concentration) exceeded 100 mmol/l.

Resistance

HIV

– 1 strains with reduced sensitivity to tenofovir and K65R replacement in the reverse transcriptase gene were isolated in vitro and in some patients. Tenofovir disoproxil fumarate should be avoided in patients who have previously received antiretroviral therapy and whose strains contain the K65R mutation.

In clinical trials in patients who had previously received antiretroviral therapy, the anti-HIV activity of 300 mg of tenofovir disoproxil fumarate against HIV-1 strains with resistance to nucleoside inhibitors was evaluated. The results showed that patients with HIV who expressed 3 or more thymidine analog-related mutations, including M41L or L210W substitutions in reverse transcriptase, showed a reduced response to 300 mg tenofovir disoproxil fumarate therapy.

HBV resistance

No mutations were found in HBV polymerase associated with resistance to tenofovir disoproxil fumarate. In cell models, HBV variants expressing rtV173L, rtL180M, and rtM2041/V substitutions associated with lamivudine and telbivudine resistance demonstrated sensitivity to tenofovir 0.7-3.4 times higher than that of the wild-type virus.

HBV strains expressing substitutions rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V associated with entecavir resistance showed a sensitivity to tenofovir 0.6-6.9 times greater than that of the wild-type virus.

HBV strains expressing rtA181V and rtN236T substitutions associated with adefovir resistance showed a sensitivity to tenofovir 2.9-10 times greater than that of the wild-type virus.

Viruses containing the rtA 181 T replacement remained sensitive to tenofovir, and the EC50 values were 1.5 times higher than those of the wild-type virus.

Pharmacokinetics: Tenofovir disoproxil fumarate is a water-soluble prodrug ester that is rapidly converted in vivo to tenofovir and formaldehyde. Tenofovir is converted intracellularly to tenofovir monophosphate and the active ingredient is tenofovir diphosphate.

Suction

After oral use of tenofovir disoproxil to HIV-infected patients, byezro fumarate is absorbed and converted to tenofovir.

use of multiple doses of tenofovir disoproxil fumarate with food to HIV-infected patients resulted in mean (coefficient of variation,% [CV,%]) values for tenofovir Cmax, AUC, and Cmin of 326 (36.6%) ng / ml,3324 (41.2%) ng*h/ml, and 64.4 (39.4%) ng/ml, respectively.

The maximum concentrations of tenofovir are observed in the blood serum within 1 hour after ingestion on an empty stomach and within 2 hours when it is taken with food. When tenofovir disoproxil fumarate was administered to patients on an empty stomach, the bioavailability was approximately 25%. use of tenofovir disoproxil fumarate with a fat-rich diet increased bioavailability, with the AUC of tenofovir increasing by approximately 40% and the Cmax by approximately 14%. After the first dose of tenofovir disoproxil fumarate obtained after a high-fat meal, the median serum Cmax was in the range of 213 to 375 ng / ml. However, taking tenofovir disoproxil fumarate with low-calorie food does not significantly affect the pharmacokinetics of tenofovir.

Distribution

After intravenous use, the steady-state distribution concentration of tenofovir was estimated at approximately 800 ml / kg. After oral use of tenofovir disoproxil fumarate, tenofovir is distributed to many tissues, with the highest concentrations observed in the kidneys, liver and intestinal epithelium in different parts of the intestine (preclinical studies).

In vitro binding of tenofovir to plasma or serum proteins was less than 0.7 and 7.2%, respectively, in the range of tenofovir concentrations from 0.01 to 25 mcg / ml.

Metabolism

In vitro studies have shown that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Moreover, at concentrations significantly exceeding (approximately 300 times) Those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the major human CYP450 isoforms involved in biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2).

Tenofovir disoproxil fumarate at a concentration of 100 mmol / L had no effect on any of the CYP450 isoforms, with the exception of CYP1A1/2, where a small (6%) but statistically significant decrease in the metabolism of the CYP1A1/2 substrate was observed. Based on this information, it can be concluded that there is a low probability of clinically significant interactions between tenofovir disoproxil fumarate and drugs whose metabolism is mediated by CYP450.

Deduction

Tenofovir is mainly excreted by the kidneys, both by filtration and by the active tubular transport system, and after intravenous use, approximately 70-80% of the dose is excreted unchanged in the urine. Total clearance was estimated at approximately 230 ml / h / kg (approximately 300 ml / min). Renal clearance was estimated at approximately 160 ml / h / kg (about 210 ml / min), which exceeds the glomerular filtration rate. This indicates that tubular secretion is an important part of tenofovir elimination.

After oral use, the final half-life of tenofovir is 12 to 18 hours.

Studies have shown that the active tubular transport system of secretion involves the uptake of tenofovir by proximal tubular cells via human organic anionic transporters (hOAT) 1 and 3, and its excretion in the urine using the multi-drug resistance marker protein 4 (MRP 4).

Linearity-non-linearity

The pharmacokinetics of tenofovir did not depend on the dose of tenofovir disoproxil fumarate in the range from 75 to 600 mg and did not change with repeated use at any dose level.

Pharmacokinetics in special patient groups

Elderly patients

Pharmacokinetics of tenofovir in elderly patients (older than 65 years) not studied.

Gender

Limited data on the pharmacokinetics of tenofovir in women indicate that there is no significant gender-specific exposure.

Race

No specific pharmacokinetic studies have been conducted in different ethnic groups.

Children

with HIV-1

Pharmacokinetic parameters of tenofovir at steady state were evaluated in 8 children (aged 12-18 years) with a body weight > 35 kg infected with HIV-1. Mean (±SD) Cmax and AUCtau values were 0.38 ± 0.13 mcg / ml and 3.39 ± 1.22 mcg * h / ml, respectively.

The exposure to tenofovir that was achieved in adolescents who received daily doses of 300 mg of tenofovir disoproxil fumarate orally was similar to that achieved in adults who received single daily doses of 300 mg of tenofovir disoproxil fumarate.

Chronic hepatitis B

Steady-state exposure to tenofovir in children (ages 12 to 18 years) infected with hepatitis B virus who received an oral daily dose of 300 mg of tenofovir disoproxil fumarate was similar to that achieved in adults who received doses of 300 mg of tenofovir disoproxil fumarate once a day.

The pharmacokinetics of 300 mg tenofovir disoproxil fumarate have not been studied in children under 12 years of age or in children with impaired renal function.

Impaired renal function

The pharmacokinetic parameters of tenofovir were determined after use of a single dose of 300 mg of tenofovir disoproxil fumarate to 40 adult patients without HIV and HBV infection with varying degrees of renal impairment, which were determined according to the initial value of creatinine clearance (creatinine clearance) (renal function is not impaired if creatinine clearance is > 80 ml/min, mild impairment – if creatinine clearance is 50-79 ml/min, moderate impairment – with creatinine clearance 30-49 ml/min and severe impairment – with creatinine clearance 10-29 ml/min).

Compared with patients with normal renal function, the mean (%CV) exposure to tenofovir increased from 2,185 (12%) ng*h/ml in subjects with creatinine clearance > 80 ml/min to 3,064 (30%) ng*h/ml,6,009 (42%) ng*h/ml, and 15,985 (45%) ng * h/ml in patients with mild, moderate, and severe renal impairment, respectively.

It is expected that an increase in the interval between drug use will lead to higher peak plasma concentrations and lower Cmin levels in patients with impaired renal function compared to patients with normal renal function. The clinical significance of this is unknown.

In patients with end-stage renal insufficiency (CC

It is recommended that the interval between doses of 300 mg of tenofovir disoproxil fumarate be changed in adult patients with CC

Pharmacokinetics of tenofovir in non-hemodialysis patients with CC The pharmacokinetics of tenofovir in children with renal insufficiency have not been studied. Data on dosage recommendations are not available.

Impaired liver function

A single dose of 300 mg of tenofovir disoproxil fumarate was administered to patients not infected with HIV and HBV, with varying degrees of hepatic impairment, as defined by the Child-Pugh classification.

In patients with impaired liver function, no significant changes in the pharmacokinetics of tenofovir were observed, which suggests that there is no need for dose adjustment. Mean (%CV) values of Cmax and AUC0-∞ of tenofovir were 223 (34.8%) ng / ml and 2,050 (50.8%) ng*h/ml, respectively, in individuals without hepatic impairment,289 (46.0%) ng/ml and 2,310 (43.5%) ng*h/ml in individuals with moderate hepatic impairment,305 (24.8%) ng/ml, and 2,740 (44.0%) ng*h/ml in individuals with severe hepatic impairment.

Intracellular pharmacokinetics

It was found that in non-dividing human peripheral blood mononuclear cells (MCPC), the half-life of tenofovir diphosphate is approximately 50 hours, while in MCPC stimulated by phytohemagglutinin, it is approximately 10 hours.

Indications

HIV-1 infection

Treatment of HIV-1 infection in adults in combination with other antiretroviral drugs.

Treatment of HIV-1 infection in children aged 12-18 years with resistance to nucleotide reverse transcriptase inhibitors, or toxicity that precludes the use of first-line antiretroviral drugs.

Hepatitis B infection

Treatment of chronic hepatitis B in adults with:

• compensated liver disease with signs of active viral replication, persistent increased serum alanine aminotransferase (ALT) activity and histologically confirmed active inflammatory process and/or fibrosis;
• proven HBV resistance to lamivudine;
• decompensated liver disease.

Treatment of chronic hepatitis B in children aged 12-18 years with

• compensated liver disease with signs of an active inflammatory process and active viral replication, which is confirmed by constant increased ALT activity in blood serum and histologically confirmed active inflammatory process and / or fibrosis.

Use during pregnancy and lactation

Pregnancy

Data obtained from a sample of average volume in pregnant women (from 300 to 1000 pregnancy outcomes) indicate that there are no malformations or toxic effects on the fetus/newborn that would be associated with taking tenofovir.

Animal studies have not indicated toxic effects on reproductive function. Thus, if necessary, the possibility of using tenofovir during pregnancy may be considered.

Breast-feeding period

Studies have shown that tenofovir is excreted in breast milk. Data on the effect of tenofovir on newborns/children are insufficient. Therefore, tenofovir should not be used during breast-feeding.

In general, women infected with HIV and HBV should not breastfeed to avoid transmission of HIV and HBV to the child.

Fertility

There are no data available on the effect of tenofovir on human fertility. Animal studies do not indicate a harmful effect of tenofovir on fertility.

Contraindications

-Hypersensitivity to the Active ingredient or any other component of the drug.

– Children under 12 years of age and body weight

– Children aged 12-18 years with impaired renal function (there are no recommendations on the dosage regimen).

– Severe renal insufficiency (CC

– Lactation period.

– Concomitant use with other drugs containing tenofovir,

– Concomitant use with adefovir.

– In patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution:

– In patients with diabetes mellitus; in elderly patients (over the age of 65 years).

– In patients with impaired renal function (see section “Special instructions”).

– In patients concurrently receiving other drugs: possessing nephrotoxic effects (aminoglycosides, amphotericin b, foscarnet, ganciclovir, pentamidine, vancomycin, interleukin-2, cidofovir); tacrolimus, nonsteroidal anti-inflammatory drugs; HIV protease inhibitors, reinforced with ritonavir or cobicistat;

– in patients with indication of disease of liver disease, including hepatitis.

– Co-use of tenofovir and didanosine is not recommended.

Side effects

Summary of the

HIV-1 and hepatitis B safety profile

Renal impairment, renal failure, and proximal tubulopathy (including Fanconi syndrome), which sometimes resulted in bone abnormalities (rarely fractures), have rarely been reported in patients treated with tenofovir. Monitoring of renal function is recommended for patients taking tenofovir.

HIV-1

Adverse reactions during treatment with tenofovir in combination with other antiretroviral drugs can be expected in almost one-third of patients. Such reactions, as a rule, are disorders of the gastrointestinal tract from mild to moderate severity. Approximately 1% of patients treated with tenofovir discontinued treatment due to gastrointestinal reactions.

Lactic acidosis, hepatomegaly with adipose dystrophy and lipodystrophy are associated with taking tenofovir.

Concomitant use of tenofovir and didanosine is not recommended, as this may lead to an increased risk of adverse reactions.

Rarely reported cases of pancreatitis and lactic acidosis, sometimes fatal.

Hepatitis B infection

Adverse reactions with tenofovir can be expected in almost one quarter of patients, mostly minor. In clinical trials involving HBV-infected patients, the most common adverse reaction to tenofovir was nausea (5.4%). Cases of exacerbation of hepatitis B have been reported in patients on therapy, as well as in patients who have stopped treatment for hepatitis B.

Brief information on adverse reactions

Evaluation of adverse reactions to tenofovir is based on safety data obtained from clinical trials and post-marketing analysis. All adverse reactions are listed in table 1.

HIV-1 clinical trials

The evaluation of adverse reactions from HIV-1 clinical trials is based on the results of two studies in which 653 previously treated patients took tenofovir (n = 443) or placebo (n = 210) in combination with other antiretroviral drugs for 24 weeks, as well as data from a double-blind comparative controlled study in which 600 previously untreated patients took 300 mg of tenofovir disoproxil fumarate (n = 299) or stavudine (n = 301). in combination with lamivudine and efavirenz for 144 weeks.

Clinical studies of hepatitis B

The assessment of adverse reactions from hepatitis B clinical trials is mainly based on the results of two double-blind comparative controlled trials in which 641 patients with chronic hepatitis B with compensated liver function received 300 mg of tenofovir disoproxil fumarate daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks. Adverse reactions that occurred during 288 weeks of continuous treatment were consistent with the known safety profile of tenofovir.

Patients with decompensated liver disease

The safety profile of tenofovir in patients with uncompensated liver disease was evaluated in a double-blind, active, controlled trial in which adult patients received either tenofovir (n= 45), emtricitabine + tenofovir (n = 45), or entecavir (n = 22) for 48 weeks.

In the tenofovir group,7% of patients discontinued treatment due to adverse reactions; 9% of patients had a confirmed elevated serum creatinine > 0.5 mg/dl or a confirmed serum phosphate concentration over 48 weeks >

After 168 weeks,16% (7/45) of patients in the tenofovir group,4% (2/45) in the emtricitabine + tenofovir group, and 14% (3/22) in the entecavir group had impaired tolerability. 13% (6/45) of patients in the tenofovir group,13% (6/45) in the emtricitabine + tenofovir group, and 9% (2/22) in the entecavir group had a confirmed elevated serum creatinine > 0.5 mg / dl or a confirmed serum phosphate concentration > At week 168, in this population of patients with decompensated hepatic insufficiency, the mortality rate was 13% (6/45) in the tenofovir group,11% (5/45) in the emtricitabine + tenofovir group, and 14% (3/22) in the entecavir group. The proportion of hepatic cell carcinoma was 18% (8/45) in the tenofovir group,7% (3/45) in the emtricitabine + tenofovir group, and 9% (9/22) in the entecavir group.

Patients with an initially higher Child-Pugh score had a higher risk of developing serious adverse reactions (see section “Special instructions”).

Patients with HBV resistance to lamivudine

In a randomized double-blind study in which 280 lamivudine-resistant patients received tenofovir (n = 141) or emtricitabine/tenofovir (n = 139) for 96 pedels, no new adverse reactions were detected.

Adverse reactions with a potential (or at least possible) association with treatment are listed below by organ system class and frequency. Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions are defined by frequency as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), infrequent (≥ 1/1000 to <1/100), and rare (≥ 1/10,000 to

Table 1. Summary of adverse reactions associated with tenofovir based on clinical studies and post-marketing analysis

Organ system classes and frequency	Adverse reactions
Metabolic and nutritional disorders
Very often	Hypophosphatemia 1
Infrequently	Hypokalemia 1
Rarely	Lactic acidosis 3
Nervous system disorders
Very often	Vertigo
Is Common	Headache
Disorders of the gastrointestinal tract
Very often	Diarrhea, vomiting, and nausea
Are Common	Abdominal pain, bloating, flatulence
Infrequently	Pancreatitis 3
Liver and biliary tract disorders
are common	Increased activity of “hepatic” transaminases
Rarely	Fatty liver disease 3, hepatitis
Skin and subcutaneous tissue disorders
Very often	Skin rash
Rarely	Angioedema
Musculoskeletal and connective tissue disorders
Infrequently	Rhabdomyolysis 1, muscle weakness 1
Rarely	Osteomalacia (manifested by bone pain and bone fractures in some cases)1,2, myopathy 1
Kidney and urinary tract disorders
Infrequently	Increased creatinine
Rarely	Acute renal failure, renal failure, acute tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephritis (including acute interstitial nephritis)2, nephrogenic diabetes insipidus
General disorders and disorders at the injection site
Very often	Asthenia
Is Common	Fatigue

1 An adverse reaction may occur as a consequence of proximal tubulopathy. It is not considered to be causally related to tenofovir in the absence of this disease.

2 An adverse reaction was identified during a post-marketing study, but was not observed during randomized controlled clinical trials or the extended access program to tenofovir. The frequency category was determined by statistical calculations based on the total number of patients taking tenofovir in randomized controlled trials and the extended access program (n = 7319).

3 For more information, please refer to the section below.

Description of individual adverse reactions of HIV-1 and hepatitis B

Impaired renal function

Since tenofovir can lead to impaired kidney function, it is recommended to monitor their function. Proximal tubulopathy usually disappeared or improved after discontinuation of tenofovir. However, in some patients, discontinuation of tenofovir did not completely restore reduced creatinine clearance.

Patients at risk of developing renal insufficiency (for example, patients with an initial risk of renal insufficiency, concomitant HIV infection, concomitant therapy with nephrotoxic drugs) are at an increased risk of incomplete recovery of renal function, despite the withdrawal of tenofovir (see the section “Special instructions”).

HIV-1

Interaction with didanosine

Concomitant use of tenofovir and didanosine is not recommended, as this leads to an increase in systemic exposure to didanosine by 40-60%, which may increase the risk of adverse reactions associated with didanosine. Rarely reported cases of pancreatitis and lactic acidosis, sometimes fatal.

Lipids, lipodystrophy and metabolic disorders

Combination antiretroviral therapy has been associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia.

Combined antiretroviral therapy has been associated with redistribution of adipose tissue in HIV-infected patients (lipodystrophy), including loss of subcutaneous fat on the limbs and face, increased intraperitoneal and visceral fat, hypertrophy of the mammary glands, and accumulation of fat in the dorsocervical region (“buffalo hump”).

In a 144-week controlled clinical trial among patients previously untreated with antiretroviral drugs, which was conducted to compare tenofovir with stavudine in combination with lamivudine and efavirenz, it was observed that the risk of lipodystrophy with tenofovir was significantly lower than with stavudine. The tenofovir group also had significantly lower average increases in fasting triglycerides and total cholesterol than the comparison group.

Immune recovery syndrome

HIV-infected patients with severe immunodeficiency may experience an inflammatory response to asymptomatic or residual opportunistic infections at the time of initiation of combined antiretroviral therapy. Autoimmune disorders (such as Graves ‘ disease) have also been reported; however, data on the time of onset of such events vary widely, and these cases may have occurred several months after the start of treatment.

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with well-known risk factors, late-stage HIV infection, or long-term use of combination antiretroviral therapy. The frequency of occurrence of this phenomenon is unknown.

Lactic acidosis and severe hepatomegaly with fatty degeneration

Lactic acidosis, which is usually accompanied by fatty liver disease, has been reported with the use of nucleoside analogues. Treatment with nucleoside analogues should be discontinued in the presence of symptomatic hyperlactemia and metabolic lactic acidosis, progressive hepatomegaly, or a rapid increase in aminotransferase levels.

Hepatitis B infection

Exacerbation of hepatitis during treatment

In studies among patients who had not previously taken nucleoside analogues, an increase in ALT levels during treatment exceeding the upper limit of normal by more than 10 times, and exceeding the initial level by more than 2 times, was observed in 2.6% of patients treated with tenofovir. ALT elevation, which had a median time to onset of 8 weeks, then disappeared with continued treatment. In most cases, such increases in ALT were associated with a decrease in viral load ≥2 log10 copies/ml, which preceded or coincided with an increase in ALT. During treatment, it is recommended to periodically monitor liver function.

Exacerbation of hepatitis after discontinuation of treatment

Patients infected with HBV experienced clinical and laboratory signs of hepatitis exacerbation after discontinuation of HBV-active drugs.

Chronic hepatitis B

The assessment of adverse reactions is based on a single randomized clinical trial involving 106 children (ages 12-18 years) with chronic hepatitis B treated with 300 mg tenofovir disoproxil fumarate (n = 52) or placebo (n = 54) for 72 weeks.

Adverse reactions that were observed in children treated with tenofovir were consistent with those observed in clinical studies of tenofovir in adults. A decrease in BMD was observed in children infected with hepatitis B virus. The Z-criterion for BMD observed in patients who received tenofovir was lower than that in patients who received placebo.

Other special patient groups

Elderly patients

Tenofovir has not been studied in patients over 65 years of age. Elderly patients are more likely to have reduced renal function, so special care should be taken during treatment with tenofovir in patients of this age category.

Patients with impaired renal function

Since taking tenofovir can lead to kidney damage, it is recommended to carefully monitor renal function in adult patients with impaired renal function taking the drug.

It is contraindicated to use tenofovir in children from 12 to 18 years of age with impaired renal function.

Interaction

Interaction studies were conducted only in adults.

Based on the results of in vitro experiments and the known route of elimination of tenofovir, the possibility of CYP450-mediated interactions involving tenofovir and other drugs is low.

Simultaneous use is not recommended

Tenofovir is contraindicated in combination with other medications containing tenofovir.

Tenofovir should not be used concomitantly with adefovir.

Didanosine

Concomitant use of tenofovir and didanosine is not recommended (see section “Special instructions” and table 2).

Medications that are excreted by the kidneys

Since tenofovir is primarily excreted by the kidneys, concomitant use of tenofovir with drugs that reduce renal function or compete for active tubular secretion by transport proteins hOAT 1, hOAT 3 or MRP 4 (for example, with cidofovir) may increase the concentration of tenofovir in the blood serum and /or drugs taken simultaneously.

Tenofovir should be avoided with concomitant or recent use of nephrotoxic medicinal products (e. g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2) (see section “Special instructions”).

Given that tacrolimus may affect renal function, careful monitoring is recommended when it is co-administered with tenofovir.

Other interactions

Interactions between tenofovir, protease inhibitors, and non-protease inhibitor antiretroviral agents are shown in Table 2 below (increase indicated by “↑”, decrease indicated by “↓”, no change indicated by “↔”, twice daily indicated by “b. i. d. ” and once daily indicated by “q. d. “).

Table 2. Interactions between tenofovir and other medicinal products

Medicinal product in therapeutic areas (dose in mg)	Effect on drug levels, mean percentage change in AUC, Cmax, Cmin	Recommendation for concomitant use with tenofovir disoproxil fumarate 300 mg
ANTI-INFECTIVE MEASURES
Antiretroviral drugs
Protease inhibitors
Atazanavir / Ritonavir (300 mg q. d. /100 mg q. d. /300 mg q. d. )	Atazanavir: AUC: ↓ 25% Cmax: ↓ 28% Cmin : ↓ 26% Tenofovir: AUC: ↑ 37% Cmax: ↑ 34% Cmin: ↑ 29%	No dose adjustment is required. Increased exposure to tenofovir may increase tenofovir-related adverse events, including renal pathology. Renal function should be carefully monitored.
Lopinavir / Ritonavir (400 mg b. i. d. / 100 mg b. i. d. /300 mg q. d. )	Lopinavir/Ritonavir: There is no significant effect on lopinavir/ritonavir FC parameters. Tenofovir: AUC: ↑ 32% Cmax: ↔ Cmin: ↑ 51%	No dose adjustment is required. Increased exposure to tenofovir may increase tenofovir-related adverse events, including renal pathology. Renal function should be carefully monitored.
Darunavir/ Ritonavir (300 mg / 100 mg b. i. d. / 300 mg q. d. )	Darunavir: There is no significant effect on the FC parameters of darunavir/ritonavir. Tenofovir: AUC: ↑ 22% Cmin: ↑ 37%	No dose adjustment is required. Increased exposure to tenofovir may increase tenofovir-related adverse events, including renal pathology. Renal function should be carefully monitored.
Nucleoside reverse transcriptase inhibitors
Didanosine	Concomitant use of tenofovir and didanosine results in a 40-60% increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse events. Rare, sometimes fatal, cases of pancreatitis and lactic acidosis have been reported. Concomitant administration of tenofovir and didanosine at a dose of 400 mg / day was associated with a significant reduction in CD4 cell count, possibly due to cell-to-cell interaction, which increases phosphorylated (i. e. active)CD4 cells. didanosine. Reducing the dosage of didanosine to 250 mg, which is administered together with tenofovir, was associated with reports of a high rate of virological failure in several combinations studied for the treatment of HIV-1 infection.	Concomitant use of tenofovir and didanosine is not recommended.
Adefovir	AUC:↔, Cmax: ↔	Tenofovir should not be used concomitantly with adefovir.
Entecavir	AUC:↔, Cmax: ↔	There were no clinically significant pharmacokinetic interactions when tenofovir was co-administered with enzecavir.

Studies conducted with other medicinal products

No clinically significant pharmacokinetic interactions were observed when tenofovir was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (enhanced ritonavir), methadone, ribavirin, rifampicin, tacrolimus, and the hormonal contraceptive norgestimate/ethinyl estradiol.

Tenofovir should be taken simultaneously with food, as food increases the bioavailability of tenofovir.

How to take, course of use and dosage

Inside with food. The tablet should be swallowed whole, washed down with water. Tablets should not be chewed or broken.

Treatment should be initiated and supervised by a doctor with experience in treating HIV and / or chronic hepatitis B.

The choice of tenofovir for the treatment of HIV-1-infected patients who have previously received treatment should be based on checking the presence of individual viral resistance and/or the patient’s treatment history.

Adults

The recommended dose of the drug for the treatment of HIV and chronic hepatitis B is 300 mg once a day inside, with food.

Chronic hepatitis B

The optimal duration of treatment is unknown. Discontinuation of treatment can be considered as follows:

– Treatment of HBeAg-positive patients without cirrhosis should be continued for at least 6-12 months after confirmation of HBe seroconversion (disappearance of HBeAg and HBV DNA with the appearance of anti-HBe) or until HBS seroconversion, or until loss of effectiveness. After discontinuation of treatment, it is necessary to regularly check the levels of ALT and hepatitis B virus DNA in the blood serum in order to detect possible late relapses of viremia.

– Treatment of patients with HBeAg-negative hepatitis B without cirrhosis should continue at least until HBS seroconversion or signs of treatment failure appear. In the case of prolonged treatment lasting more than 2 years, it is recommended to regularly review the treatment to confirm whether it is acceptable for the patient to continue the chosen therapy.

Children from 12 to 18 years

of age with HIV-1: at the age of 12 to 18 years and with a body weight ≥ 35 kg, the recommended dose of the drug is 300 mg once a day inside, with food. The tablet should be swallowed whole, washed down with water. Tablets should not be chewed or broken.

In exceptional cases, the Virfoten tablet can be taken immediately after it is dissolved in approximately 100 ml of water, orange or grape juice.

Chronic hepatitis B: at the age of 12-18 years and with a body weight ≥ 35 kg, the recommended dose of the drug is 300 mg once a day inside, with food. The optimal duration of treatment has not yet been determined.

Safety and efficacy of tenofovir in children with chronic hepatitis B aged 2-12 years and overweight

Missed dose

• If a dose has been missed and less than 12 hours have elapsed from the usual time of taking the dose, the patient should take the drug as soon as possible with food and return to the usual regimen of taking the drug.
• If, in the case of a missed dose, more than 12 hours have passed and the time for taking the next dose of the drug is approaching, then the patient should not take the missed dose, but take the next dose in accordance with the usual regimen of taking the drug.

If the patient vomits within 1 hour after taking the drug, another 1 dose should be taken. If the patient vomits more than 1 hour after taking the drug, then another 1 dose should not be taken.

Special patient groups

Elderly patients

To date, there are no data on the basis of which recommendations can be made regarding dosage for patients over the age of 65 years.

Impaired renal function

Tenofovir is excreted in the urine, so patients with impaired renal function have a longer period of elimination of tenofovir from the body.

Adults

Data on the safety and efficacy of tenofovir in adult patients with moderate to severe renal impairment (CC Long-term safety assessment of patients with mild renal impairment (creatinine clearance 50-80 ml/min) has not been performed. For this reason, patients with impaired renal function should be treated with tenofovir when the potential benefit of treatment outweighs the potential risk of harm. Correction of the dosage interval is recommended for patients with creatinine clearance < 50 ml/min.

Mild renal impairment (creatinine clearance 50-80 ml / min). Limited data obtained from clinical studies suggest that the once-daily tenofovir dosage regimen should be maintained for patients with minor renal impairment.

Moderate renal impairment (creatinine clearance 30-49 ml / min). Taking the drug at a dose of 300 mg every 48 hours is recommended based on the results of modeling the pharmacokinetic data of a single dose in volunteers who do not have HIV and HBV infection, with varying degrees of impaired renal function, including end-stage renal failure requiring hemodialysis. However, this dosage has not been confirmed in clinical studies. Therefore, the clinical response to treatment and renal function in these patients should be carefully monitored.

Severe renal impairment (CC Due to the inability to adjust the dosage regimen, the use of the drug in patients of this group is contraindicated.

Children

It is not recommended to use tenofovir in children with impaired renal function.

Impaired liver function

No dose adjustment is necessary for patients with hepatic impairment. Patients with chronic hepatitis B (with or without HIV co-infection) should be carefully monitored if they have stopped taking tenofovir, as there is a risk of exacerbation of hepatitis after discontinuation of the drug.

Overdose

Symptoms: in case of overdose, the patient should be monitored for signs of toxicity, and if necessary, symptomatic and supportive therapy is prescribed.

Treatment: tenofovir can be eliminated by hemodialysis, and the median clearance of tenofovir is 134 ml/min. It is not known whether tenofovir can be eliminated by peritoneal dialysis.

Special instructions

General information

Before starting tenofovir therapy, an HIV antibody test should be offered to all patients infected with the hepatitis B virus

(HIV-1).

Although stable antiretroviral therapy resulting in sustained viral suppression significantly reduces the risk of transmission of the virus through sexual contact, the risk cannot be completely excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Chronic hepatitis B

Patients should be warned that the ability of tenofovir to prevent the risk of transmission of HBV to others through sexual contact or blood has not been proven. Appropriate precautions should be taken.

Concomitant use with other medicinal products

The drug is contraindicated for use with other drugs containing tenofovir.

Tenofovir should not be used concomitantly with adefovir.

Concomitant use of tenofovir and didanosine is not recommended. Concomitant use of tenofovir and didanosine leads to a 40-60% increase in systemic exposure to didanosine, which may increase the risk of adverse events associated with didanosine (see section “Interaction with other drugs”). Rarely reported pancreatitis and lactic acidosis, sometimes fatal. Concomitant use of tenofovir and didanosine at a dose of 400 mg / day was associated with a significant reduction in CD4 cell count, possibly due to cell-to-cell interaction, which increases phosphorylated (i. e. active)CD4 cells. didanosine. The use of didanosine at a reduced dosage of 250 mg together with tenofovir therapy was associated with reports of a high rate of virological failure in several studied combinations for the treatment of HIV-1 infection.

Triple therapy with nucleosides/nucleotides

There have been reports of high rates of virological failure and early-stage resistance in patients with HIV infection when tenofovir was combined with lamivudine and abacavir, as well as with lamivudine and didanosine once daily.

Effects on kidney function and bone tissue in adults

Effects on kidney function

Tenofovir is mainly excreted by the kidneys. Renal failure, impaired renal function, elevated creatinine, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir in clinical practice.

Monitoring of kidney function

It is recommended to determine creatinine clearance in all patients before starting treatment with tenofovir and monitor renal function (creatinine clearance and serum phosphate levels) after 2-4 weeks of treatment, after 3 months of treatment, and every 3-6 months after in patients without risk factors for impaired renal function.

For patients at increased risk of renal failure, more frequent monitoring of renal function should be considered.

Management of patients with impaired renal function

If the serum phosphate level is <1.5 mg / dl (0.48 mmol / L) or the creatinine clearance is reduced to

Discontinuation of tenofovir treatment should also be considered in patients with a decrease in creatinine clearance to < 50 ml/min or a decrease in serum phosphate levels to < 50 ml / min.

Discontinuation of tenofovir treatment should also be considered in cases of progressive decline in renal function, if no other cause has been identified.

Concomitant use with other drugs and the risk of nephrotoxicity

Tenofovir should be avoided with concomitant or recent use of nephrotoxic medications (e. g., aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2). If concomitant use of tenofovir and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.

Acute renal failure has been reported after initiation of high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs)therapy in patients treated with tenofovir who have risk factors for renal dysfunction. Renal function should be monitored appropriately when tenofovir is co-administered with NSAIDs. A high risk of kidney damage has been reported in patients receiving tenofovir in combination with a protease inhibitor enhanced with ritonavir or cobicistat. These patients require careful monitoring of renal function.

In patients with risk factors for renal impairment, co-use of tenofovir with an enhanced protease inhibitor should be carefully evaluated.

Clinical evaluation of the use of tenofovir has not been performed in patients taking drugs that are also excreted by the kidneys, through the transport proteins of human organic anion transporters (hOAT) 1 and 3 or MRP4 (for example, cidofovir, a well-known nephrotoxic drug). These renal transport proteins may be responsible for tubular secretion and, in part, renal elimination of tenofovir and cidofovir. Therefore, the pharmacokinetics of drugs that are also excreted by the kidneys, including the transport proteins hOAT 1 and 3 or MRP4, may change in the case of simultaneous use. In the absence of an emergency, the simultaneous use of drugs that are excreted in the same ways through the kidneys is not recommended. If such use cannot be avoided, renal function should be monitored weekly (see section “Interactions with other medicinal products”).

Impaired renal function

The renal safety of tenofovir has been studied to a very limited extent in patients with impaired renal function (CC

Adult patients with creatinine clearance < 50 ml / min, including patients requiring hemodialysis

Data on the safety and efficacy of tenofovir in patients with impaired renal function are limited. For this reason, tenofovir should only be used if the potential benefits of treatment outweigh the potential risks. Use of tenofovir in patients with severe renal impairment (CC

Effects on bone tissue

In a controlled 144-week clinical trial comparing tenofovir with stavudine in combination with lamivudine and efavirenz among HIV-infected adults who had not previously received antiretroviral treatment, both groups showed small decreases in BMD in the femur and spine. The decrease in spinal BMD and changes from baseline bone metabolism biomarkers were significantly more pronounced in the tenofovir group at week 144. The decrease in femoral BMD was significantly more pronounced in this group up to 96 weeks. However, after 144 weeks, there was no increase in the risk of fractures or signs of clinically significant bone diseases.

Pathological changes in bone tissue (sometimes leading to fractures) can be caused by damage to the proximal tubules of the kidneys (see the section “Side effects”). If you suspect or detect abnormal changes in bone tissue, you should consult the appropriate specialist.

Effect on kidney function and bone tissue in children from 12 to 18 years of age

Long-term effects on bone tissue and toxic effects on the kidneys in children have not been definitively established. In addition, the reversibility of toxic effects on the kidneys is not fully established. Therefore, it is recommended to use a multi-pronged approach to adequately determine the benefit/risk ratio of treatment on a case-by-case basis, decide on appropriate follow-up during treatment (including whether to discontinue therapy), and consider whether additional medications should be used.

Monitoring of kidney function

Before starting treatment, it is necessary to assess renal function (creatinine clearance and serum phosphate levels), and it is also necessary to monitor during treatment, as for adults (see above).

Management of patients with impaired renal function

If any paediatric patient receiving tenofovir has serum phosphate levels If renal impairment is suspected or detected, a nephrologist should be consulted to consider discontinuing treatment with tenofovir.

Discontinuation of tenofovir treatment should also be considered in cases of progressive decline in renal function when no other cause has been identified.

Co-use and risk of nephrotoxicity

Follow the same guidelines that apply to adults (see above).

Impaired renal function

It is not recommended to use tenofovir in children with impaired renal function (see the section “Dosage and use”). Tenofovir therapy should not be initiated in children with impaired renal function, and treatment should also be discontinued in those children who have developed impaired renal function during tenofovir therapy.

Effects on bone tissue

Tenofovir may cause a decrease in BMD. The effect of changes in BMD associated with tenofovir on bone tissue in the long term and on the risk of future fractures is currently unknown (see section “Pharmacodynamics”). If bone pathology is detected or suspected in children, consult an endocrinologist and / or a nephrologist.

Liver diseases

Data on safety and efficacy for patients after liver transplantation are very limited.

Data on the safety and efficacy of tenofovir in patients with chronic hepatitis B, decompensated cirrhosis of the liver and grade > 9 according to the Child-Pugh classification are limited. Such patients may have a higher risk of serious adverse reactions from the liver and kidneys. As a result, it is necessary to carefully monitor the parameters of the hepatobiliary system and renal function in this category of patients.

Exacerbation of hepatitis

Exacerbation during treatment

Spontaneous exacerbations of chronic hepatitis B are relatively frequent and are characterized by a temporary increase in serum ALT levels. After starting antiviral treatment, some patients may have elevated serum ALT levels (see section “Side effects”). In patients with compensated liver disease, an increase in serum ALT levels is usually not accompanied by an increase in serum bilirubin concentration or decompensation of liver function.

Patients with cirrhosis of the liver may have an increased risk of decompensation of liver function after an exacerbation of hepatitis, so they should be carefully monitored during treatment.

Exacerbation after discontinuation of treatment

Exacerbation of hepatitis has also been reported in patients who have stopped treatment for hepatitis B. Exacerbations after discontinuation of therapy are usually associated with an increase in the concentration of hepatitis B virus DNA, and most of them are resolved without additional intervention. However, severe exacerbations, including deaths, have been reported. Within 6 months after discontinuation of hepatitis B treatment, it is necessary to regularly monitor the functional state of the liver according to clinical and laboratory parameters. If necessary, it may be advisable to resume treatment for hepatitis B.

For patients with advanced liver disease or cirrhosis, discontinuation of treatment is not recommended, as exacerbation of hepatitis after discontinuation of therapy can lead to decompensation of liver function.

In patients with decompensated cirrhosis, the exacerbation of hepatitis is particularly serious, sometimes fatal.

Concomitant infection with hepatitis C or D viruses

There are no data on the efficacy of tenofovir in patients with concomitant hepatitis C or D virus infection.

Co-infection with HIV-1 and hepatitis B virus

Due to the risk of developing HIV resistance in patients with co-infection with HIV/HBV, tenofovir should only be used as part of an appropriate antiretroviral combination regimen.

Patients who have previously been diagnosed with liver pathology, including chronic active hepatitis, have an increased incidence of liver function abnormalities during combined antiretroviral therapy, and they should be monitored in accordance with standard practice.

If the course of liver disease worsens in such patients, the need for a break in treatment or discontinuation of treatment should be considered. However, it should be noted that an increase in ALT levels may be part of a positive HBV antiviral response to tenofovir therapy, see “Exacerbation of hepatitis”above.

Lactic acidosis

Lactic acidosis, usually accompanied by fatty liver disease, has been reported with the use of nucleoside analogues.

Preclinical and clinical data indicate that the risk of lactic acidosis, as an effect of drugs from the class of nucleoside analogues, for tenofovir is low. However, since tenofovir is structurally similar to nucleoside analogues, this risk cannot be excluded.

Early signs (symptomatic hyperlactatemia) include mild digestive symptoms (nausea, vomiting, and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and / or deep breathing), or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality rate and can be accompanied by pancreatitis, liver or kidney failure. Lactic acidosis usually occurs after several months of treatment.

Treatment with nucleoside analogues should be discontinued in the presence of symptomatic hyperlactatemia and metabolic / lactic acidosis, progressive hepatomegaly, or a rapid increase in the level of aminotransferases.

Caution should be exercised when prescribing nucleoside analogues to any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver disease (including certain medications and alcohol).

Treatment with interferon-alpha and ribavirin in patients with concomitant hepatitis C virus infection may pose a particular risk.

Patients at increased risk should be closely monitored.

Lipodystrophy

In patients with HIV infection, combined antiretroviral therapy was associated with the redistribution of adipose tissue in the body (lipodystrophy).

The long-term consequences of these phenomena are currently unknown. Data on the mechanism of development are incomplete. There is a hypothesis that the development of visceral lipomatosis is associated with the use of protease inhibitors and the development of lipoatrophy with the use of nucleoside reverse transcriptase inhibitors.

The increased risk of lipodystrophy was due to individual factors, such as the elderly age of patients, and drug-related factors, such as the long duration of antiretroviral therapy and the resulting metabolic disorders.

The clinical examination should include an assessment of physical signs of adipose tissue redistribution in the body. You should pay attention to the indicators of fasting serum lipids and blood glucose levels. Dyslipidemia should be adjusted according to clinical recommendations.

Tenofovir is structurally related to nucleoside analogues, so the risk of developing lipodystrophy cannot be excluded. However,144-week data obtained in HIV-infected patients who had not previously been treated with antiretroviral drugs indicate that the risk of lipodystrophy with tenofovir was lower than with stavudine when they were used in combination with lamivudine and efavirenz.

Mitochondrial disorders In

vitro and in vivo, it has been shown that nucleoside and nucleotide analogues lead to various degrees of mitochondrial damage. There have been reports of mitochondrial disorders in HIV-negative newborns exposed to intrauterine and / or postnatal exposure to nucleoside analogues.

The main adverse events reported were hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These phenomena are often short-lived. There were reports of some neurological disorders that started later (hypertension, seizures, abnormal behavior).

To date, it is not known whether the neurological disorders are temporary or permanent. All children exposed in utero to nucleoside or nucleotide analogues, even HIV-negative newborns, should be closely monitored for signs or symptoms and undergo a thorough examination for possible mitochondrial disorders. The available data do not affect the current national recommendations that HIV – positive pregnant women should receive antiretroviral therapy to prevent vertical transmission of HIV.

Immune recovery syndrome

At the beginning of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may experience an inflammatory reaction to the causative agents of asymptomatic or residual opportunistic infections and lead to severe clinical conditions or increased severity of symptoms. Usually, such reactions are observed within the first weeks after the start of treatment.

Examples include cytomegalovirus retinitis, generalized and / or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. You should monitor any symptoms of inflammation and, if necessary, prescribe timely treatment.

Autoimmune diseases (such as Graves ‘ disease) have also been reported to accompany immune reactivation; however, data on the time of onset of such events vary widely, and these cases may have occurred several months after the start of treatment.

Osteonecrosis

Although the etiology of osteonecrosis is considered to be multifactorial (including the use of glucocorticosteroids, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly frequently in patients with advanced HIV infection and / or long-term use of combined antiretroviral therapy. Patients should be advised to seek medical advice if they experience aches or pains in their joints, stiffness in their joints, or difficulty moving.

Elderly patients

Tenofovir has not been studied in patients over 65 years of age. Older patients are more likely to have impaired renal function, so caution should be exercised when treating elderly patients with tenofovir.

Influence on the ability to drive vehicles and mechanisms:

No specific studies have been conducted to study the effect of tenofovir on the ability to drive vehicles and use mechanisms. Patients should be informed of reports of dizziness during treatment with tenofovir. If dizziness occurs, you should refrain from performing these types of activities, affecting the ability to drive a car and work with mechanisms.

Storage conditions

Keep out of the reach of children in a dark place, at a temperature not exceeding 25 °C.

Shelf

life is 4 years.

Do not use after the expiration date.

Active ingredient

Tenofovir

Conditions of release from pharmacies

By prescription

Dosage form

Tablets