TENOFOLEK - instructions for use, dose, side effects, contraindications

Component	Amount, mg
Inside the pellet core granules
Active substance
Tenofovir disoproxil fumarate (in terms of 100% substance)	300,00
Excipients
Croscarmellose sodium	20,00
Lactose Monohydrate	110,00
Microcrystalline cellulose (Avicel PH 101)	66,68
Pregelatinized starch	66,66
Sheath of granules of a core of a tablet
Microcrystalline cellulose (Avicel PH 101)	60,00
Croscarmellose sodium	33,66
Magnesium stearate	10,00
Tablet core weight	667,00
Casing of the tablet
Opaprai II white 32K18425:	26,68
- lactose monohydrate	40,61 %
- hypromellose	28,42 %
- titanium dioxide	22,85 %
- triacetin	8,12%
Weight of a tablet	693,68

Description:

Biconvex tablets of oval form, covered film shell, from white to almost white, with an embossed "I" on one side and "36" on the other side.

Pharmacotherapeutic group:Antiviral agent

ATX: & nbsp

J.05.A.F.07 Tenofovir

Pharmacodynamics:

Mechanism of action

Tenofovir disoproxil fumarate is a fumarate salt of tenofovir prodrug of disoproxil. 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 the obligate chain terminator, by means of constructively expressed cellular enzymes. Tenofovir diphosphate has an intracellular half-life of 10 hours in activated peripheral blood mononuclear cells and 50 hours at rest. Tenofovir diphosphate inhibits 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 the laboratory strain of HIV-1wp in 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 HIV_BaL 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

Antiviral activity of tenofovir against HBV in vitro evaluated on a cell line HepG2 2.2.15. The importance of the₅₀ for tenofovir were in the range from 0.14 to 1.5 μmol / l, and the value of CC50 (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 disoproxil 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, anti-HIV activity of 300 mg of tenofovir, dizoproxil fumarate, against HIV-1 strains was tested for resistance to nucleoside inhibitors. 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, rtL180M and rtM204I/V, associated with resistance to lamivudine and telbivudine, demonstrated a sensitivity to tenofovir of 0.7-4.4 times the sensitivity of the wild-type virus.

HBV strains expressing substitution rtL180M, rtT184G, rtS202G/I, rtM204V and rtM250V, associated with resistance to entecavir, showed a sensitivity to tenofovir of 0.6-6.9 times greater than that of wild-type virus. HBV strains expressing substitution rtA181V 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 rt A181T, remained sensitive to tenofovir, EC50 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 vitro 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 C_max, AUC and C_min 326 (36.6%) ng / ml, 3324 (41.2%) ng'ch / ml and 64.4 (39.4%) ng / ml, respectively. The maximum concentration of tenofovir is observed in the blood serum within 1 hour after taking an empty stomach and within 2 hours when it is taken with food. When receiving tenofovir disoproxil fumarate, fasted patients had bioavailability of approximately 25%.The use of tenofovir, a dysoproxil fumarate with a fat-rich diet, increased bioavailability, AUC Tenofovir increased by approximately 40%, and C_m_Oh - approximately 14%. After the first dose of tenofovir, dizoproxil fumarate, obtained after ingesting fat-rich foods, median C_max in the serum was in the range of values from 213 to 375 ng / ml. However, the use of tenofovir with disoproxil fumarate e low-calorie food does not significantly affect 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 are not substrates of enzymes 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 a small (6%), but statistically significant decrease in the substrate metabolism CYP1A1/2. On the basis of this information, it can be concluded that the occurrence 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). Renal clearance was estimated at approximately 160 ml / h / kg (about 210 ml / min), which exceeds the glomerular filtration rate.This indicates that tubular secretion is an important part of the excretion of tenofovir. After oral administration, the final half-life of tenofovir is between 12 and 18 hours.

The studies revealed that the active tubular transport secretion system involves the absorption of tenofovir by proximal tubule cells by means of organic human anionic transporter (hОАТ) 1 and 3, and its 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 from 75 to 600 mg and did not change with repeated administration at any dose level.

Pharmacokinetics the special 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 tenofovir in equilibrium were evaluated in 8 children (age 12 to 18 years) with a body weight ≥ 35 kg infected with HIV-1. The mean (± SD) the C_m_Oh and AUC_tau were 0.38 ± 0.13 μg / ml and 3.39 ± 1.22 μGh / ml, respectively. The exposure of tenofovir, which was achieved in adolescents who received daily doses of 300 mg of tenofovir, dizoproxil fumarate, was similar to the exposure that was achieved in adults who received single daily doses of 300 mg of tenofovir, dizoproxil fumarate.

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

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

Impaired renal function

The parameters of the pharmacokinetics of tenofovir were determined after administration of a single dose of 300 mg of tenofovir dizoproxil fumarate to 40 adult patients,HIV-free and HBV-infected patients with renal dysfunction of varying degrees, which were determined according to baseline creatinine clearance (KK) (renal function is not compromised if KK> 80 ml / min, mild disorder - if KK is 50-79 ml / min, moderately expressed violation - with QC 30 - 49 ml / min and severe violation - with QC 10-29 ml / min). In comparison with patients with normal renal function, the mean (% CV) the exposure of tenofovir increased from 2185 (12%) ng'h / ml in persons with CK> 80 ml / min to 3064 (30%) ng / hr, respectively, 6009 (42%) ng'ch / ml and 15985 (45%) ng'h / ml in patients with mild, moderate and severe renal impairment. 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 C_min in patients with impaired renal function compared to patients with normal renal function. The clinical significance of this is unknown.

In patients with terminal renal failure (CC <10 mL / min) who needed hemodialysis, the concentrations of tenofovir between dialysis increased significantly within 48 hours, reaching an average value of C_m_Oh 1032 ng / ml and mean AUC_0-48_h 42857 ng'ch / 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 kidney failure have not been conducted. 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 a liver function disorder of varying degrees determined by the Child-Pugh 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 value of C_m_Ohand AUC_0-∞Tenofovir was 223 (34.8%) ng / ml and 2050 (50.8%) ng'ch / ml, respectively,in persons without a violation of liver function, 289 (46.0%) ng / ml and 2310 (43.5%) ng'ch / ml in persons with moderate impaired liver function 305 (24.8%) ng / ml, and 2740 (44.0%) ng'h / ml in those with severe liver dysfunction.

Intracellular pharmacokinetics

It was found that in non-fissionable mononuclear cells of human peripheral blood (PBMC), the half-life of tenofovir diphosphate is approximately 50 hours, whereas in PBMCs stimulated with phytohemagglutinin it is approximately 10 hours.

Indications:

HIV-1 infection

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

Treatment of HIV-1 infection in children aged 12 to 18 years with the presence of resistance to 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 lamivudine;

- decompensated 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 elevated activity of ALT in the serum and histologically confirmed by the active inflammatory process and / or fibrosis.

Contraindications:

- Hypersensitivity to any of the components of the drug;

- children under 12 years of age or body weight <35 kg (efficacy and safety not established);

- children aged 12 to 18 years with impaired renal function (no recommendations on dosing regimens);

- severe renal insufficiency (creatinine clearance less than 30 ml / min or chronic renal failure when hemodialysis is required (safety not established in this patient population);

- the period of breastfeeding;

- deficiency of lactase, lactose intolerance, glucose-lactose malabsorption, since the preparation contains lactose;

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

Carefully:

- Patients with diabetes mellitus;

- age over 65;

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

- patients who simultaneously take other medications: possessing nephrotoxic action (aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamycin, Vancomycin, interleukin-2, cidofovir); tacrolimus; nonsteroidal anti-inflammatory drugs; didanosine; HIV protease inhibitors, potentiated with ritonavir or a cobicystate (see "Interactions with other drugs" and "Special instructions");

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

Pregnancy and lactation:

Pregnancy

Data from a sample of the average volume in pregnant women (300 to 1,000 pregnancies) indicate a lack of developmental or toxicological effects on the fetus / 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 / infants are inadequate. therefore tenofovir should not be used during breastfeeding. In general, women infected with HIV and HBV are not recommended to breast-feed in order to avoid the transmission of HIV and HBV to the child.

Fertility

There is no evidence of the effect of tenofovir 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 TENOFOLEC® for the treatment of HIV-1 infected patients who had previously received treatment should be based on checking for individual viral resistance and / or the history of the patient's treatment.

Adults

The recommended dose of TENOFOLEK® 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 HBe seroconversion (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-negative 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, which lasts for more than 2 years, it is recommended to regularly re-review the treatment.

Children from 12 to 18 years old

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

In exceptional cases, the tablet of the TENOFOLEK® preparation can be taken immediately after its dissolution in 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 of ≥35 kg, the recommended dose of TENOFOLEK® 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 tenofovir 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 it took less than 12 hours from the usual dose-taking time, the patient should be taken as soon as possible tenofovir together with food and return to the usual mode of taking the drug. If, in case of a missed dose, more than 12 hours pass and the time of the next dose is approaching, the patient should not take the missed dose, but take the next dose in accordance with the usual regimen.

If within 1 hour after taking the drug TENOFOLEK® the patient has vomiting, one more pill should be taken.If vomiting in the patient occurred more than 1 hour after taking the drug TENOFOLEK®, then one 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.

Impaired renal function

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

Adults

Data on the safety and efficacy of tenofovir in adult patients with moderate and severe renal dysfunction (CK <50 mL / min) are limited. Evaluation of safety indicators in patients with mild renal impairment (KK 50-80 ml / min) in the long term was not performed. For this reason, patients with impaired renal function tenofovir It is necessary to apply 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 mild nights (KK 50-80 ml / 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)

The intake of 1 tablet of TENOFOLEK® 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 the terminal stage of 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 inability to correct the dosage regimen, the use of TENOFOLEK® for patients in this group 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 stopped taking the drug TENOFOLEK®, since after the drug is discontinued there is a risk of exacerbation of hepatitis.

Side effects:

Brief information on the safety profile of HIV-1 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 receiving tenofovir, monitoring of kidney function is recommended (see section "Special instructions").

HIV-1

Adverse reactions in the treatment of tenofovir in combination with other antiretroviral drugs can be expected in almost one third of patients. Such reactions, as a rule, represent violations from the gastrointestinal tract from mild to moderate severity. Approximately 1% of patients treated with tenofovir, stopped treatment due to reactions from the gastrointestinal tract.With the use of tenofovir, such phenomena as lactic acidosis, hepatomegaly with fatty dystrophy and lipodystrophy are associated (see section "Special instructions").

It is not recommended simultaneous use of tenofovir and didanosine, 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 fatal outcome (see section "Special instructions").

Hepatitis B

Adverse reactions with the use of tenofovir may be expected in almost one quarter of patients, mostly minor. In clinical studies involving patients infected with HBV, the most common 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 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 tenofovir, 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 Wis compensated liver function received 300 mg of tenofovir disoproxil fumarate dailyn = 426) or adefovir dipivoxyl 10 mg daily (n = 215) for 48 weeks. Adverse reactions that were observed during 288-week continuous treatment corresponded to the known tenofovir safety profile.

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 a confirmed elevated serum creatinine ≥ 0.5 mg / dl or a confirmed serum phosphate concentration of < 2 mg / dL; there were no statistically significant differences between the group of combined treatment on the basis of tenofovir and the entecavir group. 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 of <2 mg / dl was observed.

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 emtricitabine + tenofovir 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 group emtricitabine + tenofovir 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 trial in which 280 lamivudine-resistant patients received tenofovir for 96 weeks (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. Frequency adverse reactions are defined as: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100) and rarely (from ≥ 1 / 10,000 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 liver³, 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)², 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 tenofovir in the absence of this disease.

² Adverse reaction has been established during the post-marketing studies, but has not been observed during the randomized controlled clinical studies or the program expanded access to tenofovir. The frequency category was established according to statistical calculations based on the total number of patients taking tenofovir in 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-1 and hepatitis B

Impaired renal function

Because the tenofovir can lead to disruption of the kidneys, it is recommended to monitor their function (see section "Special instructions").

Proximal tubulopathy, as a rule, disappeared or was noted improvement after cancellation of tenofovir. However, in some patients cancellation of tenofovir did not completely lead to the reduction of the reduced level of QC. Patients at risk of developing renal failure (eg, patients with a baseline risk of renal failure, concomitant HIV infection, concomitant nephrotoxic therapy drugs) are at increased risk of incomplete recovery of kidney function, despite the elimination of tenofovir (see section "Special instructions").

HIV-1

Interaction with didanosine

Simultaneous use of tenofovir and didanosine is not recommended, as the ego leads to an increase in systemic exposure to didanosine by 40-60%, which may increase the risk of side effects associated with didanosine (see "Interactions with other drugs.") Rarely reported cases of pancreatitis and lactic acidosis, sometimes with a fatal outcome.

Lipids, lipodystrophy and metabolic disorders

Combined antiretroviral therapy was associated with metabolic disorders such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia and hyperlactatemia.

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

In a 144-week controlled clinical trial, among patients who had not previously been treated with antiretroviral agents to compare tenofovir with stavudine in combination with lamivudine and efavirenz, it was observed that the risk of lipodystrophy in the case of tenofovir 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

Osteonecrosis has been reported, in particular in patients with well-known risk factors, late stage HIV infection, or long-term use of combined 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 hyperlactatemia and metabolic lactic acidosis, progressive hepatomegaly or a rapid increase in aminotransferase activity (see section "Special instructions").

Hepatitis B

Exacerbation of hepatitis during treatment

In the study, among patients who had not previously taken nucleoside analogues, an increase in ALT activity during treatment with an exceedance of the upper limit of the norm by more than 10 times and an exceedance of the initial level by more than 2 times was observed in 2.6% of patients,treated with tenofovir. The rise of 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 stopping the use of drugs that are active against HBV, 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 (ages 12 to 18 years) with chronic hepatitis B who were treated with 300 mg of tenofovir dizoproxil fumaraten = 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 bone mineral density (BMD) was observed in children infected with the hepatitis B virus, Z - the MIC test, observed in patients who received tenofovir, was lower than that in patients who received a placebo.

Other special patient groups

Elderly patients

The study of tenofovir among patients over the age of 65 years was not 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

Since the use of tenofovir can lead to kidney damage, it is recommended that the kidney function in adult patients with impaired renal function tenofovir. Contraindicated apply tenofovir in children from 12 to 18 years with a violation kidney 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 supportive 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

Tenofovir should not be used concomitantly with other medicines containing tenofovir.

Tenofovir should not be used concomitantly with adefovir.

Didanosine

Simultaneous use of tenofovir and didanosine is not recommended (see section "Special instructions" 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 or recent use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, and interleukin-2) (see section "Specific guidance").

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

Other interactions

The interaction between tenofovir, protease inhibitors and antiretroviral agents that are not protease inhibitors is presented below in Table 2 (the increase is indicated by "↑", the decrease is "↓", no change "↔", twice a day - "b.i.d.", once a day - "q.d.").

Table 2.

The interaction between tenofovir and other drug drugs

Medicinal preparation according to therapeutic directions (dose in mg)	Effect on drug levels, mean percentage change AUC, FROMmOh, Cmin	Recommendation regarding the simultaneous use with tenofovir dizoproxil fumarate 300 mg
ANTI-INFECTIOUS
Antiretroviral
Protease Inhibitors
Atazanavir / Ritonavir (300 q.d./100 q.d./300 q.d.)	Atazanavir: AUC: ↓ 25 % FROMmOh: ↓ 28 % Cmin: ↓ 26 % Tenofovir: AUC: ↑ 37 % FROMmah: ↑ 34 % Cmin: ↑ 29 %	Correction of the dose is not required. The increased exposure to tenofovir may increase the associated adverse effects with tenofovir, including renal pathology. Kidney function should be carefully monitored.
Lopinavir / Ritonavir (400 b.i.d./100 b.i.d. /300 q.d)	Lopinavir / Ritonavir: There is no significant effect on the pharmacokinetics of lopinavir / ritonavir. Tenofovir: AUC: ↑ 32% Stax: ↔ Cmin: ↑ 51%	Correction of the dose is not required. The increased exposure to tenofovir may increase the associated adverse effects with tenofovir, including renal pathology.
Darunavir / Ritonavir (300/100 b.i.d / 300 q.d)	Darunavir: There is no significant effect on the pharmacokinetics of darunavir / ritonavir. Tenofovir: AUC: ↑ 22% Cmin: ↑ 37%	Correction of the dose is not required. The increased exposure to tenofovir may increase the associated adverse effects with tenofovir, including renal pathology. Kidney function should be carefully monitored.
Nucleoside reverse transcriptase inhibitors
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.Reported infrequent, sometimes lethal, cases of pancreatitis and lactic acidosis. 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, which increases the phosphorylated (i.e., 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: ↔ FROMmOh: ↔	Tenofovir should not be used concomitantly with adefovir.
Entecavir	AUC: ↔ FROMmOh: ↔	There were no clinically significant pharmacokinetic interactions with simultaneous use of tenofovir with entecavir.

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 norgestimate / ethinyl estradiol.

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

Special instructions:

Are common

Before starting therapy with tenofovir, an antibody test for HIV should be offered to 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, however, the risk can not 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 the blood has not been proven. Appropriate precautions should be taken.

Simultaneous use with other medicinal products

- Tenofovir should not be used with other medicines containing tenofovir.

- Tenofovir 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 ddI related to didanosine (see "Interactions with Other Drugs" section). Rarely reported on 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, possibly due to intercellular interaction, which increases the phosphorylated (i.e., active) didanosine. The use of didanosine at a reduced dosage of 250 mg, together with tenofovir 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 with lamivudine and didanosine according to the regimen of administration once a day.

Effect on kidney function and bone 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, hypophosphatemia, and proximal tubulopathy (including Fanconi syndrome) with tenofovir in clinical practice (see "Side-Effects" section).

Control of kidney function

It is recommended that the CC be determined in all patients before starting treatment with tenofovir and monitoring kidney function (QA and serum phosphate) after 2-4 weeks of treatment, at 3 months of treatment, and every 3-6 months after 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 serum phosphate levels <1.5 mg / dL (0.48 mmol / L) or QC are reduced to <50 ml / min in the patient receiving tenofovir, it is necessary to reassess the function of the kidneys within 1 week, including determining the level of glucose in the blood, potassium in the blood and the concentration of glucose in the urine.It should also be considered whether withdrawal of treatment with tenofovir should be withdrawn in patients with reduced QC to <50 ml / min or a decrease in serum phosphate levels to <1.0 mg / dL (0.32 mmol / L). The withdrawal of tenofovir treatment should also be considered in the event of a progressive decline in renal function if no other cause has been identified.

Joint use with other drugs and risk of nephrotoxicity

Tenofovir should be avoided with simultaneous or recent use of nephrotoxic drugs (eg, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir and interleukin-2). If simultaneous use of tenofovir and nephrotoxic drugs is not possible, weekly monitoring of kidney function is necessary. Cases of acute renal failure were reported after initiating therapy with a high dose or several non-steroidal anti-inflammatory drugs (NSAIDs) in patients who received tenofovir and having risk factors for renal dysfunction. Renal function should be monitored appropriately by the simultaneous use of tenofovir and NSAIDs. A high risk of kidney damage has been reported in patients receiving tenofovir in combination with a protease inhibitor, ritonavir-enhanced 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 tenofovir with an enhanced protease inhibitor should be carefully analyzed. Clinical evaluation of the use of tenofovir was not conducted in patients taking medications, which are also excreted by the kidneys through transport proteins of organic human anion transportershOAT) 1 and 3 or MRP 4 (eg, cidofovir, a known nephrotoxic drug). These kidney transport proteins may be responsible for tubular secretion and, in part, the 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 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 tenofovir against 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 requiring hemodialysis

Data on the safety and efficacy of tenofovir 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 requiring hemodialysis is contraindicated.

Effects on bone tissue

In a controlled 144-week clinical trial comparing tenofovir with stavudine in combination with lamivudine and efavirenz in HIV-infected adult patients who had not previously received antiretroviral treatment, small decreases in the BMD in the femur and spine were observed in both groups.

Decrease in the BMD of the 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 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) may be due to 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.

Influence on kidney function and bone tissue in children aged 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 toxic effects on the kidney is not fully established. Therefore, it is recommended to use a multilateral approach to adequately determine in each individual case the benefit / risk ratio of treatment,making a decision on appropriate follow-up during treatment (including deciding to discontinue therapy) and considering the appropriateness of using additional drugs.

Control of kidney function

Before starting 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), renal function should be reassessed within 1 week, including blood glucose, blood potassium and glucose concentrations in urine. If there is a suspicion of renal impairment or detection, it is necessary to consult with a nephrologist to consider the need to cancel tenofovir treatment. The withdrawal of tenofovir treatment should also be considered in the case of progressive decline in renal function, when no other cause has been determined.

Joint use and risk of nephrotoxicity

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

Impaired renal function

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 impaired renal function, and it is also necessary to cancel treatment in those children who have developed renal dysfunction during tenofovir therapy.

Effects on bone tissue

Tenofovir may cause a decrease in BMD. The effect of TDF-related changes in BMD 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.

Liver disease

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 a> 9 Child-Pugh score 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

Exacerbation during treatment

Spontaneous exacerbations of chronic hepatitis B are relatively frequent and are characterized by a temporary increase in ALT activity in the blood serum. After the initiation of antiviral treatment, in some patients, the activity of ALT in the blood serum may increase (see the "Side effect" section). In patients with compensated liver disease, an increase in ALT activity in serum is usually not 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 on the exacerbation of hepatitis in patients who have stopped treatment of hepatitis B.Exacerbations after the abolition of therapy are usually associated with an increase in the concentration of the DNA of the hepatitis B virus, and most of them are resolved without additional interventions. However, severe exacerbations, including lethal cases, have been reported. Within 6 months after stopping the treatment of hepatitis B, it is necessary to regularly monitor the functional state of the liver according to clinical and laboratory parameters. If necessary, it may be advisable to resume treatment for hepatitis B. For patients with 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 virus infection and D are absent.

Concomitant HIV-1 infection and hepatitis B virus

Due to the risk of developing HIV resistance in patients with concomitant HIV / HBV infection tenofovir should only be used as part of the appropriate antiretroviral combination regimen. Patients whose wound has 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, such patients should consider the need for interruption in treatment or withdrawal of treatment. However, it should be noted that increased ALT activity may be part of a positive antiviral response to HBV for tenofovir 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 analogues, for tenofovir is low. But, since tenofovir structurally similar to nucleoside analogs, this risk can not be ruled out.Early signs (symptomatic hyperlactatemia) 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 hyperlactatemia and metabolic / lactic acidosis, progressive hepatomegaly or a rapid increase in the activity of aminotransferases. Caution should be exercised when assigning nucleoside analogues to any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver disease (including certain drugs and alcohol). Interferon-alpha and ribavirin treatment of patients with concomitant hepatitis C virus infection,may pose 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 use of nucleoside reverse transcriptase inhibitors. The increased risk of lipodystrophy was due to individual factors, such as the elderly age of patients, and factors associated with the 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 lipodystrophy 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 the nucleotide and nucleotide analogs mitochondria lead to varying degrees of shock. Mitochondrial dysfunction received on the development of communication in HIV-negative infants exposed in utero and / or postnatal exposure to nucleoside analogues. The main undesirable phenomena reported were hematologic disorders (anemia, neutropenia) 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. All 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. The 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 in HIV-infected patients with severe immunodeficiency, an inflammatory response to pathogens of 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 the start of treatment.Examples include cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumocystis (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 osteonecrosis 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 with prolonged use of combined antiretroviral therapy. Patients should be advised to seek medical advice if there is aches and pains in the joints, joint stiffness or difficulty in moving.

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 tenofovir on the ability to drive vehicles and use mechanisms have not been conducted. 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.

Packaging:

For 30 tablets in a can of polymer with a cover with protection from opening by children, equipped with a self-adhesive label. Inside the jars, a bag with a desiccant (silica gel) is additionally placed. Free space in the pot is filled with cotton absorbent cotton. To control the first opening, the neck of the jar is hermetically sealed with an aluminum foil membrane. Each bank, along with instructions for medical use, is placed in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 of the year.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004325

Date of registration:05.06.2017

Expiration Date:05.06.2022

The owner of the registration certificate:NANOLEC, LTD. NANOLEC, LTD. Russia

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Information update date: & nbsp13.11.2017

Illustrated instructions

Instructions

TENOFOLEK® (Tenofolek®)