Universal reference book for medicines
Product name: SEBIVO ®

Active substance: telbivudine

Type: Antiviral drug active against hepatitis B virus

Manufacturer: NOVARTIS PHARMA (Switzerland) manufactured by NOVARTIS PHARMA STEIN (Switzerland)
Composition, form of production and packaging
Tablets covered with a film membrane
from white to slightly yellow, oval, slightly rounded, with bevelled edges, labeled "LDT" on one side.

1 tab.

telbivudine 600 mg

[PRING] core - microcrystalline cellulose - 88.4 mg, povidone (polyvinylpyrrolidone) - 15 mg, sodium carboxymethyl starch (type A) - 15 mg;
top layer -microcrystalline cellulose - 73.1 mg, sodium carboxymethyl starch type A - 15 mg, magnesium stearate - 8.2 mg, silicon dioxide colloidal anhydrous - 5.3 mg.
The composition of the film shell: premix white (hypromellose, macrogol (polyethylene glycol 4000), talc, titanium dioxide (E171)) - 22 mg.

14 pcs.
- blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2013.

PHARMACHOLOGIC EFFECT

An antiviral drug, a synthetic thymidine analogue of a nucleoside.

It blocks the activity of the hepatitis B virus DNA polymerase enzyme. Telbivudine is effectively phosphorylated by cellular kinases to the active form of triphosphate, which has a half-life in the cell for 14 hours. Telbivudine-5'-triphosphate competitively binds and inhibits DNA polymerase (reverse transcriptase) of the hepatitis B virus, interaction of the enzyme with its endogenous substrate - thymidine-5'-triphosphate.
The inclusion of telbivudine-5'-triphosphate into the structure of the viral DNA causes its chain to break and suppress the replication of the hepatitis B virus. The drug more clearly inhibits the synthesis of the second (50% effective concentration [EC50] = 0.12-0.24 μmol) of the molecular chain of the hepatitis B virus, than the first (EC50 + 0.4 - 1.3 μmol). Telbivudine-5'-phosphate in concentrations up to 100 μmol did not inhibit DNA polymerase (?,? Or?) Of human cells. The drug in concentrations up to 10 μmol did not have a significant toxic effect on the structure of mitochondria, as well as on the content and function of DNA and did not increase the formation of lactic acid in the human body.
Telbivudine has specific antiviral activity against hepatitis B virus. The drug is not effective against other RNA and DNA viruses, including HIV.

When Telbivudine was administered for 104 weeks in HBeAg-positive patients, development of a therapeutic response (HBV DNA <5 log 10 copies / ml, normalization of ALT activity and disappearance of HBeAg) was noted in 63% of cases, the average decrease in HBV DNA content was 5.74 log 10 copies / ml, normalization of ALT activity was observed in 70% of patients, HBV DNA was not detected (polymerase chain reaction) in 56% of patients.

In HBeAg-negative patients, the development of a therapeutic response (HBV DNA <5 log 10 copies / ml, normalizing ALT level) was observed in 78 weeks of cases with the treatment with telbivudine, the average decrease in HBV DNA content was 5 log 10 copies / ml, normalization of ALT activity was observed in 78% of patients, HBV DNA was not detected (PCR reaction) in 82% of patients.

According to biopsy data, at 52 weeks of treatment, a decrease in inflammation in 71% of patients and an improvement in the existing signs of Ishak fibrosis in 42% of patients was revealed.

A decrease in the HBV DNA content below the sensitivity threshold (less than 300 copies / ml) with telbivudine at a dose of 600 mg / day for 104 weeks was noted in 56.0% of HBeAg-positive and 82% of HBeAg-negative patients.

During this period, among HBeAg-positive patients, HBeAg and HBeAg-seroconversion were observed in 35% and 30% of patients, respectively.

The use of telbivudine in HBeAg-positive patients with high ALT activity (excess of UGN more than 2 times), which were the most suitable contingent of patients for interferon treatment, showed a significantly higher proportion of patients who achieved seroconversion by week 104 (36%), which remained in the majority of patients for 52 weeks after the abolition of therapy.

For patients whose hepatitis B virus DNA concentration in the blood serum is reduced to an undetectable level by the 24th week of drug treatment, the development of seroconversion of HBeAg in anti-HBe, preservation of undetectable hepatitis B virus DNA concentration, normal ALT level with a minimal risk of resistance development within 1 year.

Telbivudine in studies in vitro in concentrations of up to 10,000 μmol and in healthy volunteers at a dose of up to 1800 mg / day had no cardiotoxic effect and caused no change in the QT interval or any other ECG parameters.

Hepatitis B virus, resistant to antiviral therapy

There is insufficient data on the use of telbivudine in patients infected with hepatitis B virus, resistant to lamivudine.
In vitro, telbivudine is active against M204V (a single mutation) of the lamivudine-resistant strain of the hepatitis B virus, but does not show activity against lamivudine-resistant strains L180M / M204V (double mutation) and M204I (single mutation) of hepatitis B virus.
There is insufficient data on the use of telbivudine in patients infected with hepatitis B virus, resistant to adefovir.
In vitro, telbivudine exhibits activity against the N236T adefovir-resistant strain of the hepatitis B virus.
The clinical resistance to telbivudine, associated with the YMDD mutation of the hepatitis B virus (M204V), was negligible.
In the treatment with telbivudine, no L180M / M204V strains, as well as previously unknown or specific telbivudine-resistant mutational strains, were detected.
PHARMACOKINETICS

Suction

In healthy volunteers, after 1-4 hours (an average of 2 hours) after taking the medication internally at a dose of 600 mg C max, telbivudine in blood plasma was 3.69 ± 1.25 μg / ml.
AUC was 26.1 ± 7.2 μg / h / ml. C min was 0.2-0.3 μg / ml.
With the appointment of the drug 1 time / day, the equilibrium state is reached after 5-7 days with accumulation of approximately 1.5 times and the estimated T 1/2 1/2hour. The absorption of telbivudine and the systemic effect on the organism did not change with a single dose of 600 mg along with the food.

Distribution

The binding of telbivudine to human plasma proteins in vitro is low (about 3.3%).
The apparent V d of telbivudine exceeds the total amount of fluid in the body, suggesting a wide distribution of telbivudine in tissues. Telbivudine is equally distributed between blood plasma and intracellular fluid.
Metabolism

Metabolites of telbivudine were not identified after 14 C-telbivudine was administered to humans.

Telbivudine is not a substrate, inhibitor, or inducer of the cytochrome P450 enzyme system.

Excretion

After reaching C max, a decrease in the concentration of telbivudine in the plasma occurs bi-exponentially with T 1/2 of the final phase of 40-49 h.

Telbivudine is excreted primarily by excretion through the kidneys in an unchanged form.
The renal clearance of telbivudine corresponds to the normal glomerular filtration rate, which suggests its elimination mainly by passive diffusion. After taking telbivudine inside once in a dose of 600 mg, approximately 42% of the dose appears in the urine for 7 days.
Pharmacokinetics in special clinical cases

There are no significant differences in the pharmacokinetics of telbivudine, depending on sex and race.

Pharmacokinetic features of the use of Sebivo in children are not established.

The pharmacokinetics of telbivudine when taken in a single dose was studied in patients who did not suffer from chronic viral hepatitis, with varying degrees of renal dysfunction (CK score).
In patients with moderate or severe renal dysfunction (CK ≥ 50 mL / min), bioavailability and a decrease in the total clearance of telbivudine are observed. When appointing patients with moderate or severe impairment of renal function of telbivudine, the interval between doses of the drug should be increased. Patients with terminal stage of kidney disease should receive telbivudine after hemodialysis. Hemodialysis (up to 4 hours) reduces the systemic effect of telbivudine by approximately 23%. After the hemodialysis, correction of the dosage regimen is carried out depending on the value of the SC. With regular hemodialysis, dosage adjustment is not required.
The pharmacokinetics of telbivudine after administration in a single dose of 600 mg was studied in patients who did not suffer from chronic viral hepatitis with impaired liver function of mild, moderate and severe degree.
Compared with patients with normal liver function, there was no change in the pharmacokinetics of telbivudine. Do not need to change the dose of Sebivo in patients with impaired liver function.
INDICATIONS

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

DOSING MODE

For the treatment of chronic hepatitis B, the recommended dose of Sebivo is 600 mg (1 tab.) 1 time / day inside regardless of food intake.

Sebivo can be used to treat chronic hepatitis B in patients with impaired renal function .
In patients with impaired renal function with QC? 50 ml / min dosage adjustment is not required. In patients with SC <50 ml / min , a correlation of the interval between doses is necessary, as shown in the table:
Creatinine clearance (ml / min) Dose Sebivo

? 50 600 mg 1 time / 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

Patients on hemodialysis should take Sebivo after a hemodialysis session.

In patients with impaired liver function, dose adjustment is not required.

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

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

SIDE EFFECT

Safety evaluation of Sebivo was performed in more than 1500 people who received telbivudine at a dose up to 1800 mg / 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 frequency of development of adverse events was assessed as follows: occurring frequently (? 1/100; <1/10), infrequently (? 1/1000; <1/100).
In each group, the reactions are listed in order of decreasing clinical importance.
From the side of the central nervous system and peripheral nervous system: often - mild dizziness (1.5%), headache;
infrequently - peripheral neuropathy, dysgeusia, hypoesthesia, paresthesia, sciatica.
From the respiratory system: often - cough.

On the part of the digestive system: often - increased levels of amylase in the blood, diarrhea, increased lipase levels, nausea, abdominal pain.

On the part of the hepatobiliary system: often - increasing the level of ALT;
sometimes an increase in the AST level.
From the skin and subcutaneous tissue: often - a rash.

From the musculoskeletal system: often - increase in the level of CK in the blood;
sometimes - myopathy, arthralgia, myalgia, pain in the extremities, back pain, muscle spasms, neck pain, side pain.
Common disorders: often - increased fatigue of a weak degree (4%);
sometimes - moderate fatigue (0.3%), discomfort.
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.

CONTRAINDICATIONS

- the use of telbivudine at a dose of 600 mg / day along with pegylated interferon alpha-2a (180 μg 1 time / week) and interferon alpha;

- use of the drug in children and adolescents under the age of 18 is not recommended due to insufficient data on efficacy and safety;

- Hypersensitivity to telbivudine or any component of the drug.

With caution

Since telbivudine is excreted primarily by renal excretion, patients with SC <50 mL / min, incl.
who are on hemodialysis, it is recommended to increase the interval between doses of the drug. In addition, when telbivudine is used with other drugs that affect kidney function, it is possible to increase plasma concentrations of telbivudine and / or concomitant medications.
The safety and effectiveness of telbivudine in patients after liver transplantation has not been established.
Pharmacokinetic parameters of telbivudine in the equilibrium state did not change against the background of repeated use in combination with cyclosporine. If telbivudine therapy is required in patients after liver transplantation, who receive or are receiving therapy with immunosuppressants that affect kidney function (eg, cyclosporine or tacrolimus), kidney function should be monitored during and after the end of Sebivo.
Sufficient clinical experience in the use of Sebivo in patients aged 65 years and older is not.
Caution should be exercised in appointing Sebivo to patients in this age group, given the greater frequency of decreased renal function due to concomitant diseases or simultaneous use of other drugs in this category of patients.
Studies on the use of Sebivo in patients with hepatitis B concomitant infections (HIV, hepatitis C and hepatitis D) have not been conducted.

PREGNANCY AND LACTATION

There are no clinical data on the use of telbivudine in pregnant women.
Sebivo can be used in pregnancy if the expected benefit to the mother exceeds the potential risk to the fetus.
Data on the effect of telbivudine on the transmission of the hepatitis B virus from the mother to the fetus are absent.
Steps should be taken to prevent neonatal infection with the hepatitis B virus.
There are no special recommendations for women of childbearing age .

It is not known whether telbivudine is excreted in human milk.
Women taking Sebivo should not breast-feed.
APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with impaired renal function with CK> 50 ml / min, dose adjustment is not required.
In patients with SC <50 ml / min, a correlation of the interval between doses is necessary, as shown in the table:
Creatinine clearance (ml / min) Dose Sebivo

> 50 600 mg 1 time / 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

Patients on hemodialysis should take Sebivo after a hemodialysis session.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

In patients with impaired liver function, dose adjustment is not required.

APPLICATION FOR CHILDREN

It is not recommended to use the drug in children and adolescents under the age of 18 due to a lack of data on efficacy and safety.

APPLICATION IN ELDERLY PATIENTS

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

SPECIAL INSTRUCTIONS

Patients who discontinued treatment with hepatitis B with Sebivo had severe cases of exacerbation of hepatitis B. Clinical and laboratory monitoring of liver function is recommended for at least several months after discontinuation of treatment of hepatitis B. If necessary, hepatitis B therapy should be resumed.

By the 52nd week of treatment with the drug, an increase in the level of CK (grade 3/4) was noted in 7.5% of patients taking telbivudine and 3.1% of patients taking lamivudine.
The average level of CK was higher in patients taking telbivudine. However, from 53 weeks of treatment with telbivudine, there was no increase in the level of CK. In most cases, the increase in the level of CKD was asymptomatic. Usually, on the background of constant therapy with the drug, there was a decrease in the concentration of CK.
For several weeks, months after the start of treatment with the drug, there have been cases of uncomplicated myopathy (persistent diffuse pain and muscle tension and / or muscle weakness of unclear etiology, regardless of the degree and time of increase in the level of CK).
Myopathy was also observed when other synthetic thymidine analogues of nucleosides were taken.
The factors provoking the development of myopathy in patients receiving telbivudine treatment are unknown.

Patients should immediately inform the doctor of any cases of developing persistent pain, muscle tension, or muscle weakness.
When confirming myopathy, the drug should be discontinued.
There is no evidence that the use of Sebivo reduces the risk of transmitting the hepatitis B virus through sexual contact or through blood.

Impact on the ability to drive vehicles and manage mechanisms

Specific recommendations are not provided.

OVERDOSE

There were no cases of an overdose of Sebivo.
Telbivudine is well tolerated in doses up to 1800 mg / day, 3 times the recommended daily dose. The maximum tolerated dose of telbivudine has not been determined.
Treatment: In case of an overdose, it is necessary to cancel telbivudine and, if necessary, prescribe appropriate general supportive therapy.

DRUG 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 at concentrations 12 times the therapeutic levels did not inhibit metabolic processes involving microsomal isoenzymes 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4 cytochrome P450 in the liver.
In animals, telbivudine does not induce cytochrome P450 isoenzymes. Considering these results and the known path telbivudine elimination, there is a low potential for interactions with other medications Sebivo in step CYP450 metabolism.
Telbivudine Pharmacokinetic parameters at steady state did not change after repeated use in combination with lamivudine, adefovir dipivoxil, cyclosporin or peginterferon alpha-2a or tenofovir.
In a pilot clinical study on the combination of telbivudine 600 mg / day and peginterferon alfa-2a (180 mg 1 time per week n / k) was observed increased risk of peripheral neuropathy. Care must be taken when assigning Sebivo in combination with peginterferon alfa-2a.
It is not known whether the risk of myopathy is increased by the development of the simultaneous use of telbivudine with drugs that cause myopathy. In the appointment of Sebivo with drugs that cause myopathy, should assess the potential benefits of therapy and the potential risk of myopathy and ensure monitoring of patients for early detection of pain, muscle tension or muscle weakness of unknown etiology.
It is recommended to avoid concurrent use with inteferonom alpha.
Monotherapy with nucleoside / nucleotide analogue or their reception in combination with antiretroviral drugs observed cases of acidosis and severe hepatomegaly with steatosis, including fatal.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children at a temperature of no higher than 30 ° C.
Shelf life - 3 years.
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