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

Lamivudine 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-5'-tri phosphate inhibits RNA and DNA-dependent reverse transcriptase of HIV insignificantly. The main mechanism of its action is the blocking of the synthesis of the growing DNA chain in the process of 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 emergence of changes in M184V site of the viral genome, which is closely linked to the active site 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 site 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, with respect to 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 CD4-lymphocytes. Determined that lamivudine in combination with zidovudine or zidovudine and other drugs significantly reduces the risk of progression of HIV infection and death. In 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 lamivudine, effective against strains of HIV with mutations in the locus M184V.

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 the gastrointestinal tract. Bioavailability of lamivudine in adults after oral administration is usually 80-85%. Average time (t_m_Oh) to 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.

Taking lamivudine together with food causes an increase t_max and a decrease in C_m_Oh up to 47%), however, does not affect the overall degree of absorption (calculated on the basis of the area under the concentration-time curve). Therefore, when taking lamivudine with food, dose adjustment is not required.

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) in comparison with the half-life of it from the plasma (5-7 hours). There are data that the pharmacokinetic parameters of lamivudine when taken at a dose of 300 mg once a day in the 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 lamivudine 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 groups of patients

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. The data show that AUC in children aged 2-6 years can be reduced by 30% compared with other age groups.

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 of lamivudine 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 nonpregnant. 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 adults and children (as part of combination therapy with other antiretroviral drugs).

Contraindications:

Hypersensitivity to lamivudine and other components of the drug.

Children weighing up to 30 kg.

Renal insufficiency, creatinine clearance <30 ml / min (for this dosage form).

Carefully:

Renal insufficiency, creatinine clearance 30- <50 ml / min; pancreatitis (including in history); peripheral neuropathy (including in the anamnesis).

Pregnancy and lactation:

Pregnancy

Data on the safety of lamivudine during pregnancy is currently insufficient. Studies have shown that lamivudine penetrates the placenta. Lamivudine It should be used during pregnancy only if the expected benefit for 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. In newborns and children under the age of 1 year, whose mothers during pregnancy and childbirth took drugs from the group of nucleoside reverse transcriptase inhibitors, cases of a slight transient increase in serum lactic acid concentration, apparently due to mitochondrial dysfunction, were described.The clinical significance of the temporary increase in the concentration of lactic acid in the serum is not 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 intake of nucleoside reverse transcriptase inhibitors during pregnancy and its effect on postnatal development has not been proven. Therefore, HIV-infected women during pregnancy, however, are recommended to take antiretroviral drugs to prevent vertical transmission of HIV.

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; wherein its concentration in breast milk practically does not differ from its concentration in serum (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 lamivudine is allowed only by a specialist with experience in the treatment of HIV infection.

Lamivudine is administered orally regardless of food intake (before, during or after meals).

To ensure the accuracy of dosing, the tablet should be swallowed completely without division.

To treat children and those patients who are difficult to swallow tablets, another dosage form (oral solution) is intended.

Categories of patients

Adults and adolescents with a body weight of more than 30 kg

The recommended dose is 300 mg per day. You can appoint 150 mg 2 times a day or 300 mg per day in one session.

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

In patients with impaired renal function of medium and severe degree, the concentration of lamivudine in plasma is increased due to a decrease in the clearance of lamivudine. Therefore, when creatinine clearance is 30 - 50 ml / min, the dose of the drug is -150 mg once a day. In adolescents with a body weight of more than 30 kg with impaired renal function, the same regimen of dose reduction is recommended, depending on the value of creatinine clearance, as in adults.For renal insufficiency and clearance of creatinine <30 ml / min, another dosage form - oral solution - should be used.

In patients on hemodialysis (dialysis sessions 2-3 times a week, lasting not less than 4 hours), after the initial dose reduction, in accordance with the creatinine clearance, further further correction of the dose is not required throughout the period of hemodialysis.

Patients with impaired hepatic function

Patients with hepatic insufficiency of moderate and severe degree of dose reduction of lamivudine are not required, unless a violation of liver function is accompanied by renal insufficiency. With hepatic insufficiency and compensated renal function, dose adjustment is not required.

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 following classification of undesirable reactions is used depending on the frequency of occurrence: very often (> 1/10), often (> 1/100, <1/10), sometimes. (> 1/1000, <1/100), rarely (> 1 / 10,000, <1/1000), very rarely (<1/10000).

From the hematopoiesis: infrequently - neutropenia, anemia, thrombocytopenia; very rarely - aplasia of the erythroid bone marrow.

From the side of metabolism: often - increasing the concentration of lactic acid in the serum, rarely - lactic acidosis; redistribution / accumulation of subcutaneous fat; the frequency of development depends on many factors, including from a specific combination of antiretroviral drugs.

From the nervous system: often - headache, insomnia; very rarely paresthesia; cases of development of peripheral neuropathy are described, but the association of this complication with lamivudine therapy has not been proved.

From the gastrointestinal tract: often - nausea, vomiting, pain in the upper abdomen, diarrhea; rarely - pancreatitis, although the association of this complication with lamivudine therapy is not proven; increased serum amylase activity.

From the hepatobiliary system: infrequently - transient increase in the activity of liver enzymes; rarely - hepatitis.

From the skin and its derivatives: often - a rash, alopecia.

From the osteomuscular system and connective tissue: often - arthralgia. muscle disorders; rarely rhabdomyolysis.

From the respiratory system and mediastinal organs: often - cough, nasal symptoms.

Other: often - a feeling of fatigue, malaise, fever.

Osteonecrosis has been reported in patients with risk factors such as late stages of HIV infection or long-term combined antiretroviral therapy (incidence is unknown).

Overdose:

Symptoms

There are few 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 lamivudine overdose.

Treatment

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

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 tubular 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.

Interferon and ribavirin. There is no evidence of possible pharmacokinetic and pharmacodynamic interactions in the co-administration of ribavirin and lamivudine, but fatal cases of hepatic insufficiency in co-infected patients (HIV and hepatitis C) who received antiretroviral therapy together with interferon alfa andribavirin.

Zidovudine. With the simultaneous use of lamivudine and zidovudine, a moderate (by 28%) increase in C_m_Oh 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 dose reduction 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:

Treatment with lamivudine 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 tableted dosage forms is not recommended, therefore, for the treatment of children and those patients who have difficulty in swallowing tablets, a medicinal form for oral administration is intended. 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 risk of HIV transmission to other people during sexual intercourse or blood transfusion. Therefore, patients should take appropriate precautions. In patients receiving lamivudine or other antiretroviral drugs, opportunistic infections or other complications may develop, so they should be carefully monitored by a physician with experience in HIV treatment.

Impaired renal function

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

Pancreatitis

Several cases of pancreatitis developed in patients who received lamivudine. However, it remains unclear whether this complication is caused by lamivudine or HIV infection itself. When there is abdominal pain, nausea, vomiting, or characteristic changes in biochemical parameters in a patient receiving lamivudine, pancreatitis should be excluded. It is necessary to suspend the drug until the diagnosis of pancreatitis is not ruled out.

Lactic acidosis / severe hepatomegaly with fatty liver dystrophy

In HIV-infected patients (mainly women) who took antiretroviral drugs from the group of nucleoside analogues as monotherapy or in combination with lamivudine, cases of lactic acidosis, which was usually accompanied by severe hepatomegaly and fatty liver dystrophy, including fatal outcome, were described. 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 (dyspnea). 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 liver dysfunction (including hepatomegaly and fatty liver dystrophy even in the absence of a marked 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, incl. decrease in the amount of peripheral fat and increase in visceral fat, weight loss of limbs and face, increase in mammary glands and fat deposition on the back of the neck and back ("buffalo buffalo"), as well as increased serum lipid concentrations and glucose levels in the blood. Although one or more of the above unwanted reactions associated with a common syndrome, often called lipodystrophy, can cause all drugs from classes of protease inhibitors and nucleoside reverse transcriptase inhibitors, the accumulated evidence suggests that there are differences between individual representatives of these classes of drugs in the ability to induce these unwanted reactions.It should also be noted that lipodystrophy syndrome has a multifactorial etiology; for example, the stage of HIV infection, the elderly age and the duration of antiretroviral therapy play an important, possibly synergistic role in the development of this complication. The long-term effects of these undesirable reactions are not currently established. Clinical examination of patients should include an assessment of physical signs of fat tissue redistribution. Serum lipids and glucose levels should also be measured. Disorders of lipid metabolism should be adjusted, guided by their clinical manifestations.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency during the onset of antiretroviral therapy (Apt) possibly exacerbation of the inflammatory process caused by asymptomatic or sluggish opportunistic infection, which can cause serious deterioration or worsening of symptoms. As a rule, similar reactions were observed in the first weeks or months after the onset Apt. The most significant examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infection and pneumocystis pneumonia. Any symptoms of inflammation should be immediately identified and treatment should begin without delay. Also, in conditions of restoration of immunity, the development of autoimmune diseases (Graves' disease, polymyositis, Guillain-Barre syndrome) is possible, however, the development of these diseases can be registered even several months after the start of treatment.

Mixed infection caused by HIV and hepatitis B virus

In some patients with chronic hepatitis B, after the withdrawal of lamivudine, clinical or laboratory signs of hepatitis recurrence may appear, which can have serious consequences in decompensating liver function. After the termination of lamivudine therapy in patients with co-infection caused by HIV and hepatitis B virus, it is necessary to monitor biochemical parameters of liver function and markers of hepatitis B virus replication.

Hepatic decompensation (some fatal) in patients with co-infected HIV-1 / hepatitis B who received combination antiretroviral therapy and interferon alfa together with ribavirin or without ribavirin. Patients receiving this combination therapy should closely monitor the development of toxic effects, especially liver failure. It is possible to stop the use of lamivudine, reduce the dose or abolish interferon alfa, ribavirin with worsening of clinical symptoms, including liver failure (for example,> 6 points in Child-Pugh classification).

Preventive maintenance after probable infection of a HIV:

If a person infected with HIV is likely to be infected through the blood (for example, via an injection needle), a combination therapy of zidovudine and lamivudine should be prescribed urgently (within 1-2 hours after the 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 have not been accumulated enough; controlled studies were not conducted. Despite the rapid onset of treatment with antiretroviral drugs, seroconversion can not be ruled out.

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

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Form release / dosage:

Film coated tablets 150 mg.

Packaging:

For 60 tablets in polyethylene bottles of white color, sealed with a screwed polypropylene lid on the inner side of the center with a round cylindrical cavity with tightened paper and sealed with aluminum foil. One bottle together with the instruction for use is placed in a cardboard box.

For 10 tablets in a blister of PVC film / aluminum foil. For 6 or 10 blisters together with the instructions for use are placed in a cardboard box.

Storage conditions:

In a dry, the dark place 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.

Terms of leave from pharmacies:On prescription

Registration number:LP-001999

Date of registration:13.02.2013 / 29.03.2016

Expiration Date:13.02.2018

The owner of the registration certificate:Aurobindo Pharma Co., Ltd.Aurobindo Pharma Co., Ltd. India

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Representation: & nbspAurobindo Pharma, ZAOAurobindo Pharma, ZAO

Information update date: & nbsp11.02.2018

Illustrated instructions

Instructions

Lamivudine (Lamivudine)