Lamihop 3

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LAMIXOP Z

Composition:

Active substances: 1 film-coated tablet contains lamivudine 150 mg and zidovudine 300 mg;

Excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, Opadry White 13B58802 coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex capsule-shaped tablets, film-coated, white in color, with a break line on one side and embossing «ML 6» on the other side.

Pharmacotherapeutic group. Antiviral agents for 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 (TF). Lamivudine-TF and zidovudine-TF are competitive inhibitors of human immunodeficiency virus reverse transcriptase. However, the primary mechanism of antiviral activity is incorporation as a monophosphate into the viral DNA chain, resulting in chain termination of its replication. The triphosphates of lamivudine and zidovudine exhibit significantly lower affinity for host cell DNA polymerase.

In vitro, lamivudine demonstrates low cytotoxicity toward peripheral lymphocytes, lymphocytic and monocytic-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.

It has been demonstrated that the combination of lamivudine and zidovudine reduces HIV viral load and increases CD4 cell counts. Recent clinical data indicate that lamivudine, either in combination with zidovudine or as part of other treatment regimens containing zidovudine, significantly reduces the risk of disease progression and mortality.

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

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

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

Pharmacokinetics.

Absorption

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

The bioequivalence of Lamihop 3 was evaluated compared to the combination of lamivudine 150 mg and zidovudine 300 mg. Additionally, the effect of food on the extent and rate of absorption was studied. Lamihop 3 was shown to be bioequivalent to the separate 150 mg lamivudine and 300 mg zidovudine tablets administered on an empty stomach. After administration of Lamihop 3, peak concentrations of lamivudine and zidovudine are 1.5 (1.3–1.8) mg/mL and 1.8 (1.5–2.2) mg/mL, respectively. The median time to peak concentration (t_max) 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 following administration of Lamihop 3 with food are similar to those observed under fasting conditions, although the rate of absorption (C_max, t_max) is reduced. Based on these data, Lamihop 3 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 does not impact the clinical effect 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

Following intravenous administration, the mean volume of distribution for lamivudine and zidovudine was found to be 1.3 and 1.6 L/kg, respectively. At therapeutic doses, lamivudine exhibits linear pharmacokinetics and binds only minimally to plasma proteins (less than 36% to serum albumin in vitro).

Protein binding of zidovudine ranges from 34% to 38%. Lamihop 3 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-serum concentration ratios for lamivudine and zidovudine, measured 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 by 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'-glucuronyl zidovudine, which is present in both urine and plasma. After intravenous administration, 3’-amino-3’-deoxythymidine has been identified as a metabolite of zidovudine.

Elimination

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

Based on limited data, there is a potential for zidovudine accumulation in patients with hepatic impairment 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.

Lamichop Z is contraindicated in patients with known hypersensitivity to lamivudine, zidovudine, or any component of the medicinal product.

Zidovudine is contraindicated in patients with neutrophil counts below 0.75×10⁹/L or hemoglobin levels below 7.5 g/dL or 4.65 mmol/L; therefore, Lamichop Z is contraindicated in this patient group (see section "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

The medicinal product contains lamivudine and zidovudine; therefore, any interactions characteristic of either of these agents individually are also applicable to Lamichop Z. 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, the potential for interactions with antiretroviral protease inhibitors, non-nucleosides, and other medicinal products primarily metabolized by P450 enzymes is unlikely.

Interaction studies have been conducted only in adults. The interactions described below are not exhaustive but include investigated drug classes.

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

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

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, primarily in acute situations, with medicinal products 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 Lamichop Z and any of these agents is necessary, renal function and haematological parameters should be monitored and dosage of one or more components of therapy should be reduced as necessary.

Limited clinical study data indicate no significant increase in the risk of interaction between zidovudine and co-trimoxazole (see above information regarding interaction of lamivudine with co-trimoxazole), aerosolized pentamidine, pyrimethamine, or acyclovir when used at prophylactic doses.

Special precautions for use.

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

This section includes specific warnings and precautions applicable to both lamivudine and zidovudine. Additional precautions and warnings specific to the combination drug Lamihop Z are not available.

When dose adjustments of active substances are required, it is recommended to use individual formulations of lamivudine and zidovudine (see section "Method of administration and dosage"). 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 develop in patients receiving Lamihop Z or any other antiretroviral therapy. Therefore, these patients should remain under continuous clinical supervision by physicians experienced in managing HIV infection.

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

Hematological 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, for example, once every one to three months. In cases of severe anemia or myelosuppression during treatment with Lamihop Z, or in patients with pre-existing compromised bone marrow (i.e., hemoglobin less than 9 g/dL (5.59 mmol/L) or neutrophil count less than 1.0 × 10⁹/L), dose adjustment of zidovudine may be required (see section "Method of administration and dosage"). Because the dose of the fixed-dose combination cannot be reduced, 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. 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 zidovudine use. Early symptoms (symptomatic hyperlactatemia) 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 muscle weakness).

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

Lactic acidosis typically occurs after several months or more of treatment.

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

Zidovudine should be administered with caution in any patients (especially 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 receiving alpha-interferon and ribavirin are at particular risk.

Patients at increased risk require ongoing monitoring.

Mitochondrial function disorders: Nucleoside and nucleotide analogues may cause mitochondrial dysfunction of varying degrees, particularly pronounced with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors during intrauterine and/or postnatal periods, primarily in treatment regimens including zidovudine. The main adverse reactions reported were hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events were often transient. Neurological disorders (hypertonia, seizures, behavioral disturbances) have been rarely reported, occurring with delayed onset 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 who presents with severe clinical disorders of unknown etiology, 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

Zidovudine treatment is associated with loss of subcutaneous fat, linked to mitochondrial toxicity. The frequency and severity of lipoatrophy are related to cumulative exposure. This loss of fat deposits, most evident in the face, limbs, and buttocks, may be irreversible even after switching to a zidovudine-free treatment regimen. Patients should be regularly assessed for signs of lipoatrophy during zidovudine and zidovudine-containing product therapy. If lipoatrophy is suspected, therapy should be changed to an alternative treatment regimen.

Body weight and metabolic parameters

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy. Contributing factors 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 disorders should be based on clinical indications.

Immune reconstitution syndrome: In HIV-infected patients with severe immunodeficiency, an inflammatory response to asymptomatic or residual opportunistic infections may occur during combined antiretroviral therapy (cART), potentially causing severe clinical conditions or symptom exacerbation. These reactions typically occur within the first few weeks or months of cART. Relevant examples include cytomegalovirus-induced retinitis, generalized or focal mycobacterial infections, or Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis 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; however, their onset is more variable and may occur many months after initiating treatment.

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

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

In patients with chronic hepatitis B or C undergoing combined antiretroviral therapy, there is an increased risk of severe and potentially fatal hepatic adverse events. 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 Lamihop Z 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 4 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 liver function deterioration during combined antiretroviral therapy and should be monitored according to standard practice. If signs of worsening liver disease appear 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 increased risk of anemia (see section "Interaction with other medicinal products and other forms of interaction").

Osteonecrosis: Although the etiology of osteonecrosis is considered multifactorial, cases have been reported particularly in patients with advanced HIV disease and/or long-term use of combined antiretroviral therapy (cART).

Lamihop Z should not be prescribed with other medicinal products containing lamivudine or those containing emtricitabine.

Combined use of lamivudine and cladribine is not recommended.

Use during pregnancy or breastfeeding.

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, zidovudine use in pregnant women followed by treatment of newborns has been shown to reduce the rate of mother-to-child transmission of HIV infection. A large amount of data from pregnant women who received lamivudine or zidovudine does not indicate teratogenic toxicity (over 3000 cases of first-trimester exposure, of which more than 2000 involved both lamivudine and zidovudine). The risk of malformations is considered unlikely, supported by this extensive dataset.

The active substances of the medicinal product 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 patients co-infected with hepatitis who are receiving lamivudine-containing treatments such as Lamihop Z and subsequently become pregnant, the possibility of hepatitis relapse upon discontinuation of lamivudine should be considered.

Mitochondrial dysfunction: In vitro and in vivo use of nucleoside and nucleotide analogues has demonstrated that they can cause varying degrees of mitochondrial damage. Reports exist of mitochondrial dysfunction in HIV-negative children exposed to nucleoside analogues in utero and/or in the postnatal period (see section "Special precautions for use").

Breastfeeding

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

Based on data from more than 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. Safety data for lamivudine use in infants under three months of age are lacking.

After a single 200 mg dose of zidovudine administered to HIV-infected women, the average concentration of zidovudine was similar in maternal milk and blood serum.

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

Ability to influence reaction speed when driving or operating machinery.

No specific studies have been conducted on this issue. Given the pharmacological profile of the drug, there is no reason to expect any harmful effect. However, the patient's clinical status and the adverse effect profile of lamivudine and zidovudine should be taken into account when assessing the ability to perform such tasks.

Method of Administration and Dosage

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

Lamichop Z can be taken with or without food.

To ensure complete dose administration, the tablet should preferably be swallowed whole, without crushing. For patients unable to swallow the whole tablet, it may be crushed and mixed with a small amount of food or liquid and taken immediately after crushing.

Adults and children weighing at least 30 kg

The recommended dose of Lamichop Z is 1 tablet twice daily.

Children weighing from 21 to 30 kg

The recommended oral dose of Lamichop Z is half a tablet in the morning and 1 tablet in the evening.

Children weighing from 14 to 21 kg

The recommended oral dose of Lamichop Z 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 trial data using lamivudine and zidovudine as individual components. There may be a risk 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 of half a tablet three times daily may be considered.

Lamichop Z 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 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, as well as for patients unable to swallow tablets, lamivudine and zidovudine are available as oral solutions.

In situations where treatment with one of the components of Lamichop Z needs to be discontinued or its dose reduced, separate formulations of lamivudine and zidovudine (available as tablets/capsules or oral solution) should be used.

Renal impairment: Concentrations of lamivudine and zidovudine are increased in patients with impaired renal function due to reduced clearance. Therefore, in patients with reduced renal function (creatinine clearance ≤50 mL/min), separate formulations of lamivudine and zidovudine are recommended to allow appropriate dose adjustment of the active substances. Physicians should consult the medical instructions 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 lamivudine pharmacokinetics 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 receive lamivudine and zidovudine as separate formulations. Physicians should consult the medical instructions for these medicinal products.

Dose adjustment in patients with hematological adverse effects

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 × 10⁹/L. Since dose adjustment of Lamichop Z is not feasible, lamivudine and zidovudine should be administered as separate formulations. Physicians should consult the medical instructions for these medicinal products.

Dosing in elderly patients

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

Overdose

Data on overdose are limited. No specific signs or symptoms of acute lamivudine or zidovudine overdose, other than those described in the section "Adverse Reactions," have been reported. No fatal cases have been reported, and all patients recovered.

In case of overdose, the patient should be closely monitored for toxicity (see section "Adverse Reactions"), and standard supportive therapy should be administered as needed. Lamivudine is dialyzable; therefore, sustained hemodialysis may be used in overdose, although this has not been specifically studied. Hemodialysis and peritoneal dialysis have limited effect on zidovudine elimination but may accelerate the removal of its glucuronide metabolite. For further information, physicians may refer to the instructions for use of lamivudine and zidovudine.

Adverse Reactions

Adverse effects have been reported during antiretroviral therapy in HIV-infected patients receiving lamivudine and zidovudine, both individually and in combination. For many of these effects, it remains unclear whether they are related to the use of lamivudine, zidovudine, or the broad range of other medications used in the treatment of HIV disease, or are a consequence of the disease itself. Since Lamichop Z contains a combination of lamivudine and zidovudine, the type and severity of adverse effects are expected to be consistent with those associated with these two components. There is no evidence of increased toxicity due to concomitant administration of these two components.

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

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

During antiretroviral therapy, patients may experience increased body weight and elevated levels of lipids and glucose in the blood (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 initiation of combination antiretroviral therapy (cART). Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported during immune reconstitution; however, the onset of these conditions is more variable and may occur many months after the start 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 (cART). Frequency is unknown (see section "Special Warnings and Precautions for Use").

Lamivudine

The adverse reactions listed below, considered at least possibly related to treatment, are categorized by system organ class and absolute frequency of occurrence. Frequency of adverse effects is classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000). Within each frequency group, adverse effects 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 Digestive System 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, elevated serum amylase levels

Hepatobiliary Disorders

Uncommon: Transient elevations in liver enzymes (AST, ALT)

Rare: Hepatitis

Skin and Subcutaneous Tissue Disorders

Common: Rash, alopecia

Rare: Angioedema

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 occur more frequently at higher doses (1200–1500 mg/day) and in patients with advanced HIV disease (particularly those with reduced bone marrow reserve prior to treatment initiation), especially in patients with CD4 cell counts below 100/mm³ (see section "Special Warnings and Precautions for Use").

The incidence of neutropenia is also increased in patients who have low neutrophil count, 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 categorized by system organ class and absolute frequency of occurrence. Frequency of adverse effects is classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000). Within each frequency group, adverse effects are listed in decreasing order of severity.

Blood and Lymphatic System Disorders

Common: Anemia (which may require blood transfusions), neutropenia, and leukopenia

These occur more frequently at higher doses (1200–1500 mg/day) and in patients with advanced stages of HIV (particularly those with reduced bone marrow reserve prior to treatment), especially in patients with CD4+ cell counts below 100/mm³. Dose reduction or discontinuation of therapy may be necessary due to these adverse effects (see section "Special Warnings and Precautions for Use"). The incidence of neutropenia is also increased in patients with low neutrophil count, 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 Digestive System 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 condition depends on multiple 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, mental slowing, seizures

Cardiovascular System 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: Oral mucosal pigmentation, taste alteration, dyspepsia, pancreatitis

Hepatobiliary Disorders

Common: Elevated 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, hyperhidrosis

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 events consistently decreases during the first weeks of zidovudine therapy.

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

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

Prescription category. Prescription only.

Manufacturer.

MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and place of business.

Phase II, Plot No. 12, 15, 21, 23, 24, 25, 26, 27, 28 and 30, Survey No. 366, Premier Industrial Estate, Kachigam, Daman, 396210, India