Lazivudine

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

Composition:

Active substances: lamivudine, zidovudine;

One tablet contains lamivudine 150 mg and zidovudine 300 mg;

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, oval, film-coated tablets of white or almost white color, with convex upper and lower surfaces. When broken, the core surrounded by a single continuous layer is visible under magnification.

Pharmacotherapeutic group.

Antiviral agents for systemic use. Direct-acting antiviral agents. Antiviral agents for the treatment of HIV infection, combinations. ATC code J05AR01.

Pharmacological properties.

Pharmacodynamics.

Lamivudine and zidovudine are potent selective inhibitors of HIV-1 and HIV-2. Lamivudine is highly synergistic with zidovudine in inhibiting HIV replication in cell culture. Both agents are sequentially metabolized by intracellular kinases to their 5'-triphosphates (TP). Lamivudine-TP and zidovudine-TP are competitive inhibitors of human immunodeficiency virus (HIV) reverse transcriptase. However, the primary mechanism of antiviral activity is incorporation as a monophosphate into the viral DNA chain, resulting in chain termination. The triphosphates of lamivudine and zidovudine exhibit significantly lower affinity for host cell DNA polymerase.

In vitro, lamivudine demonstrates low cytotoxicity toward peripheral lymphocytes, lymphocyte and monocyte-macrophage cell lines, and various other bone marrow progenitor cells. Thus, lamivudine has a high in vitro therapeutic index.

Zidovudine and stavudine retain their antiretroviral activity against lamivudine-resistant HIV-1.

Clinical evidence has demonstrated that the combination of lamivudine and zidovudine reduces HIV viral load and increases CD4 cell counts. Recent clinical data indicate that lamivudine, in combination with zidovudine or other zidovudine-containing regimens, significantly reduces the risk of disease progression and mortality.

In some patients, treatment with lamivudine and zidovudine may lead to the emergence of HIV isolates with reduced in vitro susceptibility to nucleoside analogues to which they have been exposed. Clinical data exist showing that lamivudine, in combination with zidovudine, delays the development of zidovudine resistance in antiretroviral-naïve patients.

Lamivudine and zidovudine are widely used as components of antiretroviral therapy, combined with other antiretroviral agents of the same class (nucleoside reverse transcriptase inhibitors) or from other classes (protease inhibitors, non-nucleoside reverse transcriptase inhibitors).

Combination antiretroviral therapy containing lamivudine is effective both in antiretroviral-naïve patients and in patients with the M184V viral mutation.

Post-exposure prophylaxis. International guidelines (Centers for Disease Control and Prevention, June 1998) recommend that following accidental exposure to HIV-infected blood, such as a needlestick injury, a combination of zidovudine and lamivudine should be initiated immediately (within 1–2 hours). In cases of high risk of infection, a protease inhibitor should be added to the regimen. Antiretroviral prophylaxis should be continued for four weeks. Despite prompt initiation of antiretroviral therapy, seroconversion remains possible.

Pharmacokinetics.

Absorption

Lamivudine and zidovudine are well absorbed from the gastrointestinal tract. The bioavailability of lamivudine in adults following oral administration is 80–85%, and that of zidovudine is 60–70%.

After administration, the peak plasma concentration (Cmax) of lamivudine and zidovudine is 1.5 (1.3–1.8) mg/mL and 1.8 (1.5–2.2) mg/mL, respectively. The median time to reach peak concentration (tmax) for lamivudine and zidovudine is 0.75 (0.50–2.00) hours and 0.50 (0.25–2.00) hours, respectively. The extent of absorption and elimination half-life of lamivudine and zidovudine are similar whether administered with or without food, although the rate of absorption (Cmax, tmax) is reduced when taken with food. Based on these data, the drug may be administered independently of food intake.

Administration of crushed tablets mixed with a small amount of food or liquid does not affect the pharmaceutical quality of the product and therefore will not impact the clinical efficacy of the drug. This conclusion is based on the physicochemical and pharmacokinetic properties of the active ingredients and dissolution profile data of tablets containing lamivudine and zidovudine in water, provided that the patient ingests 100% of the crushed tablet immediately after crushing.

Distribution

Intravenous administration studies of lamivudine and zidovudine have shown that the mean volume of distribution is 1.3 and 1.6 L/kg, respectively. At therapeutic doses, lamivudine exhibits linear pharmacokinetics and binds minimally to plasma proteins (less than 36% to serum albumin in vitro).

Zidovudine protein binding ranges from 34% to 38%. The drug does not participate in drug interactions involving displacement from protein binding sites.

Lamivudine and zidovudine penetrate into the central nervous system (CNS) and reach cerebrospinal fluid (CSF). The mean CSF-to-plasma concentration ratios of lamivudine and zidovudine 2–4 hours after oral administration are approximately 0.12 and 0.5, respectively. The actual extent of CNS penetration of lamivudine and zidovudine and its correlation with clinical efficacy remain unknown.

Metabolism

Lamivudine is primarily eliminated unchanged via renal excretion. The potential for metabolic interactions with other drugs is low due to its limited hepatic metabolism (5–10%) and low plasma protein binding.

50–80% of zidovudine is eliminated via renal excretion as its major metabolite, 5'-glucuronide zidovudine, which is detectable in both urine and plasma. Following intravenous administration, 3’-amino-3’-deoxythymidine has been identified as a metabolite of zidovudine.

Elimination

The elimination half-life of lamivudine is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, and lamivudine is primarily eliminated by the kidneys (over 70%) via the organic cation transport system. Studies have shown that lamivudine elimination is impaired in renal impairment; therefore, dose reduction of lamivudine is required when creatinine clearance is ≤50 mL/min (see section "Dosage and administration").

Limited data suggest that in patients with hepatic impairment, accumulation of zidovudine may occur due to reduced glucuronidation. Dose reduction of zidovudine may be necessary in patients with severe hepatic impairment.

Clinical characteristics.

Indications.

Treatment of HIV infection.

Contraindications.

Hypersensitivity to lamivudine, zidovudine, or to any of the components of the medicinal product.

Neutrophil count below 0.75 x 10⁹/L or hemoglobin level below 7.5 g/dL, or 4.65 mmol/L (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interactions.

The medicinal product contains lamivudine and zidovudine; therefore, any interactions characteristic of each of these agents may also occur with Lazivudine. Clinical studies have shown that there are no clinically significant interactions between lamivudine and zidovudine.

Zidovudine is primarily metabolized by UDP-GT enzymes; concomitant administration of inducers or inhibitors of UDP-GT enzymes may alter zidovudine exposure. Lamivudine is eliminated by the kidneys. Active renal secretion of lamivudine into urine occurs via organic cation transporters (OCT); co-administration of lamivudine with OCT inhibitors or nephrotoxic medicinal products may increase lamivudine exposure.

Lamivudine and zidovudine are not significantly metabolized by cytochrome P450 enzymes (such as CYP3A4, CYP2C9, or CYP2D6), and they do not inhibit or induce this enzyme system. Therefore, interactions with antiretroviral protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and other medicinal products primarily metabolized by P450 enzymes are unlikely.

Interaction studies have been conducted only in adults. The interactions described below are not exhaustive but include the studied classes of medicinal products.

Abbreviations: ↑ – increase; ↓ – decrease; ↔ – no significant changes; AUC – area under the pharmacokinetic concentration/time curve; Cmax – maximum observed concentration; CL/F – apparent clearance after oral administration.

Exacerbation of anaemia associated with the use of ribavirin has been observed in patients receiving zidovudine as part of combination HIV therapy, although the precise mechanism remains unclear. Concomitant use of ribavirin and zidovudine is not recommended due to an increased risk of developing anaemia (see section "Special precautions").

Consideration should be given to replacing zidovudine in such combination antiretroviral therapy. This is particularly important for patients with a history of zidovudine-induced anaemia.

Concomitant use, mainly in acute situations, with agents that are potentially nephrotoxic or have myelosuppressive properties (e.g. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine, and doxorubicin) may also increase the risk of zidovudine-related adverse effects. If concomitant administration of zidovudine with any of these agents is necessary, renal function and haematological parameters should be monitored and dosage of one or more of the drugs should be reduced as needed.

Limited clinical study data suggest no significant increase in the risk of interaction between zidovudine and co-trimoxazole (see above information on interaction concerning lamivudine and co-trimoxazole), aerosol pentamidine, pyrimethamine, and acyclovir when used at prophylactic doses.

Special precautions for use.

Although effective viral suppression through antiretroviral therapy has been shown to substantially reduce the risk of sexual transmission, residual risk cannot be excluded. Preventive measures to prevent transmission should be implemented in accordance with national guidelines.

This section includes special warnings and precautions applicable to both lamivudine and zidovudine. No additional precautions or warnings specific to the combination drug Lazivudin are available.

When dose adjustments of the active substances are required, it is recommended to use individual formulations of lamivudine and zidovudine (see section "Dosage and administration"). In such cases, physicians should refer to the instructions for medical use of these medicinal products.

Concomitant use of stavudine and zidovudine should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Opportunistic infections. Opportunistic infections and other complications of HIV infection may continue to occur in patients receiving Lazivudin or any other antiretroviral agent. Therefore, these patients should remain under regular clinical supervision by physicians experienced in managing HIV infection.

Haematological adverse reactions. Anaemia, neutropenia, and leucopenia (usually secondary to neutropenia) may occur in patients treated with zidovudine. These are most commonly observed when high doses of zidovudine (1200–1500 mg daily) are used in patients with advanced stages of HIV infection and in individuals who had reduced bone marrow reserve prior to treatment. Therefore, haematological parameters must be carefully monitored in patients receiving the drug (see section "Contraindications"). These haematological changes are usually not observed during the first four to six weeks of therapy. Patients with advanced HIV infection should have blood tests performed at least once every two weeks during the first three months of treatment and at least once a month thereafter.

Haematological adverse reactions occur rarely in patients with early stages of HIV infection. Depending on the patient's overall condition, blood tests may be performed less frequently, e.g., once every one to three months. In cases of severe anaemia or myelosuppression during treatment with Lazivudin, or in patients with already compromised bone marrow (i.e., haemoglobin less than 9 g/dL (5.59 mmol/L) or neutrophil count less than 1.0 × 10^9/L), dose adjustment of zidovudine may be required (see section "Dosage and administration"). Because dose reduction of the fixed-dose combination is not possible, separate formulations of zidovudine and lamivudine should be prescribed. Physicians should consult the instructions for medical use of these medicinal products.

Pancreatitis. Isolated cases of pancreatitis have been reported in patients treated with lamivudine and zidovudine. However, it remains unclear whether these cases are related to drug treatment or are a consequence of the underlying disease itself. If a patient presents clinical signs or symptoms suggestive of pancreatitis, or if biochemical markers are elevated, pancreatitis should be suspected and the drug discontinued until pancreatitis is ruled out.

Lactic acidosis. Cases of lactic acidosis, usually associated with hepatomegaly and hepatic steatosis, have been reported during treatment with zidovudine. Early symptoms (symptomatic hyperlactataemia) include benign gastrointestinal symptoms (nausea, vomiting, and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing), or neurological symptoms (including motor weakness).

Lactic acidosis has a high mortality rate and may be associated with pancreatitis, hepatic or renal failure.

Lactic acidosis usually occurs after several months of treatment.

If symptomatic hyperlactataemia and metabolic acidosis/lactic acidosis, progressive hepatomegaly, or rapidly increasing aminotransferase levels occur, zidovudine treatment should be discontinued.

Zidovudine should be prescribed with caution in patients (particularly obese women) with hepatomegaly, hepatitis, or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and those receiving treatment with alpha-interferon and ribavirin represent a high-risk group.

Patients at increased risk require ongoing monitoring.

Mitochondrial function disorders. Nucleoside and nucleotide analogues may cause varying degrees of mitochondrial dysfunction, particularly with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors during the intrauterine and/or postnatal period; this primarily involved treatment regimens containing zidovudine. The main adverse reactions reported were haematological disorders (anaemia, neutropenia) and metabolic disturbances (hyperlactataemia, hyperlipasaemia). These adverse reactions were often transient. Rarely, delayed-onset neurological disorders (hypertonia, seizures, behavioural disturbances) have been reported after drug exposure. Whether such neurological disorders are transient or permanent remains unknown. These disorders should be considered in any child exposed to nucleoside and nucleotide analogues in utero or presenting with severe clinical disorders of unknown aetiology, particularly neurological disorders. These data do not affect current recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical transmission of HIV.

Lipoatrophy. Treatment with zidovudine is associated with loss of subcutaneous fat, linked to mitochondrial toxicity. The frequency and severity of lipoatrophy depend on cumulative exposure. Such loss of fat deposits, most evident in the face, limbs, and buttocks, may be irreversible even after switching to a zidovudine-free regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and zidovudine-containing medicinal products (Lazivudin and Trizivir). If lipoatrophy is suspected, therapy should be changed to an alternative regimen.

Body weight and metabolic parameters

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Factors influencing these levels may also include disease control and lifestyle changes. In some cases, there is evidence supporting a treatment effect on increased lipid levels, whereas increased body weight lacks such confirmation. Monitoring of serum lipid and blood glucose levels should be performed according to established HIV treatment protocols. Treatment of lipid abnormalities should be based on clinical indications.

Immune reconstitution syndrome. In HIV-infected patients with severe immunodeficiency, initiation of combination antiretroviral therapy (cART) may result in an inflammatory response to asymptomatic or residual opportunistic infections, potentially causing severe clinical conditions or symptom exacerbation. These reactions typically occur within the first few weeks or months of cART. Examples include cytomegalovirus retinitis, generalized or focal mycobacterial infections, or Pneumocystis jirovecii pneumonia (previously known as Pneumocystis carinii pneumonia). Any inflammatory conditions should be promptly investigated and treated if necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution, although their onset is more variable and may occur several months after starting treatment.

Liver disease. If lamivudine is used concomitantly for the treatment of both HIV infection and hepatitis B virus infection, additional information on the use of lamivudine for hepatitis B treatment is available in the instructions for medical use of the medicinal product Zeffix.

The safety and efficacy of zidovudine in patients with severe hepatic impairment have not been established.

In patients with chronic hepatitis B or C undergoing combination antiretroviral therapy, there is an increased risk of severe and potentially fatal hepatic adverse reactions. When antiviral agents for the treatment of hepatitis B or C are used concomitantly, the instructions for medical use of these medicinal products should be consulted.

If treatment with Lazivudin is discontinued in patients co-infected with hepatitis B virus, liver function tests and markers of hepatitis B virus replication should be monitored periodically for four months, as discontinuation of lamivudine may lead to hepatitis flare.

Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased risk of hepatic dysfunction during combination antiretroviral therapy and should be monitored according to standard practice. If signs of worsening liver disease occur in such patients, interruption or discontinuation of treatment should be considered.

Patients co-infected with hepatitis C virus. Concomitant use of ribavirin and zidovudine is not recommended due to an increased risk of anaemia (see section "Interaction with other medicinal products and other forms of interaction").

Osteonecrosis. Although the aetiology of osteonecrosis is considered multifactorial, cases have been reported particularly in patients with advanced stages of HIV disease and/or long-term use of combination antiretroviral therapy.

Lazivudin should not be administered with other medicinal products containing lamivudine or with medicinal products containing emtricitabine.

Combination use of lamivudine and cladribine is not recommended.

Use during pregnancy or breastfeeding.

Fertility

Animal studies have shown no evidence of effects of either zidovudine or lamivudine on male or female fertility. There are no data on the effects of these two drugs on human fertility. It has been established that zidovudine does not affect sperm count, morphology, or motility in men.

Pregnancy

When deciding on the use of antiretroviral medicinal products for the treatment of HIV infection in pregnant women, and thus for reducing the risk of vertical transmission of HIV to the newborn, data from animal studies and clinical experience in pregnant women should be considered. In this regard, it has been demonstrated that the use of zidovudine in pregnant women, followed by treatment of newborns, reduces the frequency of mother-to-child transmission of HIV infection. A large amount of data from pregnant women who received lamivudine or zidovudine do not indicate teratogenic toxicity (over 3000 first-trimester exposures, including over 2000 cases involving both lamivudine and zidovudine). The risk of malformations is considered unlikely, supported by this extensive dataset.

The active substances in Lazivudin may inhibit cellular DNA replication, and in one animal study, zidovudine was shown to be a transplacental carcinogen. The clinical significance of these findings is unknown.

For female patients co-infected with hepatitis who are taking lamivudine-containing medicinal products such as Lazivudin and subsequently become pregnant, the possibility of hepatitis relapse upon discontinuation of lamivudine should be considered.

Mitochondrial dysfunction. In vitro and in vivo studies with nucleoside and nucleotide analogues have demonstrated that they cause varying degrees of mitochondrial damage. Reports of mitochondrial dysfunction have been documented in HIV-negative children exposed to nucleoside analogues in utero and/or postnatally (see section "Special precautions for use").

Breastfeeding period

Both lamivudine and zidovudine are excreted into human breast milk at concentrations similar to those found in blood serum.

Based on data from over 200 mother/infant pairs receiving HIV treatment, lamivudine concentrations in infant serum from breastfeeding mothers receiving HIV treatment were very low (<4% of maternal serum concentrations) and gradually decreased to undetectable levels by the time infants reached 24 weeks of age. There are no data on the safety of lamivudine in infants under three months of age.

After a single 200 mg dose of zidovudine in HIV-infected women, average zidovudine concentrations were similar in breast milk and blood serum.

HIV-infected women are recommended not to breastfeed their infants under any circumstances to avoid transmission of HIV infection.

Ability to influence the speed of reactions when driving or operating machinery.

No specific studies have been conducted on this issue. The pharmacological properties of these drugs suggest a low likelihood of such effects. The patient's clinical condition and the nature of adverse reactions associated with lamivudine and zidovudine should be taken into account.

Method of Administration and Dosage

Treatment is prescribed by a physician experienced in managing HIV-infected patients.

The medicinal product can be taken with or without food.

To ensure accurate dosing, tablets must be swallowed whole and not crushed. For patients who have difficulty swallowing, it is recommended to split and crush the tablets and mix them with a small amount of semisolid food or liquid. The entire amount of the resulting mixture should be consumed immediately after crushing.

Adults and children weighing at least 30 kg

The recommended dose of the medicinal product is 1 tablet twice daily.

Children weighing from 21 to 30 kg

The recommended dose of the medicinal product is half a tablet in the morning and 1 tablet in the evening.

Children weighing from 14 to 21 kg

The recommended dose of the medicinal product is half a tablet twice daily.

The dosing regimen for children weighing from 14 to 30 kg is primarily based on pharmacokinetic modeling and supported by clinical data from studies using lamivudine and zidovudine as individual components. There is a possibility of zidovudine pharmacokinetic overdose; therefore, careful safety monitoring is required. If gastrointestinal intolerance occurs in patients weighing from 21 to 30 kg, an alternative dosing regimen may be used: half a tablet three times daily.

Children weighing less than 14 kg

Lazivudine should not be used in children weighing less than 14 kg, as the doses of active ingredients cannot be adequately adjusted according to the child's body weight. These patients should receive lamivudine and zidovudine as separate medicinal products, in accordance with the prescribed dosing recommendations for these drugs. For these patients and for patients unable to swallow tablets, lamivudine and zidovudine are available as oral solutions.

In situations where it is necessary to discontinue one of the components of Lazivudine or reduce its dose, separate formulations of lamivudine and zidovudine, available as tablets/capsules or oral solution, may be used.

Renal Impairment

Concentrations of lamivudine and zidovudine are increased in patients with impaired renal function due to reduced clearance. Therefore, for patients with reduced renal function (creatinine clearance ≤50 mL/min), separate formulations of lamivudine and zidovudine are recommended to adjust the dosage of active ingredients. Physicians should consult the prescribing information for these medicinal products.

Hepatic Impairment

Limited data in patients with liver cirrhosis suggest that zidovudine accumulation may occur in patients with hepatic impairment due to reduced glucuronidation. Data from patients with moderate to severe hepatic impairment indicate that the pharmacokinetics of lamivudine are not significantly affected by hepatic dysfunction. However, dose adjustment of zidovudine may be necessary in patients with severe hepatic impairment; therefore, these patients should be prescribed separate formulations of lamivudine and zidovudine. Physicians should consult the prescribing information for these medicinal products.

Dose Adjustment in Patients with Hematological Adverse Reactions

Dose adjustment of zidovudine may be required if hemoglobin levels fall below 9 g/dL (or 5.59 mmol/L) or neutrophil count drops below 1.0 × 10^9/L. Since dose adjustment of Lazivudine is not feasible, lamivudine and zidovudine should be administered as separate formulations. Physicians should consult the prescribing information for these medicinal products.

Elderly Patients

Specific data are lacking; however, special attention should be paid to this patient group due to the potential for age-related decline in renal function or changes in hematological parameters.

Children

For the treatment of children weighing less than 14 kg, separate formulations of lamivudine and zidovudine should be used in accordance with the prescribing information for these drugs.

Overdose

No specific signs or symptoms of acute lamivudine and zidovudine overdose have been identified beyond those described in the section "Adverse Reactions." No fatal cases have been reported, and all patients' conditions normalized.

In the event of overdose, the patient should be monitored for early detection of signs of intoxication, and standard supportive therapy should be administered. Since lamivudine is dialyzable, continuous hemodialysis may be used in overdose management; however, clinical experience in this regard is limited. Hemodialysis and peritoneal dialysis appear to be poorly effective in eliminating zidovudine from the body but may accelerate the elimination of its metabolite (glucuronide). More detailed information is available in the prescribing information for lamivudine and zidovudine.

Adverse Reactions

Adverse reactions have been reported during therapy in HIV-infected patients receiving lamivudine or zidovudine alone, as well as their combination. For many of these reactions, it remains unclear whether they are related to the use of lamivudine, zidovudine, or the broad range of other medicinal products used in the treatment of HIV disease, or are a result of the disease itself. Since Lazivudin contains a combination of lamivudine and zidovudine, the type and severity of adverse reactions can be expected to be associated with these two components. No data indicating increased toxicity due to the concomitant administration of these two components have been identified.

Lactic acidosis, sometimes fatal, has been reported with the use of zidovudine and is usually associated with severe hepatomegaly and hepatic steatosis (see section "Special Warnings and Precautions for Use").

Subcutaneous fat loss has been observed with zidovudine use, most noticeable in the face, limbs, and buttocks. Patients receiving Lazivudin should be frequently monitored for signs of lipoatrophy. If such manifestations occur, Lazivudin therapy should be discontinued (see section "Special Warnings and Precautions for Use").

During antiretroviral therapy, increases in body weight and levels of lipids and glucose in the blood may occur (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 during combination antiretroviral therapy. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported during immune reconstitution, although their onset is more variable and may occur many months after initiation of treatment (see section "Special Warnings and Precautions for Use").

Cases of osteonecrosis have been reported, primarily in patients with well-recognized risk factors, advanced stage of HIV infection, or long-term exposure to combination antiretroviral therapy. The frequency of osteonecrosis cases is unknown (see section "Special Warnings and Precautions for Use").

Lamivudine

The adverse reactions listed below, considered at least possibly related to treatment, are presented by system organ class and absolute frequency of occurrence. The frequency of adverse reactions is classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Blood and Lymphatic System Disorders

Uncommon: neutropenia and anemia (sometimes severe), thrombocytopenia.

Very rare: pure red cell aplasia.

Metabolism and Nutritional Disorders

Very rare: lactic acidosis.

Nervous System Disorders

Common: headache, insomnia.

Very rare: peripheral neuropathy (or paresthesia).

Respiratory, Thoracic and Mediastinal Disorders

Common: cough, nasal symptoms.

Gastrointestinal Disorders

Common: nausea, vomiting, abdominal pain or cramps, diarrhea.

Rare: pancreatitis, increased serum amylase levels.

Hepatobiliary Disorders

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

Rare: hepatitis.

Skin and Subcutaneous Tissue Disorders

Common: rash, alopecia.

Rare: angioneurotic edema.

Musculoskeletal and Connective Tissue Disorders

Common: arthralgia, muscle disorders.

Rare: rhabdomyolysis.

General Disorders and Administration Site Conditions

Common: fatigue, malaise, fever.

Zidovudine

The adverse reaction profile is similar in adults and adolescents. The most serious adverse reactions include anemia (which may require blood transfusions), neutropenia, and leukopenia. These are more commonly observed with higher doses of the drug (1200–1500 mg per day) and in patients with advanced stages of HIV infection (especially those with reduced bone marrow reserve prior to treatment initiation), particularly in patients with CD4 cell counts below 100/mm³ (see section "Special Warnings and Precautions for Use").

The frequency of neutropenia also increases in patients who had low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels at the start of zidovudine therapy.

The adverse reactions listed below, considered at least possibly related to treatment, are presented by system organ class and absolute frequency of occurrence. The frequency of adverse reactions is classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Blood and Lymphatic System Disorders

Common: anemia (which may require transfusions), neutropenia, and leukopenia.

More commonly observed with higher doses (1200–1500 mg per day) and in patients with advanced stages of HIV (especially those with reduced bone marrow reserve prior to treatment), particularly in patients with CD4+ cell counts below 100/mm³. Due to these adverse effects, dose reduction or discontinuation of therapy may be necessary (see section "Special Warnings and Precautions for Use"). The frequency of neutropenia also increases in patients who had low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels at the start of zidovudine therapy.

Uncommon: thrombocytopenia and pancytopenia (with bone marrow hypoplasia).

Rare: pure red cell aplasia.

Very rare: aplastic anemia.

Metabolism and Nutritional Disorders

Rare: lactic acidosis in the absence of hypoxemia, anorexia.

Redistribution/accumulation of body fat (see section "Special Warnings and Precautions for Use"). The frequency of this occurrence depends on many factors, including the specific antiretroviral drug combination used.

Psychiatric Disorders

Rare: anxiety, depression.

Nervous System Disorders

Very common: headache.

Common: dizziness.

Rare: insomnia, paresthesia, somnolence, decreased mental acuity, seizures.

Cardiac Disorders

Rare: cardiomyopathy.

Respiratory, Thoracic and Mediastinal Disorders

Uncommon: dyspnea.

Rare: cough.

Gastrointestinal Disorders

Very common: nausea.

Common: vomiting, abdominal pain, diarrhea.

Uncommon: flatulence.

Rare: pigmentation of oral mucosa, taste alteration, dyspepsia, pancreatitis.

Hepatobiliary Disorders

Common: increased levels of liver enzymes and bilirubin.

Rare: hepatic disorders, e.g., severe hepatomegaly with steatosis.

Skin and Subcutaneous Tissue Disorders

Uncommon: rash, pruritus.

Rare: skin and nail pigmentation, urticaria, increased sweating.

Musculoskeletal and Connective Tissue Disorders

Common: myalgia.

Uncommon: myopathy.

Renal and Urinary Disorders

Rare: frequent urination.

Reproductive System and Breast Disorders

Rare: gynecomastia.

General Disorders and Administration Site Conditions

Common: malaise.

Uncommon: fever, generalized pain, asthenia.

Rare: chills, chest pain, influenza-like syndrome.

Data from placebo-controlled and open-label studies indicate that the frequency of nausea and other common clinical adverse reactions consistently decreases during the first weeks of zidovudine therapy.

Shelf life. 2 years.

Storage conditions.

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

Packaging.

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

Prescription category.

Prescription only.

Manufacturer.

JSC "Tekhnolohiya".

Manufacturer's address and place of business.

8 Stara Prorynna Street, City of Uman, Cherkasy Region, 20300, Ukraine.