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Composition:


active ingredient: tenofovir disoproxil fumarate;


1 tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil;


excipients: lactose, monohydrate; microcrystalline cellulose; croscarmellose sodium; pre-chelated starch; magnesium stearate; Opadry II light Blue dye (Y-30-10671-a) (composition: hypromellose; indigocarmine (e 132); lactose, monohydrate; titanium dioxide (E 171); triacetin).


Dosage form. Film-coated tablets.


Basic physical and chemical properties: Film — coated tablets, blue in color, almond-shaped, engraved with "H" on one side and "123" on the other.


Pharmacotherapeutic group. Antiviral agents for systemic use. Nucleoside and nucleotide reverse transcriptase inhibitors.




Pharmacological properties.


Pharmacodynamics.


Mechanism of action and pharmacodynamic effects. Tenofovir disoproxil fumarate is the fumarate salt of the propreparation tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is an analog of monophosphate nucleoside (nucleotide). Tenofovir is then converted to the active metabolite, tenofovir diphosphate, which is a mandatory end of the chain, by constructively expressed cellular enzymes. Tenofovir diphosphate has an intracellular Half – Life of 10 hours in the activated state and 50 hours at rest in peripheral blood mononuclear cells (PBMC). Tenofovir diphosphate inhibits HIV - 1 reverse transcriptase and HBV polymerase by competing for direct binding to the natural deoxyribonucleotide substrate and breaking the DNA chain after attachment to DNA. Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β and γ. In vitro assays, tenofovir at concentrations up to 300 mmol/L also showed no effect on mitochondrial DNA synthesis or lactic acid formation.


Data related to the HIV virus.


HIV antiviral activity in vitro. The concentration of tenofovir required for 50% inhibition (EC50) of the laboratory strain of wild-type HIV-1IIIB is 1-6 mmol/L in lymphoid cell lines and 1.1 mmol/L against the main HIV-1 subtype B isolates in PBMC. Tenofovir is also active against HIV-1 subtypes a, C, D, E, F, G, and O and against Vilbal in major monocyte/macrophage cells. Tenofovir is active in vitro against HIV-2 with EC50 at 4.9 mmol/L in MT-4 cells.


Resistance. HIV-1 strains with reduced susceptibility to tenofovir and the k65r mutation in reverse transcriptase were selected in vitro and from some patients (see "clinical trial results"). The use of tenofovir disoproxil fumarate in patients who have already been treated with antiretroviral drugs with strains with the K65R mutation should be avoided (see the section "special instructions for use"). In addition, the effect of tenofovir on K70E replacement in HIV-1 reverse transcriptase leads to a low level of reduced sensitivity to tenofovir.


In clinical trials in patients who have already been treated, the anti-HIV activity of tenofovir disoproxil (fumarate) at a dose of 245 MG was evaluated against HIV-1 strains with resistance to nucleoside inhibitors. The results show that patients with HIV who underwent 3 or more thymidine-analog associated mutations (TAMs) involving either the m41l or l210w reverse transcriptase mutation showed a reduced response to treatment with tenofovir disoproxil (in the form of fumarate) at a dose of 245 mg.


Data related to hepatitis B virus (HBV).


Antiviral activity against HBV in vitro: in vitro antiviral activity of tenofovir against HBV was evaluated in the HepG 2 cell line 2.2.15. EC50 values for tenofovir ranged from 0.14 to 1.5 mmol/L, with CC50 values (50% cytotoxicity concentration) > 100 mmol/L.


Resistance. No HBV mutations associated with resistance to tenofovir disoproxil fumarate have been identified. In cell analyses, HBV strains that cause rtv173l, rtL180M, and rtM204I/V mutations and are associated with lamivudine and telbivudine resistance showed sensitivity to tenofovir, which varied multiple of 0.7-3.4 compared to the sensitivity of the "wild" virus. HBV strains that cause mutations rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V associated with resistance to entecavir showed sensitivity to tenofovir, which varied many times 0.6-6.9 compared to the sensitivity of the "wild" virus. HBV strains that cause mutations associated with adefovir resistance rtA181V and rtN236T showed sensitivity to tenofovir, which varied many times 2.9-10 compared to the sensitivity of the "wild" virus. Viruses with the rtA181T mutation remained sensitive to tenofovir with EC50 values multiple of 1.5 compared to the sensitivity of the "wild" virus.


The efficacy of tenofovir disoproxil in disease compensation and decompensation has been demonstrated in virological, biochemical, and serological reactions in adult patients with HBeAg-positive and HBeAg-negative chronic hepatitis B. Patients treated included those who had not previously received treatment, patients treated with lamivudine, adefovir, dipivoxil, and patients with initial mutations of resistance to lamivudine and/or adefovir dipivoxil. Efficacy was also demonstrated based on histological responses in compensated patients.


Pharmacokinetics.


Tenofovir disoproxil fumarate is a water-soluble propreparate ester that is rapidly converted in vivo to tenofovir and formaldehyde.


Tenofovir is converted intracellularly to tenofovir monophosphate and to the active component ― tenofovir diphosphate.


Suction. After oral administration of tenofovir disoproxil to HIV-infected patients, fumarate is rapidly absorbed and converted to tenofovir. Administration of multiple doses of tenofovir disoproxil fumarate with food to HIV-infected patients resulted in average (coefficient of variation, % [CV, %]) values for tenofovir Cmax, AUC, and Cmin 326 (36.6 %) ng/mL, 3,324 (41.2 %) ng·H/ML, and 64.4 (39.4 %) ng/mL, respectively. Maximum concentrations of tenofovir are observed in the blood serum within 1 hour after administration on an empty stomach and within 2 hours when taken with food. When tenofovir disoproxil fumarate was administered orally to patients on an empty stomach, the oral bioavailability was approximately 25 %. Administration of tenofovir disoproxil fumarate to fat – rich foods increased oral bioavailability, with tenofovir AUC increasing by approximately 40% and Cmax increasing by approximately 14 %. After the first dose of tenofovir disoproxil fumarate obtained after a fat-rich meal, the median serum Cmax was in the range of 213 to 375 ng/mL. However, administration of tenofovir disoproxil fumarate with light food did not significantly affect the pharmacokinetics of tenofovir.


Distribution. After intravenous administration, the steady-state volume of distribution of tenofovir was 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 contents (preclinical studies). In vitro binding of tenofovir to plasma or serum protein was less than 0.7 and 7.2%, respectively, in the range of tenofovir concentrations from 0.01 to 25 mcg/ml.

Use in children and adolescents.


HIV-1. inpatient pharmacokinetic parameters of tenofovir were evaluated in 8 HIV-infected adolescent patients aged 12 to 18 years with a body weight ≥ 35 kg. The mean (±CB) Cmax was 0.38±0.13 mcg/ml, AUCtau was 3.39 ± 1.22 MCG·H/ML. The exposure to tenofovir achieved in adolescent patients treated daily with 245 mg of tenofovir disoproxil (as fumarate) was similar to that achieved in adult patients treated daily with 245 mg of tenofovir disoproxil (as fumarate).


Chronic hepatitis B. Effect of tenofovir in stable condition on HBV-infected patients (aged 12 to


Pharmacological studies have not been conducted in children over 12 years of age and in children with impaired renal function.


Renal disorders. The pharmacokinetic parameters of tenofovir were determined after administration of a single dose of 245 mg of tenofovir disoproxil 40 to uninfected HIV and HBV patients with renal impairment of varying degrees, determined according to the initial creatinine clearance value (normal renal function if CrCl > 80 mL/min; small disorders – at CrCl 50-79 mL/min; moderate – at CrCl 30-49 mL/min and severe – at CrCl 10-29 mL/min). Compared to patients with normal renal function, mean exposure (% CV) to tenofovir increased from 2,185 (12 %) ng·H/ML in patients with CrCl > 80 mL/min to 3,064 (30 %) ng·H/ML, 6,009 (42 %) ng·H/ML, and 15,985 (45 %) ng·H/mL, respectively. It is expected that an increase in the interval between Drug Administration will lead to higher peak plasma concentrations and lower Cmin levels in patients with renal impairment compared to patients with normal renal function. The clinical significance of this is unknown.


In patients with end‑stage renal failure (CRCL max 1,032 ng/mL and mean AUC0-48h 42,857 ng·H/ML.


It is recommended that the interval between administration of tenofovir disoproxil fumarate at a dose of 245 mg be changed in patients with creatinine clearance").


Pharmacokinetics of tenofovir in patients undergoing hemodialysis with creatinine clearance


The pharmacokinetics of tenofovir in pediatric patients with renal insufficiency have not been studied. There are no data on dosage recommendations (see "dosage and administration" and "application features").


Liver disorders. A single dose of tenofovir disoproxil 245 MG was administered to uninfected HIV and HBV patients with varying degrees of hepatic impairment, determined according to the Child‑Pugh‑Turcotte (CPT) classification. The pharmacokinetic parameters of tenofovir did not change significantly in patients with hepatic impairment, which indicated that there was no need for dose adjustment. Mean (% CV) Cmax and auc0-∞ values 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, and 305 (24.8 %) ng/mL and 2,740 (44.0 %) ng·h/ML in individuals with severe hepatic impairment.


Intracellular pharmacokinetics. In non-reproducible human peripheral blood mononuclear cells, the Half-Life of tenofovir diphosphate is approximately 50 hours, while this indicator in phytohemoglutinin-stimulated PBMs was approximately 10 hours.

Clinical characteristics.


Indications.


HIV-1 infection


Tenofovir disoproxil fumarate tablets are prescribed for the treatment of HIV-1-infected patients in combination with other antiretroviral drugs.


Tenofovir disoproxil fumarate tablets are prescribed for the treatment of HIV-1-infected adolescents with resistance to nucleoside reverse transcriptase inhibitors (NIST) or toxicity, excluding the use of first-line drugs in patients aged 12 to .


The choice of Tenofovir Disoproxil Fumarate for the treatment of HIV-1-infected patients treated with antiretroviral drugs should be based on the individual history of resistance testing / or treatment history of patients.


Hepatitis B


The drug tenofovir disoproxil fumarate is intended for the treatment of chronic hepatitis B in adults with:


* compensated liver disease, with signs of active viral replication, a constant increase in serum alanine aminotransferase (ALT) levels, and a histological manifestation of active inflammation and / or fibrosis (see the section "pharmacodynamics").


* confirmation of lamivudine-resistant hepatitis B.

* decompensated liver disease .


The drug tenofovir disoproxil fumarate is intended for the treatment of chronic hepatitis B in adolescents aged 12 to


* compensated liver disease, signs of active immune system disease, i.e. active viral replication, a constant increase in serum alanine aminotransferase (ALT) levels, and a histological manifestation of active inflammation and/or fibrosis.


Contraindications.


Hypersensitivity to the active substance or to any of the excipients.


Children under 12 years of age.


Interactions with other drugs and other types of interactions.


Interaction studies were conducted only in adults.


Taking into account the results of in vitro experiments and the known route of elimination of tenofovir, it can be concluded that the probability of CYP450-mediated interactions involving tenofovir and other drugs is low.


Simultaneous use is not recommended. Tenofovir disoproxil fumarate should not be used with other medications containing tenofovir disoproxil fumarate or tenofovir alafenamide.


Tenofovir disoproxil fumarate should not be used concomitantly with adefovir dipivoxil.


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


Medications that are excreted by the kidneys. Since Tenofovir is mainly excreted by the kidneys, concomitant use of tenofovir disoproxil fumarate with drugs that reduce renal filtration 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 used simultaneously.


The use of tenofovir disoproxil fumarate should be avoided with concomitant or recent use of nephrotoxic drugs. These are, for example, aminoglycosides, amphotericin B, foscarnet, Ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2.


Given that tacrolim may affect renal function, special supervision is recommended if it is used with tenofovir disoproxil fumarate.

Application features.


General


Before starting tenofovir disoproxil fumarate therapy, an HIV antibody test should be offered to all HBV-infected patients (see the sections "concomitant HIV-1 and hepatitis B infection"below).


HIV‑1: since effective suppression of the virus by antiretroviral treatment with Tenofovir Disoproxil Fumarate has not been proven to significantly reduce the risk of sexual transmission, a residual risk cannot be excluded. Measures to prevent transmission should be taken in accordance with national recommendations.


Chronic hepatitis B: patients should be informed that there is no evidence that tenofovir disoproxil fumarate prevents the risk of transmission to others through sexual contact or ingestion. Appropriate precautions should be taken.


Concomitant use with other medications.


- Tenofovir disoproxil fumarate should not be used with other medications containing tenofovir disoproxil fumarate or tenofovir alafemide.


- Tenofovir disoproxil fumarate should not be used simultaneously with adefovir dipivoxil.


- Concomitant use of tenofovir disoproxil fumarate and didanosine is not recommended. Concomitant use of tenofovir disoproxil fumarate and didanosine leads to a 40-60% increase in systemic exposure to didanosine, which increases the risk of didanosine-related side effects. Rare, sometimes fatal, cases of pancreatitis and lactic acidosis have been reported. Concomitant use of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg per day was associated with a significant decrease in the number of CD4 cells, possibly due to intercellular interaction that increases phosphorylated (i.e. active) didanosine. A reduced dose of 250 mg of didanosine administered together with tenofovir disoproxil fumarate therapy was associated with reports of high rates of virologically unsuccessful treatment in several studied combinations for the treatment of HIV-1 infection.


Triple therapy with nucleosides/nucleotides. There have been reports of a high frequency of virologically unsuccessful treatment and the appearance of resistance at an early stage in HIV patients if tenofovir disoproxil fumarate was combined with lamivudine and Abacavir, as well as with lamivudine and didanosine at a frequency of Administration 1 time per day.


Effects on kidneys and bones in adults


Effect on kidney function. Tenofovir is mainly excreted by the kidneys. Renal failure, renal impairment, elevated creatinine levels, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with tenofovir disoproxil fumarate in Clinical Practice (see Section "adverse reactions").


Monitoring of renal function. It is recommended to calculate creatinine clearance in all patients before starting treatment with tenofovir disoproxil fumarate and check renal function (creatinine clearance and serum phosphate levels) after 2 4 4 weeks of treatment, after 3 months of treatment, and then every 3.6 months in patients who do not have risk factors for renal disorders. In patients with an increased risk of impaired renal function, more frequent renal function checks should be performed.


Treatment of kidney diseases. If the level of phosphate in the blood serum ", proximal tubulopathy). Discontinuation of tenofovir disoproxil fumarate treatment should also be considered in patients with reduced creatinine clearance prior to discontinuation of Tenofovir Disoproxil Fumarate treatment.


Concomitant use and risk of renal toxicity. The use of tenofovir disoproxil fumarate with concomitant or recent use of nephrotoxic drugs (for example, aminoglycosides, amphotericin B, foscarnet, Ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2) should be avoided. If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents cannot be avoided, renal function should be checked weekly.


Cases of acute renal failure after starting high-dose nonsteroidal anti-inflammatory drugs (NSAIDs) or multiple NSAIDs have been reported in patients treated with tenofovir disoproxil fumarate and in patients with risk factors for impaired renal function. In the case of concomitant administration of Tenofovir Disoproxil Fumarate with NSAIDs, renal function should be monitored properly.


A higher risk of renal failure has been reported in patients receiving tenofovir disoproxil fumarate in combination with ritonavir or a cobicistat-induced protease inhibitor. Careful monitoring of renal function in these patients should be carried out (see the section "interactions with other drugs and other types of interactions"). In patients with risk factors for impaired renal function, concomitant administration of tenofovir disoproxil fumarate with a forced protease inhibitor should be carefully evaluated.


No clinical evaluation of tenofovir disoproxil fumarate has been performed in patients receiving drugs that are excreted in the same way – by the kidneys, including human organic anion transporter proteins (hOAT) 1 and 3 or MRP 4 (for example, cidofovir is a known nephrotoxic drug). These renal transport proteins may cause tubular secretion and partial renal excretion of tenofovir and cidofovir. Therefore, the pharmacokinetics of drugs that are excreted by the same renal route, including transport proteins hOAT 1 and 3 or MRP 4, may change with concomitant administration. Unless there is an urgent need, the simultaneous use of drugs that are excreted equally by the kidneys is not recommended. If such use cannot be avoided, renal function should be checked weekly (see Section "interactions with other medications and other types of interactions").


Impaired renal function. Renal safety when taking tenofovir disoproxil fumarate has been studied to a very limited extent in adult patients with impaired renal function (creatinine clearance).

Dosage and administration.


Treatment should be initiated by a doctor who has experience in the treatment of HIV infection and / or chronic hepatitis B.


Adults.


The recommended dose for the treatment of HIV or for the treatment of chronic hepatitis B is 1 tablet 1 time a day, taken orally with food.


Chronic hepatitis B. The optimal duration of treatment is unknown. Conditions for discontinuation of treatment may include:


Treatment of patients with a positive reaction to the hepatitis B virus (HBeAg) antigen without cirrhosis should continue for at least 6-12 months after confirmation of HBe seroconversion (disappearance of hepatitis B virus antigens and hepatitis B virus DNA with detection of anti-hbe) or until HBs seroconversion, or disappearance of effectiveness (see the section "application features"). After discontinuation of treatment, serum ALT and hepatitis B virus DNA levels should be regularly checked to determine any late relapses of viremia.


Treatment of patients with a negative reaction to the hepatitis B virus antigen without cirrhosis should continue at least until HBs seroconversion or signs of disappearance of treatment effectiveness appear. In the case of prolonged treatment lasting more than 2 years, it is recommended to regularly review the treatment to confirm that the chosen therapy remains suitable for the patient.


Children.


HIV‑1: for adolescents aged 12 to


Chronic hepatitis B: for adolescents aged 12 to


Missed dose.


If the patient has missed taking the next dose of tenofovir disoproxil fumarate, and less than 12 hours have passed since the proper intake, the patient should take the drug with food as soon as possible, then follow the usual schedule of taking the drug. If the patient missed taking the next dose of tenofovir disoproxil fumarate, and more than 12 hours have passed since the proper intake, that is, it is almost time to take the next dose of the drug, the patient should not take the missed dose, but simply continue taking the drug according to the schedule.


If the patient experiences vomiting within 1 hour after taking Tenofovir Disoproxil Fumarate, he should take another tablet. If vomiting occurs in a patient more than 1 hour after taking Tenofovir Disoproxil Fumarate, there is no need to take another tablet.


Tags: Tenofovir