Tenofovir-TL - instructions for use, dose, side effects, contraindications

Film shell Aquarius Prime blue [hypromellose - 62.5%, titanium dioxide - 23.62%, macrogol 3350 - 6 %, triglycerides medium-chain - 6.5%, indigo carmene dye aluminum varnish - 0.5%, dye of diamond blue aluminum varnish - 0.85%, dye quinoline yellow aluminum varnish - 0.03%].......... 30, 0 mg

Description:Round biconvex tablets covered with a film coating of blue color, two layers are visible on the transverse section, the tablet core is white or almost white.

Pharmacotherapeutic group:antiviral agent.

ATX: & nbsp

J.05.A.F.07 Tenofovir

Pharmacodynamics:

Tenofovir disoproxil fumarate is a fumaric acid salt and a bisisopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo is transformed into tenofovir, an analogue of the nucleoside monophosphate (nucleotide) of adenosine monophosphate. Tenofovir in the subsequent turns into an active metabolite - tenofovir diphosphate. Tenofovir - nucleotide reverse transcriptase inhibitor, has specific activity against human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases. In the tests in vitro Tenofovir in concentrations up to 300 μmol / l had no effect on the synthesis of mitochondrial DNA and the formation of lactic acid. When using tenofovir in vitro antiviral activity was noted. In studies of combined use of the drug with HIV protease inhibitors and with nucleoside and non-nucleoside analogues of HIV-1 reverse transcriptase inhibitors, additive or synergistic effects were noted.

Antiviral activity

The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was evaluated on the lines of lymphoblastoid cells, primary monocytes / macrophages and peripheral lymphocytes blood.

EU50 (half-maximal effective concentration) was 0.04 - 8.5 μmol.

In cell culture tenofovir has shown antiviral activity against HIV-1 subtypes A, B, C, D, E, F, G, ABOUT (EC50 was in the range of 0.5-2.2 μmol), as well as the inhibitory effect on some strains of HIV-2 (EC50 was in the range of 1.6-4.9 μmol).

Antiviral activity against hepatitis B virus

The antiviral activity of tenofovir against hepatitis B virus was evaluated on the cell line HepG2 2.2.15. The indicator of effective concentration of tenofovir was in the range of 0.14 to 1.5 μmol with an effective cytotoxic concentration> 100 μmol. In cell cultures, antiviral activity studies of combinations of tenofovir with nucleoside reverse transcriptase inhibitors acting on hepatitis B virus (emtricitabine, entecavir, lamivudine and telbivudine) there was no antagonism of drug activities.

Resistance

In studies in vitro and in some patients infected with HIV-1, there was resistance to tenofovir, the occurrence of which was due to mutations (by type of substitution) M184V / I and K65R, respectively.

There were no other mechanisms of the emergence of resistance to tenofovir.

Resistance in hepatitis B

Mutations of the hepatitis B virus associated with tenofovir resistance were not identified.

Pharmacokinetics:

Suction

After oral administration of HIV-infected patients, tenofovir, dizoproxil fumarate is rapidly absorbed and converted into tenofovir. The maximum concentrations of tenofovir in the blood serum were observed one hour after taking an empty stomach and two hours after ingestion with food, the bioavailability of tenofovir from tenofovir to dysoproxil fumarate after oral administration was approximately 25%.

As a result of taking tenofovir, the disoproxyl fumarate with food increased oral bioavailability, while the area under the concentration-time curve and the average maximum concentration of tenofovir increased by approximately 40% and 14%.

After the first administration of TDF with disoproxil fumarate with food, the maximum serum concentration in the serum is from 213 to 375 mg / ml.

Distribution

The distribution volume in the equilibrium state after intravenous administration of tenofovir was approximately 800 ml / kg. The binding of tenofovir to disoproxil fumarate with human plasma proteins in vitro is less than 0.7% and 7.2%, depending on the concentration of tenofovir from 0.01 to 25 μg / ml.

Metabolism

It has been proven that neither tenofovir disoproxil fumarate nor tenofovir do not inhibit the enzymes of human cytochrome P450. Moreover, at concentrations much higher than therapeutic (more than 300 times) tenofovir does not affect metabolic processes involving other isoenzymes of cytochrome P450 (cytochrome PZA4, P2D6, P2S9, P2E1, etc.). Tenofovir disoproxil fumarate does not affect cytochrome P450 isoenzymes except for PIA1 / 2, when small, but statistically significant changes were observed (6%).

Excretion

Deprivation of tenofovir mainly occurs through the kidneys through glomerular filtration and active tubular secretion.

After a single oral dose of the drug, the elimination half-life (T1/2) of tenofovir is approximately 17 hours.

Linearity / nonlinearity

The pharmacokinetics of tenofovir does not depend on the dose of tenofovir dizoproxil fumarate (with a dosing regimen of 75 to 600 mg),as well as in cases of repeated administration of the drug at a different dosing regimen. Tenofovir disoproxil fumarate did not show significant carcinogenic activity in long-term studies in rats when taken orally. Mice had a low incidence of duodenal tumors, which were regarded as probably associated with high concentrations of tenofovir, dizoproxil fumarate, in the gastrointestinal tract when the drug was administered at a high enough dose of 600 mg / kg. The mechanism of tumor formation in mice and the potential significance of this effect in relation to humans are not fully understood. Dysoproxil fumarate test on mouse lymphoma cells in vitro Tenofovir showed a mutagenic effect, but in the study of mutagenic action in vitro in the bacterial test (Ames test), negative results were obtained. In the micronucleus test in mice in vivo with the administration of tenofovir disoproxil fumarate to males at a dosage up to 2000 mg / kg, the result was also negative. Pharmacokinetics in special populations

Limited data on the pharmacokinetics of tenofovir in women indicate a lack of significant gender differences.No pharmacokinetic studies have been conducted with the participation of children, adolescents under 18, and elderly people over 65 years of age. Special studies of pharmacokinetics in different ethnic groups were not conducted.

Indications:

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

- Treatment of chronic viral hepatitis B in adults with compensated hepatic insufficiency, signs of active viral replication, constant elevated serum activity of alanine aminotransferase (ALT), histological evidence of active inflammation and / or fibrosis.

Contraindications:

- Hypersensitivity to tenofovir and any component of the drug.

- Children under 18 years.

- Patients with creatinine clearance less than 30 ml / min, as well as patients who need hemodialysis.

- Lactation period.

- Deficiency of lactase, lactose intolerance, glucose-lactose malabsorption, t. the preparation contains lactose.

- Simultaneous reception with other drugs containing tenofovir; with didanosine, adefovir.

Carefully:

- Renal failure with a creatinine clearance greater than 30 ml / min and less than 50 ml / min.

- The elderly are over 65 years of age.

Pregnancy and lactation:

The drug Tenofovir-TL should be used during pregnancy only if the expected benefit of treatment for the mother exceeds the potential risk to the fetus. It is not recommended to breastfeed HIV-infected mothers receiving therapy with the drug Tenofovir-TL to prevent the risk of postnatal HIV transmission. Women of childbearing age during treatment should use reliable methods of contraception. Breastfeeding HIV-infected mothers should be instructed about the exclusion of breastfeeding.

Dosing and Administration:

Inside, during a meal or with a small amount of pisoup.

Treatment of HIV-1 infection: adults 300 mg (1 tablet) per day.

In the treatment of chronic hepatitis B

In the treatment of chronic hepatitis B: adults 300 mg (1 tablet) per day.

Have HBeAg-positive patients without cirrhosis treatment should be continued for at least 6-12 months after confirmation of seroconversion by HBe (disappearance HBeAg or the disappearance of the DNA of the hepatitis B virus with the detection of anti-HBe), or before seroconversion to HBs, and until the loss of effectiveness. To identify anydelayed virological relapses after the end of treatment, it is necessary to regularly check the levels of ALT and DNA of the hepatitis B virus, in the blood serum.

Have HBeAg-negative patients without cirrhosis, treatment should be continued, at least until seroconversion HBs or until the loss of effectiveness. With prolonged treatment for more than 2 years, it is recommended that the patient be examined on a regular basis to confirm that the treatment chosen for a particular patient remains adequate.

Elderly patients

Be wary of choosing a dose for elderly patients, given the high incidence of liver, kidney or heart failure, as well as concomitant diseases or other medications.

Patients with impaired renal function

For patients with mild renal impairment (creatinine clearance from 50 to 80 ml / min), taking Tenofovir-TL once a day is safe and effective, so there is no need to adjust the dose, these patients need to undergo constant monitoring of creatinine clearance and phosphate concentrations in the blood serum.In patients with creatinine clearance from 30 to 49 ml / min, the interval between doses should be adjusted in accordance with the recommendations (see Table 1).

Table 1. Correction of the dose of the drug Tenofovir-TL in patients with altered creatinine clearance

	Creatinine clearance (ml / min)¹
	>50	30-49	<30 (including patients who need hemodialysis)
Recommended interval between meals	Every 24 hours	Every 48 hours	Preparation of Tenofovir-TL is not recommended
'When calculating the ideal body weight

Antiretroviral therapy is shown, as a rule, throughout life. The duration of therapy with the drug Tenofovir-TL is determined individually by the doctor.

Patients with impaired hepatic function No dose adjustment is required.

Side effects:

The side effects noted in clinical trials and during the postgrade trial of tenofovir are given in accordance with the generally accepted systemic and organ classification, and also in decreasing frequency: very often (> 1/10), often (> 1/100, < 1/10), not often (> 1/1000 and <1/100), rarely (> 1/10000 and <1/1000) and very rarely (<1/10000).

From the system of blood and blood-forming organs: frequency unknown - neutropenia, anemia.

From the side of metabolism: very often - hypophosphatemia; not often - hyperglycemia, hypokalemia, hyperkalemia.

From the nervous system: very often - dizziness, headache, insomnia, depression.

From the respiratory system: very rarely - dyspnea.

From the gastrointestinal tract (GIT): very often - diarrhea, vomiting, nausea; often - flatulence, increased concentration of amylase, abdominal pain, bloating; rarely - pancreatitis, dyspepsia, increased lipase activity.

From the liver and bile ducts: rarely - increased activity of hepatic transaminases (most often aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase); very rarely - steatosis of the liver, hyperbilirubinemia, exacerbation of hepatitis both during treatment and after discontinuation.

From the side of the rut and podkoleno-eyuir fiber: very often - a skin rash, sometimes accompanied by itching (maculopapular rash, hives, vesicular-bule, pustular rash); rarely - angioedema, skin discoloration (mainly on the palms and / or soles of the feet).

From the side of the musculoskeletal system: not often - rhabdomyolysis, muscle weakness; rarely - osteomalacia (manifested by pain in the bones, occasionally leads to fractures), myopathy.

From the urinary system: not often - an increase in the level of creatinine; rarely - impaired renal function, including acute renal failure, acute tubular necrosis; very rarely - renal tubulopathy of the proximal type, including Fanconi syndrome; the frequency is unknown - nephritis including interstitial nephritis, nephrogenic diabetes insipidus, proteinuria, polyuria. Other: often - asthenia; not often - fatigue.

The following non-translational reactions may occur in both mono and combined retroviral therapy.

Renal failure - Symptoms are similar to monotherapy.

Metabolic disorders - hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperlactatemia, lipodystrophy, including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and vistsiralnogo fat dairy hypertrophy, obesity dorsotservikalnoe (buffalo hump).

Syndrome of restoration of immunity - inflammatory reactions may occur in response to asymptomatic or residual opportunistic infections such as cytomegalovirus retinitis,generalized and / or focal mycobacterial infection and pneumonia, autoimmune disorders, such as Graves' disease, which may occur several months after the start of treatment.

Osteonecrosis - cases of osteonecrosis have been reported, especially in patients with risk factors or with long-term combined antiviral therapy. Lactate acidosis, hepatomegaly with fatty liver dystrophy - general weakness, loss of appetite, sudden unexplained weight loss, abnormalities of the gastrointestinal tract and respiratory system (dyspnea).

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

Symptoms: signs of toxicity, such as lactate-acidosis: nausea, diarrhea, vomiting, abdominal pain; neurological symptoms: dizziness, headache, impaired consciousness. To avoid overdose, the patient should be under the supervision of a doctor.

Treatment: There is no antidote for tenofovir, therefore, in the conditions of resuscitation, standard maintenance therapy is performed before the normalization of the general condition.For replenishment of water-electrolyte balance, elimination of symptoms of vomiting, detoxification therapy and normalization of cardiac activity, you can use: microelements, antiemetics, drugs for parenteral nutrition, adsorbents, drugs stimulating cardiac activity, antiallergic drugs. In the event that it is not possible to cope with the above symptoms, the patient is referred for hemodialysis.

Hemodialysis displays approximately 10% of the dose of tenofovir dizoproxil fumarate.

Interaction:

The drug Tenofovir-TL should not be used concurrently with drugs containing tenofovir.

Didanosine. At the same time taking tenofovir with didanosine increases didanosine systemic exposure by 40-60%, and therefore increases the risk of side effects of didanosine (such as pancreatitis, lactic acidosis, including fatalities). Odnovremennno assignment tenofovir and didanosine 400 mg sutkiprivodilo to fewer SP4 lymphocytes (probably due to increased phosphorylation of intracellular interaction didanosine).The combined use of tenofovir and didanosine is not recommended.

Adefovir. Tenofovir should not be used simultaneously with adefovir, since in studies in vitro the almost identical antiviral effect of tenofovir and adefovir is shown.

Eitheavir. With simultaneous administration of tenofovir with entecavir no significant drug interactions were detected.

Atazanavir / ritonavir. Atazanavir has shown the ability to increase the concentration of tenofovir. The mechanism of such interaction is not established. It is necessary to carefully monitor the condition of patients who, together with tenofovir, receive atazanavir, in case of occurrence of undesirable phenomena associated with the use of tenofovir. When co-administered with tenofovir, it is recommended that atazanavir 300 mg together with ritovirus 100 mg. Do not take tripofovir simultaneously with atazanavir without ritonavir.

In studies on healthy volunteers, there was no clinically significant interaction with simultaneous use of tenofovir with abacavir, efavirenz, emtricitabine, lamivudine, indinavir, lopinavir / ritonavir, nelfinavir, oral contraceptives, ribavirin, saquinavir / ritonavir.

Nephrotoxic drugs. Tenofovir mainly excreted through the kidneys. Joint use of tenofovir with drugs that reduce renal function or shorten / stop active tubular secretion may lead to an increase in the serum concentration of tenofovir and / or increase the concentration of other drugs excreted by the kidneys. It is necessary to avoid the use of tenofovir simultaneously or after a recent treatment with nephrotoxic drugs, such as aminoglycosides, amphotericin B, foscarnet, pentamidine, vancomycin, tacrolimus, cidofovir or interleukin-2.

Ganciclovir, valganciclovir and cidofovir compete with tenofovir for active tubular secretion by the kidneys, resulting in increased concentration of tenofovir.

Darunavir: increases the concentration of tenofovir by 20-25%. The drugs should be used in standard doses, while carefully monitoring the nephrotoxic effect of tenofovir.

Special instructions:

Are common

Patients should be informed that treatment with antiretroviral drugs does not prevent the risk of HIV transmission to other people.During sexual intercourse, appropriate precautions should be taken.

Simultaneous use with other medicinal products

Tenofovir should not be used concurrently with drugs that contain tenofovir or adefovir. It is not recommended simultaneous use of tenofovir and didanosine.

Osteonecrosis

Although the etiology of osteonecrosis is considered multifactorial (taking glucocorticosteroids, drinking alcohol, acute immunosuppression, increased body mass index play an important role in the development of this complication), there are reports of such cases, especially in patients with progressive HIV infection / or long-term antiretroviral therapy . Patients should seek medical advice from a physician if symptoms such as lethargy, stiffness, joint pain or difficulty with movement occur.

Mitochondrial dysfunction

In conditions in vitro and in vivo the ability of nucleotide and nucleoside analogs to cause damage to mitochondria of different degrees was revealed. There have been cases of mitochondrial dysfunction in HIV-negative children exposed to nucleoside analogues in utero or immediately after birth.The main manifestations of mitochondrial dysfunction, often transient, were anemia, neutropenia, hyperlactatemia and increased lipase activity in blood plasma. Lactate acidosis, the expression of hepatomegaly with fatty dystrophy When used in HIV-infected patients, the nucleotide and nucleoside analogs, including tenofovir disoproxil fumarate in combination with other antiretroviral drugs, reported cases of lactic acidosis and a marked increase in size of the liver and its steatosis, including fatal cases. Due to the high risk of developing lactic acidosis, special care should be taken when administering tenofovir to patients (especially women with excessive body weight) with hepatomegaly and fatty liver disease, with hepatitis, and in the presence of risk factors for liver damage. Clinical or laboratory signs of lactic acidosis can be detected several months after the start of treatment, but the development of this complication is possible in a shorter time. If the patient develops clinical (from the digestive system - nausea, vomiting, abdominal pain, general malaise,loss of appetite, weight loss; impaired breathing; neurologic symptoms - impaired motor function, muscle weakness) or laboratory (lactate levels in the serum above 5 mmol / l) signs of lactic acidosis, or severe hepatotoxicity, therapy with tenofovir should be suspended.

Patients infected with both HIV and hepatitis B or C virus The risk of hepatotoxic effect of antiretroviral drugs in patients with co-infected HIV infection and the hepatitis B or C virus is higher than in the presence of only HIV infection. Therefore, patients with chronic hepatitis B or C who simultaneously take antiretroviral drugs are at increased risk of adverse effects on the liver with possible fatal outcome. These patients should be carefully monitored, both clinically and laboratory.

In patients infected with both HIV and hepatitis B virus, severe exacerbations of hepatitis may occur after discontinuation of therapy with tenofovir. In some cases, it may be necessary to resume therapy for viral hepatitis.In patients with severe liver disease (cirrhosis), it is not recommended to discontinue treatment, since the aggravation of hepatitis that occurs after the abolition of therapy can lead to decompensation of liver function. Patients infected with HIV and hepatitis B virus should be closely monitored, both clinically and laboratory, for at least 6 months after stopping therapy with tenofovir. It is recommended that all HIV-infected patients be tested for the presence of viral hepatitis B before initiating antiretroviral therapy.

Caution should be exercised when assigning nucleotide and nucleoside analogues to patients with concomitant hepatitis C who receive interferon alfa and ribavirin in connection with the high risk of lactate-acidosis. Such patients should undergo thorough clinical and laboratory monitoring.

Patients with impaired renal function

Tenofovir is excreted mainly by the kidneys. There were kidney abnormalities, including cases of kidney failure, acute kidney failure, increased creatine kinase levels and Fanconi syndrome (renal tubule damage with severe hypophosphatemia), which are associated with the use of tenofovir.

All patients are recommended to determine the clearance of creatinine before the start of therapy, as well as during therapy with tenofovir and according to clinical indications. In patients with the threat of renal failure, regular monitoring of the clearance of creatinine and phosphorus in serum should be performed.

Therefore, the potential benefits of taking the drug Tenofovir-TL should be evaluated in comparison with the potential risk of toxic effects on the kidneys. It is necessary to avoid the use of the drug Tenofovir-TL simultaneously with nephrotoxic drugs or after the recent use of such drugs.

Diseases of the liver

Hepatotoxic reactions occur at different times against combined antiretroviral therapy. The risk of developing hepatotoxicity with combined antiretroviral therapy is higher in patients with underlying liver function impairment. For patients with liver disease receiving tenofovir in combination antiretroviral therapy, careful monitoring should be conducted; if signs of impaired liver function appear, consideration should be given to the possibility of interrupting or canceling therapy.

Triple therapy with nucleosides

A decrease in the frequency of the virologic response in the administration of triple therapy with nucleosides was reportedtenofovir in combination with abacavir and lamivudine), as well as the development of resistance at an early stage of using this combination when taking medications 1 time per day.

Effect on the bone system

A clinical study showed a decrease in bone mineral density in the bones of the lumbar region and femur during treatment with tenofovir. Most cases of reduction in bone mineral density were observed during the first 24 to 48 weeks and persisted for 144 weeks of study. It is necessary to observe the condition of the bone tissue of HIV-infected patients with pathological bone fractures in the history and risk of osteopenia. If an anomaly is suspected from the bony system, an appropriate examination should be carried out.

Lipodystrophy

In patients receiving antiretroviral therapy, there was a redistribution / accumulation of fatty tissue, including central obesity, an increase in adipose tissue in the dorso-cervical region ("buffalo buffalo"),decrease in the volume of peripheral fatty tissue (reduction of fat tissue in the limb region), reduction of subcutaneous fat in the facial area, there may be mammary gland hypertrophy and "cushingoid appearance." The mechanism and the long-term effects of these effects are currently unknown. Causality was not established.

Early virological inefficiency

Clinical studies involving HIV-infected patients have shown that a number of therapeutic regimens involving only three nucleoside reverse transcriptase inhibitors are generally less effective than

triple regimens suggesting the use of two nucleoside reverse transcriptase inhibitors in combination with either a non-nucleoside reverse transcriptase inhibitor or an HIV-1 protease inhibitor. In particular, it was reported about early virological inefficiency and high incidence of mutations (by type of replacement), causing the development of resistance. On this basis, regimes involving the use of three nucleoside inhibitors should be used with caution.Patients whose treatment regimens require the use of only three nucleoside inhibitors should be carefully monitored; in such cases, it is also recommended to consider the possibility of changing the treatment regimen. Immunodeficiency Syndrome

In HIV-infected patients receiving combined antiretroviral therapy, the immune reconstitution syndrome was observed.

Against the background of the restoration of the immune function at the onset of combined antiretroviral therapy, the asymptomatic or residual opportunistic infections may be exacerbated (infection caused by Mycobacterium avium and / or Pneumocystis jirovecii, cytomegalovirus infection, pneumonia or tuberculosis), which may require additional examination and treatment. Such reactions are usually observed in the first few weeks or months of antiretroviral therapy, patients should be carefully monitored by specialists with experience in the treatment of patients with HIV disease. Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity,However, the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

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

The drug Tenofovir-TL acts on the central nervous system and can cause dizziness, headache and other symptoms. It can also cause muscle weakness, myopathy. These adverse events can pose a danger to people during driving and engage in activities related to the concentration of attention during the period of taking this drug. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:

Film-coated tablets, 300 mg.

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 30 or 60 tablets in a jar (bottle) polymer for medicines or a jar (bottle) for medicines made of plastic. Free space in the jar (bottle) is filled with cotton absorbent medical cotton.

Each jar (bottle), 3 or 6 contour squares, together with the instruction for use, is placed in a pack of cardboard box.

Packaging:film coated tablets, 300 mg (contour pack) 10 x 3/6 (carton pack); film coated tablets, 300 mg (cans / bottles) 30/60 x 1 (carton pack)

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002508

Date of registration:23.06.2014

The owner of the registration certificate:TECHNOLOGY OF DRUGS, LTD. TECHNOLOGY OF DRUGS, LTD. Russia

Manufacturer: & nbsp

TECHNOLOGY OF DRUGS, LTD. Russia

Information update date: & nbsp17.09.2015

Illustrated instructions

Instructions

Tenofovir-TL (Tenofovir)