Epivir - instructions for use, dose, side effects, contraindications

Components	Content, mg / tab.
*Core tablet:*
Active substance
Lamivudine	300,0
Excipients
Microcrystalline cellulose	277,5
Carboxymethyl starch sodium (sodium starch glycolate)	18,0
Magnesium stearate	4,5
*Opadry® gray with the following composition (mg / tab):*
Hypromellose	9,5
Titanium dioxide	4,1
Macrogol 400	1,2
Polysorbate 80	0,2
Iron Oxide Dye Oxide	0,1

Description:

The tablets covered with a film membrane, diamond-shaped, gray color with an engraving “GX EJ7” on one side.

Pharmacotherapeutic group:Antiviral [HIV] agent

ATX: & nbsp

J.05.A.F.05 Lamivudine

Pharmacodynamics:

Mechanism of action

Epivir is a highly effective selective inhibitor of HIV-1 and HIV-2 replication in vitro. Also active against HIV strains resistant to zidovudine. Inside the cells lamivudine is metabolized to 5'-triphosphate (active form), the half-life of which from the cells is 16-19 hours. Lamivudine-3'-triphosphate to a small extent inhibits RNA and DNA-dependent reverse transcriptase of HIV. The main mechanism of its action is the blocking of the synthesis of the growing DNA chain in reverse transcription of HIV. Shown, that lamivudine has an additive or synergistic effect on other antiretroviral drugs, especially zidovudine, inhibiting HIV replication in cell culture.

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

In studies in vitro 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. In this way, 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 changes in the codon M184V a viral genome that is closely linked to the active center of HIV reverse transcriptase. HIV-1 strains with mutations M184V can appear as in vitro, and in the body of patients receiving combined antiretroviral therapy, including lamivudine. Such strains of the virus are characterized by a reduced sensitivity to lamivudine and a weak ability to replicate in vitro. In vitro HIV-resistant strains that are resistant to zidovudine may acquire sensitivity to it in the case of simultaneous development of resistance to lamivudine.The clinical significance of this phenomenon is not established.

Mutations in the codon M184V lead to the emergence of cross-resistance of HIV only to drugs from the group of nucleoside reverse transcriptase inhibitors. Zidovudine and stavudine remain active in HIV-1 strains resistant to lamivudine. Abacavir antiretroviral activity against HIV-1 strains having M184V mutation resistant to lamivudine. In strains of HIV with M184V mutations determined no more than 4-fold decrease in sensitivity to didanosine and zalcitabine; the clinical significance of this phenomenon is not established. Tests on the sensitivity of HIV to various antiretroviral drugs in vitro They were not standardized and therefore various methodological factors can 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 SI4-lymphocytes. Determined that lamivudine in combination with zidovudine or zidovudine and other drugs significantly reduces the risk of HIV progression-infection and death. HIV strains isolated from patients who received lamivudine, there was a decrease in sensitivity to lamivudine in vitro. Combination therapy with lamivudine and zidovudine in patients who had not previously received antiretroviral therapy delayed the emergence of zidovudine-resistant strains of HIV. Lamivudine was widely used as a component of combined antiretroviral therapy in combination with other nucleoside reverse transcriptase inhibitors or preparations from other groups (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).

It is shown that combined antiretroviral therapy, including lamivudineis effective against stomas of HIV with mutations in the codon Ml 84V.

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

Pharmacokinetics:

Suction

Lamivudine is well absorbed from gastrointestinal tract. Bioavailability of lamivudine in adults after oral administration is usually 80-85%. Average time (t_max) achieve maximum concentrations (C_m_Oh) of lamivudine in the serum is about 1 hour. When lamivudine is administered at therapeutic doses (4 mg / kg / day in 2 divided doses at intervals of 12 hours) C_m_Oh is 1-1.9 μg / ml.

Reception of lamivudine together with food caused an increase t_max and a decrease in C_m_Oh (up to 47%), however, did not affect the overall degree of absorption (calculated on the basis of the curve AUC "concentration-time"), therefore, when taking lamivudine with food, dose adjustment is not required.

Two tablets of 150 mg Epivir ® are bioequivalent in terms of area under the concentration-time curve (AUC ∞), C_max and t_max one tablet of Epivir® containing 300 mg of the active ingredient.

Distribution and binding to blood 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 range of doses lamivudine has linear pharmacokinetics and binds insignificantly to plasma proteins.

Determined that lamivudine penetrates into the central nervous system (CNS) and into the cerebrospinal fluid. 2-4 hours after oral administration, the ratio of the concentrations of lamivudine in the cerebrospinal fluid and serum was approximately 0.12.

Metabolism and excretion

On average, the systemic clearance of lamivudine is approximately 0.32 l / kg / h. Lamivudine is excreted mainly by kidneys (more than 70%) by active tubular secretion (the system of organic cation transport), and also by metabolism in the liver (less than 10%).

The active form of lamivudine, intracellular lamivudine triphosphate, has a longer half-life of cells (16-19 hours) compared with the half-life of plasma from its plasma (5-7 hours). There is evidence that the pharmacokinetic parameters of lamivudine when taken at a dose of 300 mg once a day in an equilibrium state are equivalent to those when administered at a dose of 150 mg twice a day in terms of area under the concentration-time curve for 24 hours (AUC₂₄) and C_m_Oh for intracellular triphosphate.

The likelihood of adverse interaction of lamivudine with other drugs is very small due to limited metabolism in the liver, a slight degree of binding to plasma proteins and almost complete excretion of lamivudine in unchanged form.

Special patient groups

Children

In general, the pharmacokinetics of lamivudine in children is similar to that of adults.However, absolute bioavailability (approximately 55-65%) was reduced in children younger than 12 years. In addition, the systemic clearance rates are higher in young children and decrease with growth, reaching the level of adult patients by the age of 12. Recent studies have shown that the degree of drug exposure in children from 2 to 6 years can be reduced by 30% compared with other age categories. The data available at the present time indicate that lamivudine not less effective in children.

Data on the pharmacokinetics of the drug in children younger than 3 months is not enough. In newborns in the first week of life due to the immaturity of the excretory function of the kidneys and the inconstancy of the absorption parameters, the clearance of lamivudine for ingestion is lower compared with children from 3 months. up to 12 years.

Elderly patients

Data on the pharmacokinetics of lamivudine in patients older than 65 years are absent.

Patients with impaired renal function

In patients with impaired renal function, the concentration of lamivudine in plasma is increased, since its excretion from the body is slowed. Patients with a creatinine clearance less than 50 ml / min dose Epivir ® should be reduced.

Patients with impaired hepatic function

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

Pregnancy

The pharmacokinetics of lamivudine in pregnant women does not differ from that of non-pregnant women. Studies have shown that 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.

Indications:

Treatment of HIV infection in combination antiretroviral therapy in adults and children.

Contraindications:

- Hypersensitivity to lamivudine or any other component of the drug.

- Not recommended for use in children under 12 years old or having a body weight of less than 30 kg.

Pregnancy and lactation:

Pregnancy

Data on the safety of lamivudine during pregnancy is currently insufficient. Studies have shown that lamivudine penetrates the placenta.

Lamivudine should be used during pregnancy only if the expected benefit to the mother exceeds the potential risk to the fetus.Although the results of animal experiments can not always be extrapolated to humans, research data on rabbits indicate a possible risk of spontaneous abortion in early pregnancy.

Lactation

In the opinion of experts, all HIV-infected women should, whenever possible, refrain from breastfeeding in order to prevent the transmission of the virus to the baby through breast milk. After oral administration lamivudine excreted in breast milk; the concentration its content in breast milk is practically the same as its serum concentration (1-8 μg / ml). Because HIV and lamivudine penetrate into breast milk, women taking lamivudine, it is not recommended to breast-feed the baby.

Dosing and Administration:

The appointment of the drug Epivir is allowed only by a specialist with experience in the treatment of HIV infection.

Epivir is administered orally regardless of the meal (before, during or after a meal).

For the treatment of children and those patients who are difficult to swallow tablets, a dosage form is given for oral administration to ensure accurate dosing.

Tablets Epivir should be taken whole without dividing and crumbling.

Special patient groups

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

The recommended dose is 300 mg per day.

Elderly patients

At present, data on the pharmacokinetics of lamivudine in this category of patients is not enough, however, special attention should be paid to this category of patients because of the age-related decline in the excretory function of the kidneys and changes in blood counts.

Patients with impaired renal function

This dosage form is not used in this category of patients.

Patients with impaired hepatic function

In patients with moderate to severe hepatic insufficiency, a dose reduction of Epivir is not required unless a failure of the liver function is accompanied by renal insufficiency.

Side effects:

The undesirable reactions described below were noted in the treatment of HIV infection with lamivudine, both as monotherapy and when combined with other antiretroviral drugs. However, for many unwanted reactions, it is unclear whether they are caused by medications or are complications of the actual HIV infection.

The adverse events presented below are listed according to anatomophysiological classification and frequency of occurrence. Frequency of occurrence is defined as follows: Often (>1/10), often (> 1/100 and <1/10), infrequently (> 1/1 000 and <1/100), rarely (> 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-marketing surveillance.

Table 1. Frequency of occurrence of undesirable phenomena

From the hematopoietic and lymphatic system

Infrequently: neutropenia, anemia, thrombocytopenia.

Rarely: true erythrocyte aplasia.

From the side of metabolism

Often: increase in the concentration of lactic acid in the blood.

Rarely: lactic acidosis, redistribution / accumulation of subcutaneous fat cellulose.

The frequency of development depends on many factors, including the specific combination of antiretroviral drugs.

From the nervous system

Often: headache.

Rarely: paresthesia.

Cases of development of peripheral neuropathy are described, however, the relationship of this complication to Epivir® therapy has not been proven.

From the gastrointestinal tract

Often: nausea, vomiting, pain in the upper abdomen, diarrhea.

Rarely: pancreatitis, although the association of this complication with lamivudine therapy not proven, increased serum amylase activity.

From the hepatobiliary system

Infrequently: transient increase in activity of hepatic enzymes (ALT, ACT).

From the side of the rut and subcutaneous fat

Often: rash, alopecia.

From the osteomuscular system and connective tissue:

Often: arthralgia, muscle disorders.

Rarely: rhabdomyolysis.

General and local reactions

Often: a feeling of fatigue, malaise, fever.

Overdose:

Symptoms

There are limited data on the consequences of acute overdose of lamivudine in humans. There were no lethal outcomes, the condition of all patients was normalized.

There were no specific signs or symptoms of an overdose with lamivudine.

Treatment

It is recommended to monitor the patient's condition and conduct standard maintenance therapy. Because the lamivudine can be excreted from the body by dialysis, it is possible to use continuous hemodialysis, but no special studies have been conducted.

Interaction:

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

Lamivudine is excreted from the body mainly through active channeling secretion through the transport system of organic cations. The possibility of lamivudine interaction with drugs having the same elimination mechanism, for example, with trimethoprim, should be considered. Other drugs (for example, ranitidine, cimetidine) are only partially excreted by this mechanism and do not interact with lamivudine.

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

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

Trimethoprim / sulfamethoxazole. Simultaneous application 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, a reduction in the dose of lamivudine is not required. On the pharmacokinetics of trimethoprim and sulfamethoxazole lamivudine does not affect. The interaction of lamivudine with high doses of co-trimoxazole, which is 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 intracellular phosphorylation of the latter. In this regard, this combination of drugs is not recommended.

Special instructions:

The use of lamivudine as a monotherapy is not recommended.

Patients should be warned that treatment with antiretroviral drugs, including lamivudine. does not prevent the transmission of HIV to other people during sexual intercourse or contamination blood. Therefore, patients should take appropriate precautions.

In patients receiving lamivudine or other antiretroviral drugs, opportunistic infections or other complications may develop, so patients should be carefully monitored by a physician with experience of treatment patients from HIV-associated diseases.

Impaired renal function

In patients with impaired renal function of moderate and severe degree, the concentration of lamivudine in plasma is increased due to a decrease in clearance of the drug, therefore dose adjustment is required.

Pancreatitis

In patients who took lamivudine, rare cases of development of pancreatitis are described. However, it is not established whether this complication is caused by medications or the underlying disease - HIV infection. Treatment with Epivir® should be stopped immediately if clinical symptoms or laboratory evidence of pancreatitis develop (abdominal pain, nausea, vomiting, or increased biochemical markers). It is necessary to stop taking the drug before the diagnosis of pancreatitis is excluded.

Lactic acidosis and severe hepatomegaly with steatosis

There are reports of the development of lactic acidosis, severe hepatomegaly with steatosis, at including fatalities in HIV-infected patients (predominantly in women) who took antiretroviral

preparations from the group of nucleoside analogues in quality monotherapy or combinations from lamivudine. Clinical signs of developing lactic acidosis are general weakness, anorexia, rapid unexplained weight loss, symptoms of defeat gastrointestinal tract (nausea, vomiting and abdominal pain) and organs breathing (rapid and / or deep breathing) and neurological symptoms (including motor weakness).

Treatment with lamivudine always requires caution, and especially if the patient has risk factors for developing liver disease. In case of clinical or laboratory signs of lactic acidosis or hepatotoxicity (including hepatomegaly and steatosis even with no significant increase in the level of hepatic transaminases), lamivudine should be discontinued.

Caution should be exercised when using nucleoside analogues to treat any patient (especially obese women) with hepatomegaly,hepatitis or other known risk factors for liver damage and the development of liver steatosis (including the use of certain medicines and alcohol consumption).

Patients with co-infection with hepatitis C and patients who receive treatment with alpha interferon and ribavirin may constitute a special risk group.

Mitochondrial dysfunction

Research in vitro and in vivo showed that the analogues of nucleosides and nucleotides can cause a different degree of damage to the mitochondria. Cases were recorded mitochondrial dysfunction in HIV-negative children who received intrauterine and / or post-nucleoside analogues. According to reports, the main undesirable reactions were hematologic disorders (anemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipazemia). These undesirable reactions are often transient. Some neurological disorders with late onset have been reported (muscle tone increase, convulsions, behavioral disorders). Whether these neurological disorders are transient or persistent is currently unknown.Any child, even HIV-negative, exposed intrauterine effect analogues of nucleosides and nucleotides, should undergo a clinical and laboratory examination to exclusion of mitochondrial dysfunction in case of detection of appropriate signs or symptoms. These data do not affect the current national guidelines for the use of antiretroviral therapy in pregnant women to prevent the vertical transmission of HIV infection.

Redistribution of subcutaneous fat

In some patients receiving combined antiretroviral therapy, there is a redistribution and / or accumulation of adipose tissue, including the central type of obesity, dorsocervical fat deposition ("buffalo buffalo"), a reduction in the subcutaneous fat layer on the face and limbs, breast enlargement, increased serum lipids and blood glucose levels. The listed symptoms in patients can be observed together or separately.

Although one or more of the above-mentioned reactions, associated with a common syndrome, which is often referred to as lipodystrophy,can cause all preparations of classes of protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), the data indicate the existence of differences between individual representatives indicated classes of drugs in the ability to cause these side effects reaction.

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

The long-term effects of these side effects are currently unknown.

Clinical examination of patients should include an assessment of the physical signs of redistribution of adipose tissue. Serum lipids and blood glucose levels should be determined. Disorders of lipid metabolism should be treated, guided by their clinical manifestations.

Immunodeficiency Syndrome

At the beginning of treatment with antiretroviral drugs Of HIV-infected patients with severe immunodeficiency may exacerbate the inflammatory process against a background of asymptomatic opportunistic infection or its residual effects, which can cause serious deterioration or worsening of symptoms. Usually such reactions are observed during the first weeks or months after the onset antiretroviral therapy. The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumocystis pneumonia (R. Carinii). Any symptoms of inflammation should be immediately identified and if necessary begin treatment.

Autoimmune diseases (such as Graves' disease, polymyositis and Guillain-Barre syndrome) were observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after the initiation of therapy and have an atypical course.

HIV and hepatitis B infection

The results of clinical studies and post-registration data indicate that in some patients with chronic hepatitis B, when Epivir ® is withdrawn, clinical or laboratory signs of hepatitis exacerbation arise which can have serious consequences for patients with liver decompensation.After the termination of lamivudine therapy in patients with co-infection caused by HIV and hepatitis B virus, it is necessary to monitor biochemical indicators of liver function and markers of hepatitis B virus replication.

Diseases of the liver

Patients with pre-existing liver dysfunction, including active chronic hepatitis, have an increased incidence of liver dysfunction during combined antiretroviral therapy and should be monitored in accordance with accepted practice. It is necessary to consider the possibility of suspending or stopping treatment in cases of manifestations of worsening liver disease in such patients.

Osteonecrosis

Although the etiology of this disease is multifactorial (including the intake of glucocorticosteroids, alcohol consumption, severe immunosuppression, high body mass index), cases of osteonecrosis were most commonly seen in patients at a late stage of HIV infection and / or long-term combined antiretroviral therapy. Patients should consult a doctor if they experience pain and stiffness in the joints or difficulty moving.

Preventive maintenance after probable infection of a HIV

According to the international recommendations, if a person infected with HIV is likely to be infected through the blood (for example, through an injection needle), a combination therapy with zidovudine and lamivudine should be prescribed urgently (within 1-2 hours from the time of infection). In the case of a high risk of infection, a drug from the protease inhibitor group should be included in the antiretroviral regimen. Preventive treatment is recommended for 4 weeks. Data on the effectiveness of preventive treatment after accidental HIV infection are not sufficiently accumulated, controlled clinical no studies have been carried out. Despite the rapid onset of treatment with antiretroviral drugs, seroconversion can not be ruled out.

Triple Nucleoside Therapy

There were reports of a high incidence of virological failure and the development of resistance in early ethane with the concomitant use of lamivudine in combination with tenofovir dizoproxil fumarate and abacavir, and with the simultaneous administration of tenfovir with dysoproxil fumarate and didanosine once daily.The drug Epivir® should not be used concomitantly with any medication containing lamivudine or emtricitabine.

Effect on the ability to drive transp. cf. and fur:

Special studies of the effects of lamivudine on the ability to drive or move vehicles have not been carried out. However, based on the pharmacological properties of lamivudine, this effect is unlikely. Nevertheless, when assessing a patient's ability to drive a car or moving machinery, his general condition, as well as the nature of the unwanted reactions of lamivudine, should be taken into account.

Form release / dosage:Film-coated tablets, 300 mg.

Packaging:

30 tablets per bottle of high-density polyethylene, corked with a device that protects children from opening the bottle and controlling the first autopsy. The bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date stated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-000695

Date of registration:28.09.2011 / 26.11.2012

Date of cancellation:2016-06-01

The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom

Manufacturer: & nbsp

GLAXO OPERATIONS UK, Limited United Kingdom

GlaxoSmithKline Pharmaceuticals, S.A. Poland

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp24.02.2016

Illustrated instructions

Instructions

Epivir® (Epivir®)