Zidovudine

( Azidothymidine ; AZT ; Compound S ) Pronunciation: (zye-DOE-vue-deen)
Class: Nucleoside reverse transcriptase inhibitor

Trade Names

Retrovir
- Tablets, oral 300 mg
- Capsules, oral 100 mg
- Syrup, oral 50 mg per 5 mL
- Injection, solution, concentrate 10 mg/mL

Apo-Zidovudine (Canada)
Retrovir (AZT) (Canada)

Pharmacology

Inhibits replication of retroviruses, including HIV.

Pharmacokinetics

Absorption

Rapidly absorbed. T _max is 0.5 to 1.5 h. Oral bioavailability is approximately 64%.

Distribution

Zidovudine is extensively distributed. Binding to plasma protein is low, less than 38%. Apparent Vd is 1.6 L/kg.

Metabolism

Hepatic metabolism. Major metabolites are 3′-azido-3′-deoxy-5′-O-beta-D-glucopyranuronosylthymidine (GZDV) and 3′-amino-3′-deoxythymidine (AMT).

Elimination

Primarily eliminated by hepatic metabolism. Elimination half-life is 0.5 to 3 h. GZDV (74%) and zidovudine (14%) are recovered in the urine. Renal Cl is 0.34 L/h/kg.

Special Populations

Renal Function Impairment

Cl is decreased, resulting in an increased half-life and AUC of zidovudine and GZDV. A dose adjustment is necessary for patients with CrCl less than 15 mL/min and in patients undergoing hemodialysis or peritoneal dialysis.

Hepatic Function Impairment

It is expected that Cl would decrease and plasma concentration would increase.

Elderly

Pharmacokinetics have not been studied in patients older than 65 y.

Children

Pharmacokinetics in pediatric patients older than 3 mo are similar to adults. In pediatric patients from birth to 3 mo of age, the half-life was approximately 13 h. In neonates 14 days and younger, bioavailability was greater, total body Cl was slower, and half-life was longer than in pediatric patients older than 14 days.

Gender

A pharmacokinetic study in healthy men and women showed no differences in zidovudine exposure (AUC).

Pregnancy

Pharmacokinetics were similar to those of nonpregnant adults.

Breast-feeding mothers

The mean concentration of zidovudine was similar in human milk and serum.

Indications and Usage

In combination with other antiretroviral agents for the treatment of HIV-1 infections; prevention of maternal-fetal HIV-1 transmission.

Contraindications

Potentially life-threatening allergic reactions (eg, anaphylaxis, Steven-Johnson syndrome) to any component of the formulations.

Dosage and Administration

HIV Infection
Adults PO

600 mg/day in divided doses in combination with other antiretroviral agents.

IV

1 mg/kg infused over 1 h administered 5 to 6 times daily.

Children 4 wk to younger than 18 y

PO

Children weighing 4 to less than 9 kg

12 mg/kg twice daily or 8 mg/kg 3 times daily, or 240 mg/m ² twice daily or 160 mg/m ² three times daily (max, 600 mg/day).

Children weighing 9 to less than 30 kg

9 mg/kg twice daily or 6 mg/kg 3 times daily, or 240 mg/m ² twice daily or 160 mg/m ² three times daily (max, 600 mg/day).

Children weighing 30 kg or more

300 mg twice daily or 200 mg 3 times daily, or 240 mg/m ² twice daily or 160 mg/m ² three times daily (max, 600 mg/day).

Maternal-Fetal HIV Transmission
Maternal dosing (more than 14 weeks of pregnancy) PO

100 mg orally 5 times per day until the start of labor.

IV

During labor and delivery, administer IV zidovudine at 2 mg/kg over 1 h followed by a continuous IV infusion of 1 mg/kg/h until clamping of the umbilical cord.

Neonates PO

2 mg/kg every 6 h starting within 12 h after birth and continuing through 6 wk of age.

IV

Infants unable to receive oral dosing may be given zidovudine IV at 1.5 mg/kg infused over 30 min every 6 h.

Renal Function Impairment
Adults PO

100 mg every 6 to 8 h for patients maintained on hemodialysis or peritoneal dialysis.

IV

1 mg/kg every 6 to 8 h for severe renal impairment (CrCl less than 15 mL/min) and patients maintained on hemodialysis or peritoneal dialysis.

Hepatic Function Impairment
Adults

IV Reduction in the daily dose may be necessary.

Severe Anemia and/or Neutropenia

PO Dosage interruption until evidence of marrow recovery may be required in patients with significant anemia (Hgb less than 7.5 g/dL or a reduction of more than 25% from baseline) and/or significant neutropenia (granulocyte count less than 750 cells/mm ³ or a reduction of more than 50% from baseline). Dose interruption may not eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption of therapy may be appropriate using adjunctive measures, such as epoetin alfa, at recommended doses, depending on hematologic indices (eg, serum erythropoietin level) and patient tolerance.

General Advice

Oral zidovudine may be taken with or without food.
Dilute IV preparation prior to administration. Remove calculated dose from vial and add to dextrose 5% to achieve concentration of up to 4 mg/mL.
Do not mix with biologic or colloidal fluids (eg, blood products, protein solutions).
Infuse over 1 h at constant rate. Avoid rapid infusion, bolus, or IM administration.
Patients should receive zidovudine IV infusion only until oral therapy can be administered.
The IV dosing regimen equivalent to the oral administration of 100 mg every 4 hours is approximately 1 mg/kg IV every 4 h.

Storage/Stability

Store undiluted vials, capsules, tablets, and syrup between 59° and 77°F. Protect capsules from moisture and vials from light. After dilution, the solution is stable for 24 h at room temperature and 48 h if refrigerated. Administer the diluted solution within 8 h if stored at room temperature or 24 h if refrigerated.

Drug Interactions

Atovaquone, clarithromycin, fluconazole, methadone, probenecid, valproic acid

May increase serum concentration and potential toxicity of zidovudine. Monitor the effects of zidovudine. If an interaction is suspected, adjust the zidovudine dose as needed.

Clarithromycin, nelfinavir, rifamycin, ritonavir

May decrease zidovudine serum concentrations, reducing the therapeutic effect. Monitor the clinical response of the patient. If an interaction is suspected, adjust the zidovudine dose as needed.

Doxorubicin

May antagonize the effect of zidovudine. Avoid use.

Ganciclovir

Life-threatening hematologic toxicity may occur. Avoid coadministration.

Interferon

The risk of zidovudine-induced life-threatening hematologic toxicities may be increased. If coadministration cannot be avoided, close clinical and laboratory monitoring is warranted.

Phenytoin

Phenytoin levels have been reported to increase, decrease, or not change with coadministration. Zidovudine Cl is decreased. Monitor the clinical response of the patient. If an interaction is suspected, adjust the dose of either drug as needed.

Ribavirin

Ribavirin can reduce phosphorylation of zidovudine, decreasing zidovudine effectiveness. In addition, ribavirin may antagonize antiviral activity of zidovudine against HIV. Cases of hepatic decompensation (some fatal) have occurred in HIV/hepatitis C virus coinfected patients receiving this combination. Avoid coadministration.

Stavudine

Avoid concomitant use because stavudine may antagonize antiviral activity of zidovudine against HIV.

Adverse Reactions

Cardiovascular

Cardiomyopathy, syncope (postmarketing).

CNS

Headache (63%); malaise (53%); asthenia (9%); fatigue, insomnia, neuropathy (5% or more); anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, tremor, vertigo (postmarketing).

Dermatologic

Changes in skin and nail pigmentation, pruritus, rash, Stevens-Johnson syndrome, TEN, sweat, urticaria (postmarketing).

EENT

Amblyopia, hearing loss, macular edema, photophobia, taste perversion (postmarketing).

GI

Nausea (51%); anorexia (20%); vomiting (17%); constipation (6%); abdominal cramps, abdominal pain, dyspepsia (5% or more); dysphagia, flatulence, mouth ulcer, oral mucosa pigmentation, pancreatitis (postmarketing).

Genitourinary

Gynecomastia, urinary frequency, urinary hesitancy (postmarketing).

Hepatic

Elevated ALT (3%); elevated AST (1%); hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis (postmarketing).

Hematologic-Lymphatic

Anemia (22%); neutropenia (21%); granulocytopenia (2%); aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia (postmarketing).

Hypersensitivity

Sensitization reactions, including anaphylaxis and angioedema (postmarketing).

Musculoskeletal

Arthralgia, musculoskeletal pain, myalgia (5% or more); back pain, increased CPK, muscle spasm, myopathy and myositis with pathological changes, rhabdomyolysis (postmarketing).

Respiratory

Cough, dyspnea, rhinitis, sinusitis (postmarketing).

Miscellaneous

Chills (5% or more); hyperbilirubinemia (1% or less); chest pain, fat redistribution/accumulation, flu-like symptoms, generalized pain, increased LDH, vasculitis (postmarketing).

Precautions

Warnings

Hematologic toxicity

Hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced HIV-1, has been reported.

Lactic acidosis/severe hepatomegaly with steatosis

Lactic acidosis and severe hepatomegaly with steatosis (some fatal cases) have been reported with use of nucleoside analogues alone or in combination, including zidovudine and other antiretroviral agents. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Myopathy

Prolonged use has been associated with symptomatic myopathy.

Monitor

Monitor patients carefully, especially as disease progression occurs. Frequent monitoring of hematologic indices is recommended in patients with poor bone marrow reserve, particularly in patients with advanced symptomatic HIV-1 disease. Periodically monitor blood cell counts in patients with asymptomatic or early HIV-1 disease. Monitor liver function and for symptoms of lactic acidosis.

Pregnancy

Category C .

Lactation

Excreted in breast milk. HIV-infected mothers should not breast-feed.

Renal Function

May have greater risk of toxicity. Dosage reduction recommended in patients with CrCl less than 15 mL/min.

Hepatic Function

Patients with severe hepatic impairment may have greater risk of hematologic toxicity.

Fat redistribution

Redistribution/accumulation of body fat have been observed (eg, cushingoid appearance, buffalo hump, peripheral/facial wasting).

Hematologic effects

Use with caution in patients with bone marrow compromise (Hgb less than 9.5 g/dL or granulocyte count less than 1,000/mm ³ ).

Immune reconstitution syndrome

Has been reported.

Overdosage

Symptoms

Fatigue, headache, hematologic changes, vomiting.

Patient Information

Inform patients that the major toxicities of zidovudine are neutropenia and/or anemia. Inform patients that if toxicity develops, they may require transfusions or drug discontinuation. Inform patients of the extreme importance of having their blood cell counts followed closely while on therapy, especially for patients with advanced symptomatic HIV disease.
Inform patients that myopathy and myositis with pathological changes have been associated with prolonged use.
Advise patient not to share medication and not to exceed the recommended dose.
Inform patient that fever, sore throat, shortness of breath, and dizziness require immediate attention by their health care provider. These may be signs of severe anemia or decreased WBCs and may indicate a need for blood transfusion.
Tell patient to notify their health care provider of diarrhea, dyspnea, excessive sweating, GI pain, headache, insomnia, loss of appetite, muscle aches, nausea, nervousness, numbness or tingling, rash, swelling of feet and legs, taste perversions, or vomiting.
Inform patients that zidovudine is not a cure for HIV infection, and patients may continue to acquire illnesses associated with HIV infections, including opportunistic infections.
Caution patient not to take any other drugs without consulting their health care provider.
Explain that long-term effects of drug are not known at this time.
Advise patient that zidovudine therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
Advise pregnant women considering use of the drug to prevent maternal-fetal transmission of HIV that transmission may still occur in some cases despite therapy. Long-term consequences of in utero and infant exposure are unknown.
Advise breast-feeding women not to breast-feed.
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Inform patients that zidovudine can cause a rare but serious condition called lactic acidosis with liver enlargement (hepatomegaly).
Advise patients with HIV/hepatitis C virus coinfection that hepatic decomposition (some fatal) has occurred in patients receiving combination antiretroviral therapy for HIV and interferon alfa with or without ribavirin.