Sebivo (Sebivo)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceTelbivudineTelbivudine
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  • Sebivo
    pills inwards 
    Novartis Pharma AG     Switzerland
    • Dosage form: & nbspfilm coated tablets
    Composition:

    1 film coated tablet shell, contains:

    Core tablet: inner layer - active substance: telbivudine - 600 mg;

    Excipients:

    cellulose microcrystalline - 88,4 mg, povidone (polyvinylpyrrolidone) -15.0 mg, sodium carboxymethyl starch, type A - 15.0 mg,

    upper layer - Excipients: cellulose microcrystalline - 73.1 mg, sodium carboxymethyl starch, type A - 15.0 mg, magnesium stearate - 8.2 mg, silicon dioxide colloidal anhydrous - 5.3 mg. Film sheath - premix white (hypromellose, macrogol (polyethylene glycol 4000, talc, titanium dioxide E171) 22.0 mg.

    Description:

    pills oval, slightly rounded, with beveled edges, covered with a film sheath, from white to slightly yellow. On one side of the tablet is labeled "LDT".


    Pharmacotherapeutic group:antiviral agent.
    ATX: & nbsp

    J.05.A.F.11   Telbivudine

    Pharmacodynamics:

    Mechanism of action

    Telbivudine, a synthetic thymidine analogue of the nucleoside, blocks the activity of the hepatitis B virus DNA polymerase (HBV) enzyme. Telbivudine is effectively phosphorylated by cellular kinases to the active form of triphosphate, which has a half-life of 14 hours from the cell. Telbivudine-5'-triphosphate competitively binds and inhibits DNA polymerase (reverse transcriptase) of HBV, disrupting the interaction of the enzyme with its endogenous substrate - thymidine 5'-triphosphate. Inclusion of telbivudine-5'-triphosphate in the structure of viral DNA causes its termination chains and suppression of viral replication hepatitis B.

    The drug is more pronounced inhibits synthesis The second (50% effective concentration [EC50] = 0.12-0.24 pM) of the molecular the hepatitis B virus chain than the first (EC 50 = 0.4 - 1.3 pM). Telbivudine - 5-triphosphate in concentrations up to 100 pM inhibited DNA polymerase (alpha, beta or gamma) of human cells. The drug in concentrations up to 10 pM did not exert significant toxic effect on structure of mitochondria, as well as on content and function of DNA, and not increased the formation of lactic acid in the human body.

    Telbivudine has a specific antiviral activity against HBV. In vitro it was found that telbivudine activity against other RNA and DNA containing viruses, including human immunodeficiency virus (HIV). AT clinical trials, assessment of absence of telbivudine activity in there was no HIV infection.

    An activity study was conducted telbivudine for 208 weeks, in study included 502 patients (293 HBeAg-positive patients and 209 HBeAgnegative patients). At 156 and 208 week of treatment in the majority patients remained content HBV DNA is below the sensitivity threshold (less than 300 copies / ml) and normalized activity alanine aminotransferase (ALT). Patients who have the content was determined HBV DNA is below the sensitivity threshold at week 24 of treatment, have more favorable forecast for 156 and 208 weeks of treatment.

    At 293 HBeAg-positive patients total level HBeAg-conversion increased with increasing duration of therapy: 27.6% at 52 weeks, 41.6% at 104 weeks, 48.5 at 156 weeks, and 53.2% at 208 weeks of treatment. A higher level of seroconversion was observed in HBeAg- positive patients with HBV DNA content below the sensitivity threshold at week 24 of treatment (40.1% at 52 weeks, 52.5% at 108 weeks, 59.3% at 156 weeks, 65.4% at 208 weeks).

    Against the backdrop of treatment with telbivudine over a period of 5 years, a statistically significant improvement is revealed from the biopsy data. 98.2% of patients do not detect or determine minimal signs of necrotic inflammation (index on a scale Knodell <= 3) and 84.2% of patients are not identified or defined minimal signs of fibrosis (index by the scale Ishak <= 1).

    For patients who have content DNA HBV in the blood serum is reduced to an undetectable level by the 24th week of treatment with telbivudine, more characteristic is the development of seroconversion HBeAg in anti-HBe, the preservation of undetectable content DNA HBV, normal value activity alanine aminotransferase with a minimal risk of developing resistance for 1 and 2 years. Telbivudine in research in vitro in concentrations up to 10,000 μM and in healthy volunteers in a dose up to 1800 mg / day did not have cardiotoxic effect and did not cause a change in the interval QT or any other electrocardiographic parameters.

    In vitro telbivudine is not active against lamivudine-resistant strains L180M / M204V (double mutation) and M204I (single mutation) HBV. Telbivudine was active against the most common adefovirresistant strains HBV (N236T, A181T mutations).

    In clinical studies, resistance to telbivudine was mainly associated with rtM2041 mutation (often in combination with rtL180M and rtL80I / V mutations, less often with rtV27A, rtL82M, rtV 173L, rtT 1841, and rtA200V mutations).

    High content HBV DNA (more than 300 copies / ml) and increased activity of blood plasma ALT at week 24 of treatment with telbivudine are predictors of the possible formation of resistance at 104 weeks of treatment.There is insufficient data on the use of telbivudine in patients infected with the hepatitis B virus, resistant to lamivudine or adefovir.

    Pharmacokinetics:

    Absorption and bioavailability In healthy volunteers, after 1-4 hours (on average 2 hours) after ingestion of 600 mg of the drug, the maximum concentration (Cmax) of telbivudine in the blood plasma in an equilibrium state was 3.69 ± 1.25 μg / ml (mean ± standard deviation). For telbivudine, the area under the "concentration time" curve (AUC) and the minimum plasma concentration was 26.10 ± 7.2 μg / h / ml and 0.2-0.3 μg / ml, respectively.

    When application of of the drug once a day, the equilibrium state is reached after 5-7 days with accumulation of approximately 1.5 times and an expected half-life of 15 hours.

    Absorption of telbivudine and systemic effects on the body did not change with single dose of 600 mg together with food.

    Distribution

    Binding of telbivudine to plasma proteins human blood in vitro low (about 3.3%).

    Apparent volume of distribution telbivudine exceeds the total fluid in the body, which allows assume a wide distribution telbivudine in tissues. Telbivudine equally distributed between blood plasma and intracellular liquid.

    Metabolism

    Metabolites of telbivudine after applications 14C-telbivudine y rights.

    Telbivudine is not a substrate, an inhibitor, or an inducer of an enzyme cytochrome P450 systems (CY450).

    Excretion

    After reaching Cmax, decrease concentrations of telbivudine in plasma occurs bi-exponentially with the final half-life (T1/2) 40-49 hours.

    Telbivudine is excreted predominantly kidneys in unmodified form. Renal clearance of telbivudine normal glomerular velocity filtering, which suggests its elimination, mainly by passive diffusion. After taking telbivudine inside once in a dose of 600 mg approximately 42% of the dose is determined in the urine for 7 days.

    There are no significant differences pharmacokinetics of telbivudine in dependence from sex and race.

    Children

    Pharmacokinetic features use of the drug in children is not installed.

    Patients with impaired renal function

    Pharmacokinetics of telbivudine in single entry admission was studied in patients, without HBV, with varying degrees renal function disorders (assessment of clearance of creatinine). In patients with violation of kidney function medium or severe (creatinine clearance <50 ml / min), there is an increase bioavailability (AUCo-inf) and decline of the total clearance of telbivudine. When application of telbivudine patients from impaired renal function medium or severe should be increased interval between reception.

    Patients with terminal stage kidney disease telbivudine should be take after hemodialysis.

    Hemodialysis (up to 4 hours) reduces the systemic effects of telbivudine on 23%. After the hemodialysis dosage adjustment is carried out depending on the value creatinine clearance. With regular hemodialysis dosage adjustment is not it takes.

    Patients with impaired hepatic function Pharmacokinetics of telbivudine after single-entry intake of 600 mg was studied in patients, without HBV, with disturbances of function liver light, medium and severe.

    Compared with patients with unchanged liver function, changes pharmacokinetics of telbivudine are not was observed. No dose change required drug in patients with impaired function of the liver.

    Indications:

    - Chronic hepatitis B in adult patients with confirmed viral replication and active inflammatory process in the liver.

    Contraindications:

    Hypersensitivity to telbivudine or any auxiliary substance.

    Sebivo is not recommended for use in children (under the age of 18) due to insufficient data on efficacy and safety.

    Carefully:

    Impaired renal function

    Because the telbivudine is displayed mainly kidney, patients with creatinine clearance <50 ml / min, including those on hemodialysis, an increase is recommended interval of drug intake. In addition, with application of telbivudine with others medicinal drugs, affecting the function of the kidneys, it is possible to increase the concentration in the plasma blood telbivudine and / or concomitant medications. Patients after liver transplantation The safety and efficacy of telbivudine in patients after liver transplantation has not been established. Pharmacokinetic options telbivudine in the equilibrium state did not change against the background of repeated use in combination with cyclosporine. If it is necessary to conduct therapy with telbivudine in patients after liver transplantation who received or are receiving therapy with immunosuppressants that affect the function of the kidneys (for example, ciclosporin or tacrolimus), it is necessary to monitor the function of the kidneys during and after the end of the application preparation Sebivo.

    Elderly patients

    There is not enough clinical experience preparation Sebivo in patients aged 65 years and over. Care should be taken when application of the drug Sebivo u patients This age group, given the greater frequency of decreased renal function due to concomitant diseases or simultaneous application of other medicinal products drugs in this category of patients.

    Pregnancy and lactation:

    Data clinical research the use of telbivudine in pregnancy is very limited. Based on available data on the use of telbivudine in pregnant patients infected with the hepatitis B virus (literature review, post-marketing reports,data of the register of pregnant women), there was no increase in the frequency of congenital malformations, cases of spontaneous abortion, artificial termination of pregnancy due to medical conditions, as well as signs of embryo or fetotoxicity. A drug Sebivo can be used during pregnancy only if the expected benefit for the mother exceeds potential risk to the fetus. The use of telbivudine in the second and third trimesters of pregnancy combined with the passive (specific immunoglobulin against hepatitis B) and active vaccination of the newborn with a high level of viremia in the mother during pregnancy reduced the risk of intrauterine and perinatal transmission of the virus HBV from mother to child. There are no special recommendations for women of childbearing age.

    It is not known whether telbivudine with human breast milk. Women receiving a drug Sebivo, it follows refuse breastfeeding. Application Studies preparation Sebivo in patients with concomitant hepatitis AT infections (eg, HIV, hepatitis C and hepatitis D) not conducted.

    Dosing and Administration:

    For the treatment of chronic hepatitis B, the recommended dose of telbivudine is 600 mg (1 tablet) 1 time per day orally, regardless of food intake.

    Kidney Dysfunction / Renal Failure

    Sebivo can be used to treat chronic hepatitis B in patients with impaired renal function. Patients with creatinine clearance> 50 ml / min dosage adjustment is not required. In patients with creatinine clearance less than 50 ml / min, the interval between doses is necessary, as shown below;

    Creatinine clearance (ml / min)

    Doze Sebivo

    >50

    600 mg once a day

    30-49

    600 mg every 48 hours

    <30 (condition not requiring hemodialysis)

    600 mg every 72 hours

    Terminal stage of kidney disease

    600 mg every 96 hours

    Sebivo should be taken after hemodialysis.

    Dysfunction of the liver

    In patients with impaired liver function, no dose adjustment of telbivudine is required

    Children and teens

    Telbivudine is not recommended for use in children under the age of 18 due to inadequate data on efficacy and safety.

    Elderly patients

    There is no data for special recommendations on the dosage regimen in patients over the age of 65 years.

    Side effects:

    The safety assessment of Sebivo was carried out by more than 1500 people who received telbivudine in a dose up to 1800 mg per day. In comparative studies in patients with hepatitis B (1367 patients), the safety profiles of telbivudine at a dose of 600 mg / day and lamivudine at a dose of 100 mg / day were comparable.

    Telbivudine was generally well tolerated, the adverse events were mild or moderate. Termination of Sebivo therapy due to the development of adverse events, clinical progression of the disease or lack of efficacy during the first 52 weeks of treatment was observed in 0.3% of cases.

    The incidence of adverse events was assessed as follows; appearing "often" (> 1/100; <1/10), "sometimes" (> 1/1000; <1/100). In each group, the reactions are listed in order of decreasing clinical significance.

    From the central and peripheral nervous system Often: mild dizziness, headache.

    From the gastrointestinal tract (GIT)

    Often: increased levels of amylase in the blood, diarrhea, increased lipase levels, nausea. From the side of the liver

    Often: increased levels of alanine aminotransferase.

    Sometimes: increase in the level of aspartate aminotransferase.

    From the skin and subcutaneous tissue:

    Often: rash.

    From the side of the musculoskeletal system and connective tissue Often: increased levels of creatine phosphokinase (CK) in the blood;

    By 52 weeks of treatment, the elevation of the level of CK (degree 3L) 7.5% of patients who took telbivudine and in 3.1% of patients who took lamivudine.

    The average level of CK was higher in patients taking telbivudine. However, from 53 weeks of treatment with telbivudine, an increase in the level of CKK was not observed. In most cases, the increase in the level of CPK was asymptomatic. Usually, on the background of constant therapy, there was a decrease in the concentration of CK.

    Sometimes: arthralgia, myalgia.

    Common violations:

    Often: fatigue is weak (4%);

    Sometimes: fatigue is moderate (0.3%), discomfort.

    Exacerbations of hepatitis B after discontinuation of treatment

    Some patients who stopped treatment with telbivudine had severe cases of acute exacerbation of hepatitis B. There are no data on treatment of exacerbations of hepatitis B after discontinuation of therapy with telbivudine.

    Overdose:There were no cases of overdose of Sebivo. Telbivudine well tolerated in doses up to 1800 mg / day, three times the recommended daily dose.The maximum tolerated dose of telbivudine has not been determined. In case of overdose, cancel telbivudine and, if necessary, prescribe appropriate general supportive therapy.
    Interaction:

    Telbivudine is excreted mainly by the kidneys, so when Sebivo is prescribed with medications that affect kidney function, there may be an increase in plasma concentrations of telbivudine and / or concomitant medications.

    In vitro telbivudine in concentrations 12 times higher than therapeutic, did not inhibit metabolic processes taking place with the participation of microsomal isoenzymes 1A2, 2C9, 2C19, 2D26, 2E1, and 4 of the liver cytochrome P450 (RMS), which is responsible for the biotransformation of drugs. In animals telbivudine does not induce from cytochrome P450 enzymes. Given the results and known ways of elimination of telbivudine, there is a low potential for interaction of Sebivo with other drugs at the level of CYP450.

    The pharmacokinetic parameters of telbivudine in the equilibrium state did not change after repeated use in combination with lamivudine, adefovir dipivoxyl, cyclosporin or PEG-interferon-α 2a.

    Against the background of monotherapy with nucleoside / nucleotide analogues or their administration in combination with antiretroviral agents, cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal outcome, have been observed.

    Special instructions:

    Relatively frequent cases of sudden severe exacerbation of chronic hepatitis B, characterized by a transient increase in ALT activity in blood serum. In some patients, an increase in ALT activity in the serum, accompanied by a decrease in the amount of HBV DNA, may be noted after the initiation of antiviral therapy. In patients treated with telbivudine, an average of 4-5 weeks occurred before the onset of an exacerbation.

    In general, a sharp increase in ALT activity often occurs in HBeAg-positive patients than in HBcAg-negative. In Nazis with liver disease in the compensation stage, such an increase in ALT activity in the blood serum is usually not accompanied by an increase in the serum bilirubin concentration or any other signs of liver function decompensation. The risk of decompensation of liver function and subsequent exacerbation of hepatitis B can be increased in patients with cirrhosis of the liver, which should be carefully monitored.

    Exacerbation of the disease was also noted in patients who stopped treatment for hepatitis B. As a rule, the increase in ALT activity after the end of treatment is associated with an increase in the amount of the virus of HBV DNA in the blood serum, and in most cases is resolved independently. Nevertheless, there have also been cases of severe exacerbation of hepatitis B, some with a fatal outcome, in the post-treatment period. In view of the foregoing, the clinical and laboratory parameters of liver function for at least 6 months after end of treatment for hepatitis B.

    If necessary, hepatitis B therapy should be resumed.

    When telbivudine was used for 6 months, the frequency of increase in LLT activity (2 times higher than the initial value or 10 times higher than the upper limit of the norm) was similar to that in the lamivudine group. Reduction in the frequency of increase in activity of LLT was noted by the 24th week of therapy with gelbivudine. It is recommended to carry out thorough clinical and laboratory monitoring of liver function during the entire period of treatment with the drug.

    By the 104th week of treatment, an increase in the concentration of CK (degree%) was noted in 12.6% of patients taking telbivudine and 4.0% of patients taking lamivudine. The mean concentration of CK was higher in patients taking telbivudine. In most cases rise the concentration of CK was asymptomatic. As a rule, against the background of constant therapy with the drug, there was a decrease in the concentration of CK. When using telbivudine frequency development of adverse events in patients with elevated CFC concentrations was similar to that in the lamivudine group.

    Against the background of prolonged therapy with telbivudine (208 pedel), an increase in the concentration of CK (degree%) was observed in 15.9% of patients. In most cases, the increase in CK concentration was asymptomatic (74%) and transient.

    With the use of nucleosides and their analogs, cases of lactoacidosis (in the absence of gnacosemia), some with a legal outcome, have been noted. As a rule, such cases were accompanied by the presence of severe hepatomasalgia with stasatosis. Because the telbivudine is an analogue of nucleosides, in its application the risk of development of such states ns can be excluded.Treatment with analogues of nucleosides should be discontinued with a sharp increase in the activity of aminotransferases, progression of hepatomegaly or in the occurrence of lactic acidosis of unknown etiology. Evidence of the development of lactic acidosis can be such symptoms from the digestive system as nausea, vomiting and abdominal pain. Severe cases, some with a fatal outcome, were accompanied by pancreatitis, acute hepatic insufficiency, liver stasatosis, acute renal insufficiency, and high serum lactate concentration blood. Care should be taken when using analogues of nucleosides patients with hepatosgaly (in especially in patients with obesity), with hepatitis or any other risk factors for diseases liver. It should be carefully observed such patients.

    Within a few weeks and months after the start of treatment with the drug, there have been cases of uncomplicated myopathy and myalgia (constant diffuse pain and muscle tension and / or muscle weakness of an unclear ethology, regardless of the degree and time of increasing the concentration of CK).Myopathy was also observed with the use of other synthetic thymidine analogs of the nucleoside.

    Factors provoking the development of myopathy in patients receiving treatment with telbivudine, are unknown.

    Patients should immediately report to the doctor any cases of developing persistent pain, muscle tension or muscle weakness. When confirming the diagnosis of myopathy, the drug should be discontinued. In the post-marketing period, when the drug was used, cases development of rhabdomyolysis.

    It is not known whether the risk of developing myatias increases with the simultaneous use of tselbivudine and other drugs that can cause the development of mynia (for example, statins, fibrosalic acid derivatives, ciclosporin). In the case of simultaneous use of such drugs with the drug Sebivo should assess the ratio of expected benefits to the possible risk and conduct a thorough dynamic observation of these patients.

    Patients treated with gelbwooddine reported infrequent cases of peripheral neuropathy. If the suspected development of this condition, treatment with the drug should be discontinued.

    There was an increased risk of peripheral neuropathy in a clinical trial in patients receiving simultaneous therapy with telburnudine and pegylated n-interferon. Such a risk can not be ruled out with the use of other drugs of interferon (leaded or standard), in addition, currently the effectiveness of the use of such a combination of drugs has not been confirmed, and therefore tslbvudin ns follows

    apply simultaneously with preparations of a-interferon (pegylated or standard).

    Telbivudine is excreted mainly by the kidneys, therefore, it is recommended to correct the interval between doses of the drug in patients with creatinine clearance less than 50 ml / min, including those on hemodialysis or undergoing hemodialysis procedure. "Method of administration and dose"). Since there are no clinical data on the efficacy of the regimen with an extended interval, the virologic response in patients in this category should be closely monitored.

    Due to the limited data on the use of telbivudine in patients with cirrhosis without decompensation (3% of all patients), the drug should be used with caution in this category of patients.Such patients should be monitored and clinical, biochemical and virological indicators monitored during and after treatment.

    There is no adequate data on the efficacy and safety of telbivudine in patients with cirrhosis in the decompensation stage.

    In vitro telbivudine has an act of relevance to HBV strains with rtM204V / rtL180M or rtM204I mutations. Do not use telbivudine in moyoterapii in patients with established resistance to lamunvudnu. In patients without a virologic response to lamivudine therapy for 24 weeks, the use of mycotherapy with tlbivudine is questionable. There is insufficient clinical data to establish the possible benefit / risk of replacing lamivudine therapy in patients who have achieved complete suppression of HBV with telbivudine. In studies, the therapeutic response to treatment with the combination of telbivudine with lamivudine was worse than with tlbivudine, and the simultaneous use of telbivudine with lamivudine is not recommended.

    There is no data on the use of telbivudine in patients with adefovir-resistant strains of HBV (N236T, A18G mutations).According to studies on cell colonies, adefovrin-resistant strains of A181T HBV showed mutations in 1.5-4 times less sensitivity to telburnudine.

    Patients who are recommended to limit the intake of sodium with food, it should be noted that 30 ml of oral solution contains 47 mg of sodium.

    There is no evidence of safety and efficacy of tlsbivudine in patients with liver transplantation.

    Due to the lack of data on the use of Sebivo in patients over 65 years of age, it is not possible to determine whether the response to therapy in patients of this age group differs from younger patients. Care should be taken when using the drug in elderly patients due to the greater prevalence of renal dysfunction in these patients due to concomitant pathology or concurrent use of other medications.

    The data on the use of the drug in patients infected with HBV with other associated viral infection, for example, the hepatitis virus C and D) or HIV.

    Information for patients

    There is no evidence that the use of Sebivo reduces the risk of transmission hepatitis B virus through sexual contact or through blood.

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

    Given the risk of developing adverse events, carefully To carry out hazardous activities requiring increased attention and quick reactions, such as the management of transport means and mechanisms.

    Form release / dosage:
    Film-coated tablets, 600 mg. For 14 tablets in a blister of PVC / PVDC.
    2 blisters together with instructions for use in a cardboard box.
    Packaging:(14) - packings, cellular, outline (2) - packs, cardboard
    Storage conditions:

    Store at a temperature not exceeding 30 ° C

    The drug should be stored out of the reach of children.

    Shelf life:
    3 years.

    The drug should not be used after the expiration date.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-000067
    Date of registration:21.05.2007
    The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland
    Manufacturer: & nbsp
    Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC
    Information update date: & nbsp14.09.2015
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