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 Zambia HIV National Guidelines
 


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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Drugs>Antiretrovirals>
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Zidovudine (AZT)

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
10-15-2010

Zambia Specific Information

  • Available formulation in Zambia: Capsule: 100 mg; 250 mg; Oral liquid: 50 mg/5 ml; IV injection: 10 mg/ml in 20-ml vial. Tablet: 300 mg. AZT 300 mg/3TC 150 mg combination tab AZT 300 mg/3TC 150 mg/NVP 200 mg combination tab
  • AZT /3TC plus EFV or NVP is no longer first line ARV regimen in ARV-naïve patients. TDF/FTC/EFV now preferred first line regimen due to long-term potency, favorable mutation pathway, and lower incidence of anemia.
  • After TDF/FTC/EFV failure, AZT/3TC or AZT/TDF/FTC plus LPV/r is recommended second line regimen.
  • Avoid AZT in patients with Hb <10 gm/dl
  • With severe anemia (Hg <6.5 g/dl), malaria should be ruled out.
  • Due to the potential for additive bone marrow suppression with AZT co-administration, pyrimethamine, flucytosine, and other bone marrow suppressing agents should be avoided or use with caution.
Zambia Information Author: Paul A. Pham, Pharm.D.

INDICATIONS

FDA

  • Treatment of HIV infection in combination with other antiretrovirals.

FORMS

brand 
name
 
generic 
Mfg 
brand 
forms
 
cost* 
Retrovir and generic zidovudineZidovudine (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 AZT/3TCGlaxo oral
tablet
300 mg AZT/150 mg 3TC
$14.55
Trizivir AZT/3TC/ABCGlaxo oral
tablet
300 mg AZT/150 mg 3TC/300 mg ABC
$23.58

*Prices represent cost per unit specified and are representative of "Average Wholesale Price" (AWP). AWP Prices were obtained and gathered by Lakshmi Vasist Pharm D using the Red Book, manufacturer's information, and the McKesson database.

^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).
  • Combivir (AZT 300 mg + 3TC 150 mg) 1 tab PO twice-daily.
  • Trizivir (ABC 300 mg + AZT 300 mg + 3TC 150 mg) 1 tab PO twice-daily.
  • 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; postpartum: syrup 2 mg/kg q6h (or 1.5 mg/kg q6h IV) x 6 wks to the infant.

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

GI intolerance higher than with other NRTIs

COMMON

  • GI intolerance, headache ( 5-10%)
  • Insomnia, malaise, myalgia, and asthenia
  • Bone marrow suppression (anemia-usually seen within 4-6 wks and 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-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
Amphotericin B Possible additive anemia.With coadministration, monitor for anemia.
Clarithromycin AZT: No significant change in AUC.Not clinically significant. Use standard dose.
Stavudine (d4T) In vitro and in vivo antagonism.Do not co-administer. Switch to an alternative NRTI.
Dapsone Possible additive anemiaWith co-administration, monitor for anemia.
Fluconazole Slight increase in AZT half-life. No change in fluconazole PK.Not clinically significant. Use standard dose.
Flucytosine 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.
Pyrimethamine Possible additive bone marrow suppression.With co-administration, monitor for bone marrow suppression.
Rifampin AZT AUC decreasedClinical significance unknown; consider switching to rifabutin.
Sulfadiazine Possible additive bone marrow suppression.With co-administration, monitor for bone marrow suppression esp. anemia.
Trimethoprim + Sulfamethoxazole Possible additive bone marrow suppression.With co-administration, monitor for bone marrow suppression.
Tipranavir 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.
Atazanavir AZT trough decreased 30%, but no change in AUC. Clinical significance unknown. Use standard dose.
AdriamycinPossible additive bone marrow suppression.With co-administration, monitor for bone marrow suppression (esp. neutropenia).
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.
Atovaquone AZT: AUC increased by 31%.Clinical significance unknown.Use standard dose.
BuprenorphineNo change in AZT AUC.No significant interaction. Use standard dose.
ddC (Zalcitabine) Modest antiviral effect due to poor activity of ddC.Do not co-administer. Switch to an alternative NRTI.
Fatty foodAZT 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.
Hydroxyurea Possible additive bone marrow suppression.With co-administration, monitor for bone marrow suppression.
Interferon Possible additive bone marrow suppression.With co-administration, monitor for bone marrow suppression.
Methadone AZT AUC increased 43% Clinical significance unknown, but monitor for AZT-associated ADR.
ProbenecidMay increase AZT levels by inhibiting renal tubular secretion of AZT.High incidence of probenecid rash with co-administration.
Ribavirin In vitro antagonism but not in vivo.Antagonism not observed in vivo, however, pts should be closely monitored for severe anemia.
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

Pharmacology

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

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