Epivir, vials 10mg/ml, 240ml

Composition

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1 ml of the 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.

Pharmacological action

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 (active form), which has a half-life from cells of 16-19 hours. Lamivudine-5’ – triphosphate slightly inhibits HIV RNA and DNA-dependent reverse transcriptase. The main mechanism of its action is blocking the synthesis of the growing DNA chain in the process of reverse transcription of HIV. Lamivudine has been shown to have an additive or synergistic effect in relation to other antiretroviral drugs, primarily zidovudine, inhibiting HIV replication in cell culture.

Lamivudine does not interfere with normal cellular DNA metabolism and does not significantly affect the content of nuclear and mitochondrial DNA in mammalian cells.

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

Pharmacodynamic effects

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

M184V mutations lead to HIV cross-resistance only to drugs from the group of nucleoside reverse transcriptase inhibitors. Zidovudine and stavudine remain active against lamivudine-resistant HIV-1 strains. Abacavir retains anti-retroviral activity against lamivudine-resistant HIV-1 strains with only the M 184V mutation. In HIV strains with M184V mutations, no more than a 4-fold decrease in sensitivity to didanosine and salzitabine is determined; the clinical significance of this phenomenon has not been established. Tests for HIV sensitivity to various antiretroviral drugs in vitro 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 viral load of HIV-1 in the blood and increases the content of CD4+ lymphocytes. Lamivudine in combination with zidovudine or with zidovudine and other drugs significantly reduces the risk of HIV infection progression and death. HIV strains isolated from patients treated with lamivudine showed a decrease in 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).

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

More research is needed to establish the relationship between HIV sensitivity 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 use is usually 80-85%. The average time (tmax) to reach the 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), the 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 degree of absorption (calculated on the basis of the pharmacokinetic curve “concentration-time”). Therefore, when taking lamivudine with food, no dose adjustment is required.

Distribution and binding to plasma proteins

With intravenous use 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 binds to plasma proteins to a small extent. Lamivudine has been shown to penetrate the central nervous system (CNS) and the cerebrospinal fluid. 2-4 hours after oral use, the ratio of concentrations of lamivudine in the cerebrospinal fluid and serum was approximately 0.12.

Metabolism and elimination

On average, the systemic clearance of lamivudine is approximately 0.32 l / h * kg. Lamivudine is mainly excreted by the kidneys (more than 70%) by active tubular secretion (organic cation transport system), as well as by liver metabolism (less than 10%). The active form of lamivudine, intracellular lamivudine triphosphate, has a longer half-life from cells (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 once a day at steady state are equivalent to those when taken at a dose of 150 mg twice a day in terms of the area under the pharmacokinetic curve “concentration-time” for 24 hours (AUC24) and Cmax for intracellular triphosphate. The likelihood of an adverse interaction of lamivudine with other drugs is very low due to limited metabolism in the liver, a slight degree of binding to plasma proteins, and almost complete elimination of lamivudine by the kidneys in unchanged form.

Special patient groups

Overall, 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%). Indicators of systemic clearance are higher in children of the younger age group and decrease with age, reaching the level of adult patients by 12 years of age. Pharmacokinetic studies of both the liquid and tablet forms of the drug in children according to AUC0-24 indicators proved that the dosage regimen 1 time per day is equivalent to the dosage regimen 2 times a day. When taken at the recommended doses, the average AUC0-24 values reached approximately 7.1-13.7 mcg * h / ml, which is comparable to the AUC0-24 values in adults when taken once a day

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 oral clearance of lamivudine is reduced compared to other age categories due to immaturity of the excretory function of the kidneys and inconsistent absorption indicators. 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 patients with impaired renal function have an increased plasma concentration of lamivudine, as its elimination from the body is slowed down. Patients with creatinine clearance less than 50 ml / min should reduce the dose of the drug.

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

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

Indications

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

Use during pregnancy and lactation

Pregnancy

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

In newborns and children under the age of 1 year, 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 serum, apparently due to mitochondrial dysfunction, have been described.The clinical significance of a temporary increase in the concentration of lactic acid in serum has not been established. In addition, very rare cases of developmental delay, convulsive syndrome, and other neurological disorders have been reported. However, the association of these complications with the use of nucleoside reverse transcriptase inhibitors during pregnancy and their effect on postnatal development have not been proven. Therefore, it is recommended that HIV-infected women take antiretroviral drugs during pregnancy to prevent vertical transmission of HIV.

Lactation

According to experts, all HIV-infected women should stop breastfeeding whenever possible to avoid transmission of the virus to the child through breast milk. After oral use, lamivudine is excreted in breast milk; however, its concentration in breast milk practically does not differ from its concentration in serum (1-8 mcg/ml). Women taking lamivudine are not recommended to breastfeed their baby.

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

It should be used with caution in patients with renal insufficiency; pancreatitis (including in the anamnesis); peripheral neuropathy; during pregnancy and lactation.

Side effects

• Headache,
• weakness,
• fatigue,
• fever, chills,
• dizziness,
• insomnia,
• depressive disorders,
• neuropathy,
• nausea,
• diarrhea,
• vomiting,
• loss of appetite,
• anorexia,
• dyspepsia,
• pain or abdominal cramps,
• runny nose,
• cough,
• musculoskeletal pain,
• myalgia,
• arthralgia,
• neutropenia,
• anemia,
• thrombocytopenia,
• increased levels of ALT, AST, bilirubin, amylase,
• skin rash;
• in children, pancreatitis, paresthesia, peripheral neuropathy.

Interaction

The probability of a metabolic interaction of lamivudine with other drugs is extremely low, since lamivudine is very poorly metabolized, binds to plasma proteins to a small extent, and is mainly excreted unchanged by the kidneys. Lamivudine is eliminated from the body mainly by active tubular secretion through the organic cation transport system. The possibility of interaction of lamivudine with drugs that have the same mechanism of elimination, such as trimethoprim, should be considered. Other drugs (for example, ranitidine, cimetidine) are only partially eliminated by this mechanism and do not interact with lamivudine.

Drugs that are primarily excreted by active renal secretion through the organic anion transport system or through 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 Cmax of zidovudine in plasma is observed, while AUC does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Trimethoprim / sulfamethoxazole. Simultaneous use of trimethoprim / sulfamethoxazole at a dose of 160/800 mg (co-trimoxazole) increases the concentration of lamivudine in blood plasma by approximately 40% (due to interaction with trimethoprim). However, in the absence of impaired renal function, no dose reduction of lamivudine is 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.

Salzitabine. When lamivudine and salzitabine are co-administered, lamivudine may inhibit intracellular phosphorylation of the latter. In this regard, this combination of drugs is not recommended.

How to take, course of use and dosage

Treatment with Epivir, an oral solution, should be carried out by a doctor who has experience in managing patients with HIV infection. The drug Epivir, a solution for oral use, can be taken regardless of food intake. Epivir, an oral solution, is not intended as a monotherapy preparation. The drug Epivir, an oral solution, is intended for children and patients who find it difficult to swallow tablets.

Adults and adolescents with a body weight of at least 30 kg

The recommended daily dose of lamivudine is 300 mg (30 ml), which can be divided into 2 doses of 150 mg (15 ml) or taken in a single dose of 300 mg (30 ml).

Overdose

Symptoms: There are few data on the effects of acute lamivudine overdose in humans. There were no fatal outcomes, and 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, if necessary, conduct standard maintenance therapy. Since lamivudine is eliminated from the body by dialysis, continuous hemodialysis is possible, but no specific studies have been conducted.

Special instructions

Treatment with Epivir, a solution for oral use, should be carried out by a doctor who has experience in managing patients with HIV infection. In children under 3 years of age, the use of tablet dosage forms is not recommended, so for the treatment of children and those patients who find it difficult to swallow tablets, the dosage form is intended for oral use. Patients should be warned that treatment with antiretroviral drugs, including lamivudine, does not prevent the risk of HIV transmission to other people through sexual contact or blood transfusions. Therefore, patients should take appropriate precautions.

Patients receiving lamivudine or other antiretroviral drugs may develop opportunistic infections or other complications, so they should be closely monitored by a doctor with experience in treating HIV infection.

Impaired renal function

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

Pancreatitis

Several cases of pancreatitis have been reported in patients treated with 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. You should stop taking the drug until the diagnosis of pancreatitis is excluded.

Lactic acidosis / severe hepatomegaly with fatty liver disease

Cases of lactic acidosis, which was usually accompanied by severe hepatomegaly and fatty liver disease, including fatal outcomes, have been reported in HIV-infected patients (mainly women) who took antiretroviral drugs from the group of nucleoside analogues as monotherapy or in combination with lamivudine.

Symptoms that may indicate the development of lactic acidosis include: general weakness, loss of appetite, sudden unexplained weight loss, disorders of the gastrointestinal tract and respiratory system (shortness of breath and rapid breathing). Lamivudine treatment always requires caution, especially if the patient has risk factors for developing liver disease. In case of clinical or laboratory signs of lactic acidosis or impaired liver function (including hepatomegaly and fatty liver dystopia, even in the absence of a significant increase in the level of hepatic transaminases), lamivudine should be discontinued.

Redistribution of subcutaneous fat

In some patients, combined antiretroviral therapy may be accompanied by a redistribution / accumulation of subcutaneous fat, including a decrease in the amount of peripheral fat and an increase in visceral fat, weight loss of the limbs and face, an increase in 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 lipids and blood glucose levels.

Although all drugs from the classes of protease inhibitors and nucleoside reverse transcriptase inhibitors can cause one or more of the above-mentioned adverse reactions associated with the general syndrome, often referred to as lipodystrophy, accumulated data indicate that there are differences between individual representatives 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, old 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 are currently unknown.

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

Immune recovery syndrome

In HIV-infected patients with severe immunodeficiency, an exacerbation of the inflammatory process caused by an asymptomatic or slow-moving opportunistic infection may occur during the initiation of antiretroviral therapy, which may cause a serious deterioration of the condition or aggravation of symptoms.As a rule, such reactions were observed in the first weeks or months after the start of ART. The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection, and pneumocystis pneumonia. Any symptoms of inflammation should be identified immediately and treatment should be started immediately.

Mixed infection caused by HIV and hepatitis B virus

Some patients with chronic hepatitis B may develop clinical or laboratory signs of hepatitis recurrence after discontinuation of lamivudine, which can have severe consequences in case of decompensation of liver function. After the end of lamivudine therapy in patients with co-infection caused by HIV and hepatitis B virus, it is necessary to monitor the biochemical parameters of liver function and markers of hepatitis B virus replication.

Diabetes mellitus

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

Prevention after a likely HIV infection

According to international guidelines (Center for Disease Control, June 1998), in case of probable infection 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 a combination therapy with zidovudine and lamivudine. If there is a high risk of infection, a drug from the protease inhibitor group should be included in the antiretroviral therapy regimen. Preventive treatment is recommended for 4 weeks. Data on the effectiveness of preventive treatment after accidental HIV infection are insufficient; no controlled studies have been conducted. Despite the rapid start of treatment with antiretroviral drugs, the possibility of seroconversion cannot be excluded.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

Special studies of the effect of lamivudine on the ability to drive a car / mechanisms have not been conducted. However, based on the pharmacological properties of lamivudine, such an effect is unlikely. However, the general condition of the patient and the nature of lamivudine adverse reactions should be taken into account when evaluating the ability to drive a car / machinery.

Form of production

Solution for oral use.

Storage conditions

At a temperature not exceeding 25 °C.

Shelf

life is 2 years.

Active ingredient

Lamivudine

Conditions of release from pharmacies

By prescription

Dosage form

solution for topical application

Indications

HIV infection