Search The Medical Knowledge Base
Drug Details
Zidovudine 250mg capsules
- Drug Class Description
Pharmacotherapeutic group: Nucleoside analogue. ATC code: J05A F01 - Generic Name
Zidovudine - Presentation
Capsule, hard White/white size '0' hard gelatin capsules filled with white to off-white granular powder and imprinted with 'D' on white cap and '73' on white body with black ink. - Description
Each capsule contains 250 mg of zidovudine. Zidovudine 250 mg capsules, hard - Indications
Zidovudine is indicated in anti-retroviral combination therapy for Human Immunodeficiency Virus (HIV) infected adults and children. Zidovudine chemoprophylaxis is indicated for use in HIV-positive pregnant women (over 14 weeks of gestation) for prevention of maternal-foetal HIV transmission and for primary prophylaxis of HIV infection in newborn infants.
- Adult Dosage
Oral use.
Zidovudine should be prescribed by physicians who are experienced in the treatment of HIV infection.
Dosage in adults:
The usual recommended dose of Zidovudine in combination with other anti-retroviral agents is 500 or 600 mg/day in two or three divided doses.
Dosage in children:
3 months - 12 years:
The recommended dose of Zidovudine is 360 to 480 mg/m2 per day, in 3 or 4 divided doses in combination with other antiretroviral agents. The maximum dosage should not exceed 200 mg every 6 hours.
Less than 3 months:
The limited data available are insufficient to propose specific dosage recommendations (see below -maternal foetal transmission and section 5.2).
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 one hour followed by a continuous intravenous infusion at 1 mg/kg/h until umbilical cord is clamped.
The newborn infants should be given 2 mg/kg bodyweight orally every 6 hours starting within 12 hours after birth and continuing until 6 weeks old (e.g. a 3 kg neonate would require a 0.6 ml dose of oral solution every 6 hours). Infants unable to receive oral dosing should be given zidovudine intravenously at 1.5 mg/kg bodyweight infused over 30 minutes every 6 hours.
If a caesarean childbirth is planned then an intravenous form of zidovudine 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.
Refer to local, official guidelines for administration of zidovudine to neonates born to HIV-positive women.
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. Dose reduction or interruption of Zidovudine should be considered in the absence of alternative treatments (see sections 4.3 and 4.4).
Dosage in the elderly:
Zidovudine pharmacokinetics has 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:
In patients with severe renal impairment, apparent zidovudine clearance after oral zidovudine administration was approximately 50% of that reported in healthy subjects with normal renal function. Therefore a dosage reduction to 300-400 mg daily is recommended for patients with severe renal impairment with creatinine clearance < 10ml/min. Haematological parameters and clinical response may influence the need for subsequent dosage adjustment.
Haemodialysis and peritoneal dialysis have no significant effect on zidovudine elimination whereas elimination of the glucuronide metabolite is increased. For patients with end-stage renal disease maintained on haemodialysis or peritoneal dialysis, the recommended dose is 100 mg every 6-8 hours (300 mg – 400 mg daily)
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. If monitoring of plasma zidovudine levels is not feasible, physicians will need to monitor for signs of intolerance, such as the development of haematological adverse reactions (anaemia, leucopenia, neutropenia) and reduce the dose and/or increase the interval between doses as appropriate
- Contra Indications
• Hypersensitivity to zidovudine or to any of the excipients.
• Zidovudine should not be given to patients with abnormally low neutrophil counts (less than 0.75 x 109/litre) or abnormally low haemoglobin levels (less than 7.5 g/decilitre or 4.65 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.
- Special Precautions
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.
The concomitant use of rifampicin or stavudine with zidovudine should be avoided.
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. These occurred more frequently at higher dosages (1200-1500 mg/day) and in patients with poor bone marrow reserve prior to treatment, particularly with advanced HIV disease (see section 4.8).
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.
If the haemoglobin level falls to between 7.5 g/dl (4.65 mmol/l) and 9 g/dl (5.59 mmol/l) or the neutrophil count falls to between 0.75 x 109/l and 1.0 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. In patients with significant anaemia, dosage adjustments do not necessarily eliminate the need for transfusions.
Lactic acidosis: Lactic acidosis usually associated with hepatomegaly and hepatic steatosis has been reported with the use of nucleoside analogues. 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 nucleoside analogues 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 nucleoside analogues 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 toxicity: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed in utero and/or post-natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.
Lipodystrophy: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs (protease inhibitors) and lipoatrophy and NRTIs (nucleoside reverse transcriptase inhibitors) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. 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 case of concomitant antiviral therapy for hepatitis B or C, please also refer to the relevant product information for these medicinal products.
Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.
Immune reactivation syndrome: In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of combination antiretroviral therapy. Relevant examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.
Patients should be cautioned about the concomitant use of self-administered medications.
Patients should be advised that Zidovudine therapy has not been proven to prevent the transmission of HIV to others through sexual contact or contamination with blood.
Use in elderly and in patients with renal or hepatic impairment.
Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
- Interactions
Limited data suggests that co-administration of zidovudine with rifampicin decreases the AUC (area under the plasma concentration curve) of zidovudine by 48% ± 34%. This may result in a partial loss or total loss of efficacy of zidovudine. The concomitant use of rifampicin with zidovudine should be avoided.
Zidovudine in combination with stavudine is antagonistic in vitro. The concomitant use of stavudine with zidovudine should be avoided.
Probenecid increases the AUC of zidovudine by 106% (range 100 to 170%). Patients receiving both drugs should be closely monitored for haematological toxicity.
A modest increase in Cmax (28%) was observed for zidovudine when administered with lamivudine, however overall exposure (AUC) was not significantly altered. Zidovudine has no effect on the pharmacokinetics of lamivudine.
Phenytoin blood levels have been reported to be low in some patients receiving zidovudine, while in one patient a high level was noted. These observations suggest that phenytoin levels should be carefully monitored in patients receiving both drugs.
In a pharmacokinetic study co-administration of zidovudine and atovaquone showed a decrease in zidovudine clearance after oral dosing leading to a 35%±23% increase in plasma zidovudine AUC. The mode of interaction is unknown and as higher concentrations of atovaquone can be achieved with atovaquone suspension it is possible that greater changes in the AUC values for zidovudine might be induced when atovaquone is administered as a suspension. Given the limited data available the clinical significance of this is unknown.
Valproic acid, fluconazole or methadone when co-administered with zidovudine have been shown to increase the AUC with a corresponding decrease in its clearance. As only limited data are available the clinical significance of these findings is unclear but if zidovudine is used concurrently with either valproic acid, fluconazole or methadone, patients should be monitored closely for potential toxicity of zidovudine.
Concomitant treatment, especially acute therapy, with potentially nephrotoxic or myelosuppressive drugs (eg. systemic pentamidine, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of adverse reactions to zidovudine. If concomitant therapy with any of these drugs is necessary then extra care should be taken in monitoring renal function and haematological parameters and, if required, the dosage of one or more agents should be reduced.
Limited data from clinical trials do not indicate a significantly increased risk of adverse reactions to zidovudine with cotrimoxazole, aerosolised pentamidine, pyrimethamine and aciclovir at doses used in prophylaxis.
Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the administration of zidovudine and clarithromycin by atleast two hours.
- Adverse Drug Reactions
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. Dosage reduction or cessation of therapy may become necessary.
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 reactions considered at least possibly related to the treatment are listed below by body system, organ class and absolute frequency.
Assessment of frequencies:
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), not known (cannot be estimated from the available data)
Cardiac disorders Rare: Cardiomyopathy. 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. Nervous system disorders Very common: Headache. Common: Dizziness. Rare: Convulsions, loss of mental acuity, insomnia, paraesthesia, somnolence. 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. Renal and urinary disorders Rare: Urinary frequency. Skin and subcutaneous tissue disorders Uncommon: Rash and pruritus. Rare: Urticaria, nail and skin pigmentation and sweating. Musculoskeletal and connective tissue disorders Common: Myalgia. Uncommon: Myopathy. Metabolism and nutrition disorders Rare: Lactic acidosis in the absence of hypoxaemia, anorexia. General disorders and administration site conditions Common: Malaise. Uncommon: Asthenia, fever and generalised pain. Rare: Chest pain and influenza-like syndrome, chills. Hepatobiliary disorders Common: Raised blood activities of liver-derived enzymes and bilirubin concentration. Rare: Liver disorders such as severe hepatomegaly with steatosis. Reproductive system and breast disorders Rare: Gynaecomastia. Psychiatric disorders Rare: Anxiety and depression. The available data from both placebo-controlled and open-label studies indicate that the incidence of nausea and other frequently reported clinical adverse events consistently 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 events 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.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues.
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
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.
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). The frequency of this is unknown.