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/tab; 300 mg/cap | $2.97 ; $8.92 for Retrovir; $0.95 for generic (300 mg) |
IV | vial | 10mg/mL (20ml) | $32.16 | |||
oral | syrup | 10mg/mL (8oz) | $71.34 | |||
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 | $14.55; generic price (TBA) |
Trizivir | Glaxo | oral | tablet | 300 mg AZT/150 mg 3TC/300 mg ABC | $23.58 |
*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 (preferred) or 200 mg PO thrice-daily with or without food (often better tolerated with food).
- Combinations:
- Perinatal transmission protocol (ACTG 076) AZT 300 mg PO twice-daily starting from wk 14 to delivery; intrapartum: AZT IV 2 mg/kg 1st hr, then 1 mg/kg/hr until delivery.
PEDIATRIC DOSING
USUAL PEDIATRIC DOSING
DHHS guidelines
- Neonate/Infants (< 6 weeks): prevention of Perinatal Transmission, administer as soon as possible after birth, ideally within 6-12 hrs of delivery; continue through 4-6 weeks.
- ≥ 35 weeks gestation:
- 4 mg/kg/dose PO q12h OR 3 mg/kg/dose IV q12h
- ≥ 30 to < 35 weeks gestation:
- Day 0-14: 2 mg/kg/dose PO q12h OR 1.5 mg/kg/dose IV q12h
- Day 15 and beyond: 3 mg/kg/dose PO q12h OR 2.3 mg/kg/dose IV q12h
- < 30 weeks gestation:
- Day 0-28: 2 mg/kg/dose PO q12h OR 1.5 mg/kg/dose IV q12h
- Day 29 and beyond: 3 mg/kg/dose PO q12h OR 2.3 mg/kg/dose IV q12h
- Note: FDA approved dose of 2mg/kg q6h may be excessive in premature infants.
- ≥ 35 weeks gestation:
- Pediatric (6 weeks to < 18 y/o):
- 240 mg/m2/dose PO q12h
- Weight based dosing:
- 4 to < 9 kg: 12 mg/kg/dose PO q12h
- 9 to < 30 kg: 9 mg/kg/dose PO q12h
- ≥ 30 kg: 300 mg PO q12h
- Note: FDA labeling recommends the above dosing for children >4 weeks to < 18 y/o
- Adolescent (≥ 18 y/o):
- 300 mg PO q12h
PEDIATRIC RENAL DOSING
- Requires renal dosage adjustment. Insufficient data exists to recommend specific renal dosing in infants/children; consider a reduction in the dose and/or an increase in the dosing interval similar to dosage adjustments for adolescent/adults.
- Adolescents:
- CrCl ≥ 15 mL/min: usual dose
- CrCl < 15 mL/min or HD: 300 mg PO q24h, dose after HD on HD days
RENAL DOSING
DOSING FOR GLOMERULAR FILTRATION OF 50-80
300 mg twice-daily
DOSING FOR GLOMERULAR FILTRATION OF 10-50
300 mg twice-daily
DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN
300mg once-daily
DOSING IN HEMODIALYSIS
300 mg once-daily
DOSING IN PERITONEAL DIALYSIS
300 mg once-daily
DOSING IN HEMOFILTRATION
No data. Usual dose likely.
ADVERSE DRUG REACTIONS
GENERAL
GI intolerance higher than with other NRTIs
COMMON
- GI intolerance
- Headache (5-10%)
- Insomnia
- Constitutional: malaise, myalgia, and asthenia
- Bone marrow suppression: anemia-usually seen within 4-6 wks; neutropenia usually seen after 12-24 wks.
- Fingernail discoloration/hyperpigmentation
- Benign macrocytosis (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 glucoronide AZT. Drugs that induce glucuronidation may decrease AZT plasma concentrations; 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 anti viral 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 coadministration, monitor for anemia. | |
APAP (acetaminophen) | Theoretical concern of competing 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 unknown. Use standard dose. | |
AZT: AUC increased by 31%. | Clinical significance 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 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 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 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 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 effect of TAMs, but cannot overcome 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 liver to glucuronide (G-ZVD) that is renally excreted.
Protein Binding
34-38%
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
100 mg three times a day
PREGNANCY RISK
Category C: Human studies demonstrated 85% placental passage. No maternal toxicities or fetal defects noted with AZT during pregnancy. Long-term toxicity data (up to 3.9 yrs) for infants exposed to AZT in utero and post partum did not show an increased risk of adverse effects or developmental abnormalities.
BREAST FEEDING COMPATIBILITY
Mean concentration of AZT was similar in human milk and in serum. Breast feeding 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 gradual accumulation of TAMs.
- When AZT used in a TDF or ABC-containing regimen, K65R or L74V 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.
References
- Gallant JE et al: Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354:251, 2006 [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 higher with AZT/3TC+EFV (9% vs 4%),with 6% experiencing severe anemia. NRTI resistance profiles between week 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 et al: Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA 296:769, 2006 [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.
- Gulick RM et al: Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 350:1850, 2004 [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 results of this trial, triple-nucleoside regimens no longer recommended as first-line therapy in naive pts.
- Robbins GK et al: Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med 349:2293, 2003 [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. 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 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 335:1091, 1996 [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 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 317:185, 1987 [PMID:3299089]
Comment: The first trial to show 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 HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. Available at
http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf. Accessed (04/23/14) [pages O-35 to O-39]Comment: DHHS guideline recommendations for dosing of zidovudine in pediatrics.
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