Chemical formula: C₁₀H₁₃N₅O₄ Molecular mass: 267.241 g/mol PubChem compound: 35370
Zidovudine interacts in the following cases:
In patients with severe renal impairment, the recommended IV dosage is 1 mg/kg 3-4 times daily. This is equivalent to the current recommended oral daily dosage for this patient group of 300–400 mg allowing for oral bioavailability of 60-70%. Haematological parameters and clinical response may influence the need for subsequent dosage adjustment. For patients with end-stage renal disease maintained on haemodialysis or peritoneal dialysis, the recommended dose is 100 mg every 6-8 hrs (300 mg–400 mg daily).
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.
Zidovudine does not appear to affect the pharmacokinetics of atovaquone. However, pharmacokinetic data have shown that atovaquone appears to decrease the rate of metabolism of zidovudine to its glucuronide metabolite (steady state AUC of zidovudine was increased by 33% and peak plasma concentration of the glucuronide was decreased by 19%). At zidovudine dosages of 500 or 600 mg/day it would seem unlikely that a three week, concomitant course of atovaquone for the treatment of acute PCP would result in an increased incidence of adverse reactions attributable to higher plasma concentrations of zidovudine. Extra care should be taken in monitoring patients receiving prolonged atovaquone therapy.
Clarithromycin tablets reduce the absorption of zidovudine. This can be avoided by separating the administration of zidovudine and clarithromycin by at least two hours.
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.
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 co-trimoxazole, aerosolised pentamidine, pyrimethamine and aciclovir at doses used in prophylaxis.
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.
Probenecid increases the AUC of zidovudine by 106% (range 100 to 170%). Patients receiving both drugs should be closely monitored for haematological toxicity.
Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia. Consideration should be given to replacing zidovudine in a combination ART regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.
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.
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.
Zidovudine in combination with stavudine is antagonistic in vitro. The concomitant use of stavudine with zidovudine should be avoided.
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.
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. In the present case, the use in pregnant women of zidovudine, with subsequent treatment of the newborn infants, has been shown to reduce the rate of maternal-foetal transmission of HIV.
A large amount of data on pregnant women (more than 3000 outcomes from first trimester and more than 3000 outcomes from second and third trimester exposure) indicate no malformative toxicity. Zidovudine can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans based on the mentioned large amount of data.
Zidovudine has been associated with reproductive toxicity findings in animal studies. Zidovudine may inhibit cellular DNA replication and has been shown to be a transplacental carcinogen in one animal study. The clinical relevance of these findings is unknown. Placental transfer of zidovudine has been shown to occur in humans.
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.
After administration of a single dose of 200 mg zidovudine to HIV-infected women, the mean concentration of zidovudine was similar in human milk and serum. It is recommended that mothers infected by HIV do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
Zidovudine did not impair male or female fertility in rats given oral doses of up to 450 mg/kg/day. There are no data on the effect of zidovudine on human female fertility. In men, zidovudine has not been shown to affect sperm count, morphology or motility.
There have been no studies to investigate the effect of zidovudine on driving performance or the ability to operate machinery. Furthermore, a detrimental effect on such activities cannot be predicted from the pharmacology of the drug. Nevertheless, the clinical status of the patient and the adverse reaction profile of zidovudine should be borne in mind when considering the patient’s ability to drive or operate machinery.
Zidovudine IV for infusion is generally used in an in-patient hospital population and information on ability to drive and use machinery is not usually relevant.
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 (1,200-1,500 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 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) and Very rare (<1/10,000).
Common: Anaemia, neutropenia and leucopenia
Uncommon: Pancytopenia with bone marrow hypoplasia, thrombocytopenia
Rare: Pure red cell aplasia
Very rare: Aplastic anaemia
Rare: Lactic acidosis in the absence of hypoxaemia, anorexia
Rare: Anxiety and depression
Very common: Headache
Common: Dizziness
Rare: Convulsions, loss of mental acuity, insomnia, paraesthesia, somnolence
Rare: Cardiomyopathy
Uncommon: Dyspnoea
Rare: Cough
Very common: Nausea
Common: Vomiting, diarrhoea and abdominal pain
Uncommon: Flatulence
Rare: Oral mucosa pigmentation, taste disturbance and dyspepsia. Pancreatitis.
Common: Raised blood levels of liver enzymes and bilirubin
Rare: Liver disorders such as severe hepatomegaly with steatosis
Uncommon: Rash and pruritis
Rare: Urticaria, nail and skin pigmentation, and sweating
Common: Myalgia
Uncommon: Myopathy
Rare: Urinary frequency
Rare: Gynaecomastia
Common: Malaise
Uncommon: Asthenia, fever, and generalised pain
Rare: Chest pain and influenza-like syndrome, chills
Experience with zidovudine IV for Infusion treatment for periods in excess of two weeks is limited, although some patients have received treatment for up to 12 weeks. The most frequent adverse reactions were anaemia, neutropenia and leucopenia. Local reactions were infrequent.
The available data from studies of zidovudine oral formulations indicate that the incidence of nausea and other frequently reported clinical adverse reactions consistently decreased over time during the first few weeks of therapy with zidovudine.
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.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of zidovudine.
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. When such development is found, treatment with zidovudine should not be continued.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
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. 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 can occur many months after initiation of treatment.
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.
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