Lamivudine Canon, 150 mg 60 pcs

ATX code: J05AF05.

Pharmacological properties

Pharmacodynamics

. Mechanism of action

Lamivudine is a potent selective inhibitor of HIV-1 and HIV-2 replication in vitro. Lamivudine is also active against zidovudine-resistant strains of HIV. Inside cells, lamivudine is metabolized to 5′-triphosphate (active form), which has a half-life of 16-19 hours. Lamivudine-5′-triphosphate slightly inhibits RNA- and DNA-dependent reverse transcriptase (RT) of HIV. The main mechanism of action of lamivudine is to block the synthesis of the growing DNA chain during HIV reverse transcription. No in vitro antagonistic effects were observed with concomitant use of lamivudine and other antiretroviral drugs (tested substances: abacavir, didanosine, nevirapine, zalcitabine and zidovudine). Lamivudine does not disrupt normal cellular DNA metabolism and has no significant effect on nuclear and mitochondrial DNA content in mammalian cells.

In in vitro studies lamivudine has a weak cytotoxic effect on lymphocytes of peripheral blood as well as on lymphocytic and monocytic-macrophage cell lines and several other bone marrow stem cells. Thus, in vitro lamivudine has a broad therapeutic index.

Pharmacodynamic Effects

The HIV-1 resistance to lamivudine is due to a mutation in the M184V codon located close to the active center of the viral OT. This mutation has been observed both in in vitro and in HIV-1-infected patients who have been treated with combination therapy that includes lamivudine. A mutation in the M184V codon significantly reduces sensitivity to lamivudine and significantly decreases the ability of the virus to replicate according to in vitro studies. In vitro studies have shown that zidovudine-resistant virus isolates can become susceptible to its action if these isolates develop lamivudine resistance at the same time. However, the clinical significance of such changes has not yet been conclusively determined.

The M184V mutation leads to cross-resistance of HIV only to drugs from the group of nucleoside reverse transcriptase inhibitors (NRTIs). Zidovudine and stavudine retain their activity against lamivudine-resistant HIV-1 strains. Abacavir retains antiretroviral activity against HIV-1 strains with the M184V mutation that are resistant to lamivudine. HIV strains with M184V mutations have no more than a 4-fold decrease in sensitivity to didanosine and zalcitabine; the clinical significance of these phenomena has not been established. In vitro HIV sensitivity tests for various antiretroviral drugs have not been standardized, so results may be influenced by various methodological factors. In clinical studies, the use of a combination of lamivudine and zidovudine resulted in a decrease in HIV-1 in the blood and an increase in CD4+ cells. According to clinical studies, lamivudine in combination with zidovudine or with zidovudine and other drugs was found to significantly reduce the risk of progression of HIV infection and death. HIV strains isolated from patients who received lamivudine had reduced sensitivity to lamivudine in vitro.

The results of clinical studies have shown that combination therapy with lamivudine and zidovudine in patients who have not previously received antiretroviral therapy delays the emergence of zidovudine-resistant HIV strains. Lamivudine is widely used as a component of combination antiretroviral therapy in combination with other NRTIs or drugs from other groups (protease inhibitors, nucleoside reverse transcriptase inhibitors).

Combination antiretroviral therapy including lamivudine has been shown to be effective against strains of HIV with mutations in the M184V codon, as well as in patients who have not previously received antiretroviral therapy.

The relationship between HIV sensitivity to lamivudine in vitro and the clinical effect of therapy is being studied.

Pharmacokinetics

Intake

Lamivudine is well absorbed from the gastrointestinal tract. The bioavailability of lamivudine in adults after oral administration is usually 80-85%. After oral administration, the average time (tmax) to reach the maximum serum concentrations (Cmax) of lamivudine is about 1 hour. When lamivudine is administered in therapeutic doses (4 mg/kg/day in 2 doses with an interval of 12 hours), Cmax is 1-1.9 mcg/ml.

Eating lamivudine with food causes an increase in tmax and a decrease in Cmax (up to 47%), but has no effect on overall absorption (calculated on the basis of AUC – area under the pharmacokinetic curve “concentration-time”). Therefore, no dose adjustment is required when taking lamivudine with food.

Chopping the tablets and taking them with a small amount of semi-solid food or liquid does not change the pharmacological properties of the drug, so no change in the clinical effect should be expected. These conclusions are based on the physicochemical and pharmacokinetic characteristics of the active ingredient and the in vitro dissolution data of lamivudine tablets in water, assuming that the patient immediately takes 100% of the crushed tablet.

The intake of 150 mg of lamivudine twice daily is bioequivalent to the intake of 300 mg once daily in terms of AUC∞, Cmax, tmax values. In adults taking the drug in tablet form and in the form of oral solution is bioequivalent to the values of AUC∞ and Cmax.

Differences in absorption between adult patients and children were observed.

Distribution and binding to plasma proteins

In intravenous administration of lamivudine, the volume of distribution averages 1.3 L/kg and the half-life averages 5-7 hours.

Lamivudine has linear pharmacokinetics when used in therapeutic doses and has limited binding to plasma albumin (in in vitro studies 16-36% of the drug was bound to serum albumin).

Lamivudine has been found to penetrate into the central nervous system (CNS) and cerebrospinal fluid. Two to four hours after oral administration, the ratio of lamivudine concentrations in CSF to serum was approximately 0.12. The true degree of penetration as well as the relationship to clinical efficacy is unknown.

Metabolism and excretion

The average systemic clearance of lamivudine is approximately 0.32 L/kg/h. Lamivudine is excreted primarily by the kidneys (over 70%) through active tubular secretion (organic cation transport system) and slightly through metabolism in the liver (less than 10%).

The active form of lamivudine, intracellular lamivudine triphosphate has a longer elimination half-life from cells (16-19 hours) compared to its elimination half-life from blood plasma (5-7 hours). According to the data received from 60 healthy volunteers, pharmacokinetic parameters of lamivudine at a dose of 300 mg once daily at equilibrium are equivalent to those of lamivudine triphosphate at a dose of 150 mg twice daily on AUC24 and Cmax values for lamivudine triphosphate.

The likelihood of adverse interactions of lamivudine with other drugs is very low due to limited metabolism, low degree of binding to plasma proteins and almost complete renal excretion of lamivudine unchanged.

Particular patient groups

Children

The absolute bioavailability of lamivudine (approximately 58 – 66%) was lower and more variable in children younger than 12 years.

Pharmacokinetic studies of lamivudine in oral solution and film-coated tablets in children showed that taking the drug once daily was equivalent in AUC0-24 to taking the drug twice daily at the same total daily dose.

There are insufficient data on pharmacokinetics of the drug in children younger than 3 months of age. In neonates in the first week of life, due to immature renal excretory function and variable absorption rates, clearance of lamivudine when taken orally is reduced compared to older children. Thus, to achieve the same effect in adults and children, the recommended dose for neonates is 2 mg/kg 2 times per day. There are no data on the use of the drug in infants older than 1 week.

In children, higher AUC∞ and Cmax values of lamivudine in blood plasma were obtained when taking the drug in tablet form compared to the values obtained when taking the drug in oral solution form. In children who received lamivudine as an oral solution according to the recommended dosing regimen, plasma lamivudine exposure was within the range obtained in adults.

In children who received lamivudine in tablet form according to the recommended dosing regimen, plasma lamivudine exposure was higher than in children who received lamivudine in oral solution form, because patients in tablet form receive higher doses per mg/kg body weight and lamivudine in tablet form has a higher bioavailability.

Patients in the elderly

There are no data on the pharmacokinetics of lamivudine in patients older than 65 years.

Patients with impaired renal function

In patients with impaired renal function the concentration of lamivudine in plasma is increased because its elimination from the body is delayed. In patients with creatinine clearance less than 50 ml/min, the dose of lamivudine should be reduced.

Patients with hepatic impairment

The data on the use of lamivudine in patients with moderate to severe hepatic impairment indicate that hepatic impairment does not significantly affect the pharmacokinetics of lamivudine.

Indications

HIV infection, HepatitisTreatment of HIV infection as part of combined antiretroviral therapy for adults and pediatric patients.

Active ingredient

Lamivudine

Composition

Composition per tablet:

the active ingredient:

Lamivudine 150 mg;

auxiliary substances:

sodium carboxymethyl starch 12.5 mg,

corn starch pregelatinized 33 mg,

magnesium stearate – 3.3 mg,

povidone K-30 5 mg,

microcrystalline cellulose – 126.2 mg.

film coating:

Opadray II white – 10 mg, including: polyvinyl alcohol 4.69 mg, macrogol (polyethylene glycol) – 2.36 mg, talc – 1.74 mg, titanium dioxide – 1.21 mg.