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Zidovudine


Pronunciation

 (zye DOE vyoo deen)


U.S. Brand Names

 Retrovir®


Synonyms

 Azidothymidine; AZT; Compound S; ZDV


Generic Available

 No


Canadian Brand Names

 Apo-Zidovudine®; AZT™; Novo-AZT; Retrovir®


Use

 Management of patients with HIV infections in combination with at least two other antiretroviral agents; for prevention of maternal/fetal HIV transmission as monotherapy


Use - Unlabeled/Investigational

 Postexposure prophylaxis for HIV exposure as part of a multidrug regimen


Pregnancy Risk Factor

 C


Pregnancy Implications

 Zidovudine crosses the placenta. The use of zidovudine reduces the maternal-fetal transmission of HIV by ~70% and should be considered for antenatal and intrapartum therapy whenever possible. The Perinatal HIV Guidelines Working Group considers zidovudine the preferred NRTI for use in combination regimens during pregnancy. In HIV infected mothers not previously on antiretroviral therapy, treatment may be delayed until after 10-12 weeks gestation. Cases of lactic acidosis/hepatic steatosis syndrome have been reported in pregnant women receiving nucleoside analogues. It is not known if pregnancy itself potentiates this known side effect; however, pregnant women may be at increased risk of lactic acidosis and liver damage. Hepatic enzymes and electrolytes should be monitored frequently during the 3rd trimester of pregnancy in women receiving nucleoside analogues. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).


Lactation

 Enters breast milk/not recommended


Contraindications

 Life-threatening hypersensitivity to zidovudine or any component of the formulation


Warnings/Precautions

 Often associated with hematologic toxicity including granulocytopenia, severe anemia requiring transfusions, or (rarely) pancytopenia. Use with caution in patients with bone marrow compromise (granulocytes <1000 cells/mm 3 or hemoglobin <9.5 mg/dL); dosage adjustment may be required in patients who develop anemia or neutropenia. Lactic acidosis and severe hepatomegaly with steatosis have been reported, including fatal cases; use with caution in patients with risk factors for liver disease (risk may be increased in obese patients or prolonged exposure) and suspend treatment with zidovudine in any patient who develops clinical or laboratory findings suggestive of lactic acidosis (transaminase elevation may/may not accompany hepatomegaly and steatosis). Prolonged use has been associated with symptomatic myopathy. Reduce dose in patients with renal impairment. Zidovudine has been shown to be carcinogenic in rats and mice.


Adverse Reactions

>10%:

Central nervous system: Severe headache (42%), fever (16%)

Dermatologic: Rash (17%)

Gastrointestinal: Nausea (46% to 61%), anorexia (11%), diarrhea (17%), pain (20%), vomiting (6% to 25%)

Hematologic: Anemia (23% in children), leukopenia, granulocytopenia (39% in children)

Neuromuscular & skeletal: Weakness (19%)

1% to 10%:

Central nervous system: Malaise (8%), dizziness (6%), insomnia (5%), somnolence (8%)

Dermatologic: Hyperpigmentation of nails (bluish-brown)

Gastrointestinal: Dyspepsia (5%)

Hematologic: Changes in platelet count

Neuromuscular & skeletal: Paresthesia (6%)

<1%, postmarketing and/or case reports: Amblyopia, anaphylaxis, angioedema, anxiety, aplastic anemia, back pain, cardiomyopathy, chest pain, confusion, constipation, cough, CPK increased, depression, diaphoresis, dizziness, dysphagia, dyspnea, flatulence, flu-like syndrome, generalized pain, gynecomastia, hearing loss, hemolytic anemia, hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, LDH increased, leukopenia, loss of mental acuity, lymphadenopathy, macular edema, mania, mouth ulcer, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV disease), oral mucosal pigmentation, pancreatitis, pancytopenia with marrow hypoplasia, paresthesia, photophobia, pruritus, pure red cell aplasia, rash, rhabdomyolysis, rhinitis, seizure, sensitization reactions, sinusitis, skin and nail pigmentation changes, somnolence, Stevens-Johnson syndrome, syncope, taste perversion, toxic epidermal necrolysis, tremor, urinary frequency, urinary hesitancy, urticaria, vasculitis, vertigo


Overdosage/Toxicology

 Symptoms of overdose include nausea, vomiting, ataxia, and granulocytopenia. Erythropoietin, thymidine, and cyanocobalamin have been used experimentally to treat zidovudine-induced hematopoietic toxicity, yet none are presently specified as the agent of choice. Treatment is supportive.


Drug Interactions

 Substrate (minor) of CYP2A6, 2C8/9, 2C19, 3A4

Atovaquone: Atovaquone may decrease zidovudine clearance, increasing zidovudine AUC ~35%

Bone marrow suppressants/cytotoxic agents: Concomitant use may increase risk of hematologic toxicity. (May be seen with adriamycin, dapsone, flucytosine, vincristine, vinblastine.)

Doxorubicin: May decrease the antiviral activity of zidovudine (based on in vitro data). Avoid concurrent use.

Fluconazole: Fluconazole may decrease clearance and metabolism of zidovudine

Ganciclovir: Concomitant use may increase risk of hematologic toxicities; monitor hemoglobin, hematocrit, and white blood cell count with differential frequently; dose reduction or interruption of either agent may be needed

Interferon-alpha: Concomitant use may increase risk of hematologic toxicities; monitor hemoglobin, hematocrit, and white blood cell count with differential frequently; dose reduction or interruption of either agent may be needed

Phenytoin: Decreased plasma levels of phenytoin may be seen. Phenytoin may decrease clearance of zidovudine.

Probenecid: Probenecid may increase zidovudine levels. Myalgia, malaise, and/or fever and maculopapular rash have been reported with concomitant use.

Ribavirin: Concomitant use of ribavirin and nucleoside analogues may increase the risk of developing lactic acidosis (includes adefovir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine). May decrease the antiviral activity of zidovudine (based on in vitro data); avoid concurrent use.

Stavudine: Zidovudine may decrease the antiviral activity of stavudine (based on in vitro data). Avoid concurrent use.

Valproic acid: Valproic acid may increase plasma levels of zidovudine; monitor for possible increase in side effects (AUC increased by 80%)


Stability

 Solution for injection should be diluted with D5W to a concentration of 4 mg/mL; the solution is physically and chemically stable for 24 hours at room temperature and 48 hours if refrigerated; attempt to administer diluted solution within 8 hours, if stored at room temperature or 24 hours if refrigerated to minimize potential for microbially contaminated solutions; store undiluted vials at room temperature and protect from light


Compatibility

 Stable in D5W, NS

Y-site administration: Compatible: Acyclovir, allopurinol, amifostine, amikacin, amphotericin B, amphotericin B cholesteryl sulfate complex, aztreonam, cefepime, ceftazidime, ceftriaxone, cimetidine, cisatracurium, clindamycin, dexamethasone sodium phosphate, dobutamine, docetaxel, dopamine, doxorubicin liposome, erythromycin lactobionate, etoposide, filgrastim, fluconazole, fludarabine, gatifloxacin, gemcitabine, gentamicin, granisetron, heparin, imipenem/cilastatin, linezolid, lorazepam, melphalan, metoclopramide, morphine, nafcillin, ondansetron, oxacillin, paclitaxel, pentamidine, phenylephrine, piperacillin, piperacillin/tazobactam, potassium chloride, ranitidine, remifentanil, sargramostim, teniposide, thiotepa, tobramycin, trimethoprim/sulfamethoxazole, trimetrexate, vancomycin, vinorelbine. Variable (consult detailed reference): Meropenem, TPN

Compatibility when admixed: Variable (consult detailed reference): Meropenem


Mechanism of Action

 Zidovudine is a thymidine analog which interferes with the HIV viral RNA dependent DNA polymerase resulting in inhibition of viral replication; nucleoside reverse transcriptase inhibitor


Pharmacodynamics/Kinetics

Absorption: Oral: 66% to 70%

Distribution: Significant penetration into the CSF; crosses placenta

Relative diffusion from blood into CSF: Adequate with or without inflammation (exceeds usual MICs)

CSF:blood level ratio: Normal meninges: ~60%

Protein binding: 25% to 38%

Metabolism: Hepatic via glucuronidation to inactive metabolites; extensive first-pass effect

Half-life elimination: Terminal: 60 minutes

Time to peak, serum: 30-90 minutes

Excretion:

Oral: Urine (72% to 74% as metabolites, 14% to 18% as unchanged drug)

I.V.: Urine (45% to 60% as metabolites, 18% to 29% as unchanged drug)


Dosage

Prevention of maternal-fetal HIV transmission:

Neonatal: Note: Dosing should begin 6-12 hours after birth and continue for the first 6 weeks of life.

Oral:

Full-term infants: 2 mg/kg/dose every 6 hours

Infants 30 weeks and <35 weeks gestation at birth: 2 mg/kg/dose every 12 hours; at 2 weeks of age, advance to 2 mg/kg/dose every 8 hours

Infants <30 weeks gestation at birth: 2 mg/kg/dose every 12 hours; at 4 weeks of age, advance to 2 mg/kg/dose every 8 hours

I.V.: Infants unable to receive oral dosing:

Full term: 1.5 mg/kg/dose every 6 hours

Infants 30 weeks and <35 weeks gestation at birth: 1.5 mg/kg/dose every 12 hours; at 2 weeks of age, advance to 1.5 mg/kg/dose every 8 hours

Infants <30 weeks gestation at birth: 1.5 mg/kg/dose every 12 hours; at 4 weeks of age, advance to 1.5 mg/kg/dose every 8 hours

Maternal (may delay treatment until after 10-12 weeks gestation): Oral (per AIDSinfo 2003 guidelines): 200 mg 3 times/day or 300 mg twice daily until start of labor

During labor and delivery, administer zidovudine I.V. at 2 mg/kg over 1 hour followed by a continuous I.V. infusion of 1 mg/kg/hour until the umbilical cord is clamped

Children 3 months to 12 years for HIV infection:

Oral: 160 mg/m 2 /dose every 8 hours; dosage range: 90 mg/m 2 /dose to 180 mg/m 2 /dose every 6-8 hours; some Working Group members use a dose of 180 mg/m 2 every 12 hours when using in drug combinations with other antiretroviral compounds, but data on this dosing in children is limited

I.V. continuous infusion: 20 mg/m 2 /hour

I.V. intermittent infusion: 120 mg/m 2 /dose every 6 hours

Adults:

Oral: 300 mg twice daily or 200 mg 3 times/day

I.V.: 1-2 mg/kg/dose (infused over 1 hour) administered every 4 hours around-the-clock (6 doses/day)

Prevention of HIV following needlesticks (unlabeled use): 200 mg 3 times/day plus lamivudine 150 mg twice daily; a protease inhibitor (eg, indinavir) may be added for high risk exposures; begin therapy within 2 hours of exposure if possible

Patients should receive I.V. therapy only until oral therapy can be administered

Dosing interval in renal impairment: Clcr<10 mL/minute: May require minor dose adjustment

Hemodialysis: At least partially removed by hemo- and peritoneal dialysis; administer dose after hemodialysis or administer 100 mg supplemental dose; during CAPD, dose as for Clcr<10 mL/minute

Continuous arteriovenous or venovenous hemodiafiltration effects: Administer 100 mg every 8 hours

Dosing adjustment in hepatic impairment: Reduce dose by 50% or double dosing interval in patients with cirrhosis


Administration

Oral: Administer around-the-clock to promote less variation in peak and trough serum levels; may be administered without regard to food

I.M.: Do not administer I.M.

I.V.: Avoid rapid infusion or bolus injection

Neonates: Infuse over 30 minutes

Adults: Infuse over 1 hour


Monitoring Parameters

 Monitor CBC and platelet count at least every 2 weeks, MCV, serum creatinine kinase, viral load, and CD4 count; observe for appearance of opportunistic infections


Dietary Considerations

 May be taken without regard to food.


Patient Education

 Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug will not cure HIV; use appropriate precautions to prevent spread of HIV to other persons. Take as directed; may be taken without regard to food. Take around-the-clock. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations unless approved by prescriber). May cause headache or insomnia; if these persist notify prescriber. Report unresolved nausea or vomiting; signs of infection (eg, fever, chills, sore throat, burning urination, flu-like symptoms, fatigue); unusual bleeding (eg, tarry stools, easy bruising, or blood in stool, urine, or mouth); pain, tingling, or numbness of toes or fingers; skin rash or irritation; or muscle weakness or tremors. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.


Additional Information

 Potential compliance problems, frequency of administration and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.


Anesthesia and Critical Care Concerns/Other Considerations

 Does not reduce risk of transmitting HIV infections. Potential compliance problems, frequency of administration and adverse effects should be discussed with patients before initiating therapy to help prevent the emergence of resistance.


Dental Health: Effects on Dental Treatment

 No significant effects or complications reported


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 No information available to require special precautions


Mental Health: Effects on Mental Status

 May cause anxiety, confusion, depression, dizziness, drowsiness, insomnia, or mania


Mental Health: Effects on Psychiatric Treatment

 Granulocytopenia is common; avoid clozapine and carbamazepine. Valproic acid may decrease the clearance of zidovudine. GI side effects are common; concurrent use with SSRIs may produce additive effects.


Dosage Forms

Capsule: 100 mg

Injection, solution: 10 mg/mL (20 mL)

Syrup: 50 mg/5 mL (240 mL) [contains sodium benzoate; strawberry flavor]

Tablet: 300 mg


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International Brand Names

 Adovi® (ID); Apo-Zidovudine® (CA, TR); Aviral AZT® (CO); Azitidin® (CZ); Azotine® (AR); Azovir® (PL); AZT Biocrom® (AR); AZT™ (CA); Crisazet® (AR); Enper® (AR); Exovir® (AR); Iduvo® (AR); Isadol® (MX); Novo-AZT (CA, RO); Paravir® (PL); Retrovir® (AR, AT, AU, BD, BE, BG, CA, CL, CZ, DE, DK, EC, ES, FI, FR, GB, HK, HR, ID, IE, IL, IN, IT, KW, LU, NO, NZ, PL, PT, RO, SE, SG, TH, TR, YU); Retrovir AZT® (BR, CH, CL, CR, DO, GT, HN, MX, NL, PA, RU, SV); T.O.Vir® (TH); Zetrotax® (AR); Zidis® (TH); Zidosan® (YU); Zidovir® (BR, IN); Zidovudina® (CO); Zidovudina Combino Pharm® (ES); Zidovudina Filaxis® (AR); Zidovudina Tuteur® (AR); Zidovudin® (CR, GT, PA); Zidovudine® (AR); Zydowin® (IN)


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