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

Name of components	Amount, mg
Active substance
Lamivudine	100,0
Excipients
Microcrystalline cellulose	116,55
Carboxymethyl starch of sodium type A	6,75
Magnesium stearate	1,70
Film sheath
Rape yellow-brown	5,6

Composition of the film shell:

Colour	Name of components	Amount,% m / m
Fall yellow-brown	Hypromellose	70,0
	Titanium dioxide	16,3
	Iron oxide red	0,5
	Iron oxide yellow	4,2
	Macrogol 400	8,0
	Polysorbate 80	1,0

Description:Yellowish-brown, biconvex, capsular-shaped, film-coated tablets, engraved on one side of the tablet with the inscription "GX CG5".

Pharmacotherapeutic group:An antiviral agent.

ATX: & nbsp

J.05.A.F.05 Lamivudine

Pharmacodynamics:Mechanism of action
Lamivudine is an antiviral drug with a high activity against hepatitis B virus (HBV), which is proven on tested cell lines and in experimental infection of animals.
Both in infected and uninfected cells lamivudine is metabolized to lamivudine triphosphate, which is the active form of the parent compound.In vitro, the intracellular half-life of lamivudine triphosphate in hepatocytes is 17-19 hours. Lamivudine triphosphate is a substrate for DNA polymerase of the hepatitis B virus. The inclusion of lamivudine triphosphate in a chain of viral DNA and the subsequent chain termination block further formation of viral DNA. Lamivudine triphosphate does not affect the normal cellular metabolism of deoxynucleotides. It is also a weak inhibitor of mammalian α- and β-DNA polymerases. In addition, lamivudine triphosphate does not significantly affect the DNA content of mammalian cells. In studies to determine the possible effect on the structure of mitochondria, as well as on the content and function of DNA, lamivudine had no significant toxic effects. Lamivudine has a very weak ability to reduce the content of mitochondrial DNA, briefly enters its chain and does not inhibit mitochondrial DNA γ-polymerase.

Pharmacokinetics:Suction
Lamivudine is well absorbed from the gastrointestinal tract. Its bioavailability in adults after oral administration is usually 80-85%. When ingested, the mean time (T_max) reaching the maximum serum concentration (C_max) is approximately 1 hour. When the drug is administered in therapeutic doses, that is, 100 mg once a day, C_max is approximately 1.1-1.5 μg / ml, the lowest level of concentration was 0.015-0.20 μg / ml.
Reception of lamivudine together with food lengthens T_max and reduces C_max (up to 47%), while eating does not affect the overall degree of absorption of lamivudine, calculated on the basis of AUC (pharmacokinetic curve "concentration-time"). In this way, lamivudine can be taken regardless of food intake.
Distribution
At intravenous introduction the volume of distribution lamivudina makes on the average 1,3 l / kg. In the therapeutic range of doses lamivudine has a linear pharmacokinetics and binds insignificantly to plasma proteins.
The limited data showed that lamivudine penetrates into the central nervous system and reaches the cerebrospinal fluid. After 2-4 hours after oral administration, the ratio of the concentrations of lamivudine in the cerebrospinal fluid and serum is approximately 0.12.
Metabolism
Most of the lamivudine is excreted unchanged by the kidneys.The probability of metabolic interaction of lamivudine with other drugs is low due to limited metabolism of the drug in the liver (5-10%) and a low degree of binding to plasma proteins.
Excretion
Systemic clearance of lamivudine averages about 0.3 l / h / kg. The half-life is approximately 5-7 hours. Most lamivudine is excreted unchanged by the kidneys through glomerular filtration and active secretion with the help of the organic cation transport system. The share of renal clearance accounts for about 70% of lamivudine excretion.
Special patient groups
Children
The pharmacokinetics of lamivudine in children does not differ from the pharmacokinetics in adults. However, in children, lamivudine clearance, adjusted depending on body weight, is higher than in adults, which is reflected in a decrease in AUC in children. The highest clearance of lamivudine is observed in children aged 2 years and is reduced to 12 years, when its values become similar to those in adults. The equilibrium AUC of lamivudine was comparable in children when administered at a dose of 3 mg / kg 1 time per day and in adults with 100 mg / day.
The recommended dose of lamivudine for children 2 to 11 years, component 3 mg / kg 1 time a day (up to 100 mg 1 time per day), capable of providing comparable with adult dose (100 mg per day) exposure lamivudine. Data on the pharmacokinetics of lamivudine in children under 2 years of age are limited.
Elderly patients
In elderly patients, the age-related decrease in renal function does not have a significant clinical effect on the excretion of lamivudine when creatinine clearance is less than 50 mL / min.
Patients with impaired renal function
Studies have shown that in patients with renal insufficiency, renal dysfunction affects the excretion of lamivudine from the body. Patients with creatinine clearance less than 50 ml / min dose of lamivudine should be reduced.
Patients with impaired hepatic function
According to the results of studies involving patients with hepatic insufficiency (not infected with HIV and HBV), it was established that lamivudine is well tolerated by this category of patients, without causing changes in laboratory parameters or the profile of unwanted reactions of lamivudine. The violation of liver function does not affect the pharmacokinetics of lamivudine.Limited data on patients who underwent liver transplantation demonstrate that a disturbed liver function has a slight effect on the pharmacokinetics of lamivudine, unless combined with renal failure.
Pregnant
In women in late pregnancy, the pharmacokinetics of lamivudine when administered is similar to that of non-pregnant women.

Indications:Zephix® is indicated for the treatment of chronic hepatitis B in adults with:

compensated liver disease with signs of active viral replication, a continuous increase in serum alanine aminotransferase (ALT) activity and histological signs of an active inflammatory process in the liver and / or fibrosis. The possibility of starting lamivudine treatment should be considered only if the use of an alternative antiviral agent with a higher genetic barrier is not available or contraindicated;
decompensated liver disease in combination with a second drug that does not have cross-resistance to lamivudine.

Contraindications:

Hypersensitivity to lamivudine or any other component of the drug;
patients with impaired renal function, with creatinine clearance less than 50 ml / min;
Children under 18 years of age (for this dosage form).

Pregnancy and lactation:Fertility
In studies of reproductive function in animals no effect on the fertility of males or females was found.
Pregnancy
A large number of data obtained in pregnant women (more than 1000 women who received the drug) indicate the absence of toxicity associated with congenital malformations. Zeffix ® can be used during pregnancy in the presence of clinical indications. If the pregnancy occurred during treatment with Zephix®, it should be borne in mind that after the withdrawal of Zephix®, the exacerbation of hepatitis may develop.
Breastfeeding period
Based on data from more than 200 mother-child pairs receiving treatment for HIV infection, the serum concentration of lamivudine in breast-fed infants whose mothers received treatment for HIV infection is very low (less than 4% of serum concentration of the mother) and gradually decreases to a level that can not be detected after reaching the age of 24 weeks.The total amount of lamivudine that the baby takes through the breast milk is very small and, thus, can lead to an exposure that does not have the optimal antiviral effect. The presence of hepatitis B in the mother is not a contraindication to breastfeeding the baby if the newborn has adequate prophylaxis for hepatitis B at birth, and there is no evidence that a low concentration of lamivudine in breast milk leads to side effects in children who are breastfeeding. Thus, the possibility of breastfeeding can be seen in mothers receiving Zephix® for HBV treatment, taking into account the benefits of breastfeeding for a child and the benefits of therapy for a woman. In cases where HBV transmission from mother to child occurred despite adequate prevention, consideration should be given to the possibility of stopping breastfeeding to reduce the risk of mutations of resistance to lamivudine in a newborn.
Mitochondrial dysfunction
It has been demonstrated in vitro and in vivo that nucleoside and nucleotide analogues cause damage to mitochondria of varying degrees.There are reports of mitochondrial dysfunction in children exposed to nucleoside analogues in utero and / or after birth.

Dosing and Administration:The drug Zeffix® should be taken orally, regardless of food intake.
During treatment with Zephix®, the doctor must monitor the patient's compliance with the dosing regimen and the therapy regimen.
Zephix® should be taken in accordance with official guidelines.
Adults
The recommended dose of Zephix® is 100 mg once a day.
In patients with decompensated liver disease, Zeffix® should always be used in combination with a second drug that does not have cross-resistance to lamivudine to reduce the risk of resistance and achieve rapid virus suppression.
Duration of therapy
The optimal duration of treatment is not established.
- In patients with HBeAg-positive chronic hepatitis B (CHB) without cirrhosis, treatment should be performed for at least 6-12 months after confirmation of seroconversion of HBeAg (disappearance of HBeAg and HBV DNA with detection of HBeAb) to limit the risk of recurrence of viremia or before seroconversion of HBsAg or decrease in efficacy.Should regularly monitor the serum ALT and HBV DNA after treatment discontinuation to detect late relapse of viremia.
- Patients with HBeAg-negative chronic hepatitis B (prenuclear mutation site) without cirrhosis treatment should be conducted at least until HBs seroconversion or signs of declining efficiency. With prolonged treatment, it is recommended that a regular evaluation be conducted to confirm the appropriateness of continuing the selected treatment for the patient.
- Patients with decompensated liver disease or cirrhosis and in patients with liver transplant is not recommended to stop treatment. In the event of discontinuation of Zephix®, periodic monitoring of patients for signs of recurrence of hepatitis should be performed.
Clinical resistance
Patients with HBeAg-positive or HBeAg-negative chronic hepatitis B development YMDD (tyrosine-methionine-aspartate-aspartate) mutant variant HBV can lead to reduced therapeutic response to a drug Zeffiks®, as evidenced by an increase in HBV DNA and ALT activity in comparison with the indices before treatment.In order to reduce the risk of resistance in patients receiving Zerix® monotherapy, treatment should be considered if the serum level of HBV DNA remains at a detectable level within 24 weeks of treatment or more. Patients with a YMDD mutant variant of HBV should consider the possibility of adding an alternative drug without cross-resistance to lamivudine. For the treatment of patients with concomitant HIV infection currently receiving or planning to initiate treatment with Zephix® or a combination of lamivudine and zidovudine, the dose of lamivudine administered for HIV infection should be maintained (usually 150 mg twice daily in combination with other antiretroviral drugs).
Special patient groups
Patients with impaired renal function
The drug in this dosage form is contraindicated in patients with creatinine clearance less than 50 ml / min.
Patients with impaired hepatic function
Data obtained from patients with impaired hepatic function, including those in patients with terminal hepatic impairment, waiting for a liver transplant, show that the pharmacokinetics of lamivudine in liver function disorders does not change significantly.Based on these data, with liver failure, if it is not accompanied by renal insufficiency, dose adjustment of Zephix® is not required.
Elderly patients
In elderly patients, the usual age-related decline in renal function does not have a clinically significant effect on lamivudine exposure, except for patients with creatinine clearance below 50 mL / min.
Children
The safety and efficacy of Zephix® in children and adolescents under the age of 18 years have not been established.

Side effects:According to clinical studies conducted with patients with chronic hepatitis B, Zephix® therapy is well tolerated. Frequency of occurrence of undesirable reactions and changes in laboratory parameters (except for increased activity of enzymes alanine aminotransferase (ALT) and creatine phosphokinase (CK)) is similar in the use of Zephix and placebo. The most common adverse reactions are general malaise and fatigue, pain and discomfort in the throat, respiratory tract infections, headache, discomfort and abdominal pain, nausea, vomiting and diarrhea.The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems and frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥ 1/10), often (≥1 / 100 and <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10,000 and < 1/1000), very rarely (<1/10 000, including individual cases).
Frequency of occurrence of undesirable reactions is established for the most part of events, the corresponding data for calculating the frequency of occurrence are not available. Very often and often occurring adverse reactions were determined from clinical studies, the background frequency of placebo was not taken into account in the calculations. Undesirable reactions during the use of the drug, revealed during post-registration studies, were classified as rare or very rare.
The incidence of adverse events in clinical trials
Immune system disorders
Rarely: angioedema.
Disturbances from the liver and bile ducts
Very often: an increase in the activity of enzymes (ALT), which is more typical for patients after completing a course of lamivudine treatment than for patients in the placebo group.However, in controlled trials involving patients with compensated liver function receiving lamivudine or placebo, there was no significant difference in the incidence of increased ALT activity, in combination with an increase in bilirubin concentration and / or signs of hepatic insufficiency. It has not been established whether the exacerbation of chronic hepatitis C is associated with lamivudine therapy or a previous underlying disease.
There were reported cases of exacerbation of hepatitis, detected primarily by increasing serum ALT activity, during and after discontinuation of lamivudine treatment. Most of the phenomena were resolved without treatment, however, in very rare cases, fatal cases were observed.
Disturbances from musculoskeletal and connective tissue
Often: increased enzyme activity (CK).
Allergic reactions
Often: skin rash, itchy skin.
Post-registration research data
In addition to the undesirable reactions established during clinical trials, post-marketing use of Zephix® has revealed the following undesirable reactions.
Violations of the blood and lymphatic system
Very rarely: thrombocytopenia.
Disturbances from musculoskeletal and connective tissue
Often: muscle disorders, including myalgia and spasms.
Very rarely: rhabdomyolysis.
In patients with HIV infection, cases of pancreatitis and peripheral neuropathy (or paresthesia) have been observed, but the association of these complications with lamivudine therapy has not been proven. There was no significant difference in the incidence of these complications in the groups of patients with chronic hepatitis B who were taking Zephix® or placebo.
In patients with HIV infection who received combined therapy with nucleoside analogs, lactic acidosis was observed, which was usually accompanied by severe hepatomegaly and fatty liver dystrophy. There are separate reports of the same adverse reactions in patients with hepatitis B with decompensated hepatic insufficiency, but there is no data to confirm the association of these complications with the use of Zephix®.

Overdose:Symptoms
Experimental studies in animals have shown,that very high doses of lamivudine do not have toxic effects. There are limited data on the long-term consequences of taking high doses of lamivudine in humans. Nevertheless, there were no fatalities, the condition of all patients was normalized. Specific signs and symptoms of lamivudine overdose were not revealed in these cases.
Treatment
In case of an overdose, it is recommended to monitor the patient's condition and conduct standard maintenance therapy. Because the lamivudine is withdrawn by dialysis, continuous hemodialysis is possible to treat an overdose of the drug, but no special studies have been performed.

Interaction:Studies of inter-drug interactions were performed only in adult patients. The probability of metabolic interaction of lamivudine with other drugs is low due to limited metabolism of lamivudine, a slight degree of binding to blood plasma proteins and excretion of the drug mainly by the kidneys in unchanged form. Most of lamivudine is excreted by active secretion (the system of transport of organic cations).Consideration should be given to the possibility of interacting with other concomitantly used drugs, in particular those whose main mechanism of excretion is active renal secretion using the organic cation transport system, for example, with trimethoprim. Other drugs (in particular, ranitidine and cimetidine) are only partially excreted by this mechanism and do not interact with lamivudine.
Drugs that are excreted primarily through active transport of organic anions or by glomerular filtration do not appear to enter into clinically significant interactions with lamivudine.
Trimethoprim + sulfamethoxazole: simultaneous application of trimethoprim + sulfamethoxazole at a dose of 160 mg + 800 mg leads to an increase in lamivudine exposure by about 40%. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. However, in the absence of renal failure, there is no need to reduce the dose of lamivudine.
Zidovudine: while simultaneous use of lamivudine and zidovudine, a moderate (by 28%) increase in C_max zidovudine, but the AUC did not change significantly. Zidovudine did not affect the pharmacokinetics of lamivudine.
Interferon-alpha: The pharmacokinetic interaction of lamivudine with interferon-alpha was not observed with the simultaneous use of these drugs. In patients who simultaneously received lamivudine and immunosuppressants (eg, ciclosporin A), clinically significant adverse interactions were not observed, however, no special studies of interactions were conducted.
Emtricitabine: with simultaneous admission lamivudine can inhibit intracellular phosphorylation of emtricitabine. therefore emtricitabine should not be used simultaneously with lamivudine. In addition, Zephix® should not be used concomitantly with other drugs containing lamivudine.
Cladribine: in vitro lamivudine inhibits intracellular phosphorylation of cladribine, which leads to a potential risk of loss of cladribine efficacy when used simultaneously in clinical settings. Some clinical data confirm the possibility of interaction between lamivudine and cladribine. Therefore, simultaneously apply lamivudine and cladribine Not recommended.

Special instructions:At the beginning and with the continuation of Zephix® treatment, the patient's condition should be monitored regularly by a physician with experience in the management of chronic hepatitis B. In patients with moderate or severe renal impairment, the AUC is increased due to reduced renal clearance, so in the treatment of patients with creatinine clearance 50 mL / min, do not use Zephix®.
Exacerbation of hepatitis B
Exacerbation of therapy
Spontaneous exacerbations of chronic hepatitis B are relatively frequent and are characterized by a transient increase in ALT activity in serum. After the initiation of antiviral therapy in some patients, the activity of ALT may increase in the serum when the concentration of HBV DNA is reduced. In patients with compensated liver disease, this increase in ALT activity in serum is usually not accompanied by an increase in serum bilirubin concentration or signs of hepatitis decompensation.
Long-term therapy revealed viral subpopulations of HBV with reduced sensitivity to lamivudine (HBV with YMDD mutation).In some patients, the appearance of HBV with a mutation of YMDD can lead to an exacerbation of hepatitis, mainly determined by increased serum ALT activity and the reoccurrence of HBV DNA. In patients with a mutation of YMDD HBV, consideration should be given to switching to or adding an alternative drug in the absence of cross-resistance to lamivudine based on therapeutic guidelines.
Exacerbation after discontinuation of therapy
Acute exacerbation of hepatitis, usually determined by increased ALT activity in the serum and the re-emergence of HBV DNA. was observed in patients who discontinued hepatitis B therapy. In controlled phase III studies with a period of observation without active therapy, the frequency of increase in ALT activity after discontinuation of therapy (more than 3 times the original value) was higher in those receiving lamivudine of patients (21%) compared with placebo-treated patients (8%). However, the proportion of patients with increased ALT activity after discontinuation of therapy in combination with an increase in bilirubin concentration was low and the same in both treatment groups. The recipients lamivudine patients, most cases of increased ALT activity after discontinuation of therapy occurred between 8 and 12 weeks after discontinuation of therapy. Most of the phenomena were resolved, but several cases with a fatal outcome were noted. When discontinuing therapy with Zephix®, periodic monitoring of patients with clinical signs and functional liver samples (ALT activity and serum bilirubin concentration) should be performed for at least four months and then for clinical reasons.
Exacerbation in patients with decompensated hepatic cirrhosis
In patients after transplantation and patients with decompensated liver cirrhosis, the risk of active replication of the virus is increased. Due to the minimal liver function in these patients, re-activation of hepatitis with discontinuation of Zephix® therapy or loss of efficacy during therapy can lead to severe decompensation or even decompensation with a fatal outcome. These patients should be monitored for clinical, virologic and serological parameters associated with hepatitis B,liver and kidney function and antiviral response during therapy (at least every month) and, in the event of discontinuation of therapy for any reason, for at least 6 months after discontinuation of therapy. Controlled laboratory parameters should include, as a minimum, ALT activity in blood serum, bilirubin concentration, albumin, blood urea nitrogen, creatinine and virologic status: HBV antigens / antibodies and HBV DNA concentration in serum if possible. In patients with signs of liver failure during or after therapy, monitoring should be performed more often, depending on the situation. Data on the positive effect of re-administration of Zephix® in patients with signs of recurrent hepatitis after therapy is not enough.
Chronic hepatitis B with delta agent or hepatitis C
The effectiveness of Zeffix® in patients with concomitant infection of chronic hepatitis B with delta agent or hepatitis C is not established. It is recommended that Zephix® should be used with caution in such patients.
Immunosuppressive therapy
Data on the use of lamivudine in HBeAg-negative (mutation in the precord zone) of patients and patients receiving concomitant immunosuppressive therapy, including chemotherapy for cancer, are limited. The drug Zephix® in these patients should be used with caution.
Monitoring
During therapy with Zephix®, patients should be monitored regularly. ALT activity and serum HBV DNA concentration should be monitored at 3-month intervals, and the HBeAg concentration in HBeAg-positive patients should be evaluated every 6 months.
Concomitant HIV infection
In the treatment of patients with concomitant HIV infection who are currently receiving or are planning to receive lamivudine or a combination of lamivudine-zidovudine, treatment should be given at the dose recommended for HIV infection (usually 150 mg twice daily in combination with other antiretroviral drugs ). In patients with concomitant HIV infection without the need for antiretroviral therapy, there is a risk of HIV mutation when using only Zephics® for the treatment of chronic hepatitis B.
Transmission of hepatitis B
Data on transmission of hepatitis B virus from mother to fetus in pregnant women receiving lamivudine therapy are not available. Standard recommended procedures for the immunization of infants for the prevention of hepatitis B should be followed.
Patients should be informed that appropriate precautions should continue to be followed, as there has been no evidence of a reduction in the risk of transmission of hepatitis B virus to others during lamivudine therapy. Interactions with other medications
Zephix® should not be taken with any other medicines containing lamivudine, or with medicinal products containing emtricitabine.
The drug Zephix® is not recommended for use in combination with cladribine. Lactoacidosis and severe hepatomegaly with fatty liver dystrophy Lactatacidosis has been reported (in the absence of hypoxemia), sometimes fatal, usually with concomitant severe hepatomegaly and fatty liver dysfunction, with the use of nucleoside analogues. Because the lamivudine is a nucleoside analogue, this risk can not be ruled out.Treatment with nucleoside analogues should be discontinued with a rapid increase in aminotransferase activity, progressive hepatomegaly, or metabolic acidosis / lactic acidosis for an unknown reason. Moderate symptoms of digestive disorders, such as nausea, vomiting and abdominal pain, may be signs of developing lactic acidosis. Severe cases, sometimes fatal, were accompanied by pancreatitis, hepatic insufficiency / fatty liver disease, renal insufficiency and elevated serum lactate concentration. Nucleoside analogues should be used with caution in all patients (especially overweight women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and fatty liver disease (including the use of certain drugs and alcohol use). Patients with concomitant hepatitis C infection taking interferon-alpha and ribavirin, can be particularly at risk. It should be especially closely monitored the health status of such patients.
Mitochondrial dysfunction
In vitro and in vivo, it has been proven that nucleoside and nucleotide analogues cause mitochondrial damage of varying severity. Mitochondrial dysfunction in children exposed to nucleoside analogues in utero and / or after birth was reported. The main undesirable reactions were hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). There are reports of late manifestations of certain neurological disorders (hypertonicity, convulsions, inadequate behavior). Neurological disorders can be either transient or permanent. Follow-up clinical and laboratory monitoring of the health of all children exposed in utero to nucleoside and nucleotide analogues should be carried out and, in case of manifestation of characteristic signs or symptoms, a complete examination should be conducted for possible mitochondrial dysfunction.

Effect on the ability to drive transp. cf. and fur:Patients should be informed of cases of malaise and fatigue during treatment with lamivudine.It is necessary to take into account the clinical status of the patient and the profile of unwanted reactions of lamivudine when assessing a patient's ability to drive vehicles and work with mechanisms.

Form release / dosage:Tablets, film-coated, 100 mg.

Packaging:For 14 tablets in a double aluminum foil blister. For 1, 2 or 6 blisters together with instructions for use in a cardboard pack.

Storage conditions:Store at a temperature not exceeding 30 ° C.
Keep out of the reach of children.

Shelf life:3 years.
Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N011613 / 01

Date of registration:24.06.2010 / 16.09.2016

Expiration Date:Unlimited

The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia

Manufacturer: & nbsp

GLAXO OPERATIONS UK, Limited United Kingdom

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp2016-11-07

Illustrated instructions

Instructions

Zeffix® (Zeffix®)