LAMIVUDINE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMIVUDINE (LAMIVUDINE)

Composition:

Active substance: lamivudine;

1 tablet contains lamivudine 150 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, hypromellose (hydroxypropylmethylcellulose), titanium dioxide (E 171), polysorbate 80, polyethylene glycol 400 (macrogol 400).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, rhombic-shaped, film-coated tablets with convex upper and lower surfaces, with a break line on each side. When broken and examined under a magnifying glass, the core surrounded by a single continuous layer is visible.

Pharmacotherapeutic group. Direct-acting antiviral agents. Nucleoside and nucleotide reverse transcriptase inhibitors. Lamivudine.

ATC code J05AF05.

Pharmacological Properties

Pharmacodynamics

The primary mechanism of action of lamivudine is the inhibition of HIV reverse transcriptase. Lamivudine triphosphate is a selective inhibitor of HIV-1 and HIV-2 replication in vitro; it is also active against zidovudine-resistant HIV strains. When used in combination with zidovudine, lamivudine reduces the amount of HIV-1 and increases the number of CD4 cells, significantly decreasing the risk of disease progression and mortality.

Synergistic effects of lamivudine and zidovudine in suppressing HIV replication have been demonstrated in cell cultures. Development of resistance to lamivudine in zidovudine-resistant virus strains has been shown to restore sensitivity to zidovudine. In vitro, the drug exhibits weak cytotoxic effects on peripheral blood lymphocytes, lymphocytic and monocytic-macrophage cell lines, and bone marrow cells, indicating a wide therapeutic index.

Pharmacokinetics

The bioavailability of lamivudine is 80–85%. Peak plasma concentration (Cmax) is reached on average within 1 hour and, when administered at the average therapeutic dose (4 mg/kg/day in two doses 12 hours apart), ranges from 1 to 1.9 µg/mL. Cmax is reduced when the drug is taken with food, but its bioavailability is not affected by food intake.

Administration of crushed tablets mixed with a small amount of food or liquid does not affect the pharmaceutical quality of the drug and therefore will not affect the clinical efficacy of the drug, provided the patient ingests 100% of the crushed tablet immediately after crushing.

This conclusion is based on the physicochemical and pharmacokinetic properties of the active ingredient and dissolution profile data of lamivudine-containing tablets in water.

The average volume of distribution is 1.3 L/kg, and the average elimination half-life is 5–7 hours. Lamivudine exhibits linear pharmacokinetics at therapeutic doses and has low plasma protein binding. Some data indicate that lamivudine penetrates into the central nervous system and cerebrospinal fluid. Two to four hours after oral administration, the ratio of lamivudine concentration in cerebrospinal fluid to plasma concentration is 0.12. The clinical significance of this finding is unknown.

The average systemic clearance of lamivudine is approximately 0.32 L/kg/hour. The drug is primarily eliminated by the kidneys (>70%) via active tubular secretion, with a minor portion (<10%) metabolized in the liver. The active intracellular metabolite, lamivudine triphosphate, has a prolonged intracellular half-life (16–19 hours) compared to the elimination half-life of lamivudine itself (5–7 hours).

Elimination of lamivudine is impaired in cases of reduced renal function, regardless of whether this is due to kidney disease or age-related decline. In such cases, dose adjustment is required (see section "Dosage and Administration").

The potential for drug interactions with lamivudine is low due to its limited metabolism, low plasma protein binding, and nearly complete renal excretion in unchanged form.

The pharmacokinetics of lamivudine in children are generally similar to those in adults. However, the absolute bioavailability of the oral solution (55–65%) was lower and more variable in children under 12 years of age. Systemic clearance in children under 12 years was higher and decreased to reach adult levels (see section "Dosage and Administration"). Studies have shown that single daily dosing of the recommended daily dose of lamivudine (either as tablets or oral solution) results in similar AUC0–24 values as twice-daily dosing. With recommended dosing regimens, mean AUC0–24 values range from approximately 7.1 to 13.7, which are comparable to AUC0–24 values observed with single daily dosing of the recommended daily dose of lamivudine in adult patients.

Clinical characteristics.

Indications.

Lamivudine in combination with other antiretroviral agents is indicated for the treatment of HIV infection.

Contraindications.

The drug is contraindicated in patients with a history of hypersensitivity to lamivudine or to any of the other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

The likelihood of metabolic interaction is low, considering the limited metabolism of the drug, its low protein binding, and its almost complete renal excretion in unchanged form.

Lamivudine is primarily eliminated via active organic cation secretion. Potential interactions with concomitantly administered drugs should be considered, especially when the primary route of elimination involves the renal organic cation transport system (e.g., trimethoprim). Other active substances (e.g., ranitidine, cimetidine) are only partially eliminated via this pathway and therefore do not interact with lamivudine. Active substances primarily eliminated via active organic anion secretion or glomerular filtration are unlikely to cause clinically significant interactions with lamivudine.

Ribavirin. Although there is no evidence of pharmacokinetic or pharmacodynamic interaction between ribavirin and lamivudine when administered concurrently, cases of hepatic decompensation (sometimes fatal) have been reported in patients co-infected with HIV and hepatitis C who were receiving combination therapy with antiretroviral agents and interferon-alpha with or without ribavirin.

Zidovudine. A moderate increase in zidovudine peak levels (28%) has been observed when zidovudine and lamivudine are administered together, although overall exposure is not significantly altered. Zidovudine does not affect the pharmacokinetics of lamivudine (see section "Pharmacological properties. Pharmacokinetics").

Zalcitabine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when these two drugs are administered concurrently. Therefore, lamivudine is not recommended for use in combination with zalcitabine.

Lamivudine metabolism does not involve CYP3A enzymes; therefore, interactions with medicinal products metabolized by the CYP3A enzyme system are unlikely.

Co-trimoxazole. Administration of trimethoprim/sulfamethoxazole 160 mg/800 mg (co-trimoxazole) increases lamivudine concentrations by 40% due to the presence of trimethoprim, but a clinically significant effect is not expected. Dose adjustment of lamivudine is not necessary unless the patient has renal impairment (see section "Dosage and administration"). Patients should be monitored for lamivudine toxicity if there is severe renal impairment or if high doses of trimethoprim/sulfamethoxazole are used (e.g., for treatment of Pneumocystis jirovecii pneumonia).

Lamivudine tablets should not be taken with other medicinal products containing lamivudine (see section "Special precautions for use").

Lamivudine in vitro inhibits the intracellular phosphorylation of cladribine, potentially leading to a loss of cladribine efficacy when used concomitantly in clinical practice. Some clinical reports also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended (see section "Special precautions for use").

Special precautions for use.

HIV transmission. Patients should be aware that antiretroviral therapy does not reduce the risk of HIV transmission through sexual contact; therefore, appropriate preventive measures must be used. Lamivudine is not recommended for use as monotherapy.

Renal impairment. In patients with moderate to severe renal impairment, plasma concentrations of lamivudine increase due to reduced clearance. Therefore, dosage adjustments are required (see section "Posology and method of administration").

Mitochondrial dysfunction. Nucleoside and nucleotide analogues may cause mitochondrial dysfunction of varying severity, particularly when used concomitantly with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside analogues in utero and/or during the postnatal period. The most commonly reported adverse effects include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipidemia).

These events are often transient. Late-onset neurological disorders (hypertonia, seizures, abnormal behavior) have also been reported. It is currently unknown whether such neurological disorders are transient or permanent.

All children, even those who are HIV-negative, exposed to nucleoside or nucleotide analogues in utero should be monitored clinically and through laboratory testing. These data do not affect current recommendations for antiretroviral therapy in pregnant women to prevent vertical HIV transmission.

Triple nucleoside analogue therapy. High rates of virological failure and early emergence of resistance have been reported when lamivudine is used in combination with tenofovir disoproxil fumarate and abacavir, as well as with tenofovir disoproxil fumarate and didanosine once daily.

Lactic acidosis/severe hepatomegaly with steatosis. Cases of lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported in patients receiving treatment for HIV infection with individual or combined nucleoside analogue antiretrovirals, including lamivudine. These cases have occurred predominantly in women. Obesity and prolonged exposure to nucleoside analogues are considered risk factors. Clinical symptoms suggestive of symptomatic hyperlactatemia, which may indicate the development of lactic acidosis, include general weakness, anorexia, nausea, vomiting, abdominal pain, rapid weight loss, gastrointestinal symptoms, respiratory symptoms (dyspnea and tachypnea), and neurological disorders, including motor disturbances. Therefore, lamivudine should be used with caution, especially in patients with risk factors for liver disease. Lactic acidosis has a high fatality rate and may be associated with pancreatitis, liver, or kidney damage. Lactic acidosis usually occurs after several months of treatment. If a patient develops clinical or laboratory signs of lactic acidosis or hepatotoxicity (which may include hepatomegaly and steatosis, even in the absence of marked transaminase elevations), lamivudine therapy should be discontinued. Caution is advised when prescribing nucleoside analogues to any patient (especially women with excess body weight) who has hepatomegaly, hepatitis, or other known risk factors for liver injury and hepatic steatosis (including use of certain medications and alcohol consumption). Patients co-infected with hepatitis C and those receiving treatment with alpha-interferon and ribavirin are at particular risk. Such patients require close monitoring.

Redistribution of body fat. Redistribution or accumulation of body fat, including central obesity, increased fat deposits in the dorsocervical area ("buffalo hump"), and decreased fat in the limbs and face, breast enlargement, elevated serum lipid levels, and increased blood glucose levels, have been observed in some patients receiving combination antiretroviral therapy.

As with other drugs in the class of protease inhibitors and nucleoside reverse transcriptase inhibitors, specific symptoms suggestive of lipodystrophy may occur. The risk of developing these symptoms varies with different drugs in this class.

Furthermore, the lipodystrophy syndrome is multifactorial in etiology, with contributing factors such as the stage of HIV disease, patient age, and duration of antiretroviral therapy.

The long-term consequences of the above-mentioned adverse effects are currently unknown.

During clinical examination, attention should be paid to physical signs of fat redistribution, and serum lipid and blood glucose levels should be monitored. Treatment of lipid metabolism disorders should be managed according to the patient's clinical condition.

Patients co-infected with hepatitis B virus. Clinical data indicate that in patients co-infected with hepatitis B virus, hepatitis flare may occur upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. Therefore, in patients co-infected with HIV and hepatitis B virus, liver function tests and markers of hepatitis B virus replication should be monitored periodically.

Weight and metabolic parameters. Increases in weight and levels of lipids and blood glucose may occur during antiretroviral therapy. Such changes may be directly related to the disease or lifestyle. Regarding lipid level reductions, in some cases, these may be associated with treatment; however, there is no convincing evidence linking weight gain to any specific treatment. Appropriate measures should be taken to monitor blood lipid and glucose levels, in accordance with established guidelines for HIV infection management. Lipid abnormalities should be managed with appropriate clinical interventions.

Pancreatitis. Isolated cases of pancreatitis have been reported. However, it is not fully established whether these are related to antiretroviral therapy or are a consequence of HIV infection. If early clinical signs or laboratory symptoms indicating pancreatitis development occur, treatment should be discontinued.

Immune reconstitution syndrome. In HIV-infected patients with advanced immunodeficiency, initiation of antiretroviral therapy may trigger an inflammatory response to asymptomatic or residual opportunistic infections, leading to severe clinical conditions or symptom exacerbation. These reactions typically occur within the first weeks or months of antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and/or focal infections caused by mycobacteria, or Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory conditions should be promptly investigated and treated if necessary. Autoimmune disorders (such as Graves' disease, autoimmune hepatitis, polymyositis, and Guillain-Barré syndrome) have also been reported during immune reconstitution, although their onset is more variable and may occur months after starting therapy and sometimes present atypically.

Opportunistic infections. In HIV-infected patients with advanced immunodeficiency, inflammatory reactions to asymptomatic and residual opportunistic infections may occur at the initiation of combination antiretroviral therapy. Therefore, patients should remain under close clinical monitoring by physicians experienced in managing HIV-related diseases.

Liver disorders. Caution should be exercised when administering lamivudine to any patient co-infected with hepatitis B. Lamivudine is an inhibitor of hepatitis B virus replication. Patients with chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of developing severe and potentially fatal hepatic adverse effects. When used concomitantly with other antiviral agents for the treatment of hepatitis B and C, refer to the respective product information for these agents.

Discontinuation of lamivudine or virological failure due to lamivudine resistance may lead to worsening liver function and hepatitis flare.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, are at increased risk of liver function deterioration during combination antiretroviral therapy and should be under medical supervision. In case of signs of worsening liver disease, interruption or discontinuation of treatment should be considered (as outlined in the "Special precautions for use" section).

Osteonecrosis. Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, and high body mass index), cases have been reported primarily in patients with advanced disease and/or prolonged use of combination antiretroviral therapy. Patients should be advised to seek medical attention if they experience joint pain, stiffness, or movement disorders.

Lamivudine must not be used with other medicinal products containing lamivudine. Due to the development of resistance or lack of additive antiretroviral effects, the drug should not be used with emtricitabine (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of lamivudine with cladribine is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Human data on the safety of lamivudine use during pregnancy are limited. Studies in humans have shown that lamivudine crosses the placenta. The use of lamivudine during pregnancy is justified only if the expected benefit to the mother outweighs the potential risk to the fetus. Animal studies in rabbits indicate a risk of early embryonic death.

Mild, transient elevations in serum lactate levels, possibly due to mitochondrial dysfunction, have been reported in newborns and infants exposed to nucleoside reverse transcriptase inhibitors during pregnancy or delivery. The clinical significance of these elevated serum lactate levels is unknown.

There are also isolated reports of developmental delay, seizures, and other neurological disorders. However, a causal relationship between these manifestations and exposure to nucleoside reverse transcriptase inhibitors during pregnancy or delivery has not been established. These data do not affect recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical HIV transmission.

Healthcare experts recommend that HIV-infected women avoid breastfeeding their infants to prevent transmission of HIV infection. Following oral administration, lamivudine is excreted into human breast milk at concentrations similar to those in plasma (1–8 mcg/mL). Since both lamivudine and the virus are excreted into breast milk, breastfeeding is not recommended for mothers taking lamivudine.

Ability to affect reaction speed when driving or operating machinery.

Relevant clinical study data are lacking; however, the pharmacology of lamivudine does not suggest any negative impact. Nevertheless, when assessing a patient's ability to drive or operate machinery, their clinical condition and the adverse effect profile of lamivudine should be taken into account.

Method of Administration and Dosage

Treatment with lamivudine should be prescribed by a specialist experienced in the management of HIV infection.

Lamivudine may be taken regardless of food intake.

To ensure the full dose is administered, it is preferable to swallow the tablet whole, without crushing. For patients who cannot swallow the whole tablet, the oral solution formulation may be used. Alternatively, the tablet may be crushed and mixed with a small amount of food or liquid, which should be taken immediately.

Adults and adolescents with body weight ≥30 kg

The recommended dose of lamivudine is 300 mg per day (1 tablet twice daily or 2 tablets once daily).

Children with body weight from 21 to 30 kg

The recommended dose of lamivudine is ½ tablet in the morning and 1 tablet in the evening, or 1½ tablets once daily.

Children with body weight from 14 to 21 kg

The recommended dose of lamivudine is ½ tablet twice daily or 1 tablet once daily.

Children with body weight below 14 kg

The oral solution formulation is recommended.

Children under 3 months of age

There is insufficient data on the use of this medicinal product in this age group.

Patients with renal impairment

In patients with moderate to severe renal impairment, lamivudine concentrations increase due to reduced clearance. Therefore, dosage reduction is required for patients with creatinine clearance below 50 mL/min. In children with renal impairment, the dose should be reduced in the same proportional ratio.

Patients with hepatic impairment

Data obtained from treating patients with moderate and severe hepatic impairment show that lamivudine has no significant effect on liver function. Therefore, dose adjustment is not necessary in these cases.

Elderly patients

There are no specific data available; however, special attention should be paid to this group of patients due to age-related changes, such as reduced renal function and changes in hematological parameters.

Children

Can be used for treatment of children with body weight of 14 kg and above. For children aged 3 months and older, the drug should be administered in the form of an oral solution.

Overdose

Symptoms. Data regarding acute overdose in humans are limited. No fatal cases have been reported, and all patients recovered. No specific signs or symptoms characteristic of overdose have been identified.

Treatment. In case of overdose, the patient should be closely observed and standard supportive therapy should be administered as needed. Since lamivudine is dialyzable, hemodialysis may be used, although this treatment method has not been sufficiently studied.

Adverse Reactions

Adverse events have been reported during treatment of HIV infection with lamivudine, both as monotherapy and in combination with other antiretroviral agents. In many cases, it remained unclear whether the adverse event was related to the use of the drug or was a consequence of the underlying disease.

To define the frequency of adverse effects, the following classification is used: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000).

Haematological parameters

Uncommon: anaemia, neutropenia, thrombocytopenia.

Very rare: pure red cell aplasia.

Metabolism and nutrition disorders

Common: hyperlactataemia.

Rare: lactic acidosis (see section "Special precautions").

Redistribution/accumulation of body fat (see section "Special precautions").

The frequency of this occurrence depends on many factors, including the specific antiretroviral drug combination.

Nervous system disorders

Common: headache, insomnia.

Very rare: paraesthesia. Cases of peripheral neuropathy have been reported.

Respiratory system disorders

Common: cough, cold symptoms.

Gastrointestinal disorders

Common: nausea, vomiting, abdominal pain and cramps in the upper abdomen, diarrhoea.

Rare: pancreatitis, increased serum amylase levels.

Hepatobiliary disorders

Uncommon: transient elevations in liver enzymes (AST, ALT).

Rare: hepatitis.

Skin disorders

Common: rash, alopecia.

Rare: angioneurotic oedema.

Musculoskeletal system disorders

Common: arthralgia, myopathy.

Rare: rhabdomyolysis.

Other

Common: fatigue, malaise, fever.

Cases of lactic acidosis, sometimes fatal, have been reported with nucleoside analogues, associated with severe hepatomegaly and hepatic steatosis (see section "Special precautions").

Combination antiretroviral therapy is associated with metabolic disturbances such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia (see section "Special precautions").

In HIV-infected patients with severe immunodeficiency, inflammatory reactions to asymptomatic or residual opportunistic infections may occur at the initiation of combination antiretroviral therapy (see section "Special precautions").

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV-infected patients, including loss of peripheral subcutaneous fat, increased intra-abdominal and visceral fat, breast enlargement, and fat accumulation in the dorso-cervical area ("buffalo hump").

Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution; however, the onset is more variable and may occur many months after initiation of treatment, sometimes presenting with atypical features (see section "Special precautions").

Cases of osteonecrosis have been reported primarily in patients with advanced disease and/or long-term use of combination antiretroviral therapy. Frequency is unknown (see section "Special precautions").

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C. Keep out of the reach of children.

Packaging.

60 tablets in a container. 1 container per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

JSC "Technolog".

Manufacturer's address and place of business.

8 Stara Prorizna Street, Uman, Cherkasy region, 20300, Ukraine.