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Didanosine (Videx)
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Class
Background
Manufacturer for U.S. Market
Approval
Generic Approvals
Formulation and Dosing
Clinical Use
Combinations
Use in Initial vs Subsequent Therapy
Factors Affecting Adherence
Resistance
Implications of didanosine resistance for treatment with other antiretrovirals
Implications of resistance to other antiretrovirals for treatment with didanosine
References
Related Resources
DHHS Guidelines
Characteristics of NRTIs
Drug Interactions with NRTIs
Adverse Events of ARVs
Dosage Adjustments for ARV-ARV Drug Interactions (Adult Dosing)
Interactions Database
Stanford Resistance Figures/Notes
Drug Labeling (Package Inserts)
Didanosine (Videx)
Enteric-coated capsules (Videx EC)
Class

Prodrug of deoxyadenosine nucleoside analogue

Background
Manufacturer for U.S. Market

Bristol-Myers Squibb

Approval

FDA approval of didanosine was granted in 1991 for adult and pediatric use. Initial approval (for patients intolerant to, or experiencing progression of HIV disease on, zidovudine) was based on increases in CD4 T-lymphocyte counts on didanosine therapy. As more definitive evidence of clinical benefit (delayed disease progression) became available, approval was expanded to include HIV infection in which antiretroviral treatment is indicated.

A comparison of didanosine with zidovudine monotherapy in adults with advanced HIV disease (1) found that zidovudine was superior in previously untreated subjects, while didanosine was superior (in terms of mortality or progression to AIDS) in subjects with 8-16 weeks of prior zidovudine therapy. A subsequent study (2) of adults with CD4 counts between 200 and 500 cells/µL found didanosine to be superior to zidovudine in delaying progression to AIDS or death. A comparison of didanosine and zidovudine monotherapy in children (3) found longer survival with didanosine.

Generic Approvals

The FDA has approved generic versions of didanosine for use in the United States and has granted other formulations "tentative approved" status for purchase and use as part of the President's Emergency Plan for AIDS Relief (PEPFAR) in resource-limited countries.

Formulation and Dosing

For a decade, didanosine was available only in tablet form (requiring crushing or chewing) or as a powder (requiring suspension in water). In 2000, a capsule containing enteric-coated beadlets became available. In the United States, manufacture of the tablet formulation was discontinued and didanosine is available in enteric-coated capsules and pediatric powder for oral solution. Chewable buffered tablets and buffered powder or oral solution (for adults) are available in some parts of the world. The enteric-coated capsules are approved for once-daily dosing; tablets and powder are approved for twice-daily dosing.

Because didanosine is inactivated by stomach acid, dosing on an empty stomach is required.

Dosing of Didanosine
AdultWt ≥=60 kg400 mg QD (capsule or tablets)
200 mg BID (tablets)
250 mg BID (buffered powder)
Wt <60 kg250 mg QD (capsule or tablets)
125 mg BID (tablets)
167 mg BID (buffered powder)
Pediatric*Age 2 weeks to 8 months100 mg/m2 body surface area Q 12 hours (pediatric powder)
Age >8 months120 mg/m2 body surface area BID (powder or tablets)

If able to swallow capsules:

Wt 20-<25 kg: 200 mg QD
Wt 25-<60 kg: 250 mg QD
Wt ≥60 kg: 400 mg QD (adult dosage)

Abbreviations: BID = 2 times a day; Q = every; QD = once daily; wt = weight

* Didanosine is not FDA approved for children <2 weeks of age; dosage has not been determined.

Didanosine should be taken on an empty stomach, 1 hour before or 2 hours after a meal.
Dosage adjustment is recommended in renal insufficiency.
Didanosine interacts with the following antiretroviral medication: tenofovir; see Dosage Adjustments for ARV-ARV Drug Interactions for information on recommended dosing adjustment for the didanosine/tenofovir interaction.
Please consult product labeling for detailed dosing information: didanosine tablets/powder or enteric-coated capsules.
FDA Pregnancy Category B.
Clinical Use
Combinations

Many antiretroviral combinations containing didanosine have been found to be effective at suppressing HIV viral load and increasing CD4 cell counts, and in some studies, prolonging AIDS-free survival.

Didanosine should not be administered concurrently with certain medications because of additive or overlapping potential adverse effects. For example, the combination of didanosine and stavudine should be avoided because of increased toxicity (peripheral neuropathy and hyperlactatemia), and should not be used in pregnant women because of reports of lactic acidosis with pancreatitis or hepatic steatosis.

Coadministration of ribavirin with didanosine may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia, and peripheral neuropathy. Patients receiving didanosine together with other potentially neurotoxic drugs (such as isoniazid or vincristine) should be monitored closely for the development of neuropathic symptoms.

Coadministration of tenofovir with didanosine increases serum levels of didanosine; dose reduction of didanosine is recommended.(4) Didanosine tablets or powder should not be taken at the same time as indinavir or delavirdine because the buffer present in the tablets interferes with the absorption of these drugs. Didanosine enteric-coated capsules do not appear to interact with indinavir.

In a small pilot study of initial therapy, the triple-nucleoside analogue combination of didanosine + lamivudine + tenofovir, showed virologic failure in 91% of patients at week 12.(5) In 2 studies, the combination of didanosine + tenofovir + efavirenz has demonstrated high rates of early virologic failure in treatment-naive individuals with high HIV RNA and low CD4 levels at baseline.(6,7) The reasons for the failure of these combinations is not clear; pending further study, they should be avoided.

Use in Initial vs Subsequent Therapy

Adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services state that didanosine is "not recommended" for initial antiretroviral therapy, because of higher rates of toxicity than recommended nucleoside anlaogues. The combination of didanosine + stavudine is "not recommended" at any time, because of high rates of toxicity, including peripheral neuropathy, lipoatrophy, and lactic acidosis.

Didanosine may be useful in subsequent therapies (see "Resistance" below).

Factors Affecting Adherence

Symptomatic side effects of didanosine include diarrhea, which results from the large amount of buffer in the tablet and powder forms and is less of a problem with the enteric-coated capsules, and peripheral neuropathy, which may range in severity from mild to disabling. Heavy or episodically heavy alcohol use may increase the risk of potentially fatal pancreatitis. The "empty-stomach" requirement may affect adherence, especially when twice-daily dosing is used. The once-daily dosing afforded by the enteric-coated formulation may facilitate adherence, but this formulation must still be taken on an empty stomach.

There is evidence that nucleoside analogues may be associated with mitochondrial toxicity leading to potentially serious long-term side effects such as lactic acidosis and disorders of lipid metabolism.(8) It is important to assess patient motivation and discuss scheduling as well as possible side effects and strategies for their management before treatment with didanosine is initiated.

Resistance

Resistance to didanosine is associated with the selection of 1 or more of several resistance mutations.

Implications of didanosine resistance for treatment with other antiretrovirals
Mutations at codon 184, which establish resistance to lamivudine, are found in a significant proportion of isolates selected by didanosine.
The codon 151 mutation, associated with resistance to multiple nucleoside analogues, occurs infrequently but is most commonly observed in patients treated with zidovudine + didanosine or stavudine + didanosine.
Implications of resistance to other antiretrovirals for treatment with didanosine

Didanosine should be considered in choosing therapy for individuals experiencing viral recurrence on prior regimens. Resistance testing may be helpful in assessing the utility of didanosine in the individual situation, although the results of genotype testing can sometimes be ambiguous. For example, laboratory strains of HIV resistant to lamivudine by virtue of a mutation at codon 184 may show resistance to didanosine, but some clinical isolates with this mutation have been found to retain susceptibility to didanosine. Phenotypic resistance testing may be useful in this situation.

References
1.   Dolin R, Amato DA, Fischl MA, et al. Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudine. AIDS Clinical Trials Group. Arch Intern Med. 1995 May 8;155(9):961-74.
2.   Katzenstein DA, Hammer SM, Hughes MD, et al. The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team. N Engl J Med. 1996 Oct 10;335(15):1091-8.
3.   Englund JA, Baker CJ, Raskino C, et al. Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team. N Engl J Med. 1997 Jun 12;336(24):1704-12.
4.  Kearney BP, Isaacson E, Sayre J, et al. Didanosine and tenofovir DF drug-drug interaction: assessment of didanosine dose reduction. In: Program and abstracts of the 10th Conference on Retroviruses and Opportunistic Infections; February 9-14, 2002; Seattle. Abstract 533.
5.  Jemsek J, Hutcherson P, and Harper E. Poor virologic responses and early emergence of resistance in treatment naive, HIV-infected patients receiving a once daily triple nucleoside regimen of didanosine, lamivudine, and tenofovir DF. In: Program and abstracts of the 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco. Abstract 51.
6.   Podzamczer D, Ferrer E, Gatell JM, et al. Early virological failure with a combination of tenofovir, didanosine and efavirenz. Antivir Ther. 2005;10(1):171-7.
7.   Maitland D, Moyle G, Hand J, et al. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS. 2005 Jul 22;19(11):1183-8.
8.   Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther. 2000 Aug;22(8):911-36; discussion 898.