ZIDOVUDINE

Zidovudine should be prescribed by physicians who are experienced in the treatment of HIV infection.

Posology Dosage in adults and adolecents weighing at least 30 kg:

The usual recommended dose of Zidovudine in combination with other anti-retroviral agents is 250 or 300 mg twice daily.

Paediatric populationChildren weighing more than 21 kg and less than 30 kg:

The recommended dose of Zidovudine is two 100 mg capsules twice daily in combination with other antiretroviral agents.

Children weighing at least 14 kg and less than or equal to 21 kg:

The recommended dose of Zidovudine is one 100 mg capsule taken in the morning and two 100 mg capsules taken in the evening.

Children weighing at least 8 kg and less than 14 kg:

The recommended dose of zidovudone is one 100 mg capsule twice daily. 2). Weight (kg) In the morning In the evening Daily dose (mg) 8-13 one 100 mg capsule one 100 mg capsule 200 14-21 one 100 mg capsule two 100 mg capsules 300 22-30 two 100 mg capsules two 100 mg capsules 400 Alternatively children weighing at least 28 kg to 30 kg (included) could take: 28-30 one 250 mg capsule one 250 mg capsule 500 “Other pharmaceutical formulations containing zidovudine is available for dosing children less than 8kg and for those children above 8kg unable to swallow capsules”.

Dosage in the prevention of maternal-foetal transmission:

Pregnant women (over 14 weeks of gestation) should be given 500 mg/day orally (100 mg five times per day) until the beginning of labour. During labour and delivery zidovudine should be administered intravenously at 2 mg/kg bodyweight given over one hour followed by a continuous intravenous infusion at 1 mg/kg/h until the umbilical cord is clamped.

g. 6 ml dose of oral solution every 6 hours). 5 mg/kg bodyweight infused over 30 minutes every 6 hours. In case of planned caesarean, the infusion should be started 4 hours before the operation. In the event of a false labour, then the zidovudine infusion should be stopped and oral dosing restarted.

Dosage adjustments in patients with haematological adverse reactions:

Substitution of zidovudine should be considered in patients whose haemoglobin level or neutrophil count fall to clinically significant levels. Other potential causes of anaemia or neutropenia should be excluded. 4).

Dosage in the Elderly:

Zidovudine pharmacokinetics have not been studied in patients over 65 years of age and no specific data are available. However, since special care is advised in this age group due to age-associated changes such as the decrease in renal function and alterations in haematological parameters, appropriate monitoring of patients before and during use of Zidovudine is advised.

Dosage in renal impairment:

The recommended dose for patients with severe renal impairment (creatinine clearance < 10ml/min) and patients with end-stage renal disease maintained on haemodialysis or peritoneal dialysis is 100 mg every 6 to 8 hrs (300-400 mg daily).

2).

Dosage in hepatic impairment:

Data in patients with cirrhosis suggest that accumulation of zidovudine may occur in patients with hepatic impairment because of decreased glucuronidation. Dosage reductions may be necessary but, due to the large variability in zidovudine exposures in patients with moderate to severe liver disease, precise recommendations cannot be made.

4). Method of administration Oral use.

The adverse reaction profile appears similar for adults and children. The most serious adverse reactions include anaemia (which may require transfusions), neutropenia and leucopenia. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with advanced HIV disease (especially when there is poor bone marrow reserve prior to treatment), and particularly in patients with CD4 cell counts less than 100/mm3.

4). The incidence of neutropenia was also increased in those patients whose neutrophil counts haemoglobin levels and serum vitamin B12 levels were low at the start of zidovudine therapy. The following events have been reported in patients treated with zidovudine.

The adverse events considered at least possibly related to the treatment (adverse drug reactions, ADR) are listed below by body system, organ class and absolute frequency. Frequencies are defined as Very common (≥ 1/10), Common (≥ 1/100 to <1/10), Uncommon (≥ 1/1,000 to <1/100), Rare (≥ 1/10,000 to <1/1,000), Very rare (<1/10,000) Blood and lymphatic system disorders Common: Anaemia, neutropenia and leucopenia.

Uncommon:

Pancytopenia with bone marrow hypoplasia, thrombocytopenia.

Rare:

Pure red cell aplasia.

Very rare:

Aplastic anaemia.

Metabolism and nutrition disorders Rare:

Lactic acidosis in the absence of hypoxaemia, anorexia.

Psychiatric disorders Rare:

Anxiety and depression.

Nervous system disorders Very common:

Headache.

Common:

Dizziness.

Rare:

Convulsions, loss of mental acuity, insomnia, paraesthesia, somnolence.

Cardiac disorders Rare:

Cardiomyopathy Respiratory, thoracic and mediastinal disorders Uncommon: Dyspnoea.

Rare:

Cough.

Gastrointestinal disorders Very common:

Nausea.

Common:

Vomiting, diarrhoea and abdominal pain.

Uncommon:

Flatulence.

Rare:

Pancreatitis, oral mucosa pigmentation, taste disturbance and dyspepsia.

Hepatobiliary disorders Common:

Raised blood levels of liver enzymes and bilirubin Rare: Liver disorders such as severe hepatomegaly with steatosis.

Skin and subcutaneous tissue disorders Uncommon:

Rash and pruritis.

Rare :

Urticaria, nail and skin pigmentation and sweating.

Musculoskeletal and connective tissue disorders Common:

Myalgia.

Uncommon:

Myopathy.

Renal and urinary disorders Rare:

Urinary frequency.

Reproductive system and breast disorders Rare:

Gynaecomastia.

General disorders and administration site disorders Common:

Malaise.

Uncommon:

Asthenia, fever and generalised pain.

Rare:

Chest pain and influenza-like syndrome, chills. The available data from both placebo-controlled and open-label studies indicate that the incidence of nausea and other frequently reported clinical adverse reactionsconsistently decreases over time during the first few weeks of therapy with zidovudine.

Adverse reactions with zidovudine for the prevention of maternal-foetal transmission: In a placebo-controlled trial, overall clinical adverse reactions and laboratory test abnormalities were similar for women in the zidovudine and placebo groups.

However, there was a trend for mild and moderate anaemia to be seen more commonly prior to delivery in the zidovudine treated women. In the same trial, haemoglobin concentrations in infants exposed to zidovudine for this indication were marginally lower than in infants in the placebo group, but transfusion was not required.

Anaemia resolved within 6 weeks after completion of zidovudine therapy. Other clinical adverse reactions and laboratory test abnormalities were similar in the zidovudine and placebo groups. It is unknown whether there are any long-term consequences of in utero and infant exposure to zidovudine.

4). Treatment with zidovudine has been associated with loss of subcutaneous fat which is most evident in the face, limbs and buttocks. Patients receiving zidovudine should be frequently examined and questioned for signs of lipoatrophy.

4). 4) 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 arise. 4). Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).

). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Zidovudine is not a cure for HIV infection or AIDS. Patients receiving Zidovudine or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection. 5).

Haematological Adverse Reactions:

Anaemia (usually not observed before six weeks of Zidovudine therapy but occasionally occurring earlier), neutropenia (usually not observed before four weeks therapy but sometimes occurring earlier) and leucopenia (usually secondary to neutropenia) can be expected to occur in patients receiving Zidovudine.

8). Haematological parameters should be carefully monitored. For patients with advanced symptomatic HIV disease it is generally recommended that blood tests are performed at least every two weeks for the first three months of therapy and at least monthly thereafter.

Depending on the overall condition of the patient, blood tests may be performed less often, for example every 1 to 3 months. 0 x 109/l, the daily dosage may be reduced until there is evidence of marrow recovery; alternatively, recovery may be enhanced by brief (2-4 weeks) interruption of Zidovudine therapy.

Marrow recovery is usually observed within 2 weeks after which time Zidovudine therapy at a reduced dosage may be reinstituted. 3).

Lactic acidosis:

Lactic acidosis usually associated with hepatomegaly and hepatic steatosis has been reported with the use of zidovudine. Early symptoms (symptomatic hyperlactatemia) include benign digestive 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 and may be associated with pancreatitis, liver failure, or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with zidovudine should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering zidovudine to any patient (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 treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely.

Mitochondrial dysfunction following exposure in utero:

Nucleoside and nucleotide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues; these have predominantly concerned treatment with regimens containing zidovudine.

The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour).

Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleoside and nucleotide analogues, who presents with severe clinical findings of unknown etiology, particularly neurologic findings.

These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Lipoatrophy:

Treatment with zidovudine has been associated with loss of subcutaneous fat, which has been linked to mitochondrial toxicity. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs and buttocks, may not be reversible when switching to a zidovudine-free regimen.

Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine and zidovudine containing products (Combivir and Trizivir). Therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy development.

Weight and metabolic parameters:

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment.

For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Liver disease:

Zidovudine clearance in patients with mild hepatic impairment without cirrhosis [Child-Pugh scores of 5-6] is similar to that seen in healthy subjects, therefore no zidovudine dose adjustment is required. In patients with moderate to severe liver disease [Child-Pugh scores of 7-15], specific dosage recommendations cannot be made due to the large variability in zidovudine exposure observed, therefore zidovudine use in this group of patients is not recommended.

Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk of severe and potentially fatal hepatic adverse events. In […]

1. 65 mmol/litre). Zidovudine is contra-indicated in newborn infants with hyperbilirubinaemia requiring treatment other than phototherapy, or with increased transaminase levels of over five times the upper limit of normal.