Composition, form of production and packaging
The tablets covered with a cover of yellowish-brown color, capsular, biconcave, with an engraved inscription "GX GG5" on one side of the tablet.
1 tab.
lamivudine 100 mg
Excipients: microcrystalline cellulose, sodium starch glycolate, magnesium stearate.
Composition of the coating: yellowish-brown material for coating YS-1-17307-A (hypromellose, titanium dioxide, iron oxide red (E172), iron oxide yellow (E172), macrogol 400, polysorbate 80).
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (6) - packs of cardboard.
The solution for oral administration is clear, from colorless to pale yellow, with a fruity odor.
5 ml
lamivudine 25 mg
Excipients: sucrose, methylparahydroxybenzoate, propyl parahydroxybenzoate, citric acid, propylene glycol, sodium citrate, strawberry and banana flavors, purified water.
240 ml - vials (1) complete with a dispensing syringe and adapter for a syringe - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the print edition of 2007.
PHARMACHOLOGIC EFFECT
An antiviral drug is an analog of nucleosides. Highly active against hepatitis B virus.
In both infected and uninfected cells, lamivudine is metabolized to lamivudine triphosphate, which is the active form of the drug and serves as a substrate for DNA polymerase of hepatitis B virus. The inclusion of lamivudine triphosphate in the viral DNA chain and subsequent chain termination block further formation of viral DNA.
Lamivudine triphosphate does not disrupt the normal cellular metabolism of DNA. It is also a weak inhibitor of? - and? -DNA polymerases of mammals. Lamivudine triphosphate does not significantly affect the DNA content of cells.
In lamivudine, no significant toxic effects on the structure of mitochondria, as well as on the content and function of DNA, were not detected. Lamivudine has a very weak ability to reduce the content of mitochondrial DNA, is not included in its chain and does not inhibit? -polymerase.
PHARMACOKINETICS
Suction
After oral administration, lamivudine is well absorbed from the digestive tract. Bioavailability in adults after oral administration is usually 80-85%. C max in the blood serum is achieved on average about 1 hour. When the drug is administered at therapeutic doses (100 mg 1 time / day), C max is 1.1-1.5 Ојg / ml, C min is 0.015-0.2 Ојg / ml.
Receiving Zephix together with food leads to an increase in the time to reach C max and reduce its value (up to 47%). At the same time, food intake did not affect the overall degree of absorption of lamivudine (calculated on the basis of the "concentration-time" curve).
Distribution
With IV injection of lamivudine, V d averaged 1.3 l / kg. In the therapeutic dose range, lamivudine has a linear pharmacokinetics and binds insignificantly to plasma proteins.
Lamivudine penetrates the central nervous system and into the cerebrospinal fluid. After 2-4 hours after oral administration, the ratio of the concentrations of lamivudine in the cerebrospinal fluid and serum was approximately 0.12.
Metabolism
To an insignificant extent (5-10%) is metabolized in the liver.
Excretion
The systemic clearance of lamivudine is, on average, about 0.3 l / h / kg. T 1/2 - about 5-7 hours. The majority of lamivudine is excreted unchanged by the kidneys through glomerular filtration and active secretion (organic cation transport system). The share of renal clearance accounts for about 70% of lamivudine elimination.
Pharmacokinetics in special clinical cases
In patients with renal failure, excretion of lamivudine from the body slows down. Patients with a creatinine clearance less than 50 ml / min dose Zeffix should be reduced.
Patients with hepatic insufficiency (not infected with HIV and hepatitis B virus) tolerate lamivudine well. Disturbance of liver function does not affect the pharmacokinetics of lamivudine, unless it is combined with renal insufficiency.
In elderly patients, the age-related decrease in renal function does not significantly affect the excretion of lamivudine in patients with SC greater than 50 ml / min.
In women in late pregnancy, the pharmacokinetics of lamivudine after ingestion was similar to that of non-pregnant women.
The pharmacokinetics of lamivudine in children does not differ from the pharmacokinetics in adults. However, in children, lamivudine clearance, adjusted for weight, is higher than in adults, which is reflected in a decrease in AUC. 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 recommended dose for children from 2 to 11 years of age 3 mg / kg 1 time / day (up to 100 mg / day maximum) is able to provide a lamivudine exposure comparable to the adult dose (100 mg / day). Data on the pharmacokinetics of lamivudine in children less than 2 years of age are few.
INDICATIONS
- chronic viral hepatitis B in the background of replication of the hepatitis B virus.
DOSING MODE
Zeffix taken inside regardless of the time of food intake.
Adults and children aged 12 years and older are prescribed a drug at a dose of 100 mg 1 time / day.
Children aged 2 to 11 years - 3 mg / kg 1 time / day, but not more than 100 mg / day.
For renal failure in patients with KK less than 50 ml / min dose should be reduced. The degree of dose reduction in children with kidney failure is the same as in adults. If a dose of less than 100 mg / day is required, Zeffix should be used as a solution for oral administration. The degree of dose reduction in children with kidney failure is the same as in adults.
Data on patients on hemodialysis (dialysis sessions 2-3 times a week for 4 hours or less) show that after an initial dose reduction of Zephix in accordance with QC, further dose correction is not required throughout the period of hemodialysis.
In liver failure , if it is not accompanied by renal insufficiency, no adjustment of the dose of lamivudine is required.
SIDE EFFECT
Determination of the frequency of side effects: very often -? 10%; often -? 1%, <10%; sometimes -? 0.1%, 1%; rarely -? 0.01%, <0.1%; very rarely - <0.01%.
On the part of the digestive system: discomfort and abdominal pain, nausea, vomiting, diarrhea; very often - an increase in ALT.
Increased ALT levels were more often observed after treatment with Zyfics, than after taking placebo. It should be noted, however, that in controlled clinical trials involving patients with compensated liver function, there was no significant difference between the Zephix and placebo groups in the rate of post-therapeutic, clinically significant elevation of ALT levels, accompanied by elevated bilirubin levels and / or hepatic insufficiency. The relationship between these manifestations of hepatitis recurrence with Zyphfix or with pre-existing HIV infection has not been established.
From the musculoskeletal system: often - increased CK; very rarely - muscle disorders, including myalgia and spasms.
From the hemopoietic system: very rarely - thrombocytopenia.
Other: general malaise, fatigue, headache, respiratory tract infections.
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 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, there were cases of lactic acidosis, which was usually accompanied by severe hepatomegaly and fatty liver dystrophy. There are separate reports of the same side effects in patients with hepatitis B virus and liver failure, but there is no data to confirm the association of these complications with Zyffffs.
Zeffix is ​​well tolerated by patients with chronic hepatitis B.
CONTRAINDICATIONS
- I trimester of pregnancy;
- Hypersensitivity to lamivudine and other components of the drug.
With caution should be appointed Zeffiks in renal failure, pancreatitis (including in the history), peripheral neuropathy, in the II and III trimesters of pregnancy, lactation and children under 2 years.
PREGNANCY AND LACTATION
Data on the safety of lamivudine during pregnancy is not enough.
Lamivudine penetrates the placenta. The concentration of lamivudine in the serum of newborns at the time of birth is the same as in the serum of the mother and in the blood from the umbilical cord.
The drug is contraindicated in the first trimester of pregnancy.
The use of lamivudine in pregnancy in the II and III trimesters is possible only if the expected benefit for the mother exceeds the possible risk to the fetus.
If the pregnancy occurred during treatment with Zyfiksom, then it should be borne in mind that after the drug has been discontinued, the exacerbation of hepatitis B may develop.
After oral administration, the concentration of lamivudine in breast milk is not significantly different from its concentration in serum (1 Ојg / ml). Studies conducted on animals suggest that the concentration of lamivudine in human breast milk does not have a toxic effect on children during breastfeeding.
Information on transplacental transmission of the hepatitis B virus in pregnant women receiving Zephix is ​​absent. It is recommended to conduct a standard procedure for immunization of newborns against hepatitis B.
In experimental animal studies, lamivudine showed no evidence of teratogenicity and effects on fertility. Research data on rabbits indicate a possible risk of spontaneous abortion in the early stages of pregnancy.
APPLICATION FOR FUNCTIONS OF THE LIVER
Caution should be given to Zephix in renal failure.
For renal failure in patients with KK less than 50 ml / min dose should be reduced. The degree of dose reduction in children with kidney failure is the same as in adults. If a dose of less than 100 mg / day is required, Zeffix should be used as a solution for oral administration. The degree of dose reduction in children with kidney failure is the same as in adults.
Data on patients on hemodialysis (dialysis sessions 2-3 times a week for 4 hours or less) show that after the initial reduction in the dose of Zephix in accordance with QC, further additional dose correction is not required throughout the period of hemodialysis for additional dose adjustment
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In liver failure , if it is not accompanied by renal insufficiency, no adjustment of the dose of lamivudine is required.
APPLICATION FOR CHILDREN
With caution should prescribe the drug to children under 2 years.
Children at the age of 12 and older drug prescribed in a dose of 100 mg 1 time / day.
Children aged 2 to 11 years - 3 mg / kg 1 time / day, but not more than 100 mg / day.
SPECIAL INSTRUCTIONS
Zeffix in the form of a solution for oral administration is used to treat children and those patients who can not take the drug in the form of tablets.
During treatment with Zyficsom, patients should be monitored regularly by a doctor who has experience in the management of chronic hepatitis B.
Termination of Zoeffix therapy is possible in patients with normal biochemical parameters (ALT, AST), absence of hepatitis B DNA in the blood and seroconversion of HBeAg and / or HBsAg (no earlier than 3 months after the onset of seroconversion). Zeffix can also be canceled if further treatment is ineffective (no positive dynamics for 6 months of treatment or symptoms of exacerbation of hepatitis).
With the cancellation of Zephix, patients should be under the supervision of a physician to identify symptoms of exacerbation of hepatitis.
Termination of therapy is not recommended in the presence of symptoms of liver failure. At present, there is insufficient data on the preservation of prolonged seroconversion after the discontinuation of Zephix.
After discontinuation of treatment with Zyffexum, it is necessary to periodically monitor the overall condition of patients, and monitor the indicators of functional hepatic tests (liver transaminase activity and bilirubin content) for 4 months to identify signs of possible exacerbation of hepatitis; In the future, patients should be monitored according to the indications. At present, there is no conclusive evidence of the effectiveness of repeated treatment with Zephix in those patients who developed hepatitis exacerbation after cessation of therapy.
Patients should be under medical supervision for at least 6 months after discontinuation of treatment for any reason. The condition of patients with symptoms of liver failure should be monitored more carefully.
Data on the use of lamivudine in patients receiving concomitant immunosuppressive therapy are few.
With prolonged therapy with lamivudine, subpopulations of viral hepatitis B (YMDD strain) with reduced sensitivity to it were identified. Sometimes this kind of virus can cause an exacerbation of hepatitis.
In the treatment of patients with a combination of HIV infection and hepatitis B infection who are already receiving or will receive antiretroviral therapy including lamivudine, the dose of lamivudine usually prescribed for the treatment of HIV infection should be maintained.
Patients should be warned that treatment with Zyfiksom does not reduce the risk of transmitting hepatitis B to other people, and therefore appropriate precautions should be taken.
If it is necessary to use the drug in patients with diabetes mellitus, it should be borne in mind that each dose of oral solution (100 mg / 20 ml) contains 4 g of sucrose.
Use in Pediatrics
Recommendations for determining the effective and safe dose in children younger than 2 years are currently not enough.
Impact on the ability to drive vehicles and manage mechanisms
Special studies were not conducted. Based on the pharmacological properties of lamivudine, this effect is unlikely.
OVERDOSE
Specific symptoms of lamivudine overdose have not been revealed.
There are limited data on the consequences of taking high doses of lamivudine in humans. There were no lethal outcomes, the condition of all patients was normalized.
In experimental studies, the administration of very high doses of lamivudine did not have a toxic effect on the organs.
Treatment: recommended gastric lavage, the appointment of activated charcoal, monitoring the patient's condition and conducting standard maintenance therapy. For the withdrawal of lamivudine, continuous hemodialysis is possible, but no special studies have been performed.
DRUG INTERACTION
It should be taken into account the possibility of interaction of lamivudine with other drugs, especially with such, the main mechanism of excretion of which is active renal secretion through the system of organic cation transport (trimethoprim). Simultaneous use of trimethoprim / sulfamethoxazole (160 mg / 800 mg) increases the concentration of lamivudine in blood plasma by approximately 40%. Lamivudine does not change the pharmacokinetics of trimethoprim and sulfamethoxazole (in the absence of renal failure, there is no need to reduce the dose of lamivudine). Other drugs (eg ranitidine, cimetidine) are only partially excreted by this mechanism and do not interact with lamivudine.
Preparations that are excreted primarily through the active transport of organic anions or by glomerular filtration do not appear to enter into clinically significant interactions with lamivudine.
With the simultaneous use of lamivudine and zidovudine, there is a moderate (by 28%) increase in C max of zidovudine in plasma, while the AUC does not change significantly.
There was no pharmacokinetic interaction of Zephiks with interferon alpha, as well as with immunosuppressants (for example, with cyclosporin A).
With the simultaneous administration of lamivudine and zalcitabine, lamivudine may inhibit intracellular phosphorylation of the latter (the combination is not recommended).
Simultaneous administration of didanosine, pentamidine, sulfonamides and ethanol increases the risk of developing pancreatitis.
Dapsone, didanosine, isoniazid and stavudine increase the risk of developing peripheral neuropathy.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Tablets should be stored out of the reach of children at a temperature of no higher than 30 В° C. Shelf life - 3 years.
The oral solution should be stored out of the reach of children at a temperature of no higher than 25 В° C. Shelf life - 2 years. After opening the vial, the solution can be used for 1 month.
