Viread® (Viread®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTenofovirTenofovir
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    • Dosage form: & nbspfilm coated tablets
    Composition:

    I tablet contains:

    active substance: tenofovir disoproxil fumarate 300 mg;

    Excipients:

    Core tablet:

    starch prsgtanitized 33.33 mg, croscarmellose sodium 40.0 mg, lactose monohydrate 153.33 mg, microcrystalline cellulose 133.33 mg, magnesium stearate 6.67 mg;

    Tablet casing:

    Opadrai 11 Y-30-10671-A 26.7 mg: aluminum lignol based on indigo carmine (FD&C Blue №2) 0.398 mg, hypromellose 7.476 mg, lactose monohydrate 10.680 mg, titanium dioxide 6.010 mg. triacetin 2.136 mg.

    Description:

    The tablets are almond-shaped, covered with a film shell of light blue color, engraved on one side "GILEAD" and "4331", on the other - "300".

    On the break the tablets are white.
    ATX: & nbsp

    J.05.A.F.07   Tenofovir

    Pharmacodynamics:

    Mechanism of action

    Temofovir disoproxil fumarate is the fumarate salt of the prodrug of tenofovir, dizoproxyl.Tenofovir disoproxil is absorbed and converted to the active substance tenofovir, which is an analogue of the nucleoside monophosphate (nucleotide). Then tenofovir is converted into an active metabolite, tenofovir diphosphate, which is an obligate terminator of a primate, using constructively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of K) hours in activated peripheral blood mononuclear cells and 50 hours at rest. Tenofovir diphosphate inhibits reverse transcriptase of HIV-1 and hepatitis B virus polymerase (HBV) by competition for direct binding to the active site of the enzyme with the natural substrate of the deoxyribonucleotide and the breakage of the DNA chain after insertion into it. Tenofovir diphosphate is a weak inhibitor of cellular polymerases α, β and γ. In the analyzes in vitro Tenofovir at concentrations up to 300 μmol / L also showed no effect on the synthesis of mitochondrial DNA or on lactic acid production.

    Activity against HIV

    Activity against HIV in vitro

    The concentration of tenofovir required for 50% inhibition (EU50 - 50% effective concentration) of laboratory strain HIV-1IIIB wild type is 1-6 μmol / l in the line of lymphoid cells and 1.1 μmol / l against the primary isolates of HIV-1 subtype B in mononuclear cells of peripheral blood. 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 also shows activity in vitro against HIV-2 with a 50% effective concentration of the EU50 in 4.9 μmol / l in MT-4 cells.

    Activity against HBV

    Activity against HBV in vitro

    2

    Antiviral activity of tenofovir against HBV in vitro evaluated on a cell line IIepG2 2.2.15. EU values50 for tenofovir were in the range from 0.14 to 1, 5 μmol / L, and the CC values50(50% cytotoxic concentration) exceeded 100 μmol / l.

    Resistance

    HIV-1 strains with reduced sensitivity to tenofovir and replacement K65R in the reverse transcriptase gene were isolated in vitro and in some patients. The use of tenofovir dizoproxil fumarate should be avoided in patients who have previously received antiretroviral therapy, whose strains contain a mutation K65R.

    In clinical studies on patients who received antiretroviral therapy earlier,The anti-HIV activity of 300 mg of tenofovir, dizoproxil fumarate, versus HIV-1 strains with resistance to nucleoside inhibitors was evaluated. The results showed that patients with HIV who expressed 3 or more mutations associated with thymidine analogs, including substitutions M41L or L210W in reverse transcriptase, showed a reduced response to therapy with 300 mg of tenofovir dizoproxil fumarate.

    HBV Resistance

    There were no mutations in HBV polymerase associated with tenofovir resistance to disoproxil fumarate. In cellular models, HBV variants expressing substitutions rtV173L, rtLISOM and rtM204I/V, associated with resistance to lamivudine and telbivudine, demonstrated sensitivity to tenofovir in 0.7 - 3.4 times the sensitivity of the wild-type virus.

    FROM
    HBV strains expressing substitutions rlL180M, r(TI84G, rtS202G/l, rtM204V and rtM250V, associated with resistance to epgevavir, showed a sensitivity to tenofovir in 0.6-6.9 times greater than the wild-type virus. HBV strains. expression substitutions rtA 181V and rtN236T, associated with resistance to adefovir, demonstrated a sensitivity to tenofovir 2.9 to 10 times greater than the wild-type virus. Viruses that contain a replacement rtA 181T, remained sensitive to tenofovir, EC values ​​were 1.5 times greater than those of wild-type virus.

    Pharmacokinetics:

    Tenofovir disoproxil fumarate is a water-soluble ester of a prodrug that rapidly converts in vivo at tenofovir and formaldehyde.

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

    Suction

    After ingestion of HIV-infected patients with tenofovir, dizoproxil fumarate is rapidly absorbed and converted into tenofovir. The administration of multiple doses of tenofovir to disoproxil fumarate with food from HIV-infected patients resulted in a mean (coefficient of variation,% [CV, %]) values ​​for tenofovir Cmax, AUC and C min 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 administration on an empty stomach and within 2 hours when he was taken with a beggar. When receiving tenofovir dizoproxil fumarate by patients on an empty stomach, bioavailability was approximately 25%. The use of tenofovir, a dysoproxil fumarate with a fat-rich diet, increased bioavailability, AUC Tenofovir increased approximately 40%, and Cmax - approximately 14%.After the first dose of tenofovir, dizoproxil fumarate, obtained after the intake of the fat-rich food, the median Cmax in the serum was in the range of values ​​from 213 to 375 ng / ml. However, the use of tenofovir with disoproxil fumarate with a low-calorie diet has no significant effect on the pharmacokinetics of tenofovir.

    Distribution
    After intravenous administration, the equilibrium concentration of tenofovir distribution was estimated to be approximately 800 ml / kg. After taking tenofovir disoproxil fumarate inside, tenofovir is distributed in many tissues, with the greatest concentrations observed in the kidneys, the liver and in the intestinal epithelium in different parts of it (pre-clinical studies). In vitro the 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 μg / ml.

    Metabolism

    Research in vitro showed that neither tenofovir disoproxil fumarate, nor tenofovir ns are enzyme substrates CYP450. Moreover, at concentrations significantly exceeding (approximately 300 times) those that are observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the main isoforms CYP450 people involved in biotransformation (CYP3A4, CYP2D6, CYP2C9, CYP2E1 or CYP1A1/2). Tenofovir disoproxil fumarate at a concentration of 100 μmol / L had no effect on either of the isoforms CYP450 with the exception of CYP1A1/2, Where there was a small (6 %), but a statistically significant decrease in substrate megabolism CYP1A1/2. On the basis of 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 CYP450.

    Excretion

    Tenofovir is excreted principally by the kidneys, both by filtration and by the active tubular transport system, and after intravenous administration, approximately 70 to 80% of the dose is excreted unchanged in the urine. The total clearance was estimated at approximately 230 ml / h / kg (approximately 300 ml / min). The renal clearance was estimated at approximately 160 mL / h / kg (about 210 ml / min), which exceeds the rate of glomerular filtration. This indicates that tubular secretion is an important part of the excretion of tenofovir.After oral administration, the final half-life of tenofovir is from 12 up to 18 hours.

    Studies have found that the active tubular transport secretion system involves the absorption of tenofovir by proximal tubule cells through organic human anion transporters (hOAT) 1 and 3, and excretion into the urine using a marker protein of multidrug resistance 4 (MRP 4). Linearity-nonlinearity

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

    Pharmacokinetics in specific patient groups Elderly patients

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

    Floor

    Limited data on the pharmacokinetics of tenofovir in women indicate a lack of significant sexual impact.

    Race

    There were no specific studies of pharmacokinetics in various ethnic groups.

    Children

    HIV-1: The pharmacokinetic parameters of teiofovir in the equilibrium state were evaluated in 8 children (age 12 to 18 years) with a body weight> 35 kg, infected with HIV-1.The mean (± SD) the Cmax and AUCtau were 0.38 ± 0.13 μg / ml and 3.39 ± 0.13 μg / ml ± 1.22 μg-h / ml, respectively. The exposure of teiofovir, which was achieved in adolescents who received daily doses of 300 mg of teioofovir, diazoproxyl fumarate by mouth, was similar to that achieved in adults receiving single daily doses of 300 mg of teioofovir, dizoproxil fumarate.

    Chronic hepatitis B: The equilibrium exposure of teiofovir in children (12 to 18 years of age) infected with hepatitis B virus who received an oral daily dose of 300 mg of teioofovir, dizoproxil fumarate, was similar to the exposure achieved in adults who received 300 mg of teioofovir dizoproxil fumarate once day.

    In children under 12 years of age or in children with renal dysfunction, studies of the pharmacokinetics of 300 mg of teioofovir with disoproxil fumarate have not been conducted.

    Impaired renal function

    Parameters of pharmacokinetics of teiofovir were determined after a single dose of 300 mg of teioofovir, dizoproxil fumarate, was given to 40 adult patients without HIV infection and HBV with renal dysfunction of varying degrees, which were determined according to baseline creatinine clearance (KK) (renal function was not compromised if KK> 80 ml / min,mild violation - if the SC is 50-79 ml / min, a moderately severe disorder - with a QC of 30-49 ml / min and a severe violation - at a QC of 10-29 ml / min). Compared with patients with normal renal function, the mean (%CV) the exposure of teiofovir increased from 2,185 (12%) in the case of persons with CC> 80 ml / min to, respectively, 3,064 (30%) ng / ml, 6 009 (42%) ng h / ml and 15,985 (45%) ig h / ml in patients with mild, moderate and severe renal dysfunction. It is expected that an increase in the interval between administration of the drug will lead to higher peak concentrations in the blood plasma and lower levels Cminy 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 (CC <10 mL / min) who needed hemodialysis, the concentrations of teiofovir between dialysis were significantly lower increased within 48 hours, reaching an average value of Cmax 1032 ng / ml and mean AUC 0-48h 42857 ng * h / ml.

    It is recommended that the interval between doses of 300 mg of tenofovir, dizoproxil fumarate, be changed in adult patients with CC <50 mL / min or in patients who already have a terminal stage of renal failure and who need dialysis.The pharmacokinetics of tenofovir in patients without hemodialysis with CC <10 ml / min and in patients with terminal stage of renal failure, the control of which is carried out by peritoneal or other forms of dialysis, has not been investigated. Studies of the pharmacokinetics of tenofovir in children with renal insufficiency ns were performed. Data on recommendations for dosing are not available.

    Impaired liver function

    A single dose of 300 mg of tenofovir, dizoproxil fumarate, was taken by patients not infected with HIV and HBV, with impaired liver function of various degrees, as determined by the Child-Pyo classification. In patients with impaired hepatic function, no significant changes in the pharmacokinetics of tenofovir were noted, suggesting that there is no need for dose adjustment. Average (% CV) the Cmax and AUCo-∞ Tenofovir was 223 (34.8%) ng / ml and 2050 (50.8%) ng-h / ml, respectively, in those without impaired liver function, 289 (46.0%) ng / ml and 2310 (43, 5%) ng * h / ml in persons with moderate disturbance of the function of baking 305 (24.8%) ng / ml, and 2740 (44.0%) ng * h / ml in individuals with severe impaired liver function.

    Intracellular pharmacokinetics

    It was found that in the developing mononuclear cells of human peripheral blood (PBMC), the half-life of tenofovir diphosphate is approximately 50 hours, whereas in PBMC 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 and drugs.

    Treatment of HIV-1 infection in children aged 12 to 18 years with the presence of resistance to non-nucleoside reverse transcriptase inhibitors, or toxicity excluding the possibility of using antiretroviral drugs of the first line.

    Hepatitis B

    Treatment of chronic hepatitis B in adults with:

    - compensated liver disease, signs of active viral replication, constant elevated serum activity of alanine aminotransferase (ALT), and histologically confirmed active inflammatory process and / or fibrosis;

    - proven presence of HBV resistance to clamivudine;

    - decompiled liver disease.

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

    - compensated liver disease with signs of active inflammatory process and active replication of the virus,which is confirmed by the constant increased activity of ALT in the serum and histologically confirmed by the active inflammatory process and / or fibrosis.

    Contraindications:

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

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

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

    - Severe renal insufficiency (creatinine clearance <30 mL / min) or XPN when needed hemodialysis (safety ns set in this patient population).

    - Lactation period.

    - Simultaneous reception with other drugs containing tenofovir (see the sections "Interaction with other drugs" and "Special instructions").

    - Simultaneous admission with adefovir (see sections "Interaction with other drugs" and "Special instructions").

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

    Carefully:

    in patients with diabetes mellitus; in elderly patients (over the age of 65);

    - in patients with impaired renal function (see section "Special instructions").

    - in patients concomitantly taking other medications: those with nephrotoxic action (amioglycosides, amphotericin 13, foscarnet, ganciclovir, pentamidia, vancomycin, interleukin-2, cidofovir); tacrolimus, nassteroid anti-inflammatory drugs; HIV protease inhibitors, potentiated with ritonavir or a cobicystate (see "Interactions with other drugs" and "Special instructions");

    - in patients with a history of liver disease, including hepatitis (see section "Special instructions");

    co-administration of tenofovir and didanosine is not recommended (see the sections "Interaction with other drugs" and "Special instructions");

    Pregnancy and lactation:

    Pregnancy

    Data from a sample of the average volume in pregnant women (300 to 1000 pregnancies) indicate a lack of malformations or a toxic effect of HIV / newborn that would be associated with the use of tenofovir. Studies in animals did not indicate a toxic effect on reproductive function.Thus, if necessary, the possibility of using tenofovir during pregnancy can be considered.

    Breastfeeding period

    Studies have shown that tenofovir excreted in breast milk. Data on the effects of tenofovir on neonates / deges are inadequate. Therefore, Viread® should not be used during lactation.

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

    Fertility

    There is no evidence of the effect of Viread ® on fertility in humans. Studies in animals do not indicate a deleterious effect of tenofovir on fertility.

    Dosing and Administration:

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

    Treatment should begin and be controlled by a physician with experience in the treatment of HIV infection and / or chronic hepatitis B.

    The choice of Viread® for the treatment of HIV-1 infected patients who had previously received treatment should be based on testing whether there is individual viral resistance and / or the history of the patient's treatment.

    Adults

    The recommended dose of Viread ® for the treatment of HIV and chronic hepatitis B is 1 tablet (300 mg) once a day inside, with food.

    Chronic hepatitis B

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

    - Treatment HBeAg-positive patients without cirrhosis should continue at least 6-12 months after confirmation of seroconversion of HBe (disappearance HBeAg and HBV DNA with the appearance of anti-HBe) or before seroconversion HBs, or before loss of efficiency. After discontinuation of treatment, it is necessary to regularly check the levels of ALT and DNA of hepatitis B virus in the blood serum in order to identify possible late recurrences of viremia.

    - Treatment of patients with HBeAg-injective hepatitis B without cirrhosis should continue, at least until seroconversion HBs or the appearance of signs of treatment failure. In the case of prolonged treatment, continuing more 2 years, it is recommended that the treatment be re-reviewed on a regular basis to confirm that the patient continues to be eligible for continued therapy.

    Children from 12 to 18 years old

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

    In exceptional cases, the tablet of the drug Viread ® can be taken immediately after its dissolution into approximately 100 ml of water, orange or grape juice. Chronic hepatitis B: at the age of 12 to 18 years and with a body weight> 35 kg, the recommended dose of Viread ® is 1 tablet (300 mg) once a day inside, with food. The optimal duration of treatment has not yet been established.

    The safety and effectiveness of genofovir in children with chronic hepatitis B at the age of 2 to 12 years and with a body weight of <35 kg are not established.

    Missing dose

    If the dose was missed and passed less than 12 hours from the usual dose, the patient should take Viread ® as soon as possible with the soda and return to the usual regimen. If, in the case of a missed dose, more 12 hours and approaching the time of taking the next dose of the drug, the patient should not take the missed dose, but take the next dose in accordance with the usual regimen of taking the drug.

    If vomiting occurs within 1 hour after taking Viread®, one more pill should be taken.If vomiting in the patient occurred more than 1 hour after taking Viread ®, then 1 more tablet should not be taken.

    Special patient groups Elderly patients

    To date, there is no data on which to base recommendations for dosing for patients over the age of 65 years.

    Renal impairment

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

    Adults

    Data on the safety and efficacy of the use of genofovir in adult patients with impaired renal function of medium and severe degree (CK <50 mL / min) are limited. Assessment of safety indices in patients with mild renal impairment (KK 50-80 ml / min) was not carried out in the long term. For this reason, patients with impaired renal function tnsnofovir should be used in cases where the potential benefit of treatment exceeds the potential risk of harm. Correction of the dosing interval is recommended for patients with CC <50 ml / min.

    Violation of the function of the kidneys of mild degree (KK 50-80ml / min). Limited data from clinical studies suggest that for patients with a minor renal dysfunction, tenofovir dosage regimen should be preserved once daily.

    Violation of the function of the kidneys of medium degree (KK 30-49 ml / min). Admission of 1 tablet of Viread® every 48 hours is recommended based on the results of single-dose pharmacokinetic data modeling in volunteers without HIV and HBV infection, with varying degrees of renal dysfunction, including end-stage renal failure requiring hemodialysis. However, such dosing has not been confirmed in clinical trials. Therefore, the clinical response to treatment and renal function in such patients should be closely monitored.

    Violation of the function of the kidneys of severe degree (CK <30 ml / min) and patients on hemodialysis. Due to the impossibility of correcting the dosing regimen, the use of the drug for patients in this troupe is contraindicated.

    Children

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

    Impaired liver function

    For patients with impaired liver function, there is no need for dose adjustment. Careful monitoring of patients with chronic hepatitis B (with concomitant HIV infection or without) is necessary if they stop taking Viread ®, since after the drug is discontinued there is a risk of exacerbation of hepatitis.

    Side effects:

    Brief information about the HIV safety profile-I and hepatitis B

    Rarely reported cases of impaired renal function, renal failure and proximal tubulopathy (including Fanconi syndrome), which sometimes led to bone disease (rarely - to fractures), in patients taking tenofovir. For patients taking Viread ®, monitoring of renal function is recommended (see section "Special instructions").

    HIV-1: Adverse reactions in the treatment of tenofovir in combination with other

    Almost one third of patients can expect antiretroviral drugs. Such reactions, as a rule, represent violations from the gastrointestinal tract from mild to moderate severity. Approximately 1% of patients treated with tpofovir discontinued treatment due to reactions from the gastrointestinal tract.

    With the use of tefofovir associated phenomena such as lactic acidosis, gayatomegaly with fatty degeneration and lyiodistrophy (see section "Special instructions").

    The simultaneous use of Viread ® and didanosine is not recommended, as this may lead to an increased risk of adverse reactions (see section "Interaction with other drugs"). Rarely reported cases of pancreatitis and lactic acidosis, sometimes with a legal outcome (see section "Special instructions").

    Hepatitis B: Adverse reactions with admission of tepofovir may be expected in almost one quarter of patients, mostly minor. In clinical trials involving patients infected with HBV, the most frequent adverse reaction to tenofovir was nausea (5.4%).

    Hepatitis B exacerbations have been reported in patients on the background of therapy, as well as in patients who have stopped hepatitis B treatment (see section "Special instructions").

    Brief information about adverse reactions

    Assessment of adverse reactions to tenofovir is based on safety data obtained through clinical trials and post-registration analysis. All adverse reactions are indicated in the table 1.

    Clinical studies of HIV-1

    The evaluation of adverse reactions from clinical studies of HIV-1 is based on the results of two studies, in which 653 patients who received previous treatment received tenofovir (n = 443) or placebo (n = 210) in combination with other antiretroviral drugs for 24 weeks, as well as a double-blind, comparative controlled trial in which 600 patients who had not previously received treatment received 300 mg of tephofovir, dizoproxil fumarate (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

    Clinical studies of hepatitis B

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

    Patients with decompensated liver disease

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

    In the tenofovir group, 7% of patients discontinued treatment due to adverse reactions; 9% of patients for 48 weeks had confirmed elevated serum creatinine> 0.5 mg / dl or a confirmed serum phosphate concentration <2 mg / dl; statistically significant differences between the group of combined treatment on the basis of tenofovir and the entecavir group ns was. At 168 weeks, 16% (7/45) of the tenofovir group, 4% (2/45) of the group emtricitabine+ tenofovir and 14% (3/22) of the entecavir group showed a tolerance disorder. In 13% (6/45) of patients in the tenofovir group, 13% (6/45) of the group emtricitabine+ tenofovir and 9% (2/22) of the entecavir group, a confirmed elevated serum creatinine> 0.5 mg / dL or a confirmed serum phosphate concentration < 2mg / dl.

    At 168 weeks in this population of patients with decompensated hepatic insufficiency, the death rate was 13% (6/45) in the tenofovir group, 11% (5/45) in the group emtricitabinetenofovir and 14% (3/22) in the entecavir group.The proportion of hepatocellular cancer was 18% (8/45) in the tenofovir group, 7% (3/45) in the group emtricitabinetenofovir and 9% (9/22) in the entecavir group.

    Patients with an initially large number of points on the Child-Pugh classification had a greater 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 within 96 weeks of age received tenofovir (n = 141) or emtricitabine / tenofovir (n = 139), no new adverse reactions were identified.

    Adverse reactions with potential (or, at least, possible) communication with treatment are given below by the class of organ systems and frequency. Within each frequency group, adverse reactions are given in order of severity. Adverse reactions in frequency are defined as: very often (> 1/10), often (from> 1/100 up to < 1/10), infrequently (from> 1/1000 up to < 1/100) and rarely (from> 1/10 000 up to < 1/1000).

    Table 1

    Brief data on adverse reactions associated with the use of tenofovir, based on clinical research and post-registration analysis.

    Classes of organ systems and frequency

    Adverse Reactions

    Disorders from the metabolism and nutrition

    Often

    Hypophosphatemia1

    Infrequently

    Hypokalemia1

    Rarely

    Lactic acidosis3

    Disturbances from the nervous system

    Often

    Dizziness

    Often

    Headache

    Disorders from the gastrointestinal tract

    Often

    Diarrhea, vomiting, nausea

    Often

    Abdominal pain, swelling, flatulence

    Infrequently

    Pancreatitis3

    Disturbances from the liver and bile ducts

    Often

    Increased activity of "liver" transaminases

    Rarely

    Fatty degeneration of the liver 3, hepatitis

    Disturbances from the skin and subcutaneous tissues

    Often

    Skin rash

    Rarely

    Angioedema

    Disturbances from musculoskeletal and connective tissue

    Infrequently

    Rhabdomyolysis1, muscle weakness1

    Rarely

    Osteomalacia (manifested by pains in the bones and fractures of bones in individual cases)1’2, myopathy1

    Disorders from the kidneys and urinary tract

    Infrequently

    Increased creatinine

    Rarely

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

    General disorders and disorders at the site of administration

    Often

    Asthenia

    Often

    Fatigue

    1 Adverse reaction may occur as a consequence of proximal tubulopathy. It is not considered that it is causally associated with tfnofovir in the absence of this disease.
    2 A side-effect was established during nosgresegrassion study, but was observed during randomized controlled clinical trials or a program of expanded access to tenofovir. The frequency category was established by statistical calculations based on the total number of patients taking tenofanov in the framework of randomized controlled trials and an expanded access program (n = 7319).

    3 For more information, see the section below.

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

    Impaired renal function

    Because Viread® can lead to impaired renal function, it is recommended to monitor their function (see section "Special instructions"). Proximal tubulopathy, as a rule, disappeared or there was an improvement after the withdrawal of tenofovir. Nevertheless, in some patients, the withdrawal of tenofovir did not completely lead to the restoration of a decreased level of CC.Patients at risk of developing renal failure (eg, patients with a baseline risk of kidney failure, concomitant HIV infection, concomitant therapy with nephrotoxic drugs) are at increased risk of incomplete renal function recovery despite the withdrawal of tenofovir (see section "Specific guidance"),

    HIV-1

    Interaction with didanosine

    Simultaneous 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 side effects associated with didanosine (see section "Interaction with other drugs"). Rarely reported cases of pancreatitis and lactic acidosis, sometimes with a fatal outcome.

    Lipids, lipodystrophy and metabolic disorders

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

    Combined antiretroviral therapy was associated with the redistribution of adipose tissue in the body of HIV-infected patients (lipodystrophy),including loss of subcutaneous fat on the limbs and face, increased volume of intraperitoneal and visceral fat, mammary hypertrophy, and fat accumulation in the dorso-cervical region (buffalo hump).

    In a 144-week controlled clinical study among patients previously treated with antiretrovirals, which was performed to compare tfnofovir with stavudine in combination with lamivudip and efavirenz, it was observed that the risk of lipodystrophy in the case of tfnofovir was significantly lower than with stavudine. The tenofovir group also had a significantly lower average increase in triglycerides and total fasting cholesterol than the comparison group.

    Immunodeficiency Syndrome

    In HIV-infected patients with severe forms of immunodeficiency, the onset of combined antiretroviral therapy may result in an inflammatory response to asymptomatic or residual opportunistic infections. Also reported were autoimmune disorders (such as Graves' disease); However, the time of onset of such events varies greatly, and these cases may have occurred several months after the start of treatment.

    Osteonecrosis

    Cases of osteonecrosis have been reported, in particular in patients with well-known risk factors, late HIV infection, or long-term use of combination antiretroviral therapy. The frequency of occurrence of this phenomenon is unknown (see section "Special instructions").

    Lactic acidosis and hepatomegaly of severe degree with fatty dystrophy

    When using nucleoside analogues, lactoacidosis was reported, which is usually accompanied by fatty liver dystrophy. Treatment with analogues of nucleosides should be discontinued in the presence of symptomatic hyperlactemia and metabolic lactic acidosis, progressive hepatomegaly, or a rapid increase in the level of aminotransferase (see section "Special instructions").

    Hepatitis B

    Exacerbation of hepatitis during treatment

    Within the framework of studies among patients who had not previously taken nucleoside analogs, increased ALT levels during treatment and exceeding the upper limit of the norm more than in 10 times, and exceeding the entry level more than 2 times, was observed in 2.6% of patients treated with tfnofovir. The rise in ALT, the median time before the appearance of which was 8 weeks, later disappeared on the background of continuing 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 the increase in ALT. During treatment it is recommended to periodically monitor liver function. Exacerbation of hepatitis after withdrawal of treatment

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

    Chronic hepatitis B

    The evaluation of adverse reactions is based on one randomized clinical trial involving 106 children (age 12 to 18 years) with chronic hepatitis B who were treated with 300 mg of tenofovir disoproxil fumarate (n = 52) or placebo (n = 54) for 72 weeks . Adverse reactions, which were observed in children who received tenofovir, corresponded to those observed in clinical studies of tenofovir in adults.

    Reduction of BMD was observed in children infected with hepatitis B virus. Z-the MPC criterion observed in patients who received tenofovir, was lower than that in patients who received a placebo.

    Other special patient groups Older patients

    A study of tenofovir among patients over the age of 65 years of age was conducted. Elderly patients are more likely to have a decreased renal function, therefore, during treatment with tenofovir in this population, special care must be taken.

    Patients with impaired renal function

    Because tenofovir may cause kidney damage, it is recommended that the kidney function in adult patients with impaired renal function receiving Virsad ® is closely monitored. It is contraindicated to use tnchnofovir in children from 12 to 18 years with impaired renal function (see sections "Dosing and Administration" and "Special instructions").

    Overdose:

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

    Treatment: tenofovir can be excreted by hemodialysis, the median clearance value of tenofovir is 134 ml / min. It is not known whether it is possible to deduce tenofovir with peritoneal dialysis.
    Interaction:

    Interaction studies were conducted only in adults.

    Based on the results of experiments in vitro and the known way of deducing tenofovir the possibility of interactions mediated by CYP450, with the participation of tenofovir and other medications is low.

    Simultaneous use is not recommended

    Viread ® should not be used with other medicines containing tenofovir.

    Viread ® should not be used concomitantly with adefovir.

    Didanosine

    The simultaneous use of tenofovir and didanosine is not recommended (see section "Specific guidance" and table 2).

    Medicines that are excreted by the kidneys

    Because the tenofovir is excreted mainly by the kidneys, the simultaneous 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 (eg, with cidofovir), may increase the concentration of tenofovir in serum and / or medications taken concomitantly. It is necessary to avoid the use of tenofovir with simultaneous orthe recent use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2) (see section "Special instructions").

    Given that tacrolimus can affect the function of the kidneys, careful monitoring is recommended when it is used simultaneously with tfnofovir.

    Other interactions

    The interactions between tenofovir, protease inhibitors and antiretroviral agents, which are protease inhibitors, are presented below in Table 2 (the increase is indicated by "↑", the decrease is "↓", the absence of changes is "← →", twice a day - "b.i.d." and once a day - "q.d.").

    Interactions between tfnofovir and other medications

    table 2

    Drug

    Effect on drug levels,

    Recommendation concerning

    preparation for

    simultaneous

    therapeutic

    mean percentage change

    use with tenofovir

    areas

    AUC, Cmax, C min

    dizoproxyl fumarazine 300 mg

    (dose in mg)

    ANTI-INFECTIOUS

    Antiretroviral
    Protease Inhibitors

    Medicinal product in therapeutic directions

    (dose in mg)

    Effect on drug levels, mean percentage change

    AUC, Cmax, C min

    Recommendation concerning simultaneous use of 300 mg of dizoproxyl fumarate with genofovir

    Atazanavir / Ritonavir

    Atazanavir:

    Correction of the dose is not required. Increased exposure

    (300 q.d./100 q.d./300 q. d.)

    AUC: ↓ 25 %

    tenofovir may increase

    Cmax: ↓ 28 %

    undesirable effects associated with tenofovir,

    FROM min : ↓ 26 %

    including renal pathology. Careful

    Tenofovir: AUC: ↑ 37% Сmax: ↑ 34% Сmin: ↑ 29%

    monitor kidney function.

    Lopinavir / Ritonavir

    Lopinavir / Ritonavir.

    Correction of the dose is not required. Increased exposure

    (400 b.i.d./100 b.i.d./300

    There is no significant impact on the parameters of the FC

    tenofovir may increase

    q.d.)

    lopinavir / ritonavir.

    Tenofovir:

    associated with tenofovir undesirablee phenomena, including kidney pathology.

    AUC: ↑ 32 %

    It is necessary to carefully monitor the function

    Сmах: ← →

    Cmin: ↑ 51 %

    kidney.

    Darunavir / Ritonavir

    Darunavir.

    Correction of the dose is not required. Increased exposure

    (300/100 b.i.d./ ZOO q.d.)

    There is no significant impact on the parameters of the FC

    tenofovir may increase

    darunavir / ritonavrin.

    Tenofovir:

    Related to tenofovir, adverse events, including renal pathology.

    AUC: ↑ 22 %

    It is necessary to carefully monitor the function

    Cmin: ↑ 37 %

    kidney.


    Medicinal preparation by therapeutic direction

    (dose in mg)

    Effect on drug levels, mean percent change in AUC, Cmax, Cmin

    Recommendations for the simultaneous use with tenofovir dizoproxil fumarate 300 mg

    Nucleoside

    reverse transcriptase inhibitors

    Didanosine

    The simultaneous use of tenofovir and didanosine leads to a 40-60% increase in systemic exposure to didanosine, which may increase the risk of ddI-related adverse events. It was reported of infrequent, sometimes lethal, cases of pancreatitis and lactoaccess. Simultaneous administration of tenofovir and didanosine at a dose of 400 mg per day was associated with a significant decrease in the number of cells Cd4, possibly in connection with the intercellular interaction, that the increased phosphorylated (then its active) didanosine. The reduction in didanosine dosage to 250 mg, which is administered with tenofovir, was associated with reports of a high incidence of virological failure in several combinations studied for the treatment of HIV-1 infection.

    The simultaneous 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 with simultaneous use of tenofovir with enzacavir.

    Studies conducted with other drugs

    Clinically significant pharmacokinetic interactions were not observed with simultaneous use of tenofovir with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir-boosted), methadone, ribavirin, rifampicin, tacrolimus and hormonal contraceptive norgestimag / ethinyl estradiol.

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

    Special instructions:

    Are common

    Before beginning therapy with tfnofovir, one should propose an HIV antibody test for all patients infected with hepatitis B virus.

    HIV-1

    Despite the fact that stable antiretroviral therapy, leading to sustained suppression of the virus, significantly reduces the risk of transmission of the virus during sexual intercourse, nevertheless, the risk of nc can be ruled out completely.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 through blood is not proven. Appropriate precautions should be taken.

    Simultaneous use with other medicinal products

    Viread ® should not be used with other medicines containing tenofovir.

    Viread ® should not be used concomitantly with adefovir.

    It is not recommended simultaneous use of tenofovir and didanosine. The simultaneous use of tenofovir and didanosine leads to a 40-60% increase in the systemic exposure of didanosine. which may increase the risk of didanosine-related adverse events (see section "Interaction with other drugs"). Rarely reported pancreatitis and lactic acidosis, sometimes with a fatal outcome. Simultaneous use of tenofovir and didanosine at a dose of 400 mg per day was associated with a significant decrease in the number of cells Cd4, probably due to intercellular interaction, which increases the phosphorylated (ie, active) didanosine. The use of didanosine at a reduced dosage of 250 mg, together with tfnofovir therapy, was associated with reports of a high incidence of virologic failure in several combinations studied for the treatment of HIV-1 infection.

    Triple therapy with nucleosides / nucleotides

    There have been reports of a high incidence of virological failure and the emergence of resistance at an early stage in patients with HIV infection, if tenofovir was combined with lamivudine and abacavir, as well as lamivudine and didanosine according to the administration schedule once a day.

    Effect on renal function and adipose tissue in adults Effect on kidney function

    Tenofovir is mainly excreted by the kidneys. There have been reports of renal failure, impaired renal function, elevated creatinine, giophofathemia, and proximal tubulopathy (including Fanconi syndrome) with tenofovir in clinical practice (see "Side effect").

    Control of kidney function

    It is recommended that the CC be determined in all patients before starting treatment with genofovir and monitoring kidney function (QA 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 renal dysfunction. For patients with an increased risk of renal failure, the need for more frequent monitoring of kidney function should be considered.

    Management of patients with impaired renal function
    If the serum phosphate level <1.5 mg / dl (0.48 mmol / L) or QC is reduced to <50 ml / min in the patient receiving tenofovir, it is necessary to reassess the function of the kidneys during the first week, including determining the level of glucose in the blood, potassium in the blood and the concentration of glucose in the urine. Consideration should also be given to the need to cancel treatment with genofovir in patients with a reduction in CK to <50 ml / min or a decrease in serum phosphate levels to <1.0 mg / dL (0.32 mmol / L). The withdrawal of treatment with genofovir should also be considered in the case of progressive decline in renal function, unless no other cause has been determined.

    Joint use with other drugs and risk of nephrotoxicity It is necessary to avoid the use of tenofovir with simultaneous or recent use of nephrotoxic drugs (eg, aminoglycosides, amphotricin B, foscarnet, ganciclovir, lentamidine, vancomycin, cidofovir and interleukin-2).If simultaneous use of tenofovir and nephrotoxic drugs is not possible, weekly renal function should be monitored.

    Cases of acute renal failure were reported after initiating therapy with a high dose or several nonsteroidal anti-inflammatory drugs (NSAIDs) in patients who received tenofovir and having risk factors for renal dysfunction. Renal function should be properly monitored by the simultaneous use of tfnofovir and NSAIDs. A high risk of kidney damage has been reported in patients receiving tenofovir in combination with a protease inhibitor with enhanced ritonavir or a cobicystate. These patients require careful monitoring of kidney function (see section "Interaction with other drugs"). In patients with risk factors for renal dysfunction, co-administration of tfnofovir with an enhanced protease inhibitor should be carefully analyzed. Clinical evaluation of the use of tfnofovir ns was carried out in patients taking medications, which are also excreted by the kidneys,through transport proteins of human organic anion transporters (hOAT) I and 3 or MRP4 (eg, cidofovir, a known nephrotoxic drug). These kidney transport proteins may be responsible for tubular secretion and, in part, the excretion of tfefovir and cidofovir through the kidneys. Therefore, the pharmacokinetics of drugs that are also excreted by the kidneys, including transport proteins hOAT I and 3 or MRP 4, can be changed in case of simultaneous application. In the absence of emergency, the simultaneous use of medicines, which are withdrawn by the same routes through the kidneys, is not recommended. If this can not be avoided, the kidney function should be monitored weekly (see "Interaction with other medicines").

    Impaired renal function

    The safety of tsmofovir in relation to the kidneys has been studied to a very limited extent in patients with impaired renal function (CC <80 mL / min).

    Adult patients with CC <50 ml / min, including patients who need hemodialysis

    Data on the safety and efficacy of tsnofovir for patients with impaired renal function are limited. For this reason tenofovir It is necessary to apply only if the potential benefit of treatment exceeds potential risks. The use of tenofovir in patients with severe renal dysfunction (CK <30 ml / min) and patients who need hemodialysis is contraindicated.

    Effects on bone tissue

    In a controlled 144-week clinical trial comparing tenofovir with etawudine in combination with lamivudine and efavirenz in HIV-infected adult patients who had not received antiretroviral treatment before, small decreases in the BMD in the femur and spine were observed in both groups. Decrease Ml IK spine and changes from baseline biomarkers of bone tissue metabolism were significantly more pronounced in the tenofovir group at week 144. The decrease in the BMD of the femur was significantly more pronounced in this group up to 96 weeks. However, after 144 weeks of increased risk of fractures or signs of clinically significant pathologies of bone tissue was not observed.

    Pathological changes in bone tissue (occasionally leading to fractures) can be caused by damage to the proximal tubule of the kidney (see section "Side effect").

    If you suspect or detect pathological changes in bone tissue, consult a specialist.

    Effect on kidney function and bone tissue v children from 12 to 18 years

    The long-term consequences of the effect on bone tissue and the toxic effects on the kidneys in children have not been fully established. In addition, the reversibility of the toxic effect on the kidney has not been completely established. Therefore, it is recommended that a multilateral approach be used to adequately determine the benefit / risk ratio in each case, decide on appropriate follow-up during treatment (including deciding whether to discontinue therapy), and consider the appropriateness of using additional drugs.

    Control of kidney function

    At the beginning of treatment, it is necessary to evaluate the kidney function (QC and serum phosphate levels), and also to observe during treatment, as well as for adults (see above).

    Management of patients with impaired renal function

    If any patient of child age receiving tenofovir, serum phosphate levels <3.0 mg / dl (0.96 mmol / L), a renal function evaluation is necessary for 1 weeks, including the determination of blood glucose, potassium in the blood and the concentration of glucose in the urine. If there is a suspicion of renal impairment or detection, it is necessary to consult with the nephrologist to consider the need to cancel the treatment with tenofovir. The withdrawal of tenofovir treatment should also be considered in the case of a progressive decline in function of the nights, when no other cause has been determined.

    Joint use and risk of nephrotoxicity

    NotIt is necessary to follow the same recommendations that apply to adults (see above).

    Violation of the function of the nights

    It is not recommended to apply tenofovir in children with impaired renal function (see section "Method of administration and dose"). Do not start therapy with tenofovir in children with a disorder in the function of the nights, and it is also necessary to cancel treatment in those children of childhood who have had renal dysfunction during tenofovir therapy. Effects on bone tissue

    Viread ® may cause a decrease in BMD. The effect of changes in BMD associated with tenofovir on bone tissue in the long term and the risk of fractures in the future is currently unknown (see the section "Pharmacodynamics").

    If a bone pathology is detected or suspected, children should consult an endocrinologist and / or nephrologist.

    Diseases of the liver

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

    Data on the safety and efficacy of tenofovir for patients with chronic hepatitis B, decompensated liver cirrhosis, and grade> 9 in the Child-Pyo classification are limited. Such patients may have a higher risk of serious adverse reactions from the liver and kidneys. Therefore, the parameters of the hepatobiliary system and kidneys in this category of patients should be closely monitored.

    Exacerbation of hepatitis Aggravation during treatment

    Spontaneous exacerbations of chronic hepatitis B are relatively frequent and are characterized by a temporary increase in the level of alapipaminotrapsferase (ALT) in serum. After the onset of antiviral treatment in some patients, the level of ALT in the blood serum may increase (see section "Side effect"). In patients with compensated liver disease, an increase in serum ALT levels is usually accompanied by an increase in serum bilirubin concentration or a decompensated liver function.Patients with cirrhosis of the liver may have an increased risk of decompensating liver function after exacerbation of hepatitis, so they need careful monitoring during treatment.

    Aggravation after discontinuation of treatment

    Also reported was exacerbation of hepatitis in patients who discontinued treatment of hepatitis B. Aggravations after withdrawal of therapy are usually associated with an increase in the concentration of DNA of hepatitis B virus, and most of them are resolved without additional interventions. However, severe exacerbations, including lethal cases, have been reported. During 6 months after the cessation of treatment of hepatitis B, it is necessary to regularly monitor the functional state of the liver according to clinical and laboratory indicators. If necessary, it may be advisable to resume treatment for hepatitis B. For patients with progressive liver disease or with cirrhosis, discontinuation of treatment is not recommended, since exacerbation of hepatitis after the abolition of therapy can lead to decompensation of liver function.

    In patients with decompensated cirrhosis, exacerbation of hepatitis occurs particularly seriously, sometimes with a fatal outcome.

    Concomitant infection with hepatitis C viruses or D

    Data on the efficacy of tenofovir in patients with concomitant hepatitis C or I virus infection do not exist.

    Concomitant HIV-1 infection and hepatitis B virus

    Due to the risk of developing HIV resistance in patients with concomitant HIV / HBV infection, teiofovir should be used only as part of the appropriate antiretroviral combination regimen. Patients who have previously been diagnosed with liver disease, including chronic active hepatitis, have an increased incidence of liver function abnormalities during combined antiretroviral therapy and should be monitored in accordance with standard practice. With worsening of the course of liver disease in such patients, consideration should be given to the need for interruption in treatment or withdrawal of treatment. However, it should be noted that elevated ALT levels may be part of a positive antiviral response to HBV for ternofovir therapy, see above "Exacerbation of hepatitis."

    Lactic acidosis

    With the use of nucleoside analogues, lactic acidosis, usually accompanied by fatty liver dystrophy, has been reported.Preclinical and clinical data indicate that the risk of lactic acidosis, as an effect of drugs from the class of nucleoside analogs, for tenofovir is low. But, since tenofovir structurally similar to nucleoside analogues, this risk may not be eliminated. Early signs (symptomatic gipslaktateemia) include mild symptoms of the digestive system (nausea, vomiting and abdominal pain), nonspecific malaise, loss of appetite, weight loss, respiratory system symptoms (frequent and / or deep breathing) or neurological symptoms symptoms (including motor weakness). Lactic acidosis has a high lethality and may be accompanied by pancreatitis, hepatic or renal insufficiency. Usually, lactic acidosis is observed after several months of treatment.

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

    Care should be taken when assigning nucleoside analogues to any patient (especially women with obesity) with hepatomegaly.hepatitis or other known risk factors for liver disease and fatty liver disease (including certain drugs and alcohol). Interferon-alpha and ribavirin treatment of patients with concomitant hepatitis C virus infection may present a particular risk.

    Patients with an 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 remote consequences of these phenomena are unknown to date. Data on the mechanism of development are incomplete. There is a hypothesis about the relationship between the development of visceral lipomatosis and the intake of protease inhibitors and the development of lipoatrophy with the reception of nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy was due to individual factors, such as the elderly age of patients, and the factors associated with drug, such as the long duration of antiretroviral therapy and the resulting metabolic disorders.Clinical examination should include an assessment of the physical signs of redistribution of adipose tissue in the body. You should pay attention to the indices of lipids of blood serum fasting and the level of glucose in the blood. Dyslipidemia should be adjusted in accordance with clinical recommendations.

    Tenofovir is structurally related to nucleoside analogs, so the risk of developing l and dystrophy can not be ruled out. However, 144-week data obtained from HIV-infected patients who have not previously been treated with antiretroviral agents, indicate that the risk of lipodystrophy in the case of tenofovir was smaller than when taking stavudine, when they were used in combination with lamivudine and efavirenz. Mitochondrial disorders

    In vitro and in vivo it was shown that nucleoside and nucleotide analogues lead to damage to mitochondria of different degrees. There have been reports of the development of mitochondrial disorders in HIV-negative newborns exposed to intrauterine and / or postnatal effects of nucleoside analogues. The main undesirable phenomena reported have been hematologic disorders (anemia,neutropsinia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These phenomena are often short-lived. There were reports of some neurological disorders that began later (hypertension, seizures, abnormal behavior). To date, it is not known whether neurological disorders are temporary or permanent, lice children who have undergone intrauterine exposure to nucleoside or nucleotide analogues, even HIV-negative newborns should be under close clinical and laboratory supervision and have a thorough examination for possible presence of mitochondrial changes in case of manifestation of the corresponding signs or symptoms. Available data do not influence the current national recommendations, according to which HIV-positive pregnant women need antiretroviral therapy to prevent vertical transmission of HIV.

    Immunodeficiency Syndrome

    At the onset of antiretroviral therapy, HIV-infected patients with severe immunodeficiency may develop an inflammatory response to the causative agents of asymptomatic or residual opportunistic infections andlead to severe clinical conditions or increased severity of symptoms. Typically, such reactions are observed during the first weeks after the start of treatment. Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections, and pancreatic {Pneumocystis jirovecii) pneumonia. You should monitor any symptoms of inflammation and, if necessary, prescribe treatment in a timely manner.

    Also reported were autoimmune diseases (such as Graves' disease) that accompanied reactivation of immunity; However, the time of onset of such events varies greatly, and these cases may have occurred several months after the start of treatment.

    Osteonecrosis

    Although the etiology of osteoecrosis is considered multifactorial (including the use of glucocorticosteroids, alcohol use, the presence of severe immunosuppression, a higher body mass index), cases of osteonecrosis have been recorded especially frequently in patients with progressive HIV infection and / or long-term combined antiretroviral therapy. Patients should be advised to seek medical advice if they develop aches or pains in the joints,stiffness in the joints or difficulties in movement.

    Elderly patients

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

    Effect on the ability to drive transp. cf. and fur:

    Studies on the effect of genofovir on the ability to drive vehicles and use mechanisms have not been carried out. Patients should be informed of reports of dizziness while treating with tenofovir. When dizziness occurs, you should refrain from performing these activities.

    Form release / dosage:

    Film-coated tablets, 300 mg.

    31

    But 30 tablets in a vial of high-density polyethylene with a cover with protection from opening by children with an embedded absorber of moisture (silica gel). I, together with the instruction, are placed in a pack of cardboard.

    Packaging:(30) - polyethylene bottles (1) - packs cardboard
    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    5 years.

    Do not apply but the expiration date indicated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-000779
    Date of registration:03.10.2011
    The owner of the registration certificate:Gilead Science International Co., Ltd. Gilead Science International Co., Ltd. United Kingdom
    Manufacturer: & nbsp
    Representation: & nbspDELTA MEDICEL DELTA MEDICEL Ukraine
    Information update date: & nbsp17.09.2015
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