Active substanceLamivudineLamivudine
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  • Dosage form: & nbspfilm coated tablets
    Composition:

    The tablet contains:

    active substance lamivudine 150.0 mg / 300.0 mg;

    Excipients: cellulose microcrystalline (50 μm) 45.0 mg / 90.0 mg, microcrystalline cellulose (90 μm) 87.0 mg / 174.0 mg, sodium carboxymethyl starch (type A) 15.0 mg / 30.0 mg, magnesium stearate 3.0 mg / 6.0 mg;

    shell: opahedra gray 15WT7516 / 15V27517 (hypromellose 3sP (E464) 2.8539 mg / 5.7078 mg, hypromellose 6cP (E4 (4) 2.8539 mg / 5.7078 mg, titanium dioxide (E171) 2.4516 mg / 4, 6206 mg, macrogol-400 0.7230 mg / 1.4400 mg, polysorbate-80 (E433) 0.0900 mg / 0.1800 mg, iron oxide dye yellow (E172) 0.0108 mg / 0.0882 mg, ferric iron oxide black (E172) 0.0138 mg / 0.2556 mg).

    Description:

    Tablets 150 mg. The lozenge-shaped biconvex tablets covered with a film-coating of light gray color, with a risk on both sides and engraving "L 150 "on one side.

    Tablets 300 mg. Diamond-shaped biconvex tablets covered with a film shell of gray color with engraving "L 300 "on one side.
    Pharmacotherapeutic group:Antiviral (HIV) agent
    ATX: & nbsp

    J.05.A.F.05   Lamivudine

    Pharmacodynamics:

    Lamivudine is a highly effective selective inhibitor of HIV-1 and HIV-2 replication in vitro. Also active against HIV strains resistant to zidovudine. Inside the cells lamivudine is metabolized to 5'-triphosphate (active form), period half-life (T1 / 2) of which from the cells is 16-19 hours.Lamivudine-5-triphosphate to a small extent inhibits RNA and DNA-dependent reverse transcriptase of HIV.

    The main mechanism of its action is the blocking of the synthesis of the growing DNA chain in the process of reverse transcription of HIV. Shown, that lamivudine has an additive or synergistic effect on other antiretroviral drugs, formerly all about zidovudine, inhibiting HIV replication in cell culture.

    Lamivudine does not interfere with the normal cellular metabolism of DNA and does not have a significant effect on the content of nuclear and mitochondrial DNA in mammalian cells.

    In studies in vitro lamivudine has a weak cytotoxic effect on peripheral blood lymphocytes, as well as on lymphocytic and monocyte-macrophage cell lines and a number of other bone marrow stem cells. In this way, in vitro lamivudine has a high therapeutic index.

    One of the reasons for the development of HIV-1 resistance to lamivudine is the appearance of changes in the site M184V a viral genome that is closely linked to the active site of HIV reverse transcriptase. HIV-1 strains with mutations M184V may appear as in vitro, and in the body of patients receiving combined antiretroviral therapy, including lamivudine. Such strains of the virus are characterized by a reduced sensitivity to lamivudine and a weak ability to replicate in vitro. In vitro HIV-resistant strains that are resistant to zidovudine may acquire sensitivity to it in the case of simultaneous development of resistance to lamivudine. The clinical significance of this phenomenon is not established.

    Mutations in the site M184V lead to the emergence of cross-resistance of HIV. Only to drugs from the group of nucleoside reverse transcriptase inhibitors. Zidovudine and stavudine remain active, with respect to HIV-1 strains resistant to lamivudine. Abacavir antiretroviral activity against HIV-1 strains having M184V mutation resistant to lamivudine. In strains of HIV with M184V mutations determined no more than 4-fold decrease in sensitivity to didanosine and zalcitabine; the clinical significance of this phenomenon has not been established. Tests on the sensitivity of HIV to various antiretroviral drugs in vitro ns have been standardized, and therefore various methodological factors can influence their results.

    According to clinical studies, the use of lamivudine in combination with zidovudine reduces the viral load of HIV-1 in the blood and increases the content Cd4lymphocytes. Determined that lamivudine in combination with zidovudine or zidovudine and other drugs significantly reduces the risk of progression of HIV infection and death. HIV strains isolated from patients who received lamivudine, there was a decrease in sensitivity to lamivudine in vitro. Combination therapy with lamivudine and zidovudine in patients who had not previously received antiretroviral therapy delayed the emergence of zidovudine-resistant strains of HIV. Lamivudine was widely used as a component of combined antiretroviral therapy in combination with other nucleotide reverse transcriptase inhibitors or preparations from other groups (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).

    It is shown that combined antiretroviral therapy, including lamivudineis effective against strains of HIV with mutations in the locus M184V.

    To establish the relationship between the sensitivity of HIV to lamivudine in vitro and the clinical effect of therapy, additional studies are required.

    Pharmacokinetics:

    Suction. Lamivudine well absorbed from the gastrointestinal tract (GIT). Bioavailability of lamivudine in adults after oral administration is usually 80-85%. The mean time to reach the maximum plasma concentration (Tmax) lamivudine is about 1 hour. When using lamivudine in therapeutic doses (4 mg / kg / day in 2 divided doses with an orphanage at 12 hours), the maximum concentration in the plasma (CmOh) is 1- 1.9 μg / ml.

    The lamivudine prism together with the beggar caused an increase in TmOh and a decrease in CmOh (up to 47%), however, did not affect the overall degree of absorption (calculated on the basis of the area under the concentration-time curve - AUC). Therefore, when taking lamivudine with food, dose adjustment is not required.

    Distribution. In the therapeutic range of doses lamivudine has linear pharmacokinetics and binds insignificantly to plasma proteins. Determined that lamivudine penetrates into the central nervous system (CNS) and into the cerebrospinal fluid. 2-4 hours after oral administration, the ratio of the concentrations of lamivudine in the cerebrospinal fluid and serum was approximately 0.12.

    Metabolism and excretion. On average, the systemic clearance of lamivudine is approximately 0.32 l / kg / h. Lamivudine is excreted mainly by kidneys (more than 70%) by active tubular secretion (the system of organic cation transport), and also by metabolism in the liver (less than 10%).

    The active form of lamivudine, intracellular lamivudine triphosphate, has more long T1/2 from cells (16-19 h) compared with T1/2 its from the plasma (5-7 h). There are data that the pharmacokinetic parameters of lamivudine when taken at a dose of 300 mg once a day in an equilibrium state are equivalent to those when administered at a dose of 150 mg twice a day in terms of AUC24 and CmOh for intracellular triphosphate.

    The likelihood of adverse interaction of lamivudine with other drugs is very small due to limited metabolism in the liver, a slight degree of binding to plasma proteins and almost complete excretion of lamivudine in unchanged form.

    Pharmacokinetics in special clinical cases. In general, the pharmacokinetic profile of lamivudine in children is similar to that in adults. However, in children under 12 years of age, absolute bioavailability is reduced by 55-65%.In addition, the indicators of systemic clearance were higher in young children, decreasing with age and reaching the values ​​of adult patients by 12 years.

    In patients with impaired renal function, the concentration of lamivudine in plasma is increased, its excretion from the body is slowed down. Patients with a creatinine clearance (CK) of less than 50 ml / min require a dose adjustment of lamivudine.

    Data on the use of lamivudine in patients with moderate to severe severity hepatic insufficiency indicate that a violation of liver function does not significantly affect the pharmacokinetics of lamivudine.

    The pharmacokinetics of lamivudine in pregnant women does not differ. Studies have shown that lamivudine penetrates the placental barrier.

    Indications:

    Treatment of HIV infection in combination antiretroviral therapy for adults and children.

    Contraindications:

    Hypersensitivity to lamivudine and other components of the drug, the period of breastfeeding, children under 3 years of age or children weighing less than 14 kg (150 mg for a dosage form), children weighing less than 30 kg (for a dosage form - 300 mg tablets), patients with renal insufficiency (creatinine clearance <30 ml / min).

    Carefully:

    Patients of advanced age.Renal insufficiency (creatinine clearance 30 - <50 ml / min), pancreatitis (including in history), peripheral neuropathy (including in the anamnesis).

    Pregnancy and lactation:

    Data on the safety of lamivudine during pregnancy is currently insufficient. Studies have shown that lamivudine penetrates the placental barrier. Although the results of experimental animal studies can not always be extrapolated to humans, rabbit research indicates a possible risk of spontaneous abortion in early pregnancy. Lamivudine It should be used during pregnancy only if the expected benefit for the mother exceeds the potential risk to the fetus.

    In newborns and children under the age of 1 year, whose mothers during pregnancy and childbirth took drugs from the group of nucleoside reverse transcriptase inhibitors, cases of minor transient enhancement concentration of lactic acid in the serum, apparently due to mitochondrial dysfunction. The clinical significance of the temporary increase in the concentration of lactic acid in the serum is not established.In addition, very rare cases of developmental delay, convulsive syndrome and other neurological disorders have been reported. However, the association of these complications with the use of nucleoside reverse transcriptase inhibitors in pregnancy and the effects of lamivudine on postnatal development have not been demonstrated.

    According to experts, all HIV-infected women should, whenever possible, refuse breastfeeding in order to prevent the transmission of the virus to the baby through breast milk. After oral administration lamivudine is excreted in breast milk, and its concentration in breast milk is practically the same as its concentration in serum (1-8 μg / ml). Because HIV and lamivudine penetrate into breast milk, women taking lamivudine, it is not recommended to breast-feed the baby.

    Dosing and Administration:

    The administration of the drug is allowed only by a specialist with experience in the treatment of HIV infection.

    Inside. Regardless of food intake (before, during or after meals).

    To ensure the accuracy of dosing, the tablet should be swallowed completely without division.

    Adults and children weighing more than 30 kg the recommended dose is 300 mg per day. You can use 150 mg 2 times a day or 300 mg per day in 1 reception.

    Children with a body weight of 21-30 kg the recommended dose is 225 mg per day. In this age category, dosage forms are used that allow dosing according to this regimen.

    Children with a body weight of more than 14 kg the recommended dose is 150 mg per day. You can use half the tablets 150 mg 2 times a day (morning and evening) or 1 tablet 150 mg per day in 1 evening.

    At present, data on the pharmacokinetics of lamivudine elderly patients It is not enough, however, special attention should be paid to this category of patents because of the age-related decline in the excretory function of the kidneys and changes in blood counts.

    Have patients with impaired renal function of moderate and severe the concentration of lamivudine in plasma is increased due to a decrease in the clearance of lamivudine. Therefore, when KK less than 50 ml / min the dose of the drug should be reduced, as shown in the table below. Have children with impaired renal function it is recommended the same scheme of dose reduction depending on the value of CC, as in adults.

    Selection of a dose of lamivudine in dependence on QC in renal failure in adults and adolescents with a body weight of more than 30 kg

    QC

    (ml / min)

    Initial dose (first dose)

    The maintenance dose is the second dose of the drug (24 hours after the first dose) and subsequent doses

    30-49

    150 mg

    150 mg once a day

    15-29

    150 mg

    It is necessary to use another dosage form - oral solution

    5 -14

    150 mg

    It is necessary to use another dosage form - oral solution

    4 and less

    It is necessary to use another dosage form - oral solution

    Have patients with moderate and severe hepatic impairment a dose reduction of Lamivudine-Teva is not required unless the liver function is not accompanied by renal failure.

    Side effects:

    The frequency of side effects is classified according to the recommendations of the World Health Organization: very often - not less than 10%; often - not less than 1%, but less than 10%; infrequently - not less than 0,1%, but less than 1%; rarely - not less than 0.01%, but less than 0.1%; very rarely (including isolated cases) - less than 0.01%.

    Allergic reactions: angioedema.

    From the side of the blood and lymphatic system: infrequently - neutropenia, anemia, thrombocytopenia; very rarely - true erythrocytic aplasia.

    From the central nervous system: often - headache, insomnia; highly rarely - paresthesia, peripheral neuropathy.

    From the digestive tract: often - nausea, vomiting, pain in the upper abdomen, diarrhea; rarely - pancreatitis, increased serum amylase activity.

    From the liver and bile ducts: infrequently - a transient increase in the activity of "liver" transaminases; rarely - hepatitis.

    From the respiratory system: often - cough, symptoms of rhinitis.

    From the skin and subcutaneous tissues: often - skin rash, alopecia.

    From the side of the musculoskeletal and connective tissue: often - arthralgia, muscle disorders; rarely rhabdomyolysis.

    From the side of metabolism: often - increasing the concentration of lactate in the blood serum; rarely - lactic acidosis, redistribution / accumulation of subcutaneous fat.

    Other: often - a feeling of fatigue, malaise, fever. Osteonecrosis has been reported in patients with risk factors such as late stages of HIV infection or long-term combined antiretroviral therapy (frequency of occurrence is unknown).

    Overdose:

    Symptoms: there are few data on the consequences of acute overdose of lamivudine in humans. There were no lethal outcomes, the condition of all patients was normalized. There were no specific signs or symptoms of lamivudine overdose.

    Treatment: it is recommended to monitor the patient's condition and conduct standard maintenance therapy. Because the lamivudine is excreted from the body by dialysis, it is possible to use continuous hemodialysis, but no special studies have been performed.

    Interaction:

    With the simultaneous use of lamivudine and zalcitabine lamivudine It is able to inhibit intracellular phosphorylation of the latter. In this regard, this combination of drugs is not recommended.

    All studies on the interaction were conducted only in adults. The likelihood of metabolic interaction of lamivudine with other drugs is extremely low, since lamivudine is very poorly metabolized, binds to a small extent with plasma proteins and is excreted mainly by the kidneys in unchanged form.

    Simultaneous use of trimethoprim / sulfamethoxazole at a dose of 160/800 mg (co-trimoxazole) increases the concentration of lamivudine in blood plasma by approximately 40% (due to interaction with trimethoprim). However, in the absence of impaired renal function, a dose reduction of lamivudine is not required. On the pharmacokinetics of trimethoprim and sulfamethoxazole lamivudine does not affect. The interaction of lamivudine with co-trimoxazole in high doses, which is used for the treatment of pneumocystis pneumonia and toxoplasmosis, has not been studied.

    Lamivudine is excreted from the body mainly through active tubular secretion through the transport system of organic cations. The possibility of lamivudine interaction with drugs having the same elimination mechanism, for example, with trimethoprim, should be considered. Other drugs (for example, ranitidine, cimetidine) are only partially excreted by this mechanism and do not interact with lamivudine. Drugs that are excreted primarily through active renal secretion through the transport system of organic anions or through glomerular filtration, apparently,do not enter into clinically significant interaction with lamivudine.

    With the simultaneous use of lamivudine and zidovudine, a moderate (by 28%) increase in CmOh zidovudine in plasma, while AUC does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

    There is no evidence of possible pharmacokinetic and pharmacodynamic interactions in the co-administration of ribavirin and lamivudine, but fatal cases of hepatic insufficiency in co-infected patients (HIV and hepatitis C) who received antiretroviral therapy in conjunction with interferon alfa and ribavirin were soaked.

    With simultaneous application lamivudine can inhibit intracellular phosphorylation of emtricitabine. In addition, the mechanism of development of resistance to both lamivudine and emtricitabine is associated with a mutation in the same colon of the reverse transcriptase gene (M184V), and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. The use of lamivudine in combination with emtricitabine or fixed dose combinations containing emtricitabine, Not recommended.

    With the simultaneous administration of lamivudine and cladribine, lamivudine can inhibit intracellular phosphorylation of cladribine. In this regard, this combination of drugs is not recommended.

    Special instructions:

    Treatment with Lamivudine-Teva should be performed by a doctor with experience in managing patients with HIV infection.

    The use of lamivudine as a monotherapy is not recommended.

    In patients with impaired renal function of medium and severe degree, the concentration of lamivudine in plasma is increased, due to the decrease in clearance of the drug, therefore dose adjustment is required.

    Patients should be cautioned that treatment with antiretroviral drugs, incl. lamivudine, does not prevent the risk of HIV transmission to other people during sexual intercourse or blood transfusion. Therefore, patients must comply appropriate precautions.

    In patients receiving lamivudine or other antiretroviral drugs, opportunistic infections or other complications may develop, so they should be carefully monitored by a physician with experience in HIV treatment.

    Several cases of pancreatitis developed in patients who received lamivudine. However, it remains unclear whether this complication is caused by lamivudine or HIV infection itself. When there is abdominal pain, nausea, vomiting, or characteristic changes in biochemical parameters in a patient receiving lamivudine, pancreatitis should be excluded. It is necessary to suspend the drug until the diagnosis of pancreatitis is not ruled out.

    In HIV-infected patients (predominantly in women) who took antiretroviral preparations from the group of nucleoside analogues as monotherapy or in combination with lamivudine, described cases of lactic acidosis, which was usually accompanied by severe hepatomegaly and fatty liver dystrophy, incl. with a lethal outcome.

    Symptoms that may indicate the development of lactic acidosis include general weakness, loss of appetite, sudden unexplained weight loss, abnormalities in the gastrointestinal tract and respiratory system (dyspnea).

    Treatment with lamivudine always requires caution and, especially, if the patient has risk factors for developing liver disease.In case of clinical or laboratory signs of lactic acidosis or liver dysfunction (including hepatomegaly and fatty liver dystrophy even in the absence of a marked increase in the activity of "liver" transaminases), lamivudine should be discontinued.

    In some patients, combined antiretroviral therapy may be accompanied by a redistribution / accumulation of subcutaneous fat, incl. a decrease in the amount of peripheral fatty tissue and an increase in visceral fat, weight loss of limbs and face, enlargement of the mammary glands and the deposition of fat on the back of the neck and back ("buffalo buffalo"), as well as increased serum lipid concentrations and glucose concentrations in the blood.

    Although one or more of the above unwanted reactions associated with a common syndrome, often called lipodystrophy, can cause all drugs from classes of protease inhibitors and nucleoside reverse transcriptase inhibitors, the accumulated evidence suggests that there are differences between individual representatives of these classes of drugs in the ability to induce these unwanted reactions.

    It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, the elderly age and the duration of antiretroviral therapy play an important, perhaps synergistic role in the development of this complication.

    The long-term effects of these undesirable reactions are not currently established.

    Clinical examination of patients should include an assessment of physical signs of fat tissue redistribution. Serum lipids and glucose concentrations in the blood should also be measured. Disorders of lipid metabolism should be adjusted, guided by their clinical manifestations.

    Immunodeficiency Syndrome: in HIV-infected patients with severe immunodeficiency during the onset of antiretroviral therapy (Apt) possibly exacerbation of the inflammatory process caused by asymptomatic or sluggish opportunistic infection, which can cause serious deterioration or worsening of symptoms. As a rule, similar reactions were observed in the first weeks or months after the onset Apt. The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumocystis pneumonia. Any symptoms of inflammation should be immediately identified and start treatment in a timely manner. Also, in conditions of restoration of immunity, the development of autoimmune diseases (Graves' disease, polymyositis, Guillain-Barre syndrome) is possible, however, the development of these diseases can be registered even several months after the start of treatment.

    In some patients with chronic hepatitis B, after the withdrawal of lamivudine, clinical or laboratory signs of hepatitis recurrence may appear, which can have serious consequences in decompensating liver function. After the termination of lamivudine therapy in patients with co-infection caused by HIV and hepatitis B virus, it is necessary to monitor biochemical parameters of liver function and markers of hepatitis B virus replication. There have been cases of hepatic decompensation (some fatal) in patients with HIV-1 co-infection / hepatitis B who received combination antiretroviral therapy and interferon alfa together with ribavirin or without ribavirin.Patients receiving this combination therapy should closely monitor the development of toxic effects, especially liver failure. It is possible to convert the use of lamivudine, reduce the dose, or abolish interferon alfa, ribavirin with worsening of clinical symptoms, including liver failure (eg,> 6 Child-Pugh grade).

    According to international recommendations, if a person infected with HIV is likely to be infected through the blood (for example, through an injection needle), a combination therapy of zidovudine and lamivudine should be prescribed within 1-2 hours from the moment of infection. In the case of a high risk of infection, a drug from the protease inhibitor group should be included in the antiretroviral regimen. Preventive treatment is recommended for 4 weeks. Data on the effectiveness of preventive treatment after accidental HIV infection have not been accumulated enough; controlled studies were not conducted. Despite the rapid onset of treatment with antiretroviral drugs, seroconversion can not be ruled out.

    During the treatment is carried out to monitor patterns of peripheral blood: 1 every 2 weeks during the first 3 months of treatment, then 1 time per month. Hematologic changes appear 4-6 weeks after initiation of therapy: anemia and neutropenia develop more often in patients receiving large doses, with HIV infection started (with a reduced reserve of bone marrow before the start of therapy), neutropenia, anemia, vitamin deficiency B12. With a decrease in hemoglobin by more than 25% or a decrease in the number of neutrophils by more than 50% compared to the baseline, control of blood tests is performed more often. During the treatment period it is necessary to monitor the activity of ALT, ACT, amylase, lipase, serum TG concentration. In patients with impaired renal function, control of the concentration of urea nitrogen, creatinine in the blood serum is necessary.

    Mitochondrial dysfunction

    Research in vitro and in vivo showed that the analogues of nucleosides and nucleotides can cause a different degree of damage to the mitochondria. Mitochondrial dysfunction was recorded in HIV-negative children who received intrauterine and / or post-nucleoside analogues.The main undesirable reactions were hematologic disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipazemia). These undesirable reactions are often transient. Some neurological disorders with late onset have been reported (muscle hypertension, seizures, behavioral disorders). Whether neurological disorders are transient or persistent is currently unknown. Any child, even HIV-negative, who has undergone intrauterine exposure to nucleotide and nucleotide analogs, must undergo a clinical and laboratory examination to exclude mitochondrial dysfunction in case of revealing the relevant signs or symptoms. The data described do not affect the current national recommendations on the use of antiretroviral therapy in pregnant women, for the prevention of vertical transmission of HIV infection.

    Osteonecrosis

    Despite the fact that the etiology of this disease is multifactorial (including the intake of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index),cases of osteonecrosis were most often encountered in patients at a late stage of HIV infection and / or for a long time taking a combined antiretroviral therapy. Patients should consult a doctor if they experience pain and joint stiffness or difficulty in moving.

    Effect on the ability to drive transp. cf. and fur:Special studies of the influence of lamivudine on the ability to drive and work with machinery were not conducted. However, based on the pharmacological properties of lamivudine, such an effect is unlikely. Nevertheless, when assessing a patient's ability to drive a car or moving machinery, his general condition, as well as the nature of the unwanted reactions of lamivudine, should be taken into account.
    Form release / dosage:

    Film-coated tablets, 150 mg and 300 mg.

    Packaging:

    Tablets 150 mg. For 10 tablets in a blister of PVC / PVDC / aluminum foil. 6 blisters together with instructions for use in a cardboard pack.

    Tablets 300 mg. For 10 tablets in a blister of PVC / PVDC / aluminum foil. 3 blister along with instructions for use in a cardboard pack.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003162
    Date of registration:31.08.2015
    Expiration Date:31.08.2020
    The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel
    Manufacturer: & nbsp
    Representation: & nbspTeva Teva Israel
    Information update date: & nbsp12.03.2018
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