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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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Stavudine

Paul A. Pham, Pharm. D. and John G. Bartlett, M.D
10-25-2010

Zambia Specific Information

  • Coformulation: d4T (30 mg) + 3TC (150 mg) + NVP (200 mg); Dose: 1 tab twice daily.
  • 40 mg twice daily dosing no longer recommended due to increased risk of mitochondrial toxicity.
  • Co-administration with ddI, INH, phenytoin, and vincristine may increase the risk of peripheral neuropathy.
  • Contraindicated with AZT due to in vitro and in vivo antagonism.

REFERENCES

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* 
Zerit Stavudine (d4T)Bristol-Myers Squibboral
capsule
15 mg; 20 mg; 30 mg; 40 mg
$6.76; $7.03; $7.45; $7.60
      oral
liquid
1 mg/mL (200 mL bottle)
$84.72/bottle
Stavudine Stavudine Camber pharmaceuticals and other generic manufacturers oral
capsule
15 mg; 20 mg; 30 mg; 40 mg
$6.09; $6.33; $6.73; $6.86

*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

 

  • Wt >60 kg: 40 mg PO twice-daily (WHO recommends and data supports 30 mg PO twice-daily, less toxic and equally effective).
  • Wt <60 kg: 30 mg PO twice-daily.
  • Package insert recommends dose reduction (wt >60 kg: 20 mg twice-daily, wt <60 kg 15 mg twice-daily) for peripheral neuropathy; however, treatment with alternate agent preferred due to limited efficacy data with lower doses and potential for irreversible neuropathy with continued use.
  • WHO recommends 30 mg PO twice-daily

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Wt >60 kg dose: 30 mg twice-daily (WHO recommendation), wt <60 kg dose: 30 mg twice-daily. May consider 30 mg twice-daily.

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Wt >60 kg Cr clearance 26-50 mL: 20 mg twice-daily, wt >60 kg Cr clearance 10-25 mL/min: 20 mg once-daily ; wt <60 kg Cr clearance 26-50 mL/min:15mg twice-daily, wt <60 kg Cr clearance 10-25 mL/min:15 mg once-daily.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

Wt >60 kg: 20 mg q24h, wt <60 kg: 15mg q24h.

DOSING IN HEMODIALYSIS

Wt >60 kg dose: 20 mg q24h, wt <60 kg dose: 15 mg q24h, on days of dialysis dose post-dialysis.

DOSING IN PERITONEAL DIALYSIS

Wt >60 kg dose: 20 mg q24h. Wt <60 kg dose: 15 mg q24h, on days of dialysis dose post-dialysis.

DOSING IN HEMOFILTRATION

No data: Consider ½ of standard dose.

ADVERSE DRUG REACTIONS

COMMON

  • Peripheral neuropathy (5-24%). Onset is usually 2 to 6 mos. Reversible with early discontinuation.
  • Macrocytosis (inconsequential).
  • Lipoatrophy: caused by mitochondrial toxicity; d4T most common cause; dose dependent--may be less common or severe with 30 mg twice-daily.
OCCASIONAL

RARE

  • HIV-associated neuromuscular weakness syndrome (HANWS): ascending motor weakness, generally accompanied by lactic acidosis.
  • Esophageal ulcer (association unclear).

DRUG INTERACTIONS

Few pharmacokinetic drug interactions.  

Drug-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
AZT In vitro and invivo antagonism.Do not co-administer.
Fluconazole d4T AUC: no significant change.No significant interaction.
IDV d4T AUC: increased by 25%.Unlikely to be significant. Use standard dose.
Isoniazid May increase risk of peripheral neuropathy.Give INH with pyridoxine to decrease the risk of neuropathy. Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
ddI (EC and buffered)Additive toxicity (peripheral neuropathy, lactic acidosis, and pancreatitis).Do not co-administer, especially in pregnancy.
Metronidazole (long term)May increase risk of peripheral neuropathy (rare).Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
CisplatinMay increase risk of peripheral neuropathy.Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
DisulfiramMay increase risk of peripheral neuropathy.Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Gold compoundsMay increase risk of peripheral neuropathy.Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
HydralazineMay increase risk of peripheral neuropathyMonitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Methadoned4T AUC: decreased by 23%; Methadone: no change.Unlikely to be significant. Use standard dose.
Pyridoxine (vitamin B6) high-doseMay increase risk of peripheral neuropathy.Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Ribavirin In vitro antagonism but not in vivo.Not clinically significant. No in vivo antagonism observed.
Rifabutin d4T AUC: no significant change.No significant interaction. Use standard dose.
Thalidomide May increase risk of peripheral neuropathy.Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
VincristineMay increase risk of peripheral neuropathy.Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.

RESISTANCE

  • TAMs (41L, 67N, 70R, 210W, 215Y/F, 219 Q/E): selected by d4T and AZT; increasing d4T resistance (and NRTI cross-resistance) with increasing number of TAMs.
  • 151M complex and 69S insertion confer high-level resistance to d4T in setting of multi-NRTI resistance.
  • 184V: as with AZT, 184V mutation (associated with 3TC resistance) may increase susceptibility or delay resistance to d4T
  • 65R: can be selected by d4T, especially with non-subtype B virus; causes low-level d4T resistance

PHARMACOLOGY

Pharmacology

COMMENTS

d4T no longer recommended due to long-term toxicity, including  peripheral neuropathy, lipoatrophy, and potentially fatal lactic acidosis. Nevertheless it remains a potent agent for pts who need a thymidine analog but cannot tolerate AZT. ddI + d4T should be avoided, especially in pregnant pts.

  • Pros: well studied NRTI. Well tolerated in short term; gradual emergence of TAM-medicated resistance.
  • Cons: NRTI most commonly associated with mitochondrial toxicity, including lipoatrophy, lactic acidosis, and hepatic steatosis; ddI+d4T+EFV inferior to AZT+3TC+EFV in ACTG 384; d4T+3TC+EFV non-inferior to TDF+3TC+EFV in GS903, but with greater toxicity (neuropathy, lipoatrophy, hyperlipidemia). No longer a recommended drug in guidelines used in developed countries. Important to refrigerate (10C or lower) oral liquid formulation since significant loss of stability was observed after 4 weeks at 25C.

REFERENCES

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