Zidovudine

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

Composition:

Active substance: zidovudine;

5 ml of solution contains 50 mg of zidovudine;

Excipients: sucrose, sodium benzoate, citric acid anhydrous, glycerin, strawberry flavor, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical characteristics: colorless or pale yellow liquid with a strawberry odor.

Pharmacotherapeutic group. Direct-acting antiviral agents. Nucleoside and nucleotide reverse transcriptase inhibitors. ATC code J05AF01.

Pharmacological Properties

Pharmacodynamics

Zidovudine is an antiviral agent highly active in vitro against retroviruses, including human immunodeficiency virus (HIV).

Zidovudine is phosphorylated in both infected and uninfected cells to the monophosphate (MP) derivative by cellular thymidine kinase. Further phosphorylation of zidovudine-MP to the diphosphate (DP), and then to the triphosphate (TP) derivative, is catalyzed by cellular thymidylate kinase and nonspecific kinases, respectively. Zidovudine-TP acts as both an inhibitor and substrate of viral reverse transcriptase. Further proviral DNA formation is blocked by incorporation of zidovudine-MP into the chain, followed by chain termination. The affinity of zidovudine-TP for HIV reverse transcriptase is approximately 100 times greater than for cellular DNA polymerase alpha.

Clinical Virology

The relationship between in vitro HIV susceptibility to zidovudine and clinical response to therapy is still under investigation. In vitro sensitivity testing is not standardized, so results may vary depending on methodological factors. Reduced in vitro susceptibility to zidovudine has been reported for HIV isolates from patients receiving prolonged courses of zidovudine therapy. Available data indicate that during early stages of HIV infection, the frequency and degree of reduced in vitro susceptibility are significantly lower than in later stages of the disease.

Reduced susceptibility, with emergence of zidovudine-resistant strains, limits the clinical efficacy of zidovudine monotherapy. Clinical trial data indicate that zidovudine, particularly in combination with lamivudine, and also with didanosine or zalcitabine, leads to a significant reduction in the risk of disease progression and mortality. The addition of a protease inhibitor to the combination of zidovudine and lamivudine has been shown to provide additional benefit in delaying disease progression and improving survival compared to dual therapy alone.

The in vitro antiviral efficacy of combinations of antiretroviral agents is under investigation. Clinical and in vitro studies of zidovudine in combination with lamivudine suggest that zidovudine-resistant virus isolates may become sensitive to zidovudine again if they simultaneously acquire resistance to lamivudine. Furthermore, clinical evidence indicates that zidovudine in combination with lamivudine delays the emergence of zidovudine resistance in patients previously untreated with antiretroviral therapy.

Zidovudine and other antiretroviral agents (investigated agents: abacavir, didanosine, lamivudine, and interferon-alpha) have not shown antagonistic effects in vitro.

Resistance to thymidine analogs (one of which is zidovudine) is well characterized and results from the gradual accumulation of up to six specific mutations in HIV reverse transcriptase at codons 41, 67, 70, 210, 215, and 219.

Viruses acquire phenotypic resistance to thymidine analogs either through a combination of mutations at codons 41 and 215, or by accumulating at least four of the six mutations. These thymidine analog mutations alone do not cause a high level of cross-resistance to any other nucleosides, allowing continued use of other approved reverse transcriptase inhibitors.

Two types of multi-drug resistance mutations result: the first characterized by HIV reverse transcriptase mutations at codons 62, 75, 77, 116, and 151; the second involving the T69S mutation plus a 6-base pair insertion at the same position, leading to phenotypic resistance to AZT as well as to other approved nucleoside reverse transcriptase inhibitors. Either of these two multi-nucleoside resistance patterns severely limits future therapeutic options.

A study demonstrated that zidovudine is effective in reducing the rate of maternal-fetal transmission of HIV-1 (23% infection rate with placebo vs. 8% with zidovudine) when administered (100 mg five times daily) to HIV-positive pregnant women (from 14–34 weeks of gestation) and their newborns (2 mg/kg every 6 hours) up to 6 weeks of age. In a short-term study, use of oral zidovudine alone (300 mg twice daily), starting at 36 weeks of gestation until delivery, also reduced maternal-fetal HIV transmission (19% infection rate with placebo vs. 9% with zidovudine). These data, along with findings from a published study comparing zidovudine regimens for preventing maternal-fetal HIV transmission, showed that short-term maternal treatment (starting at 36 weeks) is less effective than long-term maternal treatment (starting at 14–34 weeks) in reducing perinatal HIV transmission.

Pharmacokinetics

Adults

Absorption. Zidovudine is well absorbed from the gastrointestinal tract, with bioavailability of 60–70% at all studied doses. In a bioequivalence study, mean (CV%) values of (Cmax), (Cmin), and AUC in 16 patients receiving 300 mg zidovudine tablets twice daily were 8.57 (54%) µM (2.29 µg/mL), 0.08 (96%) µM (0.02 µg/mL), and 8.39 (40%) h*µM (2.24 h*µg/mL), respectively.

Distribution. In intravenous administration studies, the mean terminal half-life in plasma was 1.1 hours, mean total body clearance was 27.1 mL/min/kg, and the apparent volume of distribution was 1.6 L/kg. In adults, the mean cerebrospinal fluid (CSF)/plasma concentration ratio of zidovudine 2–4 hours after dosing is approximately 0.5. Data indicate that zidovudine crosses the placenta and is detectable in amniotic fluid and fetal blood. Zidovudine has also been detected in semen and breast milk. Plasma protein binding is relatively low (34–38%), and drug interactions involving displacement from binding sites are not expected.

Biological Transformation. Zidovudine is primarily eliminated via hepatic conjugation, forming an inactive glucuronidated metabolite. The 5'-glucuronide of zidovudine is the major metabolite in both plasma and urine, accounting for approximately 50–80% of the administered dose excreted by the kidneys. 3'-amino-3'-deoxythymidine (AMT) has been identified as a metabolite of zidovudine after intravenous administration.

Elimination. Renal clearance of zidovudine significantly exceeds creatinine clearance, indicating substantial tubular secretion.

Children

Absorption. In children aged 5–6 months, the pharmacokinetic profile of zidovudine is similar to that in adults. Zidovudine is well absorbed in the intestine, with bioavailability of 60–74% across all studied doses, averaging 65%. Cmax levels were 4.45 µM (1.19 µg/mL) after a dose of 120 mg zidovudine (in solution)/m² body surface area and 7.7 µM (2.06 µg/mL) at 180 mg/m² body surface area. Doses of 180 mg/m² four times daily in children resulted in systemic exposure (24-hour AUC of 40.0 h*µM or 10.7 h*µg/mL) similar to that achieved with 200 mg six times daily in adults (40.7 h*µM or 10.9 h*µg/mL).

Distribution. After intravenous administration, the mean terminal half-life in plasma and total clearance were 1.5 hours and 30.9 mL/min/kg, respectively. In children, the mean CSF/plasma concentration ratio of zidovudine ranged from 0.52 to 0.85, as determined during oral therapy 0.5–4 hours after dosing, and was 0.87 as determined during intravenous therapy 1–5 hours after a one-hour infusion. During continuous intravenous infusion, the mean steady-state CSF/plasma concentration ratio was 0.24.

Biological Transformation. The primary metabolite is the 5'-glucuronide. After intravenous administration, 29% of the dose was recovered unchanged in urine, and 45% was excreted as glucuronide.

Elimination. Renal clearance of zidovudine significantly exceeds creatinine clearance, indicating substantial tubular secretion. Available pharmacokinetic data in neonates and young children suggest that glucuronidation of zidovudine is reduced, leading to increased bioavailability, decreased clearance, and prolonged half-life in infants under 14 days of age; thereafter, pharmacokinetics appear similar to those reported in adults.

Pregnancy

Zidovudine pharmacokinetics were studied in eight women during the third trimester of pregnancy. No evidence of drug accumulation was observed as pregnancy progressed. Zidovudine pharmacokinetics were similar to those in non-pregnant adults. Due to passive transfer of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were nearly equal to maternal plasma concentrations during delivery.

Elderly Patients

There are no specific pharmacokinetic data available for zidovudine in elderly patients.

Renal Impairment

In patients with severe renal impairment, apparent clearance of orally administered zidovudine was approximately 50% of that in healthy volunteers with normal renal function. Hemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination, whereas elimination of the inactive glucuronide metabolite is increased (see section "Special Warnings and Precautions for Use").

Hepatic Impairment

Data on zidovudine pharmacokinetics in patients with hepatic impairment are limited (see section "Special Warnings and Precautions for Use").

Clinical Characteristics

Indications

Use in combination with other antiretroviral agents for the treatment of HIV infection in children and adults.

Use in HIV-positive pregnant women (pregnancy beyond 14 weeks) for prevention of mother-to-child transmission of HIV and for primary prophylaxis of HIV infection in newborns.

Contraindications

Hypersensitivity to zidovudine or to any other component of the medicinal product.

Neutropenia (neutrophil count less than 0.75×10⁹/L) or hemoglobin levels below 7.5 g/dL (or 4.65 mmol/L) (see section "Special Warnings and Precautions for Use").

Zidovudine is contraindicated in newborns with hyperbilirubinemia requiring treatment other than phototherapy, and in newborns with transaminase levels exceeding the normal range by more than 5 times.

Interaction with Other Medicinal Products and Other Forms of Interaction

Rifampicin. Limited data indicate that concomitant administration of zidovudine with rifampicin reduces the AUC (area under the plasma concentration-time curve) of zidovudine by 48% ± 34%. This may lead to partial or complete loss of zidovudine efficacy. Concomitant use of rifampicin and zidovudine should be avoided (see section "Special Warnings and Precautions for Use").

Stavudine. Zidovudine in combination with stavudine is antagonistic in vitro. Concomitant use of stavudine and zidovudine should be avoided (see section "Special Warnings and Precautions for Use").

Probenecid. Probenecid increases the AUC of zidovudine by 106% (range 100–170%). Patients receiving both drugs should be closely monitored for hematological toxicity.

Lamivudine. A moderate increase in C_max (28%) of zidovudine is observed when administered concomitantly with lamivudine, although overall exposure (AUC) is not significantly altered. Zidovudine does not affect the pharmacokinetics of lamivudine.

Phenytoin. Low plasma levels of phenytoin have been reported in some patients receiving zidovudine, although one patient had elevated levels. These data suggest that phenytoin levels should be closely monitored when both drugs are used concomitantly.

Atovaquone. Zidovudine does not affect the pharmacokinetics of atovaquone. However, pharmacokinetic data show that atovaquone reduces the metabolism of zidovudine to its glucuronide metabolite (the area under the plasma concentration-time curve [AUC] of zidovudine increases by 33%, and C_max of the glucuronide metabolite in plasma decreases by 19%). When atovaquone is administered at doses of 500 mg/day or 600 mg/day for 3 weeks for treatment of Pneumocystis carinii pneumonia, there may be a rare increase in the frequency of adverse effects related to higher plasma levels of zidovudine. Close monitoring of the patient is required during prolonged atovaquone therapy.

Valproic acid, fluconazole, or methadone. Concomitant use with zidovudine increases its AUC and correspondingly decreases zidovudine clearance. As data are limited, the clinical significance of this interaction is unknown. Patients should be closely monitored for signs of zidovudine toxicity.

Ribavirin. Worsening of anemia associated with ribavirin use has been observed in patients receiving zidovudine as part of a combination antiretroviral regimen, although the exact mechanism remains unclear. Therefore, combining ribavirin with zidovudine is not recommended. The physician should replace zidovudine with an alternative agent in the combination antiretroviral regimen if already prescribed. This is particularly important for patients with a history of zidovudine-induced anemia.

Concomitant use, mostly in acute settings, with potentially nephrotoxic or myelosuppressive agents (e.g., systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin B, flucytosine, ganciclovir, interferon, vincristine, vinblastine, and doxorubicin) may also increase the risk of zidovudine-related adverse effects. When concomitant use of these agents is necessary, renal function and hematological parameters should be closely monitored, and dose reduction of one or more agents should be considered if needed.

Limited clinical study data do not indicate a significant increase in the risk of adverse reactions to zidovudine when used concomitantly with co-trimoxazole, aerosolized pentamidine, pyrimethamine, or acyclovir at prophylactic doses.

Clarithromycin. Clarithromycin tablets reduce the absorption of zidovudine; therefore, a two-hour interval between administration of these agents should be maintained.

Special precautions for use

The drug does not cure HIV infection or AIDS, and opportunistic infections and other complications of HIV infection may continue to occur in patients receiving zidovudine or any other antiretroviral therapy.

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

Haematological adverse reactions. Anaemia (usually not before 6 weeks of starting treatment, but occasionally earlier), neutropenia (usually not before 4 weeks of starting treatment, but sometimes earlier), and leucopenia (secondary to neutropenia) may be expected in patients receiving zidovudine. These occur more frequently when higher doses are used (1200–1500 mg/day) and in patients with low bone marrow reserve prior to treatment, particularly in advanced stages of HIV disease.

Haematological parameters should be closely monitored. In patients with advanced HIV disease, blood counts are recommended at least once every 2 weeks during the first 3 months of treatment and at least once a month thereafter. Depending on the patient's clinical condition, blood counts may be performed less frequently, for example every 1–3 months.

If haemoglobin levels decrease from 7.5 g/dL (4.65 mmol/L) to 9 g/dL (5.59 mmol/L) or neutrophil counts decrease from 0.75×10⁹/L to 1.0×10⁹/L, dosage reduction may be necessary until signs of bone marrow recovery appear; alternatively, a short (2–4 week) treatment interruption with zidovudine may accelerate recovery. Bone marrow recovery usually occurs within 2 weeks, after which therapy with zidovudine may be restarted at reduced doses. In cases of severe anaemia, reducing the zidovudine dose does not eliminate the need for blood transfusions (see section "Contraindications").

Mitochondrial dysfunction following in utero exposure

Nucleoside and nucleotide analogues may cause mitochondrial dysfunction of varying degrees, particularly pronounced when used concomitantly with stavudine, didanosine, and zidovudine. Cases of mitochondrial dysfunction have been reported in HIV-negative infants exposed to nucleoside inhibitors during the in utero and/or postnatal period, primarily in treatment regimens containing zidovudine. The main adverse reactions reported include hematological disorders (anemia, neutropenia) and metabolic disturbances (hyperlactatemia, hyperlipasemia). These events are often transient. Rarely, neurological disorders (hypertonia, seizures, behavioral disturbances) have been reported with delayed onset after drug administration. Whether such neurological disorders are transient or permanent remains unknown. The possibility of such disorders should be considered in any child exposed to nucleoside and nucleotide analogues in utero who presents with severe clinical manifestations of unknown etiology, especially neurological symptoms. These data do not affect current recommendations for the use of antiretroviral drugs in pregnant women to prevent vertical HIV transmission.

Lipoatrophy

Treatment with zidovudine is associated with loss of subcutaneous fat, linked to mitochondrial toxicity. The frequency and severity of lipoatrophy are related to 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 monitored for signs of lipoatrophy during therapy with zidovudine and zidovudine-containing products. If lipoatrophy is suspected, patients should be switched 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. There is evidence that treatment may influence increased lipid levels in some cases, whereas evidence for treatment-related weight gain is lacking. Monitoring of serum lipid and blood glucose levels should be performed according to established HIV treatment guidelines. Management of disorders related to lipid level changes should be based on clinical indications.

Liver disease. Zidovudine clearance in patients with mild hepatic impairment without cirrhosis (Child–Pugh score 5–6) is similar to that observed in healthy volunteers; therefore, dose adjustment of zidovudine is not required. For patients with moderate to severe hepatic impairment (Child–Pugh score 7–15), specific dosing recommendations cannot be made due to the wide variability in zidovudine exposure observed; therefore, zidovudine is not recommended in this patient group.

Patients with chronic hepatitis B or C undergoing combination antiretroviral therapy have an increased risk of severe and potentially fatal hepatic adverse effects. When used concomitantly with other antiviral agents for hepatitis B or C treatment, refer to the respective product information for these drugs.

Patients with pre-existing liver function abnormalities, including chronic active hepatitis, have an increased risk of liver function deterioration during combination antiretroviral therapy and should be closely monitored. If signs of liver disease worsening occur, interruption or discontinuation of therapy should be considered (see section "Dosage and administration").

Immune reconstitution syndrome. In HIV-infected patients with advanced immunodeficiency, initiation of combination antiretroviral therapy (cART) may result in an inflammatory response to asymptomatic or residual opportunistic pathogens, leading to serious clinical conditions or symptom exacerbation. These reactions typically occur within the first few weeks or months after starting cART. Relevant examples include cytomegalovirus retinitis, generalized and/or focal infections caused by mycobacteria, or Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be promptly investigated and treated if necessary. Autoimmune disorders (such as Graves’ disease, autoimmune hepatitis) have also been reported during immune reconstitution; however, their onset is more variable and may occur many months after starting treatment, sometimes presenting with atypical features.

Patients should be warned against self-administration of other medications concurrently (see section "Interactions with other medicinal products and other forms of interaction").

Use in elderly patients and patients with renal or hepatic impairment: see section "Dosage and administration".

Osteonecrosis. Although the etiology of osteonecrosis is considered multifactorial (including corticosteroid use, alcohol abuse, severe immunosuppression, high body mass index), cases have been reported predominantly in patients with advanced HIV 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.

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

Excipients

Sodium benzoate: enhanced bilirubinemia following its displacement from albumin may exacerbate neonatal jaundice, potentially progressing to kernicterus (deposition of unconjugated bilirubin in brain tissue).

Sodium: this medicinal product contains less than 1 mmol sodium (23 mg) per dose unit, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

Pregnancy

Decisions regarding the use of antiretroviral drugs to treat HIV infection in pregnant women, and thus to reduce the risk of vertical transmission to the newborn, are generally based on data from animal studies and clinical experience in pregnant women. In this case, administration of zidovudine to pregnant women followed by neonatal treatment reduces the rate of mother-to-child HIV transmission.

Extensive data from pregnant women (over 3000 outcomes in the first trimester and more than 3000 outcomes in the second and third trimesters) indicate no evidence of teratogenic toxicity. Zidovudine may be used during pregnancy if clinically indicated. The risk of congenital malformations in humans is unlikely based on the large amount of data available.

Animal studies with zidovudine indicate reproductive toxicity. Active components of the drug may inhibit DNA cellular replication, and zidovudine has shown transplacental carcinogenic properties in one animal study. The clinical significance of these findings is unknown. Transplacental passage of zidovudine in humans has been demonstrated.

Mitochondrial dysfunction: nucleotide and nucleoside analogues have been shown in vitro and in vivo to cause varying degrees of mitochondrial damage. Cases of mitochondrial dysfunction have been reported in HIV-negative infants whose mothers received nucleoside analogues during pregnancy and/or the postnatal period (see section "Special precautions for use").

Fertility

Zidovudine did not impair male or female fertility in rats administered doses up to 450 mg/kg/day. There are no data on the effect of zidovudine on female fertility. In men, zidovudine does not affect sperm count, morphology, or motility.

Breastfeeding period

After a single 200 mg dose of zidovudine administered to HIV-infected women, the average concentration of zidovudine in breast milk was similar to that in blood serum. HIV-infected women are advised not to breastfeed their infants to avoid HIV transmission.

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

Studies on the effect of zidovudine on the ability to drive or operate machinery have not been conducted. The pharmacology of zidovudine does not suggest any expected negative impact. Nevertheless, the overall health status of the patient and the drug's adverse effect profile should always be considered when determining the suitability for such activities.

Method of Administration and Dosage

Therapy should be initiated by a physician experienced in the treatment of HIV infection.

Use in the treatment of adults and children with body weight of at least 30 kg: the recommended dose of the drug in combination with other antiretroviral agents is 250 or 300 mg twice daily.

Children

Children with body weight from 9 to 30 kg: the recommended dose is 0.9 mL/kg (9 mg/kg body weight) twice daily in combination with other antiretroviral agents (e.g., a child weighing 15 kg will require 13.5 mL of oral solution twice daily). The maximum dose should not exceed 300 mg twice daily.

Children with body weight from 4 to 9 kg: the recommended dose is 1.2 mL/kg (12 mg/kg) twice daily in combination with other antiretroviral agents (e.g., a newborn weighing 5 kg will require a dose of 6 mL of oral solution twice daily).

Children with body weight less than 4 kg: available data do not allow recommendations for a specific dosage in this pediatric group.

Prevention of mother-to-fetus transmission

The recommended dose of the drug for pregnant women (pregnancy beyond 14 weeks) is 500 mg daily orally (100 mg five times daily) until the onset of labor. During labor, zidovudine should be administered intravenously at a dose of 2 mg/kg body weight over 1 hour, followed by continuous intravenous infusion of 1 mg/kg/hour until clamping of the umbilical cord.

Newborns should receive zidovudine at a dose of 0.2 mL/kg (2 mg/kg) body weight orally every 6 hours, starting within the first 12 hours after birth and continuing until the infant reaches 6 weeks of age.

Extreme caution is required when calculating doses for newborns due to the small volumes of the oral solution. To ensure accurate dosing, a syringe of appropriate size with 0.1 mL graduations should be used to provide precise oral dosing for newborns.

Examples of recommendations for neonatal dosing of Zidovudine Oral Solution for prevention of mother-to-child HIV transmission in newborns

For infants who cannot be administered the drug orally, intravenous zidovudine should be administered at a dose of 1.5 mg/kg body weight over 30 minutes every 6 hours.

In the case of a planned cesarean section, intravenous infusion should be initiated 4 hours before the start of surgery. In the event of false labor, intravenous infusion should be discontinued and oral administration resumed.

Dose adjustment in patients with hematological adverse reactions

Consideration should be given to replacing zidovudine in patients whose hemoglobin levels or neutrophil counts decrease to clinically significant levels. Other potential causes of anemia or neutropenia must be excluded. If no alternative treatment options are available, dose reduction or discontinuation of zidovudine therapy should be considered (see sections "Contraindications" and "Special precautions").

Elderly patients

The pharmacokinetics of zidovudine in patients aged 65 years and older have not been studied, so specific data are lacking. However, this patient group requires special attention, as renal function deteriorates with age and hematological parameters change. Appropriate monitoring before and during zidovudine administration is recommended.

Renal impairment

For patients with severe renal impairment (creatinine clearance < 10 mL/min) and patients with end-stage renal disease on hemodialysis or peritoneal dialysis, a dose of 100 mg every 6–8 hours (300–400 mg/day) is recommended. Further dose adjustments may be necessary based on hematological parameters and clinical response (see section "Pharmacological properties").

Hepatic impairment

Accumulation of zidovudine occurs in patients with liver cirrhosis due to reduced glucuronidation. Dose reduction may be necessary; however, due to high variability in zidovudine exposure in patients with moderate to severe liver disease, definitive recommendations cannot be provided. In the absence of plasma zidovudine level monitoring, signs of intolerance such as the development of hematological adverse reactions (anemia, leukopenia, neutropenia) should be monitored, and the dose should be reduced and/or the dosing interval extended accordingly (see section "Special precautions").

Children

Administer from birth to prevent maternal-fetal transmission.

Overdose

Symptoms and signs

After acute overdose with zidovudine, no specific symptoms or signs have been observed other than those listed as adverse reactions.

Treatment

Patients should be closely observed for signs of toxicity (see section "Adverse reactions"), and appropriate supportive therapy should be administered.

Hemodialysis and peritoneal dialysis have limited effect on the elimination of zidovudine but enhance the elimination of its glucuronide metabolite.

Further management should be based on clinical indications or in accordance with recommendations from the national toxicology center, if available.

Adverse Reactions

The nature of adverse effects in children and adults is similar.

The most serious adverse reactions include anaemia (which may require blood transfusion), neutropenia, and leukopenia. These occurred more frequently with higher doses (1200–1500 mg/day) and in patients with advanced HIV infection (especially when low bone marrow reserve was present prior to treatment), particularly in patients with CD4 cell counts below 100/mm³. Dose reduction or discontinuation of therapy may be necessary (see section "Special Warnings and Precautions for Use"). The incidence of neutropenia was also increased in patients who had low neutrophil counts, low hemoglobin levels, and low serum vitamin B12 levels at the start of zidovudine therapy. The following events have been reported in patients receiving zidovudine.

Adverse reactions considered at least probably related to treatment (drug adverse reactions) are listed below by system organ class, organ class, and absolute frequency.

Frequency of adverse effects is classified according to the following scheme: 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).

Blood and lymphatic system

Common: anaemia, neutropenia, and leukopenia.

Uncommon: pancytopenia with bone marrow hypoplasia, thrombocytopenia.

Rare: pure red cell aplasia.

Very rare: aplastic anaemia.

Metabolism and digestive disorders

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

Psychiatric disorders

Rare: restlessness, depression.

Nervous system disorders

Very common: headache.

Common: dizziness.

Rare: seizures, mental slowing, insomnia, paraesthesia, somnolence.

Cardiovascular system

Rare: cardiomyopathy.

Respiratory system

Uncommon: dyspnoea.

Rare: cough.

Gastrointestinal tract

Very common: nausea.

Common: vomiting, diarrhoea, abdominal pain.

Uncommon: flatulence.

Rare: pancreatitis, oral mucosal pigmentation, taste alteration, dyspepsia.

Hepatobiliary system

Common: increased levels of liver enzymes and bilirubin.

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

Skin and subcutaneous tissue

Uncommon: rash, pruritus.

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

Musculoskeletal and connective tissue disorders

Common: myalgia.

Uncommon: myopathy.

Renal and urinary system

Rare: frequent urination.

Reproductive system

Rare: gynaecomastia.

General disorders:

Common: malaise.

Uncommon: asthenia, fever, generalised pain.

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

According to clinical trial data, the frequency of nausea and other common adverse reactions consistently decreases during the first few weeks of zidovudine therapy.

Adverse reactions in prevention of maternal-embryonic transmission

In the study, overall clinical adverse reactions and laboratory test abnormalities were similar in women in the zidovudine and placebo groups. However, there was a trend towards a higher incidence of mild to moderate anaemia before delivery in women receiving zidovudine.

According to the same study, haemoglobin levels in infants treated with zidovudine were slightly lower than in the placebo group, but blood transfusion was not required. Anaemia resolved within 6 weeks after completion of zidovudine treatment. Other adverse effects and laboratory test changes were similar between the placebo and zidovudine treatment groups. Long-term effects of the drug on the foetus and infant are unknown.

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

Zidovudine treatment has been associated with loss of subcutaneous fat, most prominently in the face, limbs, and buttocks. Patients receiving zidovudine should be frequently monitored for signs of lipoatrophy. If such development is observed, continuation of zidovudine therapy should not be recommended (see section "Special Warnings and Precautions for Use").

Body weight, serum lipid levels, and blood glucose levels may increase during antiretroviral therapy (see section "Special Warnings and Precautions for Use").

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (cART), an inflammatory reaction to asymptomatic or residual opportunistic infections may occur. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable, and these events 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 confirmed risk factors, long-standing HIV disease, or prolonged use of combination antiretroviral therapy. The frequency of such cases is unknown (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging

240 ml of solution in a bottle, 1 bottle together with a 10 ml oral dosing syringe and a 1.5 ml dosing syringe in a cardboard box.

Prescription status

By prescription only.

Manufacturer

Hetero Labs Limited, India.

Manufacturer's address and location of its business activity

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.