Johns Hopkins ABX Guide
Zidovudine (AZT)
INDICATIONS
FDA
- Treatment of HIV infection in combination with other antiretrovirals.
FORMS
brand name | preparation | manufacturer | route | form | dosage^ | cost* |
Retrovir and generic zidovudine | Zidovudine (AZT) | Glaxo and generic manufacturers (Roxane Laboratories, Ranbaxy Laboratories, and Aurobindo Pharma). Generic manufacturer for IV zidovudine (Pharmaforce Inc.) | oral | tablet/cap | 100 mg/cap; 300 mg/tab; | $3.24 for Retrovir; 0.80 - 2.02 for generic; 0.23 - 6.02 (300 mg) for generic |
IV | vial | 10mg/mL (20ml) | $1.75 | |||
oral | syrup | 50mg/5mL (8oz) | $56.42 | |||
oral | tablet | 60 mg | not available in U.S. | |||
Combivir and generic AZT/3TC | AZT/3TC | Glaxo and generic manufacturer (Aurobindo Pharma Limited) | oral | tablet | 300 mg AZT/150 mg 3TC | $18.03; $4.42 - $15.53 for generic price |
Trizivir | Glaxo | oral | tablet | 300 mg AZT/150 mg 3TC/300 mg ABC | $32.19; $28.97 for generic; |
*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.
USUAL ADULT DOSING
Pill burden: 2 per day
- AZT 300 mg PO twice daily with or without food (often better tolerated with food).
- Combinations:
- Perinatal transmission: AZT 600 mg, then 400 mg every 3 hours (not preferred route of administration). Intrapartum: AZT IV 2 mg/kg 1st hr, then 1 mg/kg/hr for two hours (3-hour minimum). Planned C-section, begin IV AZt 3 hours prior to delivery. Unplanned C-section, consider administering loading dose prior to proceeding to delivery.
PEDIATRIC DOSING
USUAL PEDIATRIC DOSING
Neonatal Dosing
- Gestational age at birth ≥ 35 weeks
- Birth to age 4 weeks:
- Weight-based dosing: 4 mg/kg/dose PO twice daily
- Flat dosing: note, these doses approximate 4 mg/kg/dose twice daily from birth to 4 weeks
- 2 to < 3 kg: 10 mg PO twice daily
- 3 to < 4 kg: 15 mg PO twice daily
- 4 to < 5 kg: 20 mg PO twice daily
- > 4 weeks: 12 mg/kg/dose PO twice daily
- Birth to age 4 weeks:
- Gestational age at birth ≥ 30 to < 35 weeks
- Birth to age 2 weeks: 2 mg/kg PO twice daily
- 2 weeks to 6-8 weeks: 3 mg/kg PO twice daily
- > 6 weeks to 8 weeks: 12 mg/kg PO twice daily
- Gestational age at birth < 30 weeks
- Birth to age 4 weeks: 2 mg/kg PO twice daily
- 4 weeks to 8-10 weeks: 3 mg/kg PO twice daily
- >8 weeks to 10 weeks: 12 mg/kg PO twice daily
- Note: If unable to tolerate enteral medication, IV dose = 75% of oral dose, dosing interval should remain the same.
Infant / Pediatric Dosing
- 4 to < 9 kg: 12 mg/kg/dose PO twice daily
- 9 to < 30 kg: 9 mg/kg/dose PO twice daily
- ≥ 30 kg: 300 mg twice PO daily
- Alternative body surface area dosing:
- Oral: 180 - 240 mg/m2/dose PO twice daily
PEDIATRIC RENAL DOSING
- Infants > 6 weeks, children, and adolescents:
- Dose adjustments based on an oral dose of 160 mg/m2/dose every 8 hours and an intravenous dose of 120 mg/m2/dose every 6 hours
- CrCl ≥ 10 mL/min: No dosage adjustment required
- CrCl < 10 mL/min or HD: Administer 50% of dose every 8 hours
- Intermittent hemodialysis and peritoneal dialysis: Administer 50% of dose every 8 hours
- Continuous renal replacement therapy (CRRT): No dose adjustment is required
- Dose adjustments based on an oral dose of 160 mg/m2/dose every 8 hours and an intravenous dose of 120 mg/m2/dose every 6 hours
RENAL DOSING
DOSING IN HEMODIALYSIS
100 mg 3 times daily or 300 mg once daily
IV: 1 mg/kg every 6 to 8 hours
DOSING IN PERITONEAL DIALYSIS
100 mg every 6 to 8 hours
IV: 1 mg/kg 6 to 8 hours
DOSING IN HEMOFILTRATION
No data. Usual dose is likely.
Other Adult Renal Dosing Information
CrCL < 15 mL/min: 100 mg 3 times daily or 300 mg once daily
IV: 1 mg/kg every 6 to 8 hours
ADVERSE DRUG REACTIONS
GENERAL
GI intolerance is higher than with other NRTIs
COMMON
- GI intolerance: Nausea (51%), anorexia (20%), vomiting (17%)
- Headache (63%)
- Insomnia
- Constitutional: malaise (53%), myalgia, and asthenia
- Bone marrow suppression:
- Anemia-usually seen within 4-6 wks
- Neutropenia is usually seen after 12-24 wks.
- Fingernail discoloration/hyperpigmentation
- Benign macrocytosis (a crude indicator of adherence)
OCCASIONAL
- Transaminase elevation with reversible hepatitis
- Lipoatrophy
RARE
- Myopathy (with LDH and CPK elevation with ragged red fibers on muscle biopsy)
- Cardiomyopathy
- Lactic acidosis or hyperlactatemia +/- hepatic steatosis (consider in pts with progressive fatigue, abd. pain, n/v, weight loss, and/or dyspnea)
DRUG INTERACTIONS
Extensive first past liver metabolism to glucuronide AZT. Drugs that induce glucuronidation may decrease AZT plasma concentrations; the clinical significance of these potential interactions is unknown since plasma concentrations of AZT do not correlate well with antiviral activity and it is the intracellular triphosphate that exerts antiviral activity.
Drug | Effect of Interaction | Recommendations/Comments |
Adriamycin | Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression (esp. neutropenia). |
Possible additive anemia. | With co-administration, monitor for anemia. | |
APAP (acetaminophen) | A theoretical concern of competing for hepatic metabolism (glucuronidation) that has not been demonstrated in vivo. | Not clinically significant. Intermittent use of acetaminophen is considered safe. Adverse effects not consistently reported. |
AZT trough decreased 30%, but no change in AUC. | Clinical significance is unknown. Use standard dose. | |
AZT: AUC increased by 31%. | Clinical significance is unknown. Use standard dose. | |
Buprenorphine | No change in AZT AUC. | No significant interaction. Use standard dose. |
AZT: No significant change in AUC. | Not clinically significant. Use standard dose. | |
Possible additive anemia | With co-administration, monitor for anemia. | |
ddC (Zalcitabine) | Modest antiviral effect due to poor activity of ddC. | Do not co-administer. Switch to an alternative NRTI. |
Fatty food | AZT AUC decreased by 57% with a liquid fat meal. Intracellular AZT triphosphate was not measured. | Clinical significance of fatty meal unknown. Administer AZT with food since it improves GI tolerance. |
Slight increase in AZT half-life. No change in fluconazole PK. | Not clinically significant. Use standard dose. | |
Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression, esp. neutropenia. | |
Ganciclovir | Additive bone marrow suppression. | Close monitoring of CBC is recommended. Switch to alternative ART or use concomitant G-CSF if neutropenia is severe.In vitro antagonism; clinical significance unknown. |
Hydroxyurea | Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression. |
Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression. | |
AZT AUC increased 43% | Clinical significance unknown, but monitor for AZT-associated ADR. | |
Probenecid | May increase AZT levels by inhibiting the renal tubular secretion of AZT. | High incidence of probenecid rash with co-administration. |
Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression. | |
In vitro antagonism but not in vivo. | Antagonism not observed in vivo, however, pts should be closely monitored for severe anemia. | |
Rifampin | AZT AUC decreased | Clinical significance unknown; consider switching to rifabutin. |
In vitro and in vivo antagonism. | Do not co-administer. Switch to an alternative NRTI. | |
Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression esp. anemia. | |
AZT AUC decreased by approx. 42% with TPV/r 250/200 mg twice-daily co-admin. | Clinical significance is unknown. AZT intracellular triphosphate levels not measured. | |
Trimethoprim + Sulfamethoxazole | Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression. |
Valproic acid | AZT serum concentrations increased by 2-fold. | Clinical significance unknown, but monitor for AZT-associated ADR. |
Vinca alkaloids (Vincristine, Vinblastine) | Possible additive bone marrow suppression. | With co-administration, monitor for bone marrow suppression. |
RESISTANCE
- TAMs: selected by AZT and d4T. Resistance (including NRTI cross-resistance) increases with the number of TAMs. Greater resistance with 41L/L210W/T215Y pathway than withD67N/K70R/K219 pathway.
- E44D, V118I: accessory mutations that increase AZT resistance when combined with TAMs (especially M41L/L210W/T215Y).
- Q151M or T69 insertion: high-level AZT resistance and NRTI cross-resistance. Selected by AZT/ddI and ddI/d4T combinations.
- M184V: increases AZT susceptibility, partially reversing the effect of TAMs, but cannot overcome the effect of multiple TAMs.
- K65R and L74V: increase susceptibility to AZT (clinical significance unknown).
PHARMACOLOGY
MECHANISM
Intracellular phosphorylation to active zidovudine triphosphate, which competitively inhibits HIV DNA polymerase.
PHARMACOKINETIC PARAMETERS
Absorption
60% absorption; high-fat meals may decrease absorption (clinical significance unknown).
Metabolism and Excretion
Metabolized by the liver to glucuronide (G-ZVD) that is renally excreted.
Protein Binding
25% to 38%
Cmax, Cmin, and AUC
Mean steady-state Cmax=1.5 mcg/mL. AZT triphosphate intracellular levels 0.19 mcg/mL.
T1/2
Plasma: 1.1 hrs; Intracellular: 3 hrs.
DOSING FOR DECREASED HEPATIC FUNCTION
No specific dosage adjustments are provided in the manufacturer’s labeling. However, an adjustment may be necessary due to extensive hepatic metabolism.
PREGNANCY RISK
Category C: Human studies demonstrated 85% placental passage. The placenta also metabolizes zidovudine to the active metabolite. No maternal toxicities or fetal defects were noted with AZT during pregnancy. Long-term toxicity data (up to 3.9 yrs) for infants exposed to AZT in utero and postpartum did not show an increased risk of adverse effects or developmental abnormalities.
BREAST FEEDING COMPATIBILITY
The mean concentration of AZT was similar in human milk and in serum. Breastfeeding is not recommended in the U.S. in order to avoid post-natal transmission of HIV to the child, who may not yet be infected.
COMMENTS
- Pros:
- Availability of generics; extensive long-term data and clinical experience; documented efficacy in preventing perinatal and occupational transmission; effective in treating thrombocytopenia.
- Crosses blood-brain barrier, and experience with treatment of dementia.
- High-level resistance requires multiple mutations: failure of AZT/3TC-containing combinations results in the gradual accumulation of TAMs.
- When AZT is used in a TDF or ABC-containing regimen, K65R or L74V is unlikely to occur.
- Cons:
- Twice-daily dosing
- GI intolerance (especially nausea), headaches, fatigue, asthenia, anemia, neutropenia; mitochondrial toxicity, including lipoatrophy, lactic acidosis, hepatic steatosis
- High-level resistance with multiple TAMs leads to broad NRTI cross-resistance.
- AZT/3TC less effective than TDF/FTC at 48 wks, primarily because of greater drop-out due to anemia and other side effects.
Basis for recommendation
- Gulick RM, Ribaudo HJ, Shikuma CM, et al. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004;350(18):1850-61. [PMID:15115831]
Comment: Randomized, double-blind study comparing 3 regimens (AZT/3TC/ABC, AZT/3TC/EFV, AZT/3TC/ABC/EFV) as initial treatment in naive pts. After med. follow-up of 32 wks, 82 of 382 pts in the triple-nucleoside group (21%) and 85 of 765 of those in the combined EFV groups (11%) had virologic failure; time to virologic failure significantly shorter in the triple-nucleoside group (p < 0.001). Based on the results of this trial, triple-nucleoside regimens are no longer recommended as first-line therapy in naive pts.
References
- Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354(3):251-60. [PMID:16421366]
Comment: 509 treatment-nave patients randomized to receive TDF+FTC+ EFV or AZT/3TC+EFV. At 48 weeks, 77% of TDF/FTC/EFV treated pts and 68% of AZT/3TC/EFV treated patients achieved a viral load < 50 cs/mL (ITT; p=0.034). Discontinuation due to adverse events was higher with AZT/3TC+EFV (9% vs 4%), with 6% experiencing severe anemia. NRTI resistance profiles between weeks 8 and 48 for pts with HIV RNA >400 c/mL showed one TAM and 7 M184V/I mutations in AZT/3TC+EFV arm. In contrast to GS903, NRTI resistance was limited to only two M184V/I and no K65R mutations in pts w/ virologic failure on TDF+FTC+EFV. Pts in the TDF+FTC arm also had significantly greater limb fat by DXA at 48 wks than those in AZT/3TC arm.
- Gulick RM, Ribaudo HJ, Shikuma CM, et al. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. 2006;296(7):769-81. [PMID:16905783]
Comment: A continuation phase of ACTG 5095 compared AZT/3TC and AZT/ABC/3TC, each combined with EFV in treatment-naive pts. There were no significant differences between the 3 and 4-drug antiretroviral regimens; approximately 80% of pts had VL< 50 through 3 yrs.
- Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003;349(24):2293-303. [PMID:14668455]
Comment: ACTG 384: 620 pts randomized to compare sequential 3-drug regimens in 4 groups: EFV-based HAART combined with AZT/3TC or d4T/ddI OR NFV + AZT/3TC or d4T/ddI. The most effective and best-tolerated combination was AZT/3TC + EFV, with virologic failure in 14% and 23% of pts with the 1st and 2nd regimen, respectively (med. 2.3 yr follow-up). Higher rate of virologic failure in the EFV/d4T/ddI arm (31% and 58%).
- Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med. 1996;335(15):1091-8. [PMID:8813039]
Comment: 391 HIV+ subjects with CD4 200-500randomly assigned to receive AZT alone, ddI alone, AZT + ddI, or AZT + ddC. After 8 wks, the mean (+/-SE) decrease from baseline log HIV RNA was 0.26+/-0.06 for pts treated with AZT alone, 0.65+/-0.07 for ddI alone, and 0.93+/-0.10 for AZT plus ddI (p <0.001). One of the first studies to show that the risk of progression of HIV disease is strongly associated with viral load.
- Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987;317(4):185-91. [PMID:3299089]
Comment: The first trial to show a survival benefit with ART therapy. Of the 282 pts, 19 placebo recipients and 1 AZT recipient died during the study period (p< 0.001).
- Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv. Accessed (2/8/2022) [Pages L-46 to L-53].
Comment: DHHS guideline recommendations for dosing of zidovudine in pediatrics.
