Virfoten, 300 mg 30 pcs

Pharmacokinetics:

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

Absorption

After oral administration in HIV-infected patients tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir.

The ingestion of multiple doses of tenofovir disoproxil fumarate with food by 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 serum within 1 hour after fasting and within 2 hours when taken with food. When tenofovir disoproxil fumarate was administered to patients on an empty stomach, the bioavailability was approximately 25%. Administration of tenofovir disoproxil fumarate with a fat-rich meal 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 following a fat-rich meal, median serum Cmax values ranged from 213 to 375 ng/mL. However, ingestion of tenofovir disoproxil fumarate with a low-fat meal has no significant effect on tenofovir pharmacokinetics.

Distribution

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

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

Metabolism

In vitro studies have shown that neither tenofovir disoproxil fumarate nor tenofovir are substrates of CYP450 enzymes. Moreover, at concentrations significantly higher (approximately 300-fold) than 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 μmol/L had no effect on any of the CYP450 isoforms except CYP1A1/2, where there was a small (6%) but statistically significant decrease in CYP1A1/2 substrate metabolism. Based on this information, it can be concluded that there is little likelihood of clinically significant interactions between tenofovir disoproxil fumarate and drugs whose metabolism is mediated by CYP450.

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

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

The active tubular transport system of secretion has been found to include uptake of tenofovir by proximal tubule cells via human organic anion transporters (hOAT) 1 and 3, and its excretion into the urine via multidrug resistance marker protein 4 (MRP 4).

Linearity-nonlinearity

The pharmacokinetics of tenofovir were independent of the dose of tenofovir disoproxil fumarate between 75 and 600 mg and did not change with repeated administration at any dose level.

Pharmacokinetics in Special Patient Groups

Elderly Patients

The pharmacokinetics of tenofovir in elderly patients (>65 years) have not been studied.

Gender

Limited data on the pharmacokinetics of tenofovir in women indicate no significant sex-specific effects.

Race

There have been no specific studies of pharmacokinetics in different ethnic groups.

Children

HIV-1

The equilibrium pharmacokinetic parameters of tenofovir were assessed in 8 children (ages 12 to 18 years) with a body weight of > 35 kg infected with HIV-1. Mean (± SD) Cmax and AUCtau values were 0.38 ± 0.13 µg/ml and 3.39 ± 1.22 µg*h/ml, respectively.

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

Chronic hepatitis B

. Equilibrium 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 exposures achieved in adults who received once-daily doses of 300 mg of tenofovir disoproxil fumarate.

In children younger than 12 years of age or in children with impaired renal function, studies of the pharmacokinetics of 300 mg tenofovir disoproxil fumarate have not been performed.

Renal dysfunction

Parameters of tenofovir pharmacokinetics were determined after administration of a single dose of 300 mg of tenofovir disoproxil fumarate in 40 adult patients without HIV or HBV infection with varying degrees of renal impairment, determined according to baseline creatinine clearance (CK) values (renal function is not impaired if CK > 80 mL/min, mild impairment if the CK is 50-79 mL/min, moderate impairment if the CK is 30-49 mL/min, and severe impairment if the CK is 10-29 mL/min).

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

Lengthening the interval between drug administration is expected to result in 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 failure (CK < 10 mL/min) who required hemodialysis, tenofovir concentrations increased significantly between dialysis within 48 hours, reaching a mean Cmax of 1032 ng/mL and a mean AUC0-48 of 42857 ng*h/mL.

It is recommended that the interval between doses of 300 mg of tenofovir disoproxil fumarate be modified in adult patients with CK < 50 ml/min or in patients who already have end-stage renal failure and require dialysis.

The pharmacokinetics of tenofovir in patients without hemodialysis with a KC < 10 ml/min and in patients with terminal renal failure whose status is controlled by peritoneal or other forms of dialysis have not been studied. Pharmacokinetic studies of tenofovir in children with renal insufficiency have not been conducted. No data on dosing recommendations are available.

Hepatic impairment

A single dose of 300 mg of tenofovir disoproxil fumarate has been taken in patients without HIV or HBV infection with varying degrees of hepatic impairment as defined by the Child-Pugh classification.

No significant changes in tenofovir pharmacokinetic parameters were observed in patients with hepatic impairment, suggesting no need for dose adjustment. The mean (% CV) Cmax and AUC0-∞ values of tenofovir were 223 (34.8%) ng/mL and 2050 (50.8%) ng*h/mL, respectively, in those without hepatic impairment, 289 (460%) ng/mL and 2310 (43.5%) ng*h/mL in subjects with moderate hepatic impairment 305 (24.8%) ng/mL, and 2740 (44.0%) ng*h/mL in subjects with severe hepatic impairment.

Intracellular pharmacokinetics

The half-life of tenofovir diphosphate was found to be approximately 50 hours in human peripheral blood mononuclear cells (PBMCs), whereas in PBMCs stimulated with phytohemagglutinin it was 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 to 18 years with resistance to nucleotide reverse transcriptase inhibitors, or toxicity precluding the use of first-line antiretroviral drugs.

Hepatitis B

Treatment of chronic hepatitis B in adults with:

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

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

• compensated liver disease with signs of an active inflammatory process and active viral replication, as evidenced by persistently elevated ALT activity in the blood serum and histologically confirmed active inflammatory process and/or fibrosis

Pharmacological effect

Pharmacotherapeutic group:

Antiviral agent

ATX code: J05AF07

Pharmacological properties

Pharmacodynamics

Mechanism of action

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is a nucleoside monophosphate (nucleotide) analogue. Tenofovir is then converted to its active metabolite, tenofovir diphosphate, which is an obligate chain terminator, by constitutively 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 enzyme’s active site with the natural deoxyribonucleotide substrate and terminating the DNA strand after insertion into it. Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β and γ. In in vitro assays, tenofovir at concentrations up to 300 µmol/L also showed no effect on mitochondrial DNA synthesis or lactic acid production.

Activism against HIV

Anti-HIV activity in vitro

The concentration of tenofovir required for 50% inhibition (EC50 – 50% effective concentration) of wild-type laboratory strain HIV-1IIIB is 1-6 µmol/L in lymphoid cell lines and 1.1 µmol/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 HIV-1 in primary monocytes/macrophages. Tenofovir also exhibits in vitro activity against HIV-2 with a 50% effective EC50 concentration of 4.9 μmol/L in MT-4 cells.

HIV resistance

HIV-1 strains with reduced tenofovir sensitivity and a K65R mutation in the reverse transcriptase gene have been isolated in vitro and from some patients. The use of tenofovir disoproxil fumarate should be avoided in patients who have previously received antiretroviral therapy and have strains with the K65R mutation (see section “Special Instructions”).

In addition, under the influence of tenofovir, selection of strains with the K70E substitution in the HIV-1 reverse transcriptase gene occurs, which leads to a slight decrease in sensitivity to tenofovir.

Anti-HBV activity

Anti-HBV activity in vitro

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

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

HBV strains expressing the rtL180M, rtT184G, rtS202G/I, rtM204V, and rtM250V substitutions associated with entecavir resistance demonstrated 0.6- to 6.9-fold greater sensitivity to tenofovir than wild-type virus. HBV strains expressing the rtA181V and rtN236T substitutions associated with adefovir resistance demonstrated 2.9- to 10-fold greater sensitivity to tenofovir than wild-type virus. Viruses containing the rtA181T substitution remained sensitive to tenofovir, with EC50 values ​​that 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 component, tenofovir diphosphate.

Suction

After oral administration to HIV-infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxil fumarate with food to HIV-infected patients resulted in mean (% coefficient of variation [CV]) tenofovir Cmax, AUC, and Cmin values ​​of 326 (36.6%) ng/mL, 3324 (41.2%) ng*h/mL, and 64.4 (39.4%) ng/mL. respectively. Maximum concentrations of tenofovir are observed in serum within 1 hour after administration on an empty stomach and within 2 hours when taken with food. When tenofovir disoproxil fumarate was administered to patients on an empty stomach, the bioavailability was approximately 25%. Taking tenofovir disoproxil fumarate with a high-fat meal increased bioavailability, with tenofovir AUC increasing by approximately 40% and Cmax
– by approximately 14%. After the first dose of tenofovir disoproxil fumarate following a high-fat meal, the median Cmax
serum levels ranged from 213 to 375 ng/ml. However, administration of tenofovir disoproxil fumarate with a low-calorie meal does not have a significant effect on the pharmacokinetics of tenofovir.

Distribution

After intravenous administration, the steady-state distribution concentration of tenofovir was estimated to be approximately 800 ml/kg. After oral administration of tenofovir disoproxil fumarate, tenofovir is distributed into many tissues, with the highest concentrations observed in the kidneys, liver and in the intestinal epithelium at various sites (preclinical studies). In vitro, the binding of tenofovir to plasma or serum proteins was less than 0.7 and 7.2%, respectively, over a tenofovir concentration range of 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 substantially higher (approximately 300-fold) than 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 μmol/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 CYP1A1/2 substrate metabolism was observed. Based on this information, it can be concluded that there is a low likelihood of clinically significant interactions between tenofovir disoproxil fumarate and drugs whose metabolism is mediated by CYP450.

Removal

Tenofovir is eliminated primarily by the kidneys, both by filtration and the active tubular transport system, with approximately 70 to 80% of the dose being excreted unchanged in the urine after intravenous administration. Total clearance was estimated to be approximately 230 ml/h/kg (approximately 300 ml/min). Renal clearance was estimated to be 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 the elimination of tenofovir. After oral administration, the terminal half-life of tenofovir is 12 to 18 hours.

Studies have established that the active tubular secretion transport system involves the uptake of tenofovir into proximal tubular cells via human organic anion transporters (hOAT) 1 and 3, and its excretion into urine via multidrug resistance marker protein 4 (MRP 4). Linearity-nonlinearity

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

Pharmacokinetics in special groups of patients

Children

HIV-1

Steady-state tenofovir pharmacokinetic parameters were assessed in 8 HIV-1-infected children (age 12 to 18 years) weighing ≥ 35 kg. The mean (±SD) Cmax and AUCtau values ​​were 0.38 ± 0.13 μg/ml and 3.39 ± 1.22 μg*h/ml, respectively. The tenofovir exposure that was achieved in adolescents receiving 300 mg daily doses of tenofovir disoproxil fumarate was consistent with the exposure that was achieved in adults receiving single daily doses of 300 mg 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 a daily dose of 300 mg oral tenofovir disoproxil fumarate was consistent with exposures that were achieved in adults receiving single daily doses of 300 mg tenofovir disoproxil fumarate.

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

Elderly patients

The pharmacokinetics of tenofovir in elderly patients (over 65 years of age) have not been studied.

Floor

Limited data on the pharmacokinetics of tenofovir in women indicate no significant relationship with gender.

Race

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

Patients with impaired renal function

The pharmacokinetic parameters of tenofovir were determined after the administration 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 (CK) (renal function is not impaired if CL > 80 ml/min, mild impairment – if CL is 50-79 ml/min, moderately severe impairment – with CC 30-49 ml/min and severe impairment – with CC 10-29 ml/min). Compared with patients with normal renal function, mean (%CV) tenofovir exposure increased from 2,185 (12%) ng*h/mL in those with creatinine clearance >80 mL/min to, respectively, 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. Increasing the dosing interval is expected to result in 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 disease (CrCl < 10 mL/min) who required hemodialysis, interdialytic tenofovir concentrations increased significantly over 48 hours, reaching a mean Cmax of 1,032 ng/mL and a mean AUC of 0-48 42,857 ng/h/mL.

It is recommended that the dosing interval of tenofovir disoproxil fumarate 300 mg be modified in adult patients with creatinine clearance <50 mL/min or in patients with end-stage renal disease requiring dialysis.

The pharmacokinetics of tenofovir in non-hemodialysis patients with creatinine clearance <10 mL/min without hemodialysis and in patients with end-stage renal disease controlled by peritoneal or other forms of dialysis have not been studied.

The pharmacokinetics of tenofovir have not been studied in children with renal impairment. There are no data to provide dosage recommendations.

Patients with liver dysfunction

A single dose of tenofovir disoproxil fumarate 300 mg was administered to HIV- and HBV-naïve patients with varying degrees of hepatic impairment as defined by the Child-Pugh classification. In patients with impaired liver function, no significant changes in tenofovir pharmacokinetic parameters were observed, suggesting no need for dose adjustment. Average (% CV) Cmax values
and tenofovir AUCo-∞ were 223 (34.8%) ng/ml and 2,050 (50.8%) ng*h/ml, respectively, in individuals without liver dysfunction, 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 persons with severe liver dysfunction.

Intracellular pharmacokinetics

In non-dividing human peripheral blood mononuclear cells (PBMCs), the half-life of tenofovir diphosphate was found to be approximately 50 hours, while in phytohemagglutinin-stimulated PBMCs it was approximately 10 hours

Special instructions

General

HIV antibody testing should be offered to all patients infected with hepatitis B virus before initiating tenofovir disoproxil fumarate therapy.

HIV-1

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

Chronic hepatitis B

Patients should be warned that tenofovir disoproxil fumarate has not been shown to prevent the risk of transmitting HBV to others through sexual contact or blood. Appropriate precautions should be taken.

Concomitant use with other drugs

– Virfoten should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.
– Virfoten is contraindicated for use simultaneously with adefovir.
– Concomitant use of tenofovir and didanosine is not recommended. Concomitant use of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine, which may increase the risk of didanosine-related adverse events.

Pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely. Concomitant use of tenofovir disoproxil fumarate and didanosine 400 mg daily was associated with a significant decrease in CD4 cell counts, possibly due to a cell-to-cell interaction that increases phosphorylated (i.e., active) didanosine. The use of didanosine at a reduced dose of 250 mg with tenofovir disoproxil fumarate has been associated with reports of high rates of virological failure in several combinations studied for the treatment of HIV-1 infection.

Triple therapy with nucleosides/nucleotides

There have been reports of high rates of virological failure and the emergence of early resistance in patients with HIV infection when tenofovir disoproxil fumarate was combined with lamivudine and abacavir, as well as with lamivudine and didanosine, in a once-daily dosing regimen.

Effect on kidney function and bone tissue in adults

Effect on kidney function

Tenofovir is primarily eliminated by the kidneys. Renal failure, renal dysfunction, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice.

Monitoring kidney function

It is recommended to determine CK in all patients before starting treatment with tenofovir disoproxil fumarate and monitor renal function (CK and serum phosphate) after 2-4 weeks of treatment, after 3 months of treatment and every 3-6 months thereafter in patients without risk factors for renal impairment. For patients at increased risk of renal failure, more frequent monitoring of renal function should be considered.

Management of patients with renal impairment

If serum phosphate is <1.5 mg/dL (0.48 mmol/L) or creatinine clearance is reduced to <50 mL/min in a patient receiving tenofovir disoproxil fumarate, reassess renal function within 1 week, including blood glucose, blood potassium, and urine glucose (see Adverse Reactions section). Discontinuation of treatment with tenofovir disoproxil fumarate should also be considered in patients with a decrease in creatinine clearance to <50 mL/min or a decrease in serum phosphate levels to <1.0 mg/dL (0.32 mmol/L). Discontinuation of tenofovir disoproxil fumarate 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 risk of nephrotoxicity Avoid use of tenofovir disoproxil fumarate with concurrent or recent use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents cannot be avoided, renal function should be monitored weekly.Cases of acute renal failure have been reported following initiation of high-dose or multiple nonsteroidal anti-inflammatory drugs (NSAIDs) in patients receiving tenofovir disoproxil fumarate and with risk factors for renal dysfunction. Renal function should be appropriately monitored during coadministration of tenofovir disoproxil fumarate and NSAIDs. A high risk of renal impairment has been reported in patients receiving tenofovir disoproxil fumarate in combination with the protease inhibitor boosted ritonavir or cobicistat. These patients require careful monitoring of renal function (see section “Interaction with other drugs”). In patients with risk factors for renal impairment, coadministration of tenofovir disoproxil fumarate with a boosted protease inhibitor should be carefully evaluated.Tenofovir disoproxil fumarate has not been clinically evaluated in patients taking medicinal products that are also excreted renally via human organic anion transporter (hOAT) 1 and 3 or MRP4 transport proteins (eg, cidofovir, a known nephrotoxic drug). These renal transport proteins may be responsible for tubular secretion and, in part, excretion of tenofovir and cidofovir through the kidneys. Therefore, the pharmacokinetics of drugs that are also excreted by the kidneys, including transport proteins hOAT 1 and 3 or MRP4, may be altered when used concomitantly. Unless absolutely necessary, the simultaneous use of drugs that are excreted through the same routes through the kidneys is not recommended. If such use cannot be avoided, renal function should be monitored weekly.Renal dysfunctionThe renal safety of tenofovir disoproxil fumarate has been studied to a very limited extent in patients with impaired renal function (creatinine clearance < 80 ml/min).Adult patients with creatinine clearance <50 ml/min, including patients requiring hemodialysisData on the safety and effectiveness of tenofovir disoproxil fumarate in patients with impaired renal function are limited. For this reason, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment outweigh the potential risks. The use of tenofovir disoproxil fumarate is not recommended in patients with severe renal impairment (creatinine clearance <30 ml/min) and in patients requiring hemodialysis. If no other treatment is available, the dosage interval may be adjusted and renal function closely monitored.Impact on bone tissueIn a controlled 144-week clinical trial comparing tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz among antiretroviral treatment-naïve HIV-infected adults, small reductions in hip and spine BMD were observed in both groups. The decrease in spinal BMD and changes from baseline in biomarkers of bone turnover were significantly more pronounced in the tenofovir disoproxil fumarate 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 pathologies.In other studies (prospective and crossover), the most significant changes in BMD were found in patients receiving tenofovir disoproxil fumarate as part of a regimen containing a boosted protease inhibitor. Patients with osteoporosis who are at high risk of fracture should consider other treatment options.Pathological changes in bone tissue (occasionally leading to fractures) can be caused by damage to the proximal tubules of the kidneys.If pathological changes in bone tissue are suspected or detected, you should seek advice from an appropriate specialist.Effect on kidney function and bone tissue in children from 12 to 18 years of ageLong-term effects on bone tissue and toxic effects on the kidneys in children have not been fully established. In addition, the reversibility of toxic effects on the kidneys has not been fully established. Therefore, it is recommended that a multifaceted approach be used to adequately determine the benefit/risk balance of treatment in each individual case, decide on appropriate monitoring during treatment (including the decision to discontinue therapy), and consider the appropriateness of the use of additional drugs.Monitoring kidney functionBefore starting treatment, it is necessary to assess renal function (CK and serum phosphate levels), and it is also necessary to monitor during treatment, as for adults (see above).Management of patients with renal impairmentIf any pediatric patient receiving tenofovir disoproxil fumarate has a serum phosphate level <3.0 mg/dL (0.96 mmol/L), reassess renal function within 1 week, including blood glucose, blood potassium, and urine glucose concentrations. If renal impairment is suspected or detected, a nephrologist should be consulted to consider discontinuing treatment with tenofovir disoproxil fumarate. Discontinuation of tenofovir disoproxil fumarate should also be considered in cases of progressive decline in renal function when no other cause has been identified.Concomitant use and risk of nephrotoxicityThe same recommendations as for adults should be followed (see above).Renal dysfunctionThe use of tenofovir disoproxil fumarate is not recommended in children with impaired renal function. Tenofovir disoproxil fumarate therapy should not be initiated in children with renal impairment, and treatment should be discontinued in pediatric patients in whom renal impairment develops during tenofovir therapy.Impact on bone tissueVirfoten may cause a decrease in BMD. The impact of changes in BMD associated with tenofovir disoproxil fumarate on long-term bone tissue and on future fracture risk is currently unknown.
If bone pathology is detected or suspected in children, it is necessary to consult an endocrinologist and/or nephrologist.

Liver diseases

Data regarding safety and effectiveness in liver transplant patients are very limited.

Data regarding the safety and effectiveness of tenofovir disoproxil fumarate in patients with chronic hepatitis B with decompensated cirrhosis and Child-Pugh grade > 9 are limited. Such patients may be at higher risk of serious hepatic and renal adverse reactions. 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 common and are characterized by a temporary increase in alanine aminotransferase (ALT) activity in the blood serum. After starting antiviral treatment, serum ALT levels may increase in some patients (see section “Side effects”). In patients with compensated liver disease, increased serum ALT activity is usually not accompanied by increased serum bilirubin concentrations or decompensated liver function. Patients with cirrhosis may be at increased risk of liver decompensation following exacerbation of hepatitis and should be closely monitored during treatment.

Exacerbation after cessation of treatment

Exacerbations of hepatitis have also been reported in patients who discontinued hepatitis B treatment. Exacerbations after discontinuation of therapy are usually associated with increased concentrations of hepatitis B virus DNA, and most resolve without additional interventions. However, severe exacerbations, including deaths, have been reported. Within 6 months after stopping treatment for hepatitis B, it is necessary to regularly monitor the functional state of the liver according to clinical and laboratory parameters. If necessary, reinitiation of hepatitis B treatment may be appropriate. For patients with advanced liver disease or cirrhosis, discontinuation of treatment is not recommended because exacerbation of hepatitis after discontinuation of therapy may lead to decompensation of liver function.
In patients with decompensated cirrhosis, exacerbation of hepatitis is especially serious, sometimes with death.

Concomitant infection with hepatitis C or D viruses

There are no data regarding the effectiveness of tenofovir disoproxil fumarate in patients with concomitant hepatitis C or D virus infection.

Concomitant infection with HIV-1 and hepatitis B virus

Due to the risk of developing HIV resistance in patients co-infected with HIV/HBV, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen. Patients with a history of liver disease, including chronic active hepatitis, have an increased incidence of liver function abnormalities during combination antiretroviral therapy and should be monitored according to 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 increased ALT activity may be part of a positive antiviral response against HBV to tenofovir disoproxil fumarate therapy, see above “Exacerbation of hepatitis”.

Use with certain drugs acting on the hepatitis C virus

Concomitant use of tenofovir disoproxil fumarate with ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir has been shown to increase tenofovir plasma concentrations, especially when combined with an HIV treatment regimen containing tenofovir disoproxil fumarate and a booster (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in combination with ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir and a booster (ritonavir or cobicistat) has not been established. The potential risks and benefits associated with coadministration of ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir and tenofovir disoproxil fumarate in combination with a boosted HIV protease inhibitor (eg, atazanavir or darunavir) should be considered, especially in patients at increased risk of renal impairment. Patients receiving ledipasvir/sofosbuvir, velpatasvir/sofosbuvir, or velpatasvir/voxilaprevir/sofosbuvir concomitantly with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir disoproxil fumarate-related adverse reactions.

Body weight and metabolic parameters

During antiretroviral therapy, weight gain and increased plasma lipid and glucose levels are possible. These changes may be due in part to disease control and lifestyle. With regard to lipids, in some cases an increase in their levels indicates the effectiveness of treatment; while there is no convincing evidence linking weight gain to any specific treatment regimen. Monitoring of blood lipid and glucose levels is carried out in accordance with generally accepted protocols for the treatment of HIV infection. Lipid metabolism disorders should be monitored using methods accepted in clinical practice.

Mitochondrial disorders after in utero exposure

Nucleoside and nucleotide analogues can affect mitochondrial function to varying degrees. Particularly pronounced effects are caused by stavudine, didanosine and zidovudine. The development of mitochondrial disorders has been reported in HIV-negative infants exposed in utero and/or postnatally to nucleoside analogs, primarily with zidovudine-containing regimens. Among the main registered adverse reactions are hematological disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These changes were often transitory. In rare cases, late neurological disorders (hypertension, seizures, behavioral disturbances) have been reported. It is currently unknown whether the neurological impairment is transient or permanent. The possibility of such disorders of unknown etiology, especially neurological disorders, should be considered when monitoring children exposed in utero to nucleotide or nucleoside analogues. Available data do not change current national recommendations that HIV-positive pregnant women should receive antiretroviral therapy to prevent vertical transmission of HIV.

Immune reconstitution syndrome

When initiating antiretroviral therapy in HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur and lead to severe clinical conditions or increased severity of symptoms. Typically, such reactions are observed during the first weeks after starting treatment. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any symptoms of inflammation should be monitored and, if necessary, treatment should be prescribed in a timely manner.
Autoimmune diseases (such as Graves’ disease and autoimmune hepatitis) have also been reported to accompany immune reactivation; however, the timing of onset of these events varies widely and these cases may have occurred several months after the start of treatment.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (including the use of glucocorticosteroids, alcohol consumption, the presence of severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly often in patients with advanced HIV infection and/or long-term use of combination antiretroviral therapy. Patients should be advised to consult a physician if they experience joint aches or pain, joint stiffness, or difficulty moving.

Elderly patients

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

Impact on the ability to drive vehicles and machinery

No specific studies have been conducted to study the effect of tenofovir on the ability to drive vehicles and use machinery. Patients should be informed that there are reports of dizziness during treatment with tenofovir. If dizziness occurs, you should refrain from performing these activities.

Active ingredient

Tenofovir

Composition

Active ingredient:

Tenofovir disoproxil fumarate 150 mg, 300 mg

Excipients:

Each film-coated tablet contains:

Core: sodium carboxymethyl starch (Primogel) – 16.5 mg/33.0 mg, sodium stearyl fumarate – 5.9 mg/11.8 mg, croscarmellose sodium – 21.0 mg/42.0 mg, lactose monohydrate – 36.0 mg/72.0 mg, hypromellose E-15 – 4.8 mg/9.6 mg, microcrystalline cellulose (type 101) – 65.8 mg / 131.6 mg.
Ready water-soluble film coating – 9.0 mg / 18.0 mg.

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

Pregnancy

Pregnancy

Extensive data from pregnant women (more than 1000 pregnancy outcomes) indicate that there are no malformations or fetal/newborn toxicity associated with tenofovir disoproxil fumarate. Animal studies have not indicated reproductive toxicity. Therefore, if necessary, the use of tenofovir disoproxil fumarate during pregnancy may be considered.

Breastfeeding period

Studies have shown that tenofovir is excreted into breast milk. There are insufficient data on the effects of tenofovir in neonates/young children. Therefore, Virfoten should not be used during breastfeeding.
In general, women infected with HIV and HBV are not recommended to breastfeed to avoid passing HIV and HBV to their baby.

Fertility

There are no clinical data on the effects of tenofovir disoproxil fumarate on fertility. Animal studies do not indicate any harmful effects of tenofovir disoproxil fumarate on fertility.

Contraindications

• Hypersensitivity to the active substance or any other component of the drug.

• Children under 12 years of age and body weight < 35 kg (efficacy and safety have not been established).

• Children aged 12 to 18 years with impaired renal function (no recommendations on dosage regimen).

• Severe renal failure (creatinine clearance <30 ml/min) or chronic renal failure requiring hemodialysis (safety has not been established in this patient population).

• 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 65 years of age);

– in patients with impaired renal function

– co-administration with other drugs that have nephrotoxic effects, for example, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, interleukin-2, cidofovir, tacrolimus, non-steroidal anti-inflammatory drugs, HIV protease inhibitors boosted with ritonavir or cobicistat

– co-administration of tenofovir disoproxil with ledipasvir/sofosbuvir, velpatasvir/sofosbuvir or velpatasvir/voxilaprevir/sofosbuvir, especially when used concomitantly with an HIV treatment regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (booster, such as ritonavir or cobicistat)

– in patients with a history of liver disease, including hepatitis

– co-administration of tenofovir disoproxil fumarate and didanosine is not recommended

Side Effects

Security Profile Summary

HIV-1 and hepatitis B

Rarely, cases of renal dysfunction, renal failure and proximal tubulopathy (including Fanconi syndrome), sometimes leading to bone pathology (rarely fractures), have been reported in patients taking tenofovir. For patients taking tenofovir, monitoring of renal function is recommended (see section “Special Instructions”).

HIV-1

Adverse reactions when treated with tenofovir in combination with other antiretroviral drugs can be expected in up to one third of patients. These reactions typically represent mild to moderate gastrointestinal disturbances. Approximately 1% of patients treated with tenofovir discontinued treatment due to gastrointestinal reactions.

Such phenomena as lactic acidosis, hepatomegaly with fatty degeneration and lipodystrophy are associated with taking tenofovir (see section “Special instructions”).

Concomitant use of tenofovir and didanosine is not recommended as this may increase the risk of adverse reactions. Cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely.

Hepatitis B

Adverse reactions when taking tenofovir can be expected in up to one quarter of patients, mostly minor. In clinical trials in patients infected with HBV, the most common adverse reaction to tenofovir was nausea (5.4%).

Cases of exacerbation of hepatitis B have been reported in patients during therapy, as well as in patients who stopped treatment for hepatitis B.

The assessment of adverse reactions to tenofovir is based on safety data obtained during clinical trials and post-marketing analysis.

Clinical studies of HIV-1

The assessment of adverse reactions from HIV-1 clinical trials is based on two studies in which 653 treatment-naïve patients received tenofovir (n = 443) or placebo (n = 210) in combination with other antiretroviral drugs for 24 weeks, and data from a double-blind comparative controlled trial in which 600 treatment-naïve patients received 300 mg tenofovir disoproxil fumarate (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

Hepatitis B Clinical Trials

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

Patients with decompensated liver disease

The safety profile of tenofovir in patients with decompensated liver disease was assessed in a double-blind, active-controlled study in which adult patients received tenofovir (n = 45) or 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 < 2 mg/dL at 48 weeks; There were no statistically significant differences between the tenofovir-based combination group and the entecavir group. At 168 weeks, 16% (7/45) of patients in the tenofovir group, 4% (2/45) of those in the emtricitabine + tenofovir group, and 14% (3/22) of those in the entecavir group experienced intolerance. 13% (6/45) of patients in the tenofovir group, 13% (6/45) of the emtricitabine + tenofovir group and 9% (2/22) of the entecavir group had a confirmed elevated serum creatinine ≥ 0.5 mg/dL or a confirmed serum phosphate concentration < 2 mg/dL.

At week 168, in this population of patients with decompensated liver failure, 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 hepatocellular 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 initially higher Child-Pugh scores had a greater risk of developing serious adverse reactions.

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 weeks, no new adverse reactions were observed.

Adverse reactions with a potential (or at least possible) relationship to 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 by frequency are defined as: very often (≥1/10), often (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), rarely (≥1/10000 and <1/1000), very rarely (<1/10000) and the frequency is unknown (it is impossible to estimate the frequency based on the available data)

Metabolic and nutritional disorders

Very common – Hypophosphatemia

Uncommon – Hypokalemia

Rarely – Lactic acidosis

Nervous system disorders

Very common – Dizziness

Often – Headache

Gastrointestinal disorders

Very common – Diarrhea, vomiting, nausea

Common – Abdominal pain, bloating, flatulence

Uncommon – Pancreatitis

Disorders of the liver and biliary tract

Often – Increased activity of “liver” transaminases

Rarely – Fatty liver, hepatitis

Skin and subcutaneous tissue disorders

Very common – Skin rash

Rarely – Angioedema

Musculoskeletal and connective tissue disorders

Uncommon – Rhabdomyolysis, muscle weakness

Rarely – Osteomalacia (manifested by bone pain and bone fractures in some cases)1,2, myopathy1

Renal and urinary tract disorders

Uncommon – Increased creatinine

Rare – Acute renal failure, renal failure, acute tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephritis (including acute interstitial nephritis)2, nephrogenic diabetes insipidus

General and administration site disorders

Very often – Asthenia

Often – Fatigue

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

Renal dysfunction

Since tenofovir may cause renal impairment, it is recommended to monitor renal function (see section “Special Instructions”). Proximal tubulopathy generally resolved or improved after discontinuation of tenofovir. However, in some patients, discontinuation of tenofovir did not completely restore the reduced CK levels. Patients at risk of developing renal failure (eg, patients with baseline risk of renal failure, concomitant HIV infection, concomitant therapy with nephrotoxic drugs) are at increased risk of incomplete recovery of renal function despite discontinuation of tenofovir.

HIV-1

Interaction with didanosine

Concomitant use of tenofovir and didanosine is not recommended as this increases the systemic exposure of didanosine by 40-60%, which may increase the risk of didanosine-related adverse reactions (see section “Interactions with other medicinal products”). Cases of pancreatitis and lactic acidosis, sometimes fatal, have been reported rarely.

Lipids, lipodystrophy and metabolic disorders

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

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

In a 144-week controlled clinical trial in antiretroviral-naïve patients that compared tenofovir with stavudine in combination with lamivudine and efavirenz, the risk of lipodystrophy was significantly lower with tenofovir than with stavudine. The tenofovir group also had significantly lower mean increases in fasting triglycerides and total cholesterol than the comparison group.

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency at the time of initiation of combination antiretroviral therapy, an inflammatory response to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves’ disease) have also been reported, but the timing of onset of these events varies 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, advanced 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 has been reported with the use of nucleoside analogues and is usually accompanied by fatty liver disease. 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

Exacerbation of hepatitis during treatment

In studies among nucleoside analog naïve patients, ALT elevations during treatment greater than 10 times the upper limit of normal and more than 2 times the baseline level were observed in 2.6% of patients treated with tenofovir. The ALT rise, which had a median time to onset of 8 weeks, subsequently disappeared with continued treatment. In most cases, these ALT increases were associated with a decrease in viral load >2 log10 copies/mL that preceded or coincided with the ALT increase. During treatment, it is recommended to periodically monitor liver function.

Exacerbation of hepatitis after discontinuation of treatment

In patients infected with HBV, clinical and laboratory signs of exacerbation of hepatitis occurred after discontinuation of drugs active against HBV.

Chronic hepatitis B

The evaluation of adverse reactions is based on one randomized clinical trial of 106 children (age 12 to 18 years) with chronic hepatitis B who were treated with 300 mg tenofovir disoproxil fumarate (n = 52) or placebo (n = 54) for 72 weeks. Adverse reactions observed in children receiving 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 BMD Z-score 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 must be taken when treating patients in this age category with tenofovir.

Patients with impaired renal function

Because tenofovir may cause renal damage, close monitoring of renal function is recommended in adult patients with renal impairment taking the drug. Tenofovir is contraindicated in children aged 12 to 18 years with impaired renal function.

Interaction

Interaction studies were conducted in adults only.

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

Concomitant use is not recommended

Virfoten should not be used with other medicinal products containing tenofovir disoproxil fumarate or tenofovir alafenamide.

Didanosine

Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended.

Medicines that are excreted by the kidneys

Because tenofovir is eliminated primarily by the kidney, concomitant use of tenofovir disoproxil fumarate with drugs that reduce renal function or compete for active tubular secretion via the transport proteins hOAT 1, hOAT 3, or MRP 4 (e.g., cidofovir) may increase serum concentrations of tenofovir and/or concomitantly administered drugs.

Tenofovir disoproxil fumarate should be avoided with concurrent or recent use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2).

Given that tacrolimus may affect renal function, careful monitoring is recommended when coadministered with tenofovir disoproxil fumarate.

Studies conducted with other drugs

No clinically significant pharmacokinetic interactions were observed when tenofovir disoproxil fumarate was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus and a hormonal contraceptive. norgestimate/ethinyl estradiol. Tenofovir disoproxil fumarate should be taken with food because food increases the bioavailability of tenofovir.

Overdose

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

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

Storage conditions

Store in original manufacturer’s secondary packaging at temperatures below 25 0C.

Keep out of the reach of children.

Shelf life

4 years. Do not use after expiration date.

Manufacturer

Pharmasintez JSC, Russia