lamivudine | Epivir vials of 10 mg / ml, 240 ml

Release form

oral solution

Pharmacological action of

Pharmacodynamics of

Mechanism of action of

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

Pharmacodynamic effects of

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 strains of the virus are characterized by reduced sensitivity to lamivudine and poor ability to replicate in vitro. in vitro HIV strains resistant to zidovudine may become susceptible to it if resistance to lamivudine develops simultaneously. The clinical significance of this phenomenon has not been established.

M184V mutations result in 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 having 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. Tests for the sensitivity of HIV to various in vitro antiretroviral drugs have not been standardized, and therefore various methodological factors may influence their results.

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. It has been established that lamivudine in combination with zidovudine or with zidovudine and other drugs significantly reduces the risk of HIV infection progression and death. In HIV strains isolated from patients receiving lamivudine, there was 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 appearance of zidovudine-resistant strains of HIV. 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 in both “naive” patients and patients with HIV strains with the M184V mutation.

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

Pharmacokinetics

Absorption

Lamivudine is well absorbed from the gastrointestinal tract. The bioavailability of lamivudine in adults after oral administration is usually 80–85%. The average time (tmax) to reach maximum serum lamivudine concentrations (Cmax) is about 1 hour. When lamivudine is prescribed in therapeutic doses (4 mg / kg / day in 2 divided doses with an interval of 12 hours), Cmax is 1-1.9 μg / 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 concentration-time pharmacokinetic curve). Therefore, when taking lamivudine with food, dose adjustment is not required.

Distribution and binding to plasma proteins

With intravenous administration of lamivudine, the volume of distribution is an average of 1.3 l / kg, and the half-life is 5-7 hours.

In the therapeutic dose range, lamivudine has a linear pharmacokinetics and binds to plasma proteins to a small extent.

It has been found that lamivudine penetrates the central nervous system (CNS) and cerebrospinal fluid. 2–4 hours after ingestion, the ratio of the concentrations of lamivudine in cerebrospinal fluid and serum was approximately 0.12.

Metabolism and excretion of

On average, systemic clearance of lamivudine is approximately 0.32 l / h * kg. Lamivudine is excreted mainly by the kidneys (more than 70%) by 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 half-life from cells (16-19 hours) compared with its half-life from plasma (5-7 hours). There is evidence that the pharmacokinetic parameters of lamivudine when taken at a dose of 300 mg 1 time per day in equilibrium are equivalent to those when taken at a dose of 150 mg 2 times a day according to 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, an insignificant degree of binding to plasma proteins and almost complete elimination of lamivudine by the kidneys unchanged.

Special patient groups

Children

In general, the pharmacokinetics of lamivudine in children is similar to that in adults. However, the absolute bioavailability of the oral solution in children under 12 years old was lower and more variable (approximately 55–65%). The indicators of systemic clearance are higher in children of a younger age group and decrease with age, reaching the level of adult patients by 12 years. Pharmacokinetic studies of both liquid and tablet form 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 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

Pharmacokinetics of the drug in children younger than 3 months limited. In newborns in the first week of life, lamivudine clearance when ingested is reduced compared with other age categories due to immaturity of the excretory function of the kidneys and inconsistency of 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. Data on the use of the drug in newborns older than 1 week are not available.

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, since its elimination from the body is slowed down. Patients with creatinine clearance less than 50 ml / min should reduce the dose.

Patients with impaired liver function

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

Pregnancy

The pharmacokinetics of lamivudine in pregnant women are not different 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 the serum of the mother and in the blood from the umbilical cord.

Indications

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

Contraindications

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

Precautions

Use with caution in patients with renal insufficiency pancreatitis (including history of peripheral neuropathy during pregnancy and lactation.

Use during pregnancy and lactation

Pregnancy

There is currently insufficient evidence 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 the results of animal experiments cannot always be extrapolated to humans, data from rabbit studies indicate a possible risk of spontaneous abortion in early pregnancy.

In infants and children under the age of 1 year, whose mothers took drugs from the group of nucleoside reverse transcriptase inhibitors during pregnancy and childbirth, there have been cases of a slight transient increase in the concentration of lactic acid in serum, apparently due to mitochondrial dysfunction.

The clinical significance of a temporary increase in serum lactic acid concentration has not been established. In addition, very rare cases of developmental delay, convulsive syndrome 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, 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 give up breastfeeding whenever possible in order to prevent transmission of the virus to the baby through breast milk. After oral administration, lamivudine is excreted in breast milk, while its concentration in breast milk practically does not differ from its concentration in serum (1-8 Ојg / ml). Women taking lamivudine are not recommended to breastfeed.

Special instructions

Treatment with Epivir, oral solution, must be carried out by a doctor, experienced in managing 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 find it difficult to swallow tablets, a dosage form for oral administration is intended.

Patients should be warned that treatment with antiretroviral drugs, including lamivudine, does not prevent the risk of transmitting HIV to other people through sexual contact or blood transfusion. Therefore, patients should follow 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 and severe renal impairment, the concentration of lamivudine in plasma is increased due to a decrease in clearance of the drug, therefore, dose adjustment is required.

Pancreatitis

Several cases of pancreatitis have been reported in patients receiving lamivudine. However, it remains unclear whether this complication is caused by lamivudine or HIV infection itself. If you experience abdominal pain, nausea, vomiting, or characteristic changes in biochemical parameters in a patient receiving lamivudine, pancreatitis should be excluded. You should stop taking the drug until the diagnosis of pancreatitis is ruled out.

Lactic acidosis / severe hepatomegaly with fatty liver

In HIV-infected patients (mainly in 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 are usually accompanied by severe hepatomegaly and fatty liver, including fatal.

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).

Treatment with lamivudine always requires caution, especially if the patient has risk factors for liver disease. In the case of clinical or laboratory signs of lactic acidosis or impaired liver function (including hepatomegaly and fatty liver disease even in the absence of a marked increase in hepatic transaminases), lamivudine should be discontinued.

Redistribution of subcutaneous fat

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

Although all drugs from the classes of protease inhibitors and nucleoside reverse transcriptase inhibitors can cause one or more of the above undesirable reactions associated with the common syndrome, which is often called lipodystrophy, the accumulated data indicate that there are differences between the individual representatives of these classes of drugs in the ability to cause these unwanted reactions.

It should also be noted that lipodystrophy syndrome has a multifactorial etiology: for example, the stage of HIV infection, the elderly and the duration of antiretroviral therapy play an important, possibly synergistic, role in the development of this complication.

The long-term effects of these adverse reactions have not been established.

Clinical examination of patients should include an assessment of the physical signs of redistribution of adipose tissue. Serum lipid concentrations and blood glucose should also be measured. Violations of lipid metabolism must be corrected, guided by their clinical manifestations.

Immunity restoration syndrome

In HIV-infected patients with severe immunodeficiency, antiretroviral therapy may exacerbate the inflammatory process due to asymptomatic or sluggish opportunistic infection, which can cause serious deterioration or aggravation of symptoms. As a rule, similar reactions were observed in the first weeks or months after initiation of ART. The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumocystis pneumonia. Any symptoms of inflammation must be identified immediately and treatment should be started without delay.

Mixed infection caused by HIV and hepatitis B virus

Some patients with chronic hepatitis B may experience clinical or laboratory signs of hepatitis recurrence after lamivudine withdrawal, which can have serious consequences in decompensating liver function. After the end of lamivudine therapy in patients with co-infection with 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

that the recommended adult dose contains 3 g of sucrose.

Prophylaxis after probable HIV infection

According to international recommendations (Center for Disease Control, June 1998), if a person is likely to become infected through the blood of an HIV-infected person (for example, through an injection needle), it is urgent (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. Preventive treatment is recommended for 4 weeks. Data on the effectiveness of preventive treatment after accidental infection with HIV have accumulated insufficiently controlled studies have not been conducted. Despite the rapid start of antiretroviral treatment, the possibility of seroconversion cannot be ruled out.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES, MECHANISMS

There have been no special studies of the effect of lamivudine on the ability to drive a car / mechanisms. However, based on the pharmacological properties of lamivudine, such an effect is unlikely. Nevertheless, in assessing the ability to drive a car / mechanisms, the general condition of the patient, as well as the nature of the adverse reactions of lamivudine, should be taken into account.

Composition of

1 ml of oral solution contains:

active ingredient:

lamivudine 10 mg,

excipients:

sucrose

methyl and propyl parahydroxybenzoate

citric acid srdlprpl srplpl srdplprd srdl splprd srd

Dosage and administration of

Treatment with Epivir, oral solution, should be carried out by a doctor, experienced in managing patients with HIV infection.

The drug Epivir, oral solution, can be taken regardless of the meal.

Epivir, oral solution, is not intended as a monotherapy.

Epivir, 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 one dose 300 mg (30 ml).

Side effects

Headache,

weakness,

fatigue,

fever, chills,

dizziness,

insomnia,

depressive disorders,

neuropathy,

nausea,

diarrhea,

vomiting,

loss of appetite,

anorexia,

dyspepsia,

pain or colic in the stomach,

runny nose,

cough,

muscle pain, muscle pain

thrombocytopenia,

increased levels of ALT, AST, bilirubin, amylase,

skin rashes

in children - pancreatitis, paresthesia, peripheral neuropathies.

Drug interactions

The likelihood of a metabolic interaction of lamivudine with other drugs is extremely low, since lamivudine is very poorly metabolized, slightly binds to plasma proteins and excreted mainly by the kidneys unchanged.

Lamivudine is excreted primarily through active tubular secretion through an organic cation transport system. The possibility of the interaction of lamivudine with drugs that have the same excretion mechanism, for example, with trimethoprim, should be considered. Other drugs (e.g. ranitidine, cimetidine) are only partially excreted by this mechanism and do not interact with lamivudine.

Drugs that are predominantly excreted by active renal secretion through the organic anion transport system or through glomerular filtration do not appear to enter into clinically significant interactions with lamivudine.

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

Trimethoprim / sulfamethoxazole. The simultaneous use of trimethoprim / sulfamethoxazole in 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, 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. With the simultaneous administration of lamivudine and zalcitabine, lamivudine can inhibit the intracellular phosphorylation of the latter. In this regard, this combination of drugs is not recommended.

Overdose

Symptoms: There are few data on the consequences of acute overdose of lamivudine in humans. Lethal outcomes were not noted, the condition of all patients returned to normal. No specific signs or symptoms of an overdose of lamivudine were detected.

Treatment: it is recommended to monitor the patient's condition and conduct standard maintenance therapy if necessary. Since lamivudine is excreted by dialysis, continuous hemodialysis is possible, but no special studies have been conducted.

Storage conditions

At a temperature not exceeding 25 РC.

Expiration

2 years.

active substance

Lamivudine

Conditions of dispatch from

pharmacies by prescription

lekarstvennaja form

Solution to the local Application

Indications

HIV infection

Possible product names

EPIVIR RR D / VN. ACCEPTANCE 10MG / ML FL. 240ML No. 1

EPIVIR TRITISI R-D D / VN. RECEPTION 10MG / ML FL. PAT. 240ML (COMPLETE WITH ADAPT. AND WDS. DOSAGE.) No. 1 (04.13)

EPIVIR TRITISI RR D / RECEPTION INSIDE 10MG / ML FL. PAT. 240ML (COMPLETE WITH ADAPT. AND WDM. DOSAGE.) No. 1

EPIVIR TRITISI RR D / RECEPTION INSIDE 10MG / ML FL. PAT. 240ML (COMPLETED WITH ADAPT. AND SDR. DOSAGE.) No. 1 (05.

Epivir vials of 10 mg / ml, 240 ml

D LuxoSmithKline, UK