Zambian HIV Guidelines:: Didanosine

	Zambia HIV National Guidelines
	Introduction HIV Counseling and Testing Sexually Transmitted Infections (STIs) General Principles of Antiretroviral Therapy for Chronic HIV Infection in Adults and Adolescents When to Start ARV Therapy for Chronic HIV Infection in Adults and Adolescents Initial Regimen for ARV Therapy Adherence Baseline evaluation and Monitoring Calculations: Ideal Body Weight, Body Mass Index and Creatinine Clearance ARV Therapy for Individuals with Tuberculosis Co-Infection Adverse Effects and Toxicity Immune Reconstitution Inflammatory Syndrome (IRIS) Changing or Stopping ART Treatment Failure Stopping ARV Therapy Post Exposure Prophylaxis Cotrimoxazole Prophylaxis WHO Staging in Adults and Adolescents Nutrition Care and Support Palliative Care in HIV and AIDS
	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>

Didanosine

Paul A. Pham, Pharm.D. and John G. Bartlett, M.D.
06-18-2008

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.

NON-FDA APPROVED USES

FORMS

brand name	generic	Mfg	brand forms	cost*
Videx	ddI	Bristol-Myers Squibb	oral pediatric powder 2000 mg (4oz); 4000 mg (8oz)	$52.81 per 4oz; $115.30 per 8oz
Videx EC	didanosine	Bristol-Myers Squibb	oral enteric coated caps 125 mg; 200 mg; 250 mg; 400 mg	$4.29; $6.86; $8.73; $13.65
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.
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.

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

Drug	Effect of Interaction	Recommendations/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.
Allopurinol	May 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.. Clinical significance unknown. 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.
Cisplatin	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Disulfiram	May 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 compounds	May increase risk of peripheral neuropathy.	Monitor for peripheral neuropathy. Irreversible neuropathy with continued use. Avoid long term co-administration.
Hydralazine	May 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: undetectable	Applies 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.	Clinical significance unknown. 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-dose	May 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.
Vincristine	May 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.

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