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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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Didanosine

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

Zambia Specific Information

  • Available formulation in Zambia: Buffered powder for oral liquid: 100 mg; 167 mg; 250 mg packets. Capsule (unbuffered enteric-coated): 125 mg; 200 mg; 250 mg; 400 mg. Tablet (buffered chewable, dispersible): 25 mg; 50 mg; 100 mg; 150 mg; 200 mg.
  • Avoid co-administration with INH due to potential for peripheral neuropathy.
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* 
Videx ddIBristol-Myers Squibboral
pediatric powder
4 gm (8 oz)
$14.87 per 4 oz
Videx EC didanosine Bristol-Myers Squibb oral
enteric coated caps
400 mg
$14.18
Didanosine EC (generic)didanosine Barr Laboratories INC oral
capsule
200 mg, 250 mg, 400 mg
$6.16; $7.87; $12.27

*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: 1 per day (ddI EC)

  • Wt >60 kg dose: 400 mg PO once-daily. EC cap on an empty stomach (>1 hr before of >2 hrs after meals).
  • Wt <60 kg dose: 250 mg PO once-daily. EC cap on an empty stomach (>1 hr before of >2 hrs after meals).
  • Total daily dose may also be taken in 2 divided doses if GI tolerance is an issue.
  • Dose adjustment with tenofovir co-administration: <60kg, 200 mg once-daily; >60kg, 250 mg once-daily (see drug-drug interaction section for additional warnings).

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Wt >60 kg dose: 400 mg PO once-daily (tabs) or 500 mg PO once-daily (powder). Wt <60 kg dose: 250 mg PO once-daily (tabs) or 334 mg PO once-daily (powder).

DOSING FOR GLOMERULAR FILTRATION OF 10-50

50% of usual dose once-daily.

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

25% of usual dose once-daily.

DOSING IN HEMODIALYSIS

25% of usual dose once-daily, on days of dialysis give post dialysis.

DOSING IN PERITONEAL DIALYSIS

25% of usual dose (little effect on removal with PD) [Clin Pharmacol Ther. 1996;60(5):535].

DOSING IN HEMOFILTRATION

No data.

ADVERSE DRUG REACTIONS

Fewer GI side effects with EC formulation than with buffered, powder, or pediatric solution formulations

COMMON

  • Time-and dose-dependent peripheral neuropathy (5-12% of pts after 2-6 mos of therapy). Relative risk of neuropathy is 135% higher when combined with hydroxyurea (HU), 250% higher with d4T, and 680% higher with d4T + HU. Irreversible and debilitating neuropathy with continued use despite early Ssxs.
  • GI intolerance (nausea, vomiting, and diarrhea ) esp. with buffered tablets.
OCCASIONAL

  • Dose dependent pancreatitis (in 1-9% of pts, with 6% cases fatal). Risk factors associated with ddI-induced pancreatitis: alcohol use, renal failure, obesity, and concurrent use of d4T, HU, allopurinol, or pentamidine.
  • Reversible transaminase elevation. Non-cirrhotic portal hypertension resulting in esophageal variceal bleed, liver failure, and death have been reported.
  • Lipoatrophy. Best characterized with ddI+d4T; may occur when ddI used without d4T.
RARE

  • Lactic acidosis and severe hepatomegaly with steatosis (can be fatal in severe cases).
  • Rash and optic neuritis.
  • Increased risk of MI

DRUG INTERACTIONS

ddI does not interact with CYP3A4. Majority of drug interactions with buffered formulation, as buffer can decrease the absorption of some coadministered drugs.

Drug-to-Drug Interactions

Drug-to-Drug Interaction

DrugEffect of InteractionRecommendations/Comments
ATV ATV AUC: decreased by 87%; Cmin: decreased by 84% with ddI (buffered). ddI EC:ddI AUC increased by 26% and ATV AUC decreased by 11%.Administer ddI (pediatric solution) on empty stomach 2 hrs before or 1 hr after food or ATV. Use ddI EC if possible, since interaction unlikely to be significant, especially when ATV is boosted with RTV (ATV 300 mg + RTV100 mg).
d4T Increased risk of peripheral neuropathy, pancreatitis, and lactic acidosis.Do not co-administer.
Dapsone Dapsone: no change. Early single dose PK study found a decrease in dapsone serum levels, however multiple dose studies did not find a significant change in dapsone serum levels with ddI (buffer)
co-administration.
No significant interaction. Use standard dose. ddI EC not studied but interaction unlikely.
DLV DLV AUC decreased by 32%Applies to ddI buffered formulation only. Separate administration time by at least 2 hrs or use ddI EC formulation (not studied but interaction unlikely).
IDV IDV: no change (with ddI EC). IDV AUC decreased by 84% (with ddI buffered).No significant interaction with ddI EC (use standard dose). Administer IDV 1 hr before or after ddI (pediatric solution).
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.
Metronidazole May increase risk of peripheral neuropathy (rare).Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
RTV ddI AUC: decreased by 15%.Applies to pediatric solution. Clinical significance unknown. Separate ddI and RTV administration by at least 2 hrs. No data with ddI EC but interaction unlikely.
TDF ddI EC AUC: increased by 48% (fasted); ddI EC AUC: increased by 60% (fed) TDF: no change. Suboptimal response in 91% of pts with ddI/TDF/3TC.Dose adjust ddI to 250 mg PO once-daily (>60 kg) with TDF co-administration. Combination with unadjusted ddI dose may lead to CD4 decline. Do not use ddI/TDF/3TC as sole triple nucleoside regimen or NNRTI/ddI/TDF due to high rates of virologic failure.
Tetracyclines Not studied. May decrease tetracyclines serum levels due to chelation by the divalent cation of the ddI buffer.Applies to pediatric solution. Consider ddI EC or administer ddI suspension 6 hrs prior to or 2 hrs after tetracycline administration. No data with ddI EC but interaction unlikely.
Valganciclovir Not studied. ddI AUC may be significantly increased.Clinical significance unknown. Monitor for ddI toxicity (neuropathy, pancreatitis, and lactic acidosis).
Ganciclovir (IV and PO)Co-administration with ddI (buffered formulation) resulted in a 111% increased in ddI AUC. Ganciclovir AUC decreased by 21%. Clinical significance unknown, but monitor closely for ddI toxicity. No data with ddI EC.
AllopurinolMay significantly increase ddI serum levels. ddI (buffered formulation) AUC increased by 120%.PK studies conducted with ddI (buffered), but interaction also applies to ddI EC. Do not co-administer.
Cidofovir 3 mg/kg IV (with probenecid) on days 1 and 8 ddI AUC: increased by 60%. Possible inhibition of renal tubular secretion by probenecid and/or cidofovir.Applies to pediatric solution). Monitor for ddI toxicity, but unlikely to be significant since cidofovir is only administered every other wk with probenecid.
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.
Fluoroquinolone (Ciprofloxacin)Ciprofloxacin: AUC decreased by 26% with ddI (buffered). ddI: not affected.
Ciprofloxacin not affected by ddI EC.
Consider ddI EC (ciprofloxacin not affected) or administer ddI suspension 6 hrs prior to or 2 hrs after ciprofloxacin administration. Study performed with ciprofloxacin, but all other fluoroquinolones may also be significantly affected by buffered ddI.
Food ddI AUC decreased by 18-27% w/ EC formulation; AUC decreased by 47% with buffered formulation.Administer all forms of ddI on empty stomach (1 hr before or 2 hrs after meals).
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 neuropathy.Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Hydroxyurea Increased risk of pancreatitis and peripheral neuropathy.Do not co-administer.
Itraconazole Itraconazole Cmax: undetectableApplies to ddI (pediatric solution). Administer itraconazole caps at least 2 hrs after ddI suspension. No interaction with ddI EC (preferred).
Ketoconazole Ketoconazole: No change (with ddI EC). Decreased in ketoconazole absorption (with ddI buffered).No significant interaction with ddI EC (use standard dose). Administer itraconazole caps at least 2 hrs after ddI suspension.
Methadone ddI (buffered) AUC decreased by 60%. Methadone serum levels not affected. No interaction with ddI EC formulation.Do not co-administer ddI (pediatric powder) with methadone . Use ddI EC with methadone.
Pentamidine (IV)May increase risk of pancreatitis.Caution when administering to pts with history of alcoholism. Avoid in pts currently abusing alcohol.
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 Increased risk of mitochondrial toxicity FDA case reports: 21 out of 27 cases associated with pancreatitis, 5 deaths due to lactic acidosis (all 5 taking ddI + ribavirin).Contraindicated. Do not co-administer. Use an alternative NRTI.
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

  • K65R: Selected by ddI, resulting in intermediate resistance to ddI, TDF, 3TC, FTC, and low-level resistance to ABC and possibly d4T. When present with 184V, susceptibility to TDF improves, susceptibility to ABC and ddI further decreased.
  • L74V: Selected by ddI, resulting in intermediate resistance to ddI and low-level resistance to ABC. When present with 184V, causes further loss of susceptibility to ABC and ddI. May increase susceptibility to AZT, d4T, and TDF.
  • Q151M complex: High-level resistance.
  • T69S insertion: High-level resistance.
  • TAMs (41L, 210W, 215Y/F,219Q/E, 44D, 67N, 70R, 118I): Intermediate- or high-level resistance with 3 or more TAMs, especially with 41L/210W/215Y pathway.
  • 184V: slight decrease in sensitivity to ddI but not clinically significant.

PHARMACOLOGY

Pharmacology

COMMENTS

  • Pros: good clinical track record; once daily administration; excellent results in uncontrolled trials when combined with 3TC or FTC and 3rd agent
  • Cons: GI intolerance with pediatric solution; need to be taken on an empty stomach; pancreatitis, neuropathy, and mitochondrial toxicity; relative lack of controlled data in HAART era for ddI + 3TC or ddI + FTC compared to other dual-NRTI backbones; lack of coformulation; cross-resistance with TDF, ABC; not preferred as a first line NRTI in current DHHS treatment guidelines. May increase risk of MI, especially in patients with with cardiovascular risk factors. Association with non-cirrhotic portal hypertension in post-marketing reports. .

REFERENCES

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