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Zidovudine (Systemic)


VA CLASSIFICATION
Primary: AM840

Commonly used brand name(s): Apo-Zidovudine; Novo-AZT; Retrovir.

Another commonly used name is
AZT .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antiviral (systemic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

General considerations
In vitro resistance of human immunodeficiency virus (HIV) isolates to zidovudine has been reported in patients with acquired immunodeficiency syndrome (AIDS) who received zidovudine treatment for 6 months or longer. Deterioration of clinical status has been observed in some patients with resistant virus; evidence of a direct association of viral resistance with lack of drug effect continues to mount.{157} Patients can simultaneously carry several viral strains with different susceptibilities to zidovudine.{22} Reduced in vitro sensitivity of HIV to zidovudine develops at a slower rate and to a lesser degree in patients with early stages of infection than in those with advanced disease.{22}{88}{89}{90}{99}{100}{101}{111}

Zidovudine is not a cure for HIV infection. Patients treated with zidovudine may continue to develop complications of AIDS, including opportunistic infections. The treatment or prevention of these infections may require the concurrent administration of other anti-infectives.{01}{162}

Accepted

Human immunodeficiency virus (HIV) infection (treatment)—Zidovudine is indicated in combination with other antiretroviral agents for the treatment of HIV infection.{177} Antiretroviral therapy is recommended in all patients with clinical symptoms associated with HIV infection.{172} In adults, therapy also is recommended in asymptomatic patients with CD4+ T cell counts less than 200 cells per mm3 (cells/mm3) and should be offered to those with cell counts between 200 and 300 cells/mm3 regardless of HIV RNA concentration.{172}{173} However, some experts recommend initiating therapy in asymptomatic patients with CD4+ T cell counts greater than 350 cells/mm 3 if the HIV RNA concentration is greater than 30,000 copies per mL using the branched chain DNA assay or greater than 55,000 copies per mL using the Roche polymerase chain reaction assay.{172}{173} Children who should receive antiretroviral therapy include those who are less than 12 months of age, regardless of clinical, immunologic, or virologic status, and those with moderate or severe immune suppression as determined by CD4+ T cell absolute number or percentage.{173} When to initiate antiretroviral therapy in asymptomatic children 1 year of age or older is less well-defined. One approach is to initiate therapy regardless of age or symptom status.{173} Alternatively, therapy may be deferred until there is high or increasing HIV RNA copy number, rapidly declining CD4+ T cell absolute number or percentage to values approaching those indicative of moderate suppression, or development of clinical symptoms.{173} If the latter approach is taken, virologic, immunologic, and clinical status must be monitored regularly.{173}

Mother-to-child transmission of HIV-1 infection (prophylaxis) —Zidovudine is indicated for the prevention of mother-to-child transmission of HIV-1 infection as part of a regimen that includes oral zidovudine beginning between 14 and 34 weeks gestation, continuous intravenous infusion of zidovudine during labor, and administration of zidovudine syrup to the neonate for the first 6 weeks of life. However, transmission to infants may still occur in some cases despite the use of this regimen.{147}{148}{151}{162}

[Human immunodeficiency virus (HIV) infection, occupational exposure (prophylaxis)]1—Zidovudine has been used prophylactically in health care workers at risk of acquiring HIV infection after occupational exposure to the virus. Risk of transmission from a single needlestick is approximately 0.3%. Efficacy, and optimal dose and duration of prophylactic treatment are unknown at this time;{03}{14}{72}{142} however, HIV infection has occurred in persons who received zidovudine prophylaxis after a needlestick or other parenteral exposure.{02}{07}{121}{122}{123}{140}{141}

Unaccepted
Zidovudine is not effective in the treatment of infections caused by gram-positive organisms, gram-negative organisms, cytomegalovirus, vaccinia, herpes simplex, varicella zoster, anaerobes, mycobacteria, or fungi.{01}{30}

Zidovudine has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.{01}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    267.25{167}

Mechanism of action/Effect:

Virustatic;{04}{06}{28}{31} zidovudine, a structural analog of thymidine, is phosphorylated intracellularly by cellular thymidine kinase to zidovudine monophosphate. The monophosphate is converted to the diphosphate by cellular thymidylate kinase and is further converted to the triphosphate by other cellular enzymes. Zidovudine triphosphate competes with the natural substrate, thymidine triphosphate, for incorporation into growing chains of viral RNA-dependent DNA polymerase (reverse transcriptase), thereby inhibiting viral DNA replication. Once incorporated, zidovudine triphosphate also prematurely terminates the growing DNA chain since the 3´-azido group prevents further 5´ to 3´ phosphodiester linkages. Zidovudine has a 100- to 300-fold greater affinity for inhibiting HIV reverse transcriptase than it does for inhibiting human DNA polymerase.{01}{04}{05}{06}{24}{30}


Other actions/effects:

Zidovudine has been found to have activity against hepatitis B virus and Epstein-Barr virus in vitro {30}; however, one small study found that zidovudine did not markedly inhibit hepatitis B virus replication when used alone in patients with AIDS.{94} Low concentrations of zidovudine also have been shown to inhibit many strains of Enterobacteriaceae in vitro, including strains of Shigella, Salmonella, Klebsiella, Enterobacter, and Citrobacter species, and Escherichia coli. However, bacterial resistance to zidovudine develops rapidly. No activity was seen against Pseudomonas aeruginosa in vitro.{30} At very high concentrations (1.9 mcg/mL [7 micromoles per L]), zidovudine also has been shown to inhibit Giardia lamblia, although no activity has been observed against other protozoal pathogens.{01}{24}

Absorption:

Rapid and nearly complete absorption from the gastrointestinal tract following oral administration;{04}{05} {06} however, because of first-pass metabolism,{19} systemic bioavailability of zidovudine capsules and solution is approximately 65% (range, 52 to 75%). {01}{25} Bioavailability in neonates up to 14 days of age is approximately 89%,{08} and it decreases to approximately 61% and 65% in neonates over 14 days of age and children 3 months to 12 years, respectively.{169} Administration with a high-fat meal may decrease the rate and extent of absorption. {27}

Distribution:

Crosses the blood-brain barrier; distribution to cerebrospinal fluid (CSF) averages approximately 68% of the plasma concentration in children (ages three months to twelve years) and 60% of the plasma concentration in adults.{04}{05}{25}{28}{29}{30}{81}{169}

Crosses the placenta. One case report and a study in three pregnant women found that the zidovudine concentrations in the infant cord blood were slightly higher than simultaneous maternal serum concentrations, and that the amniotic fluid concentrations were several times higher than the simultaneous umbilical cord concentrations.{77}{79} The concentration of zidovudine in the central nervous system (CNS) tissue of a gestational 13-week fetus (0.01 micromole per liter) was below effective antiviral concentrations.{91}{103}

Also shown to concentrate in the semen of HIV-infected patients, with concentrations ranging from 1.3 to 20.4 times those found in the serum; zidovudine does not appear to affect the recovery of HIV from the semen, and, therefore, may not prevent sexual transmission of HIV.{30}{36}{133}

Vol D—Adults and children: 1.4 to 1.7 liters per kg (42 to 52 liters per m 2). {01}{26}{29}{31}

Protein binding:

Low (30 to 38%).{01}{24}

Biotransformation:

Hepatic; metabolized by glucuronide conjugation to major, inactive metabolite, 3´-azido-3´-deoxy-5´- O-beta- D-glucopyranuronosylthymidine (GZDV).{30}

In children under 1 year of age—The glucuronide conjugation pathway is underdeveloped at birth; however, a study done in infants older than 30 days of age found that the clearance and half-life of zidovudine were comparable to those in adults.{29}{31}{102}

Half-life:


Intracellular zidovudine-triphosphate:

Approximately 3.3 hours.{134}



Zidovudine (serum):


Adults (oral and intravenous)—

Normal renal function—Approximately 1 hour (range, 0.8 to 1.2 hours).{25}{26}{28}{32}

Renal function impairment (creatinine clearance < 30 mL per min)—1.4 to 2.9 hours.{26}{33}

Cirrhosis—Variable, depending on the degree of liver function impairment; however, one study found the half-life to be approximately 2.4 hours.{110}



Children age 2 weeks to 13 years (oral and intravenous)—

Approximately 1 to 1.8 hours.{08}{29}{30}{102}



Children up to 14 days of age—

Approximately 3 hours.{08}



Neonates (mother receiving zidovudine)—

Approximately 13 hours.{11}




GZDV (serum):


Adults (oral and intravenous)—


Normal renal function—

Approximately 1 hour.{25}{26}



Renal function impairment—

Approximately 8 hours.{26}



Anuria—

29 to 94 hours.{26}



Cirrhosis—

Variable, depending on the degree of liver function impairment; however, one study found the half-life to be approximately 2.4 hours.{110}




Time to peak concentration:

Serum—0.5 to 1.5 hours.{01}

CSF—1 hour after end of 1-hour infusion.{30}

Peak serum concentration:


Linear kinetics:

Intravenous infusion: 1 mg per kg of body weight (mg/kg) (over 1 hour)—1.5 to 2.5 micromoles per L (0.40 to 0.68 mcg/mL).{30}

Oral (capsules and solution): 2 mg/kg—1.5 to 2 micromoles per L (0.41 to 0.54 mcg/mL).{25}{30}

Continuous intravenous infusion in children (age 14 months to 12 years): Steady state concentrations—0.5 mg/kg per hour (360 per square meter of body surface area [mg/m 2] per day): 1.9 micromoles per L (0.51 mcg/mL).{29} {34}


Elimination:


Adults—
        Zidovudine: Renal; approximately 14 to 18% excreted by glomerular filtration and active tubular secretion in urine.{01}{24}{25}
        GZDV: Renal; approximately 60 to 74% recovered in urine.{01}{24}{25}
        Total of zidovudine and GZDV: Approximately 63 to 95% recovered in urine.{01}{25}
        In dialysis: Current available data vary; it appears that hemodialysis and peritoneal dialysis have a negligible effect on the removal of zidovudine.{26}{33}{81}{112} Hemodialysis does enhance the elimination of GZDV; however, dialysis clearance of GZDV is minimal compared to the clearance of GZDV in patients with normal renal function.{26}{86}{136}



Children (age 14 months to 12 years){29}
        Zidovudine: Renal; approximately 30% excreted by the kidneys.
        GZDV: Renal; approximately 45% recovered in the urine.



Precautions to Consider

Carcinogenicity

Long-term carcinogenicity studies found five malignant and two benign vaginal squamous cell tumors in 60 female mice given zidovudine in doses of 120 mg per kg of body weight (mg/kg) per day, later reduced to 40 mg/kg per day. Two out of 60 rats were found to have vaginal squamous cell carcinoma after receiving doses of 600 mg/kg per day, later reduced to 450, then 300 mg/kg per day. The tumors occurred at the end of the life span of the animals. No treatment-related tumors were seen in the 60 male mice or 60 male rats.{78}{79}{81}

Two transplacental carcinogenicity studies in pregnant mice showed carcinogenic potential. In the first study, zidovudine was administered at doses of 20 mg/kg per day or 40 mg/kg per day from day 10 of gestation through parturition and lactation and continuing in the offspring for 24 months postnatally.{162} After 24 months, an increase in incidence of vaginal tumors was observed in the offspring. In the second study, zidovudine was administered at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1000 or 450 mg/kg of nonpregnant or term body weight, respectively) from days 12 through 18 of gestation.{162} An increase in incidence of tumors was observed in the lung, liver, and female reproductive tracts in the offspring of the mice receiving the higher dose of zidovudine.{162}

Mutagenicity

Zidovudine was shown to be mutagenic in a 5178Y/TK +/- mouse lymphoma assay and positive in an in vitro cell transformation assay. Zidovudine was clastogenic in a cytogenetic assay using cultured human lymphocytes. Zidovudine was negative in one cytogenetic study in rats given a single dose; however, it was positive in mouse and rat micronucleus tests after repeated doses.{162}

Pregnancy/Reproduction
Fertility—
The effects of zidovudine on fertility have not been studied in humans.

Studies in rats given oral zidovudine at dosages up to 450 mg/kg per day showed no effect on male or female fertility.{24}

Pregnancy—
Zidovudine crosses the placenta{84}{85}{91}{162} with a cord-to–maternal blood ratio of approximately 0.8.{172} The rate of HIV transmission from pregnant women to their infants has been shown to be decreased in women treated with zidovudine compared with women treated with placebo.{146}{162} A randomized, double-blind, placebo-controlled study was conducted in HIV-positive pregnant women to evaluate the utility of zidovudine in preventing the transmission of HIV from mother to fetus.{162} In this study, oral zidovudine therapy was initiated in pregnant women between weeks 14 and 34 of gestation (median 11 weeks of therapy), and intravenous zidovudine was administered during labor and delivery. Zidovudine therapy was continued orally in the newborn after birth for 6 weeks.{162} The study showed a reduced incidence of HIV infection in the newborns of the zidovudine group; the estimated risk of infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, indicating a relative reduction in transmission risk of 68.7%.{162} No differences in pregnancy-related adverse events were noted between the zidovudine-treated and placebo groups.{162} Congenital abnormalities occurred at similar rates among the newborns of zidovudine-treated mothers and the newborns of mothers who received placebo.{162} The abnormalities noted were either problems in embryogenesis (prior to 14 weeks) or were identified on ultrasound before or immediately after the initiation of zidovudine.{162} Neither the efficacy of zidovudine therapy in preventing mother-to-child transmission of HIV-1 infection in women who had received zidovudine for a prolonged period prior to pregnancy nor the safety of zidovudine in the first trimester for the mother or fetus was evaluated in this study.{162} One survey of 43 women who took zidovudine (300 to 1200 mg per day) during various stages of pregnancy found that zidovudine was well tolerated by the mothers and was not associated with teratogenic abnormalities, premature birth, or fetal distress.{139} One early report suggested that zidovudine caused mitochondrial dysfunction with neurologic sequelae in children exposed in utero and postnatally.{175} However, review of 20,000 children born to HIV-infected women with or without exposure to zidovudine did not confirm the finding. This review failed to show any evidence of cardiac, immunologic, neurologic, or oncologic complications.{171}{176} Three small studies done in women given zidovudine during their last trimester of pregnancy found that peak plasma concentrations and the elimination half-life were similar to values reported in nonpregnant adults, although volume of distribution and plasma clearance were significantly increased during pregnancy in two of the studies.{11}{79}{103} Therapeutic plasma concentrations have been measured in the newborn infant.{77} Therapeutic levels also have been measured in the amniotic fluid of a gestational 13-week fetus; however, the concentration of zidovudine in this fetus' CNS tissue (0.01 micromole per liter) was below effective antiviral concentrations.{80}{91}

Studies in rats and rabbits given oral doses of up to 500 mg/kg per day have not shown zidovudine to be teratogenic. There was an increased incidence of fetal resorption in rats given 150 or 450 mg/kg per day of zidovudine, rabbits given 500 mg/kg per day, and mice given 0.25 mg/mL in drinking water, producing serum concentrations of 0.12 mcg/mL.{01} In an in vitro experiment with fertilized mouse oocytes, exposure to zidovudine resulted in a dose-dependent reduction in blastocyst formation.{162} In rats, 3000 mg/kg per day (resulting in peak plasma concentrations of 350 times the peak human plasma concentration) caused marked maternal toxicity and an increase in the incidence of fetal malformations.{162} Teratogenic effects were not seen in this experiment at doses of 600 mg/kg per day or less.{162}

An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to zidovudine. Physicians are encouraged by the manufacturer to register patients by calling (800) 258-4263.{162}{172} Canadian health care professionals should call (800) 668-6051 to register their patients.{170}

FDA Pregnancy Category C.{162}

Breast-feeding

Zidovudine is distributed into human breast milk.{162}{172} After administration of a single 200-mg dose, the mean concentration of zidovudine in breast milk is similar to that of serum concentrations.{162} In addition, the Centers for Disease Control and Prevention recommends that HIV-infected mothers refrain from breast-feeding their infants, to avoid risking postnatal transmission of HIV.{162}

Pediatrics

Zidovudine is approved for use in children at birth up to 12 years of age.{169} Results of uncontrolled studies showed that children with symptomatic HIV disease and a CD4 lymphocyte count of 500 per mm3 or less had a positive response to zidovudine, including improvement in neuropsychological function, immunological function, p24 antigen concentrations, and weight gain. No studies have been published addressing the efficacy of zidovudine in asymptomatic children with a CD4 lymphocyte count of 500 per mm3 or less.{125} It is also not known whether doses lower than 180 mg per square meter of body surface every 6 hours would maintain adequate CNS concentrations of zidovudine to provide improvement of HIV-related CNS disease in children.{124} The pharmacokinetics of zidovudine in children greater than 3 months of age have been found to be similar to those in adults. {169}The half-life in neonates immediately following birth was found to be 10 times that of the mother (13 vs 1.3 hours, respectively{11}{169}). The side effects seen in children, including the hematologic effects, were also similar to those seen in adults.{08}{30}{34}{41}{87} {98}{104}{105}{106}


Geriatrics


Studies have not been performed to determine the safety and effectiveness of zidovudine in the geriatric population. However, 1 case reports that a 90-year-old patient responded well to zidovudine therapy. Preliminary data indicate that the elimination rate of zidovudine may be decreased in the elderly.{113}{115}


Dental

The bone marrow–depressant effects of zidovudine may result in an increased incidence of certain microbial infections and delayed healing. {01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Atovaquone{162}    (concurrent use decreases zidovudine clearance and increases area under the plasma concentration–time curve [AUC] of zidovudine{162})


Blood dyscrasia–causing medications (see Appendix II) or
» Bone marrow depressants, other (see Appendix II) or
Radiation therapy{01}{05}    (concurrent use of these medications and/or radiation therapy with zidovudine may cause an additive or synergistic myelosuppression; dosage reductions may be required)


» Clarithromycin{74}{145}    (initial results of a dose escalation study in HIV-infected patients showed that concurrent use of zidovudine and clarithromycin resulted in a lower peak serum concentration [Cmax], lower AUC, and delayed time to peak concentration [Tmax] of zidovudine )


» Doxorubicin{168}    (in vitro studies detected an antagonistic relationship between doxorubicin and zidovudine;{168} concurrent use is not recommended{168})


Fluconazole{162}    (concurrent use of fluconazole interferes with zidovudine clearance and metabolism, increasing zidovudine AUC by 74% [range 28 to 173%] and zidovudine half-life by 128% [range -4 to 189%]{162})


» Ganciclovir{39}{109}{132}    (concurrent use with zidovudine has caused severe hematologic toxicity even when the zidovudine dose was reduced to 300 mg per day; this effect is thought to be the result of synergistic myelosuppressive toxicity rather than a pharmacokinetic interaction; concurrent administration should be used with extreme caution; hematologic parameters, such as hemoglobin, hematocrit, and white blood cell count with differential should be monitored frequently in all patients receiving both zidovudine and ganciclovir{162})


Hepatic glucuronidation–metabolized medications, other{16}{17}{30}{44}{45}    (other medications metabolized by hepatic glucuronidation, such as acetaminophen, aspirin, benzodiazepines, cimetidine, indomethacin, morphine, and sulfonamides, may, in theory, compete with zidovudine for metabolism and decrease the clearance of zidovudine or the other medication; this could potentially increase the risk of toxicity of either zidovudine or the other medication)


» Interferon alfa{162}    (hematologic toxicities may occur with concurrent use; dose reduction or discontinuation of one or both of the medications may be necessary; hematologic parameters, such as hemoglobin, hematocrit, and white blood cell count with differential should be monitored frequently in all patients receiving both zidovudine and interferon alfa{162})


Lamivudine{162}    (concurrent use may increase zidovudine peak plasma concentration [Cmax]; however, AUC and total clearance of zidovudine are not significantly altered{162})


Methadone{162}    (concurrent use may increase zidovudine AUC{162})


Phenytoin{162}    (there have been several reports of decreased phenytoin plasma concentrations, and one case of increased phenytoin plasma concentration, with concurrent use; however, a pharmacokinetic interaction study showed no effect on phenytoin kinetics, but a 30% decrease in zidovudine clearance was observed with concurrent use)


» Probenecid{01}{05}{46}{76}{92}    (concurrent use inhibits hepatic glucuronidation and secretion of zidovudine through the renal tubules, resulting in increased serum concentrations and a prolonged elimination half-life; this may increase the risk of toxicity, or possibly permit a reduction in daily zidovudine dosage; however, in one small trial, a very high incidence of rash was observed in patients receiving probenecid concurrently with zidovudine; influenza-like symptoms, such as myalgia, malaise, and/or fever, have also occurred{162})


» Ribavirin{30}{40}    (in vitro studies have shown that, when combined, ribavirin and zidovudine are reproducibly antagonistic and should not be used concurrently; ribavirin inhibits the phosphorylation of zidovudine to its active triphosphate form)


Rifampin{162}    (concurrent use may decrease zidovudine AUC{162})


Stavudine (d4T){149}{150}    (in vitro studies detected an antagonistic antiviral effect between stavudine and zidovudine at a molar ratio of 20 to 1, respectively; concurrent use is not recommended until in vivo studies demonstrate that these medications are not antagonistic in their anti-HIV activity)


Valproic acid{162}    (valproic acid may increase zidovudine oral bioavailability by interfering with zidovudine's first-pass metabolism; an increase of zidovudine AUC of 79% ± 61% and a decrease in the plasma GZDV AUC of 22% ± 10% were observed with concurrent use; patients taking both medications should be monitored for a possible increase in zidovudine-related adverse effects; the effect of zidovudine on the pharmacokinetics of valproic acid was not evaluated{162})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Mean corpuscular volume (MCV){82}    (usually will be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression{01}    (zidovudine may cause bone marrow depression, worsening any pre-existing granulocytopenia and anemia)


Folic acid deficiency or
Vitamin B12 deficiency{03}{04}    (patients with folic acid or vitamin B12 deficiency may be more prone to anemia since zidovudine can cause impaired erythrocyte maturation, resulting in a macrocytic anemia)


» Hepatic function impairment{01}{04}    (because zidovudine is metabolized in the liver to an inactive metabolite, GZDV, hepatic function impairment may lead to accumulation of zidovudine and increased toxicity)


Hypersensitivity to zidovudine

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» CD4+ T lymphocyte count     (CD4+ T cell counts should be monitored at the time of diagnosis and generally every 3 to 6 months thereafter{172})


» Complete blood counts (CBCs)    (in patients with HIV disease who are asymptomatic or have early symptoms, CBCs are recommended monthly during the first 3 months, then every 3 months thereafter, unless indicated for other reasons.{83} CBCs are recommended at least every 2 weeks during the first 8 weeks of therapy to detect serious anemia or granulocytopenia in patients with advanced HIV disease taking zidovudine; the frequency of CBCs may be decreased to every 4 weeks after the first 2 months if zidovudine is well tolerated. Decreases in hemoglobin concentrations may occur as early as 2 to 4 weeks after the beginning of therapy, and peak falls in hemoglobin usually occur during the first 4 to 6 weeks. Granulocytopenia usually occurs after 6 to 8 weeks; when significant anemia [hemoglobin of < 7.5 grams/dL] and/or significant granulocytopenia [granulocyte count of < 750 cells/mm3] occurs, dosage adjustments, discontinuation of the drug, blood transfusions, or, in selected patients, treatment with epoetin [recombinant human erythropoietin] or GM-CSF [granulocyte-macrophage colony-stimulating factor] may be necessary. Zidovudine should not be restarted until some evidence of bone marrow recovery is evident; if bone marrow recovery occurs following dosage adjustments, gradual increases in dose may be appropriate, depending on blood counts and patient tolerance; patients should be informed of the importance of having blood counts followed closely during therapy{01}{12}{45}{98}{128})


» Drug resistance tests    (drug resistance testing [genotyping or phenotyping] is recommended when there is suboptimal viral load suppression after initiation of antiretroviral therapy or during virologic failure on an existing antiretroviral regimen; drug resistance testing also should be considered in acute HIV infection to determine if the virus transmitted was drug-resistant and to guide the change in antiretroviral therapy, if necessary{172})


» Human immunodeficiency virus (HIV) RNA, plasma    (monitoring of HIV RNA, which is an indicator of viral load, is essential when deciding to initiate or modify antiretroviral therapies;{172} HIV RNA concentrations should be measured immediately prior to and 2 to 8 weeks following initiation of antiretroviral therapy;{172} thereafter, HIV RNA should be measured every 3 to 4 months to evaluate the continuing efficacy of therapy;{172} optimally, plasma concentrations should be undetectable, i.e., less than 50 copies per mL, at 6 months;{172} if after 16 to 20 weeks of therapy HIV RNA remains detectable in plasma and a repeat test confirms the result, a modification in antiretroviral therapy should be considered{172})

    (HIV RNA should not be measured during or within 4 weeks after successful treatment of intercurrent infection, resolution of symptomatic illness, or immunization{172})


Liver function tests    (liver function tests, including serum ALT [SGPT], alkaline phosphatase, and AST [SGOT] values, and serum bilirubin concentration, should be monitored periodically since elevations, usually reversible, have been reported on rare occasions with zidovudine therapy; however, in two large placebo-controlled studies, the difference in incidence of aminotransferase elevation between the treatment and the placebo groups was not statistically significant; elevations in liver function tests in some cases may be related to reactivation of hepatitis virus or due to HIV infection itself{47}{48}{96}{97}{108})


Therapeutic drug monitoring    (there is growing evidence that measurement of drug concentrations can be used to individualize therapy, identify abnormal pharmacokinetics or noncompliance, improve response to therapy, and decrease toxicity{174})




Side/Adverse Effects

Note: Because of the complexity of this disease state, it is often difficult to differentiate between the manifestations of HIV infection and the adverse effects of zidovudine. In addition, very little placebo-controlled data are available to assess this difference, with most of the information coming from uncontrolled studies and case reports. The long-term effects of zidovudine are still not known; however, hematologic side effects are more likely to occur with higher doses and in patients with more advanced disease. {01} {96} {119}
Lactic acidosis, in the absence of hypoxemia, and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogs, including zidovudine. {162}
The most frequent side/adverse effects of zidovudine are granulocytopenia and anemia. These have been shown to be inversely related to the CD4 lymphocyte count, hemoglobin concentration, and granulocyte count at the time of therapy initiation and directly related to dosage and duration of therapy. Significant anemia most commonly occurs after 4 to 6 weeks of therapy. {01} {119}
The incidence of adverse reactions from zidovudine therapy appears to increase as the disease progresses. {162}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anemia (pale skin; unusual tiredness or weakness){24}{30}
    
leukopenia or neutropenia (fever, chills, or sore throat){30}

Note: These hematological abnormalities occur more frequently and with greater severity in patients who have more advanced HIV infection when zidovudine therapy is initiated. {162}


Incidence less frequent
    
Changes in platelet count —often increased with therapy; however, may be decreased infrequently{43}{63}{64}{65}{66}{93}

Incidence rare
    
Hepatotoxicity (abdominal discomfort; nausea; decreased appetite; general feeling of discomfort){47}{48}
    
lactic acidosis (diarrhea; fast, shallow breathing; muscle pain or cramping; shortness of breath; sleepiness; unusual tiredness or weakness)
    
myopathy (muscular atrophy, tenderness, and weakness){15}{60}{61}{62}{95}{130}{131}
    
neurotoxicity (confusion; mood or mental changes; seizures){30}{55}{56}{57}{58}{59}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent {43}
    
Headache, severe
    
insomnia (trouble in sleeping)
    
myalgia (muscle soreness)
    
nausea

Incidence less frequent {49} {51} {52} {53} {54}
    
Changes in skin pigmentation{162} (changes in skin coloring)
    
hyperpigmentation of nails (bluish-brownish bands)



Those indicating need for medical attention if they occur after medication is discontinued
    
Bone marrow depression (fever, chills, or sore throat; pale skin; unusual tiredness or weakness)




Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Symptoms of overdose {06} {67} {68} {69} {70} {71} {98}
    
Bone marrow toxicity, specifically anemia, leukopenia, thrombocytopenia (pale skin; unusual tiredness or weakness; fever, chills, or sore throat; increase in bleeding or bruising)
    
gastrointestinal disturbances (severe nausea and vomiting)
    
neurotoxicity, specifically ataxia, fatigue, lethargy, nystagmus, seizures (lack of coordination; involuntary, rapid, rhythmic movement of the eyes; convulsions)

Note: At this time, the information available on acute zidovudine overdose is limited to several case reports. These patients took between 6 and 50 grams of zidovudine. Severe nausea and vomiting are the most common symptoms after an overdose. Other reported symptoms include ataxia, nystagmus, lethargy, fatigue, and, in one patient, a single tonic-clonic seizure. One patient who took a chronic overdose of zidovudine, 500 mg five times a day for 16 days, had an increase in liver transaminases, which resolved when the dose was reduced. There is also one case report of a patient who ingested 6 grams in a suicide attempt who experienced hematologic toxicity; the lowest blood cell count occurred 8 days after the ingestion and returned to previous levels by day 20.



Treatment of overdose
Specific treatment—Zidovudine is not removed from the blood by peritoneal dialysis or hemodialysis in sufficient amounts to warrant the use of dialysis in an overdose situation. {81} {112}

Monitoring—Close observation of the patient for evidence of neurotoxicity and bone marrow suppression.

Supportive care—Supportive therapy. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zidovudine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to zidovudine

Pregnancy—Zidovudine crosses the placenta and reaches concentrations in the fetus similar to those observed in adults; zidovudine has been shown to decrease perinatal transmission of HIV





Breast-feeding—Zidovudine is distributed into breast milk; breast-feeding is not recommended in HIV-infected mothers because of the risk of passing HIV to the infant





Dental—The bone marrow–depressant effects of zidovudine may result in an increased incidence of certain microbial infections and delayed healing
Other medications, especially alfa interferons, other bone marrow depressants, clarithromycin, doxorubicin, ganciclovir, probenecid, or ribavirin
Other medical problems, especially bone marrow depression or hepatic function impairment

Proper use of this medication
Supplying patient information about zidovudine

» Importance of not taking more medication than prescribed; importance of not discontinuing medication without checking with physician

» Compliance with full course of therapy

Using a specially marked measuring spoon or other device for zidovudine oral solution

» Importance of not missing doses and taking at evenly spaced times

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician for blood tests

» Importance of not taking other medications concurrently without checking with physician

Using caution in use of regular toothbrushes, dental floss, and toothpicks; checking with physician or dentist concerning proper oral hygiene

» Avoiding sexual intercourse or using a condom to help prevent transmission of the AIDS virus to others; not sharing needles with anyone


Side/adverse effects
Signs of potential side effects, especially anemia, leukopenia or neutropenia, changes in platelet count, hepatotoxicity, lactic acidosis, myopathy, and neurotoxicity


General Dosing Information
Zidovudine monotherapy is not recommended except as prophylaxis against perinatal transmission in pregnant women with low viral loads and high CD4+ T cell counts{172} and in HIV-exposed infants during the first 6 weeks of life.{173} In adults, it is recommended that antiretroviral therapy consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) or one or two protease inhibitors (PIs).{171}{172} In children, it is recommended that antiretroviral therapy consist of one highly active PI plus two NRTIs.{173} Children who can swallow capsules may be given efavirenz plus two NRTIs or efavirenz plus nelfinavir plus one NRTI.{173}

Patients should be advised of the importance of taking zidovudine exactly as prescribed.{177} Patients should not exceed the prescribed dose{01} or dosing frequency.{174}

Zidovudine infusion should be administered at a constant rate over a period of 1 hour. It should not be administered intramuscularly or by rapid infusion or direct injection.{81}

Patients with significant anemia (hemoglobin < 7.5 grams/dL) and/or significant granulocytopenia (granulocyte count of < 750 cells/mm 3) may require interruption of zidovudine therapy{162}{173} or reduction of dosage{173} until bone marrow recovery is seen. Additionally, patients with anemia may require blood transfusions or treatment with epoetin (recombinant human erythropoetin).{45}{171}{173} Patients with granulocytopenia may require treatment with filgrastim (granulocyte colony-stimulating factor; G-CSF){12}{171}{173} or sargramostim (granulocyte-macrophage colony-stimulating factor; GM-CSF).{128}

Granulocytopenia and anemia have been shown to be inversely related to the CD4 lymphocyte count, hemoglobin concentration, and granulocyte count at time of therapy initiation, and directly related to dosage and duration of therapy. Significant anemia most commonly occurs after 4 to 6 weeks of therapy.{98}

If a patient receiving zidovudine develops unexplained dyspnea, tachypnea, or a fall in serum bicarbonate concentration, therapy with zidovudine should be suspended until the diagnosis of lactic acidosis can be ruled out, usually with a venous or arterial lactic acid concentration.{171} Treatment with zidovudine also should be suspended in the case of rapid elevations of serum aminotransferase concentrations or progressive hepatomegaly of unknown etiology. {162}

Diet/Nutrition
Zidovudine may be taken with or without food.{172}{173}{177}


Oral Dosage Forms

Note: Zidovudine, in a dose of 300 mg, is available in combination with 150 mg of lamivudine as Combivir and with 300 mg of abacavir and 150 mg of lamivudine as Trizivir.{171}{172}{173}


ZIDOVUDINE CAPSULES USP

Usual adult and adolescent dose
Human immunodeficiency virus (HIV) infection (treatment)
Oral, 600 mg of zidovudine daily in divided doses{162} (300 mg every twelve hours or 200 mg every eight hours).{165}{172}

Note: Patients with end-stage renal disease may require a reduction in dosage to 300 mg per day.{171}


Mother-to-child transmission of HIV-1 infection (prophylaxis)
Oral, 100 mg five times a day,{147}{162}{172} 200 mg every eight hours,{172} or 300 mg every twelve hours{172} beginning after fourteen weeks of gestation and continuing until the start of labor. At that time, intravenous zidovudine should be administered (see Zidovudine Injection USP).{147}{162}{172}


Usual pediatric dose
HIV infection (treatment)
Children up to 90 days of age: Oral, 2 mg per kg of body weight every six hours.{173}

Children 90 days to 12 years of age: Oral, 160 mg per square meter of body surface area every eight hours.{82}{98}{162}

Children 12 years of age and older: See Usual adult and adolescent dose.


Note: Pediatric patients with granulocytopenia may require a dose reduction to 120 mg per square meter of body surface area every six hours.{12}


Usual pediatric prescribing limits
200 mg every eight hours or 480 mg per square meter of body surface area per day.{98}{162}{165}

Strength(s) usually available
U.S.—


100 mg (Rx) [Retrovir (corn starch) ( magnesium stearate) (microcrystalline cellulose ) (sodium starch glycolate){168}]

Canada—


100 mg (Rx) [Apo-Zidovudine{163}] [Novo-AZT{164}] [Retrovir{165}]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), in a tight container.{162} Protect from light and moisture.{82}

Auxiliary labeling:
   • Continue medicine for full time of treatment.


ZIDOVUDINE ORAL SOLUTION USP

Usual adult and adolescent dose
See Zidovudine Capsules USP.

Usual pediatric dose
HIV infection (treatment)
See Zidovudine Capsules USP.

Mother-to-child transmission of HIV-1 infection (prophylaxis)
Neonate dosing: Oral, 2 mg per kg of body weight every six hours starting within eight to{172} twelve hours after birth and continuing through six weeks of age. If the infant cannot take zidovudine oral solution, intravenous zidovudine may be administered (see Zidovudine Injection USP).{147}{162}{169}

Note: If HIV infection is confirmed in the infant, zidovudine therapy should be changed to a combination antiretroviral regimen.{173}



Strength(s) usually available
U.S.—


50 mg per 5 mL (Rx) [Retrovir (sodium benzoate) (citric acid) (flavors) (glycerin) (liquid sucrose){168}]

Canada—


50 mg per 5 mL (Rx) [Retrovir{165}]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), in a tight container. Protect from light.{82}

Auxiliary labeling:
   • Continue medicine for full time of treatment.


ZIDOVUDINE TABLETS USP

Usual adult and adolescent dose
HIV infection (treatment)
600 mg daily in two to three divided doses.{162}{171}


Usual pediatric dose
Children up to 12 years of age—See Zidovudine Capsules USP.

Children 12 years of age and older—See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


300 mg (Rx) [Retrovir (hydroxypropyl methylcellulose) (magnesium stearate) (microcrystalline cellulose) (polyethylene glycol) ( sodium starch glycolate) (titanium dioxide){168}]

Canada—


300 mg (Rx) [Retrovir{165}]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F).{162}

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Parenteral Dosage Forms

ZIDOVUDINE INJECTION USP

Usual adult and adolescent dose
HIV infection (treatment)
In the U.S.: Intravenous infusion, 1 mg{159} per kg of body weight, infused over one hour, every four hours, five or six times a day (5 to 6 mg per kg of body weight per day) until oral therapy can be administered.{166}{127}

In Canada: Intravenous infusion, 1 to 2 mg per kg of body weight, infused over one hour, every four hours around the clock (six times a day) until oral therapy can be administered.{165}

Note: Intravenous administration of 1 mg per kg of body weight every four hours is equivalent to oral administration of 100 mg every four hours.{165}{166}{178}
Patients with end-stage renal disease require a reduction in dose to 1 mg per kg of body weight, infused over one hour, every six to eight hours.{165}{166}


Mother-to-child transmission of HIV-1 infection (prophylaxis), maternal dose at the start of labor and delivery
Intravenous, 2 mg per kg of total body weight over one hour, followed by a continuous infusion of 1 mg per kg of total body weight per hour until clamping of the umbilical cord.{147}{166}{172}


Usual pediatric dose
HIV infection (treatment)
Children up to 3 months of age: Intravenous infusion, 1.5 mg per kg of body weight, infused over one hour, every six hours.{173}

Children 3 months to 12 years of age: [Intravenous infusion, 120 mg per square meter of body surface area, infused over one hour, every six hours].{81}{127}{165} [Alternatively, continuous infusion of 20 mg per square meter of body surface area per hour.{173}]

Children 12 years of age and older: See Usual adult and adolescent dose.

Note: Pediatric patients with granulocytopenia may require a dose reduction to 90 mg per square meter of body surface area every six hours.{12}


Mother-to-child transmission of HIV-1 infection (prophylaxis)
Intravenous, 1.5 mg per kg of body weight over thirty minutes every six hours.{147}{166}


Usual pediatric prescribing limits
160 mg per individual dose.{127}{165}

Strength(s) usually available
U.S.—


200 mg in 20 mL (Rx) [Retrovir{166}]

Canada—


200 mg in 20 mL (Rx) [Retrovir{165}]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F). Protect from light.{81}{165}{166}

Preparation of dosage form:
Zidovudine injection must be diluted prior to administration to a concentration of no greater than 4 mg per mL in 5% dextrose injection,{165}{166}{173} 0.9% sodium chloride injection, 5% dextrose and 0.45% sodium chloride injection, lactated Ringer's injection, or 5% dextrose and lactated Ringer's injection.{165}

Stability:
After dilution, solutions are physically and chemically stable for 24 hours at room temperature (25 °C [77 °F]) and 48 hours if refrigerated (2 to 8 °C [36 to 46 °F]).{166}

It is recommended that diluted solutions be administered within 8 hours if stored at 25 °C (77 °F) or within 24 hours if refrigerated (2 to 8 °C [36 to 46 °F]) to minimize potential microbial contamination.{166}

The solution should be visually inspected prior to administration for discoloration and particulate matter. If either of these are detected, the solution should be discarded.{166}

Incompatibilities:
Zidovudine injection should not be admixed with biological or colloidal solutions (e.g., blood products, protein-containing solutions).{166}



Revised: 04/22/2002



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