Lamivudine

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

Composition:

Active ingredient: lamivudine;

1 ml of solution contains lamivudine 10 mg;

Excipients: sucrose, propylene glycol, anhydrous citric acid, sodium citrate, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), strawberry flavor, banana flavor, diluted hydrochloric acid, sodium hydroxide, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colorless or slightly yellow liquid with a fruity odor.

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 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 associated mortality.

Synergy between lamivudine and zidovudine in suppressing HIV replication has been demonstrated in cell culture. Resistance to lamivudine in zidovudine-resistant viral 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.

Absorption. Lamivudine is well absorbed from the gastrointestinal tract, with oral bioavailability in adults reaching 80–85%. Maximum serum concentration is achieved on average within 1 hour and, when administered at the average therapeutic dose (4 mg/kg/day in two doses with a 12-hour interval), ranges from 1–1.9 µg/mL. Administration of lamivudine with food prolongs t_max and reduces C_max by up to 47%. However, this does not affect the overall extent of lamivudine absorption (as calculated from the concentration-time pharmacokinetic curve); therefore, the drug may be taken regardless of food intake.

Distribution. The mean volume of distribution is 1.3 L/kg, and the mean elimination half-life is 5–7 hours. Lamivudine exhibits linear pharmacokinetics at therapeutic doses and has low plasma protein binding. Limited data indicate penetration of lamivudine 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 observation is unknown.

Metabolism. The potential for metabolic interactions with lamivudine is low due to minimal hepatic metabolism (5–10%) and low plasma protein binding.

Excretion. Mean 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%) eliminated through hepatic metabolism. The active intracellular metabolite, lamivudine triphosphate, has a prolonged intracellular half-life (16–19 hours) compared to the plasma half-life of lamivudine (5–7 hours).

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

The likelihood of adverse interactions between lamivudine and other drugs is low due to its limited metabolism, minimal plasma protein binding, and nearly complete renal excretion of unchanged drug.

Pharmacokinetics of lamivudine in children are generally similar to those in adults, although 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, whether as tablets or oral solution, results in similar AUC_0–24 values as twice-daily dosing—on average, 7.1–13.7.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to lamivudine or to any of the 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, low plasma protein binding, and almost complete renal excretion in unchanged form.

Lamivudine is primarily eliminated via active renal secretion. Potential interactions with drugs that are also primarily eliminated via active renal secretion through the organic cation transport system (e.g., trimethoprim) should be considered. Other drugs (e.g., ranitidine, cimetidine), which are only partially eliminated by this route, do not interact with lamivudine.

Drugs eliminated predominantly via active transport of organic anions or via glomerular filtration have a low potential for interaction with lamivudine.

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

Interferon-alpha. No pharmacokinetic interaction between lamivudine and interferon-alpha has been observed when administered concomitantly. No clinically significant adverse interactions have been reported with immunosuppressants (e.g., cyclosporin A), although specific studies have not been conducted.

Trimethoprim. Concomitant administration of trimethoprim/sulfamethoxazole at a dose of 160 mg/800 mg (co-trimoxazole) increases lamivudine plasma concentrations by approximately 40%. However, if the patient has normal renal function, dose adjustment of lamivudine is not required (see section "Dosage and administration"). Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. The effects of concomitant administration of lamivudine with high-dose co-trimoxazole for the treatment of Pneumocystis carinii pneumonia and toxoplasmosis have not been studied.

Zalcitabine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine; therefore, lamivudine is not recommended for use in combination with zalcitabine.

Emtricitabine. Lamivudine may inhibit the intracellular phosphorylation of emtricitabine; therefore, lamivudine is not recommended for concomitant use with emtricitabine.

Cladribine. In vitro, lamivudine enhances intracellular accumulation of cladribine, potentially leading to reduced efficacy of cladribine in clinical combination use. Some clinical reports also support a possible interaction between lamivudine and cladribine. Therefore, concomitant use of lamivudine with cladribine is not recommended.

Special precautions for use.

Lamivudine is not recommended for use as monotherapy.

Patients should be aware that treatment with current antiretroviral agents, including lamivudine, does not reduce the risk of HIV transmission via sexual contact or exposure to infected blood; therefore, appropriate preventive measures must be used.

Patients receiving lamivudine or any other antiretroviral agent remain at risk of developing opportunistic infections and other complications of HIV infection. Therefore, careful monitoring by a physician experienced in managing patients with HIV-associated infections is required.

Renal impairment: In patients with moderate to severe renal impairment, lamivudine plasma concentrations increase due to reduced clearance, necessitating dose reduction (see section "Dosage and administration").

Triple nucleoside analogue therapy: High rates of virological failure and early emergence of resistance have been reported when lamivudine is co-administered with tenofovir disoproxil fumarate and abacavir, as well as with tenofovir disoproxil fumarate and didanosine in a once-daily dosing regimen.

Pancreatitis: Isolated cases of pancreatitis have been reported in patients receiving lamivudine. However, it is not definitively established whether these cases are related to drug use or are a consequence of HIV infection. If clinical (abdominal pain, nausea, vomiting) or laboratory signs suggestive of pancreatitis occur, lamivudine therapy should be discontinued until the diagnosis of pancreatitis is excluded.

Lactic acidosis/severe hepatomegaly with steatosis: Cases of lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported during treatment of HIV infection with individual or combined nucleoside analogue antiretrovirals, including lamivudine. These cases have occurred predominantly in women. Clinical symptoms that may indicate lactic acidosis include general weakness, anorexia, and sudden weight loss, as well as gastrointestinal and respiratory symptoms (dyspnea and tachypnea). Caution should therefore be exercised when prescribing lamivudine to patients, particularly those with risk factors for liver disease. 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 treatment must be discontinued.

Mitochondrial dysfunction: Nucleotide and nucleoside analogues have been shown in vitro and in vivo to cause mitochondrial dysfunction of varying severity. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside analogues in utero or during the postnatal period. The most commonly reported adverse effects include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipidemia). These effects are often transient. Late-onset neurological disorders (hypertonia, convulsions, abnormal behavior) have also been frequently reported. Whether these neurological effects are transient or permanent is currently unknown. Any child, even those with HIV-negative status, exposed to nucleoside or nucleotide analogues in utero should be clinically and laboratory monitored for possible mitochondrial dysfunction.

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

As with all drugs in the class of protease inhibitors and nucleoside reverse transcriptase inhibitors, there is a possibility of developing one or more specific adverse symptoms generally associated with lipodystrophy. Data indicate that the risk of developing such effects may vary among different agents within 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 aforementioned 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. Management of lipid distribution disorders should be conducted according to the patient's clinical condition.

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. Such reactions typically occur within the first weeks or months of antiretroviral treatment. Examples include cytomegalovirus retinitis, generalized or focal mycobacterial infections, and Pneumocystis jirovecii (P. carinii) pneumonia. Any inflammatory conditions should be promptly investigated and treated if necessary. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been observed during the immune reconstitution phase, although their onset is more variable—these may develop months after starting treatment and sometimes present with atypical features.

Liver disease: Patients with chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse effects. When used concomitantly with other antiviral agents for the treatment of hepatitis B and C, the respective product information for these agents should be followed.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, are at increased risk of hepatic impairment during combination antiretroviral therapy and require medical monitoring. If signs of worsening liver function occur in such patients, consideration should be given to interrupting or discontinuing treatment (see section "Adverse reactions").

Patients with hepatitis B virus: Clinical data indicate that in patients co-infected with hepatitis B virus, hepatitis flare may occur upon discontinuation of lamivudine treatment, 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 regularly.

Osteonecrosis: Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, and high body mass index), cases have been observed primarily in patients with advanced disease and/or long-term 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 or emtricitabine.

Each dose of lamivudine oral solution (150 mg = 15 mL) contains approximately 3 g of sucrose, which should be considered in diabetic patients.

The product contains methylparahydroxybenzoate and propylparahydroxybenzoate, which may cause allergic reactions, possibly of delayed type.

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.

Minor transient increases in serum lactate levels, possibly due to mitochondrial dysfunction, have been reported in newborns and infants exposed to nucleoside reverse transcriptase inhibitors before birth. The clinical significance of elevated serum lactate levels is unknown. There have also been 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 agents to prevent vertical transmission of HIV in pregnant women.

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

Ability to influence the speed of reaction while driving or operating machinery.

There are no clinical data on this issue, and the pharmacology of lamivudine does not suggest any expected negative impact. However, 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.

The drug can be administered independently of food intake.

Adults and children with body weight of at least 30 kg.

The recommended dose of lamivudine is 300 mg (30 mL) once daily. Alternatively, 150 mg twice daily may be prescribed.

Children aged from 3 months with body weight below 30 kg.

The recommended dose of lamivudine is 4 mg/kg body weight twice daily or 8 mg/kg body weight once daily. The maximum dose should not exceed 300 mg (30 mL) per day.

Infants under 3 months of age.

Data on use are limited.

Patients with renal impairment.

In patients with moderate to severe renal impairment, lamivudine plasma concentrations are increased due to reduced clearance. Therefore, dosage reduction is required for patients with creatinine clearance below 50 mL/min.

Adults and children with body weight of at least 30 kg

Children aged 3 months and older with body weight up to 30 kg

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.

Specific data are lacking; however, particular attention should be paid to this group of patients due to age-related changes, such as reduced renal function and hematological abnormalities.

Children.

Can be used for treatment of children aged 3 months and older.

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 monitored and, if necessary, receive comprehensive standard supportive therapy. 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 antiretroviral therapy for HIV infection using lamivudine, both as monotherapy and in combination with other antiretroviral agents. In many cases, it remained unclear whether the adverse events were related to the drug or were consequences of the underlying disease itself.

Blood and lymphatic system disorders:
Anemia, neutropenia, thrombocytopenia, pure red cell aplasia.

Immune system disorders:
Hypersensitivity reactions, angioedema.

Metabolism and nutrition disorders:
Hyperlactatemia, lactic acidosis, redistribution/accumulation of body fat (see section "Special Warnings and Precautions for Use"). The frequency of this occurrence depends on multiple factors, including the specific antiretroviral drug combination used.

Nervous system disorders:
Headache, insomnia, paresthesia. Cases of peripheral neuropathy have been reported.

Respiratory, thoracic and mediastinal disorders:
Cough, cold symptoms.

Gastrointestinal disorders:
Nausea, vomiting, upper abdominal pain, diarrhea, pancreatitis, increased serum amylase levels.

Hepatobiliary disorders:
Transient elevations in liver enzymes (AST, ALT). Hepatitis flare-ups, initially diagnosed by increased ALT levels, occurring during treatment as well as after discontinuation of lamivudine. In most cases, laboratory parameters decrease over time; fatal outcomes have been observed very rarely.

Skin and subcutaneous tissue disorders:
Rash, pruritus, alopecia.

Musculoskeletal and connective tissue disorders:
Arthralgia, increased creatine kinase (CK) levels, muscle disorders including myalgia, muscle cramps, rhabdomyolysis.

General disorders:
Fatigue, malaise, fever.

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

Combination antiretroviral therapy has been associated with metabolic disturbances such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactatemia (see section "Special Warnings and Precautions for Use").

In HIV-infected patients with advanced immunodeficiency, inflammatory reactions to asymptomatic or residual opportunistic infections may occur upon initiation of combination antiretroviral therapy (see section "Special Warnings and Precautions for Use").

Cases of osteonecrosis have been reported, primarily in patients with confirmed risk factors, advanced HIV disease, or long-term antiretroviral therapy. The frequency of this phenomenon is unknown (see section "Special Warnings and Precautions for Use").

Shelf life. 2 years.

After opening, store for no more than 1 month.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C. Keep out of the reach of children.

Packaging.

240 ml in a glass bottle. One bottle with a 10 ml oral syringe in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "Tekhnolohiya".

Manufacturer's address and location of business activity.

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