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Table of Contents

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Didanosine

(Last updated: March 1, 2016; last reviewed: March 1, 2016)

Didanosine (ddI, Videx)
Didanosine (ddI, Videx)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Formulations
Videx Pediatric Powder for Oral Solution: Reconstituted 10 mg/mL
Videx Enteric-Coated (EC) Delayed-Release Capsules (EC Beadlets): 125 mg, 200 mg, 250 mg, and 400 mg
Generic Didanosine Delayed-Release Capsules: 125 mg, 200 mg, 250 mg, and 400 mg
Tablets for Oral Suspension: 100 mg, 150 mg, and 200 mg
Dosing Recommendations Selected Adverse Events
Neonatal/Infant Dose (Aged 2 Weeks to <3 Months):
  • 50 mg/m2 of body surface area every 12 hours
  • Manufacturer recommends 100 mg/m2 body surface area every 12 hours in this age range. The Panel members interpret pharmacokinetic (PK) data as suggesting potential increased toxicity at that dose in this age group and many would use 50 mg/m2 body surface area every 12 hours.
Infant Dose (Aged ≥3 Months to 8 Months):
  • 100 mg/m2 body surface area every 12 hours
Pediatric Dose of Oral Solution (Aged >8 Months):
  • 120 mg/m2 body surface area every 12 hours
  • Dose range: 90–150 mg/m2 body surface area every 12 hours. Do not exceed maximum adult dose; see table below.
  • In treatment-naive children ages 3–21 years, 240 mg/m2 body surface area once daily (oral solution or capsules) has effectively resulted in viral suppression.


Pediatric Dose of Videx EC or Generic Capsules
(Aged 6–18 Years and Weighing ≥20 kg)
Body Weight (kg) Dose (mg)
20 kg to <25 kg 200 mg once daily
25 kg to <60 kg 250 mg once daily
≥60 kg 400 mg once daily


Adolescent and Adult Dose
Body Weight (kg) Dose (mg)
<60 kg 250 mg once daily
≥60 kg 400 mg once daily


Pediatric/Adolescent Dose of Didanosine when Combined with Tenofovir Disoproxil Fumarate (TDF):
  • This combination should be avoided if possible because of enhanced didanosine toxicity.
  • No data on this combination in children or adolescents aged <18 years, but decrease in didanosine dose is recommended as in adults.

Adult Dose of Didanosine when Combined with TDF
Body Weight (kg) Dose (mg)
<60 kg
(limited data in adults)
200 mg once daily
≥60 kg 250 mg once daily
  • Peripheral neuropathy
  • Diarrhea, abdominal pain, nausea, and vomiting
  • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported (the risk is increased when didanosine is used in combination with stavudine).
  • Pancreatitis (less common in children than in adults, more common when didanosine is used in combination with TDF or stavudine)
  • Non-cirrhotic portal hypertension
  • Retinal changes, optic neuritis
  • Insulin resistance/diabetes mellitus
Special Instructions
  • Because food decreases absorption of didanosine, administration of didanosine on an empty stomach (30 minutes before or 2 hours after a meal) generally is recommended. To improve adherence, some practitioners administer didanosine without regard to timing of meals (see text below).
  • Didanosine powder for oral solution and tablets for oral suspension contain antacids that may interfere with the absorption of other medications, including protease inhibitors (PIs). See individual PI for instructions on timing of administration. This interaction is more pronounced for the buffered (solution) formulation of didanosine than for the enteric-coated formulation, which is protected from breakdown by gastric acid by the enteric coating instead of co-formulation with antacids.
  • Shake didanosine oral solution well before use. Keep refrigerated; solution is stable for 30 days.
  • If using tablets for oral suspension: Tablets are not to be swallowed whole. For full therapeutic effect, 2 tablets may be chewed or dispersed in water before administration. To disperse tablets: add 2 tablets to at least 1 ounce (30 mL) of water. Drink entire dispersion immediately. For children 1 or 2 tablets may be chewed or dispersed in water before administration.
Metabolism/Elimination
  • Renal excretion 50%
  • Dosing of didanosine in patients with renal insufficiency: Decreased dosage should be used in patients with impaired renal function. Consult manufacturer’s prescribing information for adjustment of dosage in accordance with creatinine clearance.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Absorption: The presence of antacids in didanosine oral solution and tablets for oral suspension has the potential to decrease the absorption of a number of medications if given at the same time. Many of these interactions can be avoided by timing doses to avoid giving other medications concurrently with didanosine oral solution.
  • Mechanism unknown: Didanosine serum concentrations are increased when didanosine is co-administered with tenofovir disoproxil fumarate (TDF) and this combination should be avoided if possible.
  • Renal elimination: Drugs that decrease renal function can decrease didanosine clearance.
  • Enhanced toxicity: Didanosine mitochondrial toxicity is enhanced by ribavirin.
  • Overlapping toxicities: The combination of stavudine with didanosine may result in enhanced toxicity. That combination should not generally be used (see below).

Major Toxicities

  • More common: Diarrhea, abdominal pain, nausea, and vomiting.
  • Less common (more severe): Peripheral neuropathy, electrolyte abnormalities, and hyperuricemia. Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been reported, and are more common with didanosine in combination with stavudine. Pancreatitis (less common in children than in adults, more common when didanosine is used in combination with TDF or stavudine) can occur. Increased liver enzymes and retinal depigmentation and optic neuritis have been reported. Fall in CD4 T lymphocyte count is reported with use of didanosine with TDF.
  • Rare: Non-cirrhotic portal hypertension, presenting clinically with hematemesis, esophageal varices, ascites, and splenomegaly, and associated with increased transaminases, increased alkaline phosphatase, and thrombocytopenia, has been associated with long-term didanosine use.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.standford.edu/DR/).

Pediatric Use

Approval
Didanosine is Food and Drug Administration (FDA)-approved for use in children as part of combination antiretroviral therapy.

Dosing

Standard Dose in Children Aged >8 months
The standard dose of didanosine oral solution in children aged >8 months is 120 mg/m2 body surface area twice daily.1,2 Doses higher than 180 mg/m2 body surface area twice daily are associated with increased toxicity.3

Special Considerations in Ages 2 Weeks to <8 Months
For infants aged 2 weeks to 8 months, the FDA recommends 100 mg/m2 body surface area per dose twice daily. However, because pharmacokinetic (PK) differences in younger infants (aged 2 weeks–3 months) compared with older children raise concern for increased toxicity in this younger age group, the Panel recommends a dose of 50 mg/m2 of body surface area twice daily for infants aged 2 weeks to 3 months, with an increase to 100 mg/m2/dose twice daily at 3 months, and finally increasing to 120 mg/m2 body surface area per dose twice daily at age 8 months (as above).

Frequency of Administration (Once-Daily or Twice-Daily)
A once-daily dosing regimen may be preferable to promote adherence, and multiple studies support the favorable PKs and efficacy of once-daily dosing of 240 mg/m2 body surface area.4

Food Restrictions
Although the prescribing information recommends taking didanosine on an empty stomach, this is impractical for infants who must be fed frequently and it may decrease medication adherence by increasing regimen complexity. A comparison showed that systemic exposure measured by area under the curve was similar whether didanosine oral solution was given to children with or without food; absorption of didanosine administered with food was slower and elimination more prolonged.5 To improve adherence, some practitioners administer didanosine without regard to timing of meals. Studies in adults suggest that didanosine can be given without regard to food.6,7 A European study dosed didanosine oral solution as part of a 4-drug regimen either 1 hour before or 1 hour after meals, but allowed the extended-release formulation to be given without food restriction and showed good virologic outcome with up to 96 weeks of follow-up.8

References

  1. Fletcher CV, Brundage RC, Remmel RP, et al. Pharmacologic characteristics of indinavir, didanosine, and stavudine in human immunodeficiency virus-infected children receiving combination therapy. Antimicrob Agents Chemother. 2000;44(4):1029-1034. Available at http://www.ncbi.nlm.nih.gov/pubmed/10722507.
  2. Nacro B, Zoure E, Hien H, et al. Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial. Bull World Health Organ. 2011;89(6):451-458. Available at http://www.ncbi.nlm.nih.gov/pubmed/21673861.
  3. Butler KM, Husson RN, Balis FM, et al. Dideoxyinosine in children with symptomatic human immunodeficiency virus infection. N Engl J Med. 1991;324(3):137-144. Available at http://www.ncbi.nlm.nih.gov/pubmed/1670591.
  4. King JR, Nachman S, Yogev R, et al. Single-dose pharmacokinetics of enteric-coated didanosine in HIV-infected children. Antivir Ther. 2002;7(4):267-270. Available at http://www.ncbi.nlm.nih.gov/pubmed/12553481.
  5. Stevens RC, Rodman JH, Yong FH, Carey V, Knupp CA, Frenkel LM. Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children. Pediatric AIDS Clinical Trials Group Protocol 144 Study Team. AIDS Res Hum Retroviruses. 2000;16(5):415-421. Available at http://www.ncbi.nlm.nih.gov/pubmed/10772527.
  6. Sanchez-Conde M, Palacios R, Sanz J, et al. Efficacy and safety of a once daily regimen with efavirenz, lamivudine, and didanosine, with and without food, as initial therapy for HIV Infection: the ELADI study. AIDS Res Hum Retroviruses. 2007;23(10):1237-1241. Available at http://www.ncbi.nlm.nih.gov/pubmed/17961110.
  7. Hernandez-Novoa B, Antela A, Gutierrez C, et al. Effect of food on the antiviral activity of didanosine enteric-coated capsules: a pilot comparative study. HIV Med. 2008;9(4):187-191. Available at http://www.ncbi.nlm.nih.gov/pubmed/18298579.
  8. Scherpbier HJ, Bekker V, Pajkrt D, Jurriaans S, Lange JM, Kuijpers TW. Once-daily highly active antiretroviral therapy for HIV-infected children: safety and efficacy of an efavirenz-containing regimen. Pediatrics. 2007;119(3):e705-715. Available at http://www.ncbi.nlm.nih.gov/pubmed/17308244.

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