Epivir, 10 mg/ml 240 ml

Indications

Treatment of HIV infection as part of combination antiretroviral therapy for adults and children.

Pharmacological effect

Pharmacodynamics

Mechanism of action

Lamivudine is a highly effective selective inhibitor of HIV-1 and HIV-2 replication in vitro and is also active against zidovudine-resistant HIV strains. Inside cells, lamivudine is metabolized to 5′-triphosphate (the active form), the half-life of which from cells is 16-19 hours. Lamivudine-5′-triphosphate slightly inhibits RNA- and DNA-dependent reverse transcriptase of HIV. The main mechanism of its action is to block the synthesis of the growing DNA strand during reverse transcription of HIV. It has been shown that lamivudine has an additive or synergistic effect in relation to other antiretroviral drugs, primarily zidovudine, inhibiting HIV replication in cell culture.

Lamivudine does not disrupt normal cellular DNA metabolism and does not have a significant effect on the content of nuclear and mitochondrial DNA in mammalian cells.

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

Pharmacodynamic effects

One of the reasons for the development of HIV-1 resistance to lamivudine is the appearance of an amino acid substitution in the 184th codon (M184V) of the viral genome, which is located near the active center of HIV reverse transcriptase. HIV-1 strains with M184V mutations can appear both in vitro and in the body of patients receiving combination antiretroviral therapy, including lamivudine. Such virus strains are characterized by reduced sensitivity to lamivudine and poor ability to replicate in vitro. in vitro, HIV strains resistant to zidovudine may become sensitive to it if they simultaneously develop resistance to lamivudine. The clinical significance of this phenomenon has not been established.

The M184V mutation leads to cross-resistance of HIV only to drugs from the group of nucleoside reverse transcriptase inhibitors. Zidovudine and stavudine retain their activity against HIV-1 strains resistant to lamivudine. Abacavir retains antiretroviral activity against lamivudine-resistant strains of HIV-1 that have only the M184V mutation. In HIV strains with M184V mutations, no more than a 4-fold decrease in sensitivity to didanosine and zalcitabine is determined; the clinical significance of this phenomenon has not been established. In vitro tests for HIV susceptibility to various antiretroviral drugs have not been standardized and therefore their results may be influenced by various methodological factors.

According to clinical studies, the use of lamivudine in combination with zidovudine reduces the HIV-1 viral load in the blood and increases the content of CD4+ lymphocytes. It has been established that lamivudine in combination with zidovudine or with zidovudine and other drugs significantly reduces the risk of progression of HIV infection and death. HIV strains isolated from patients receiving lamivudine showed decreased sensitivity to lamivudine in vitro.

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 nucleoside reverse transcriptase inhibitors or drugs from other groups (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).

Combination antiretroviral therapy, including lamivudine, has been shown to be effective both in “naive” patients and in patients with HIV strains with the M184V mutation.

Additional studies are required to establish the relationship between the sensitivity of HIV to lamivudine in vitro and the clinical effect of therapy.

Pharmacokinetics

Suction

Lamivudine is well absorbed from the gastrointestinal tract. The bioavailability of lamivudine in adults after oral administration is usually 80-85%. The mean time (tmax) to achieve maximum concentrations (Cmax) of lamivudine in serum is about 1 hour. When lamivudine is prescribed in therapeutic doses (4 mg/kg/day in 2 doses with an interval of 12 hours), Cmax is 1-1.9 mcg/ml.
Taking lamivudine with food caused an increase in tmax and a decrease in Cmax (up to 47%), but did not affect the overall extent of absorption (calculated based on the pharmacokinetic concentration-time curve). Therefore, no dose adjustment is required when taking lamivudine with food.

Distribution and binding to plasma proteins

With intravenous administration of lamivudine, the volume of distribution averages 1.3 l/kg, and the half-life is 5-7 hours.
In the therapeutic dose range, lamivudine has linear pharmacokinetics and is slightly bound to plasma proteins.
It has been established that lamivudine penetrates into the central nervous system (CNS) and into the cerebrospinal fluid. 2-4 hours after oral administration, the ratio of lamivudine concentrations in cerebrospinal fluid and serum was approximately 0.12.

Metabolism and excretion

The average systemic clearance of lamivudine is approximately 0.32 l/h*kg. Lamivudine is excreted primarily by the kidneys (more than 70%) through active tubular secretion (organic cation transport system), as well as through metabolism in the liver (less than 10%).
The active form of lamivudine, intracellular lamivudine triphosphate, has a longer cellular half-life (16-19 hours) compared to its plasma half-life (5-7 hours).

There is evidence that the pharmacokinetic parameters of lamivudine when taken at a dose of 300 mg 1 time per day at steady state are equivalent to those when taken at a dose of 150 mg 2 times per day in terms of the area under the concentration-time pharmacokinetic curve over 24 hours (AUC24) and Cmax for intracellular triphosphate.
The likelihood of adverse interactions of lamivudine with other drugs is very low due to limited metabolism in the liver, low degree of binding to plasma proteins and almost complete excretion of lamivudine unchanged by the kidneys.

Special patient groups

Children
In general, the pharmacokinetics of lamivudine in children are similar to those in adults. However, the absolute bioavailability of the oral solution in children under 12 years of age was lower and more variable (approximately 55–65%). Systemic clearance rates are higher in children of the younger age group and decrease with age, reaching the level of adult patients by 12 years. Pharmacokinetic studies of both liquid and tablet forms of the drug in children based on AUC0-24 indicators have proven that the once-daily dosing regimen is equivalent to the twice-daily dosing regimen. When taken at recommended doses, average AUC0-24 values ​​reached approximately 7.1-13.7 mcg*h/ml, which is comparable to AUC0-24 values ​​in adults when taken once daily

Data on the pharmacokinetics of the drug in children under 3 months of age are limited. In newborns in the first week of life, the clearance of lamivudine when taken orally is reduced compared to other age categories due to the immaturity of the excretory function of the kidneys and the variability of absorption rates. Thus, to achieve the same effect in adults and children, the recommended dose for newborns is 2 mg/kg 2 times a day. There are no data on the use of the drug in newborns older than 1 week.

Elderly patients
There are no data on the pharmacokinetics of lamivudine in patients over 65 years of age.

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

Patients with liver dysfunction
Data from the use of lamivudine in patients with moderate to severe hepatic impairment indicate that impaired liver function does not significantly affect the pharmacokinetics of lamivudine.

Pregnancy
The pharmacokinetics of lamivudine in pregnant women does not differ from the pharmacokinetics in adults. Studies have shown that lamivudine crosses the placenta. The concentration of lamivudine in the serum of newborns at the time of birth is the same as the concentration in maternal serum and in umbilical cord blood.

Special instructions

Treatment with Epivir, oral solution, should be administered by a physician experienced in the care of patients with HIV infection.
In children under 3 years of age, the use of tablet dosage forms is not recommended, therefore, for the treatment of children and those patients who have difficulty swallowing tablets, the dosage form is an oral solution.
Patients should be warned that treatment with antiretroviral drugs, including lamivudine, does not prevent the risk of transmitting HIV to others through sexual contact or blood transfusion. Therefore, patients should take appropriate precautions.

Patients receiving lamivudine or other antiretroviral drugs may develop opportunistic infections or other complications and should be closely monitored by a physician experienced in treating HIV infection.

Renal dysfunction

In patients with moderate to severe renal impairment, the plasma concentration of lamivudine is increased due to decreased clearance of the drug, so dose adjustment is required.

Pancreatitis

There have been several cases of pancreatitis in patients receiving lamivudine. However, it remains unclear whether this complication is caused by lamivudine or by HIV infection itself. If abdominal pain, nausea, vomiting, or characteristic changes in biochemical parameters occur in a patient receiving lamivudine, pancreatitis should be excluded. The drug should be suspended until the diagnosis of pancreatitis is excluded.

Lactic acidosis/severe hepatomegaly with fatty liver

In HIV-infected patients (mainly women) taking antiretroviral drugs from the group of nucleoside analogues as monotherapy or in combination with lamivudine, cases of lactic acidosis have been described, which is usually accompanied by severe hepatomegaly and fatty liver, including death.

Symptoms that may indicate the development of lactic acidosis include: general weakness, loss of appetite, sudden unexplained weight loss, gastrointestinal and respiratory problems (shortness of breath and rapid breathing).
Treatment with lamivudine always requires caution, especially if the patient has risk factors for developing liver disease. If clinical or laboratory signs of lactic acidosis or liver dysfunction (including hepatomegaly and fatty liver disease, even in the absence of a marked increase in liver transaminases), lamivudine should be discontinued.

Redistribution of subcutaneous fat tissue

In some patients, combination antiretroviral therapy may be accompanied by redistribution/accumulation of subcutaneous fat, incl. a decrease in the amount of peripheral fatty tissue and an increase in visceral fat, weight loss of the limbs and face, enlargement of the mammary/breast glands and fat deposition along the back of the neck and in the interscapular region of the back (“buffalo hump”), as well as an increase in serum lipid concentrations and blood glucose levels.

Although all drugs in the protease inhibitor and nucleoside reverse transcriptase inhibitor classes can cause one or more of the adverse reactions listed above associated with a common syndrome often called lipodystrophy, accumulating evidence suggests that there are differences among individual members of these drug classes in the ability to cause these adverse reactions.
It should also be noted that lipodystrophy syndrome has a multifactorial etiology: for example, the stage of HIV infection, advanced age and duration of antiretroviral therapy play an important, possibly synergistic role in the development of this complication.
The long-term consequences of these adverse reactions have not yet been established.

Clinical examination of patients should include assessment of physical signs of fat redistribution. Serum lipid concentrations and blood glucose concentrations should also be measured. Lipid metabolism disorders must be corrected based on their clinical manifestations.

Immune reconstitution syndrome

In HIV-infected patients with severe immunodeficiency, during the initiation of antiretroviral therapy, an exacerbation of the inflammatory process due to asymptomatic or indolent opportunistic infection is possible, which can cause serious deterioration of the condition or aggravation of symptoms. Typically, such reactions were observed in the first weeks or months after starting ART. The most significant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infection, and Pneumocystis pneumonia. Any symptoms of inflammation must be immediately identified and treatment initiated without delay.

Mixed infection caused by HIV and hepatitis B virus

In some patients with chronic hepatitis B, after discontinuation of lamivudine, clinical or laboratory signs of relapse of hepatitis may appear, which can have serious consequences if liver function decompensates. After completion of lamivudine therapy in patients co-infected with HIV and hepatitis B virus, it is necessary to monitor biochemical indicators of liver function and markers of hepatitis B virus replication.

Diabetes mellitus

When prescribing an oral solution in patients with concomitant diabetes mellitus, it must be remembered that the recommended dose for adults contains 3 g of sucrose.

Prevention after possible HIV infection

According to international recommendations (Center for Disease Control, June 1998), if infection is likely through the blood of an HIV-infected person (for example, through an injection needle), it is necessary to urgently (within 1-2 hours from the moment of infection) prescribe combination therapy with zidovudine and lamivudine. In case of a high risk of infection, a drug from the group of protease inhibitors should be included in the antiretroviral therapy regimen. Prophylactic treatment is recommended for 4 weeks. There is insufficient data on the effectiveness of preventive treatment after accidental HIV infection; no controlled studies have been conducted. Despite the rapid initiation of treatment with antiretroviral drugs, the possibility of seroconversion cannot be excluded.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

No specific studies have been conducted on the effect of lamivudine on the ability to drive a car/use machines. However, based on the pharmacological properties of lamivudine, such an effect is unlikely. However, when assessing the ability to drive a car/machines, the general condition of the patient should be taken into account, as well as the nature of the adverse reactions of lamivudine.

Active ingredient

Lamivudine

Composition

1 ml of oral solution contains:

active ingredient:

lamivudine 10 mg,

excipients:

sucrose; methyl and propyl parahydroxybenzoate;

citric acid (anhydrous);

propylene glycol;

sodium citrate;

purified water;

aromatic additives.

Pregnancy

Pregnancy

There is currently insufficient data on the safety of lamivudine during pregnancy. Lamivudine should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. Although results from animal experiments cannot always be extrapolated to humans, data from studies in rabbits suggest a possible risk of spontaneous abortion in early pregnancy.

In newborns and children under 1 year of age, whose mothers took drugs from the group of nucleoside reverse transcriptase inhibitors during pregnancy and childbirth, cases of a slight transient increase in the concentration of lactic acid in the serum, apparently due to mitochondrial dysfunction, have been described. The clinical significance of transient increases in serum lactic acid concentrations has not been established. In addition, very rare cases of developmental delay, seizures and other neurological disorders have been reported. However, the connection of these complications with the use of nucleoside reverse transcriptase inhibitors during pregnancy and their effect on postnatal development has not been proven. Therefore, HIV-infected women are recommended to take antiretroviral drugs during pregnancy to prevent vertical transmission of HIV.

Lactation

According to experts, all HIV-infected women should avoid breastfeeding if possible to avoid transmitting the virus to their baby through breast milk. After oral administration, lamivudine is excreted in breast milk; Moreover, its concentration in breast milk is practically no different from its concentration in serum (1-8 μg/ml). Women taking lamivudine are not recommended to breastfeed.

Contraindications

Hypersensitivity to lamivudine or any other component of Epivir. Age less than 3 months due to the fact that data on the use of the drug in this age group are limited.

With caution

Should be used with caution in patients with renal failure; pancreatitis (including a history); peripheral neuropathy; during pregnancy and lactation.

Side Effects

Headache,
weakness,
fatigue,
fever, chills,
dizziness,
insomnia,
depressive disorders,
neuropathy,
nausea,
diarrhea,
vomit,
decreased appetite,
anorexia,
dyspepsia,
pain or cramps in the abdomen,
runny nose,
cough,
musculoskeletal pain,
myalgia,
arthralgia,
neutropenia,
anemia,
thrombocytopenia,
increased levels of ALT, AST, bilirubin, amylase,
skin rashes;
in children – pancreatitis, paresthesia, peripheral neuropathies.

Interaction

The likelihood of metabolic interaction of lamivudine with other drugs is extremely low, since lamivudine is very poorly metabolized, is slightly bound to plasma proteins and is excreted primarily unchanged by the kidneys.
Lamivudine is excreted from the body primarily by active tubular secretion through the organic cation transport system. The possibility of interaction of lamivudine with drugs that have the same elimination mechanism, for example trimethoprim, should be taken into account. Other drugs (eg ranitidine, cimetidine) are only partially eliminated by this mechanism and do not interact with lamivudine.

Drugs that are primarily eliminated by active renal secretion via the organic anion transport system or by glomerular filtration do not appear to have clinically significant interactions with lamivudine.

Zidovudine. With simultaneous use of lamivudine and zidovudine, a moderate (28%) increase in the Cmax of zidovudine in plasma is observed, while the AUC does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Trimethoprim/sulfamethoxazole. Concomitant use of trimethoprim/sulfamethoxazole at a dose of 160/800 mg (co-trimoxazole) increases the plasma concentration of lamivudine by approximately 40% (due to interaction with trimethoprim). However, in the absence of renal dysfunction, a dose reduction of lamivudine is not required. Lamivudine does not affect the pharmacokinetics of trimethoprim and sulfamethoxazole. The interaction of lamivudine with high doses of co-trimoxazole, prescribed for the treatment of Pneumocystis pneumonia and toxoplasmosis, has not been studied.

Zalcitabine. When administered concomitantly with lamivudine and zalcitabine, lamivudine may inhibit intracellular phosphorylation of the latter. In this regard, this combination of drugs is not recommended.

Overdose

Symptoms: There are limited data on the effects of acute overdose of lamivudine in humans. There were no deaths; the condition of all patients returned to normal. There were no specific signs or symptoms of lamivudine overdose.

Treatment: it is recommended to monitor the patient’s condition and carry out standard supportive therapy if necessary. Since lamivudine is eliminated from the body by dialysis, continuous hemodialysis may be used, but no specific studies have been conducted.

Storage conditions

At a temperature not exceeding 25 °C.

Shelf life

2 years.

Manufacturer

Bora Pharmaceutical Services Inc., Canada