Didanosine

Pronunciation

(dye DAN oh seen)

U.S. Brand Names

Videx®; Videx® EC

Synonyms

ddI; Dideoxyinosine

Generic Available

Yes: Delayed release capsule

Canadian Brand Names

Videx®; Videx® EC

Use

Treatment of HIV infection; always to be used in combination with at least two other antiretroviral agents

Pregnancy Risk Factor

Pregnancy Implications

Cases of fatal and nonfatal lactic acidosis, with or without pancreatitis, have been reported in pregnant women. It is not known if pregnancy itself potentiates this known side effect; however, pregnant women may be at increased risk of lactic acidosis and liver damage. Hepatic enzymes and electrolytes should be monitored frequently during the 3rd trimester of pregnancy. Use during pregnancy only if the potential benefit to the mother outweighs the potential risk of this complication. Didanosine has been shown to cross the placenta. Pharmacokinetics are not significantly altered during pregnancy; dose adjustments are not needed. The Perinatal HIV Guidelines Working Group considers didanosine to be an alternative NRTI in dual nucleoside combination regimens; use with stavudine only if no other alternatives are available. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to didanosine or any component of the formulation

Warnings/Precautions

Pancreatitis (sometimes fatal) has been reported, incidence is dose related. Risk factors for developing pancreatitis include a previous history of the condition, concurrent cytomegalovirus or Mycobacterium avium-intracellulare infection, and concomitant use of stavudine, pentamidine, or co-trimoxazole. Discontinue didanosine if clinical signs of pancreatitis occur. Lactic acidosis, symptomatic hyperlactatemia, and severe hepatomegaly with steatosis (sometimes fatal) have occurred with antiretroviral nucleoside analogues, including didanosine. Hepatotoxicity may occur even in the absence of marked transaminase elevations; suspend therapy in any patient developing clinical/laboratory findings which suggest hepatotoxicity. Pregnant women may be at increased risk of lactic acidosis and liver damage.

Peripheral neuropathy occurs in ~20% of patients receiving the drug. Retinal changes (including retinal depigmentation) and optic neuritis have been reported in adults and children using didanosine. Patients should undergo retinal examination every 6-12 months. Use with caution in patients with decreased renal or hepatic function, phenylketonuria, sodium-restricted diets, or with edema, CHF, or hyperuricemia. Twice-daily dosing is the preferred dosing frequency for didanosine tablets. Didanosine delayed release capsules are indicated for once-daily use.

Adverse Reactions

As reported in monotherapy studies; risk of toxicity may increase when combined with other agents.

>10%:

Gastrointestinal: Increased amylase (15% to 17%), abdominal pain (7% to 13%), diarrhea (19% to 28%)

Neuromuscular & skeletal: Peripheral neuropathy (17% to 20%)

1% to 10%:

Dermatologic: Rash, pruritus

Endocrine & metabolic: Increased uric acid

Gastrointestinal: Pancreatitis; patients >65 years of age had a higher frequency of pancreatitis than younger patients

Hepatic: Increased SGOT, increased SGPT, increased alkaline phosphatase

Postmarketing reports: Alopecia, anaphylactoid reaction, anemia, anorexia, arthralgia, chills/fever, diabetes mellitus, dyspepsia, flatulence, granulocytopenia, hepatitis, hyperlactatemia (symptomatic), hypersensitivity, lactic acidosis/hepatomegaly, leukopenia, liver failure, myalgia, myopathy, neuritis, optic renal impairment, pain, retinal depigmentation, rhabdomyolysis, seizure, thrombocytopenia, weakness

Overdosage/Toxicology

Chronic overdose may cause pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic impairment. There is no known antidote for didanosine overdose. Treatment is symptomatic.

Drug Interactions

Drugs whose absorption depends on the level of acidity in the stomach (such as ketoconazole, itraconazole, and dapsone) should be administered at least 2 hours prior to the buffered formulations of didanosine (not affected by delayed release capsules)

Decreased effect: Buffered formulations of didanosine (tablets, pediatric oral solution) may decrease absorption of quinolones or tetracyclines, separate dosing by 2 hours; didanosine should be held during PCP treatment with pentamidine; didanosine may decrease levels of indinavir

Increased toxicity: Concomitant administration of other drugs (including hydroxyurea) which have the potential to cause peripheral neuropathy or pancreatitis may increase the risk of these toxicities

Allopurinol: May increase didanosine concentration; avoid concurrent use

Antacids: Concomitant use with buffered tablet or pediatric didanosine solution may potentiate adverse effects of aluminum- or magnesium-containing antacids

Ganciclovir: May increase didanosine concentration; monitor

Hydroxyurea: May precipitate didanosine-induced pancreatitis if added to therapy; concomitant use is not recommended

Methadone: May decrease didanosine concentration; monitor

Ribavirin: Coadministration may increase exposure to didanosine and/or its active metabolite, increasing the risk or severity of didanosine toxicities, including pancreatitis, lactic acidosis, and peripheral neuropathy. Coadministration of ribavirin with didanosine should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities; suspend therapy if signs or symptoms of toxicity are noted.

Tenofovir: Coadministration may increase exposure to didanosine and/or its active metabolite increasing the risk or severity of didanosine toxicities, including pancreatitis, lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir with didanosine should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities; specific dosing adjustment is recommended; suspend therapy if signs or symptoms of toxicity are noted.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (increases risk of pancreatitis).

Food: Decreases AUC and Cmax. Didanosine serum levels may be decreased by 55% if taken with food.

Stability

Tablets and delayed release capsules should be stored in tightly closed bottles at 15°C to 30°C; tablets undergo rapid degradation when exposed to an acidic environment; tablets dispersed in water are stable for 1 hour at room temperature. Reconstituted pediatric solution is stable for 30 days if refrigerated. Unbuffered powder for oral solution must be reconstituted and mixed with an equal volume of antacid at time of preparation.

Mechanism of Action

Didanosine, a purine nucleoside (adenosine) analog and the deamination product of dideoxyadenosine (ddA), inhibits HIV replication in vitro in both T cells and monocytes. Didanosine is converted within the cell to the mono-, di-, and triphosphates of ddA. These ddA triphosphates act as substrate and inhibitor of HIV reverse transcriptase substrate and inhibitor of HIV reverse transcriptase thereby blocking viral DNA synthesis and suppressing HIV replication.

Pharmacodynamics/Kinetics

Absorption: Subject to degradation by acidic pH of stomach; some formulations are buffered to resist acidic pH; 50% reduction in peak plasma concentration is observed in presence of food. Delayed release capsules contain enteric-coated beadlets which dissolve in the small intestine.

Distribution: Vd: Children: 35.6 L/m²; Adults: 1.08 L/kg

Protein binding: <5%

Metabolism: Has not been evaluated in humans; studies conducted in dogs show extensive metabolism with allantoin, hypoxanthine, xanthine, and uric acid being the major metabolites found in urine

Bioavailability: 42%

Half-life elimination:

Children and Adolescents: 0.8 hour

Adults: Normal renal function: 1.5 hours; active metabolite, ddATP, has an intracellular half-life >12 hours in vitro; Renal impairment: 2.5-5 hours

Time to peak: Buffered tablets: 0.67 hours; Delayed release capsules: 2 hours

Excretion: Urine (~55% as unchanged drug)

Clearance: Total body: Averages 800 mL/minute

Dosage

Treatment of HIV infection: Oral (administer on an empty stomach):

Children:

2 weeks to 8 months: 100 mg/m² twice daily

>8 months: 120 mg/m² twice daily; dosing range: 90-150 mg/m² twice daily; patients with CNS disease may require higher dose

Children <1 year should receive 1 tablet per dose and children >1 year should receive 2-4 tablets per dose for adequate buffering and absorption; tablets should be chewed or dispersed

Adolescents and Adults: Dosing based on patient weight:

Note: Preferred dosing frequency is twice daily for didanosine tablets/oral solution

Chewable tablets, powder for oral solution:

<60 kg: 125 mg twice daily or 250 mg once daily

60 kg: 200 mg twice daily or 400 mg once daily

Note: Adults should receive 2-4 tablets per dose for adequate buffering and absorption; tablets should be chewed or dispersed

Delayed release capsule (Videx® EC):

<60 kg: 250 mg once daily

60 kg; 400 mg once daily

Dosing adjustment with tenofovir (didanosine tablets or delayed release capsules; based on tenofovir product labeling):

<60 kg: 200 mg once daily

60 kg: 250 mg once daily

Dosage adjustment in renal impairment: Dosing based on patient weight, creatinine clearance, and dosage form: See table.

Dosing adjustment in hepatic impairment:

Recommended Dose (mg) of Didanosine by Body Weight

Creatinine Clearance (mL/min)	60 kg		<60 kg
Creatinine Clearance (mL/min)	Tablet¹ (mg)	Delayed Release Capsule (mg)	Tablet¹ (mg)	Delayed Release Capsule (mg)
60	400 daily or 200 twice daily	400 daily	250 daily or 125 twice daily	250 daily
30-59	200 daily or 100 twice daily	200 daily	150 daily or 75 twice daily	125 daily
10-29	150 daily	125 daily	100 daily	125 daily
<10	100 daily	125 daily	75 daily	See footnote 2.
¹Chewable/dispersible buffered tablet; 2 tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose.
²Not suitable for use in patients <60 kg with Clcr <10 mL/minute; use alternate formulation.

Patients requiring hemodialysis or CAPD: Dose per Clcr<10 mL/minute

Hemodialysis: Removed by hemodialysis (40% to 60%)

Dosing adjustment in hepatic impairment: Should be considered; monitor for toxicity

Elderly patients have a higher frequency of pancreatitis (10% versus 5% in younger patients); monitor renal function and dose accordingly

Administration

Chewable/dispersible buffered tablets: The 200 mg tablet should only be used in once-daily dosing. At least 2 tablets, but no more than 4 tablets, should be taken together to allow adequate buffering. Tablets may be chewed or dispersed prior to consumption. To disperse, dissolve in 1 oz water, stir until uniform dispersion is formed, and drink immediately. May also add 1 oz of clear apple juice to initial dispersion if additional flavor is needed. The apple juice dilution is stable for 1 hour at room temperature. Do not mix with other juices.

Pediatric powder for oral solution: Prior to dispensing, the powder should be mixed with purified water USP to an initial concentration of 20 mg/mL and then further diluted with an appropriate antacid suspension to a final mixture of 10 mg/mL. Shake well prior to use.

Monitoring Parameters

Serum potassium, uric acid, creatinine; hemoglobin, CBC with neutrophil and platelet count, CD4 cells; viral load; liver function tests, amylase; weight gain; perform dilated retinal exam every 6 months

Dietary Considerations

Videx® EC: Take on an empty stomach; administer at least 1 hour before or 2 hours after eating

Chewable/dispersible tablet: Take on an empty stomach, 30 minutes before or 2 hours after eating. Chew well or mix in water; if mixed in water, may add 2 tablespoons (1 oz) apple juice for flavor. Do not use other juices. Each chewable tablet contains 36.5 mg phenylalanine and 8.6 mEq magnesium. Sodium content of buffered tablets: 264.5 mg (11.5 mEq).

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This drug will not cure HIV; use appropriate precautions to prevent spread of HIV to other persons. Take as directed, 1 hour before or 2 hours after meals. Avoid alcohol. Chew tablets thoroughly. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. A dilated retinal eye exam is recommended every 6-12 months while on this therapy. You may be susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause dizziness or weakness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); diarrhea (boiled milk, yogurt, or buttermilk may help); or headache, back or joint pain (mild analgesics may offer relief). Report immediately any loss of sensation, numbness, or tingling in fingers, toes, or feet; persistent unresolved abdominal distress (nausea, vomiting, diarrhea); or signs of infection (burning on urination, perineal itching, white plaques in mouth, unhealed sores, persistent sore throat or cough). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Additional Information

A high rate of early virologic nonresponse was observed when didanosine, lamivudine, and tenofovir were used as the initial regimen in treatment-naive patients. Use of this combination is not recommended; patients currently on this regimen should be closely monitored for modification of therapy. Early virologic failure was also observed with tenofovir and didanosine delayed release capsules, plus either efavirenz or nevirapine; use caution in treatment-naive patients with high baseline viral loads.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Anxiety; irritability and insomnia are common; may produce depression

Mental Health: Effects on Psychiatric Treatment

May cause granulocytopenia; use caution with clozapine and carbamazepine

Dosage Forms

Capsule, delayed release: 200 mg, 250 mg, 400 mg

Videx® EC: 125 mg, 200 mg, 250 mg, 400 mg

Powder for oral solution, pediatric (Videx®): 2 g, 4 g [makes 10 mg/mL solution after final mixing]

Tablet, buffered, chewable/dispersible (Videx®): 25 mg, 50 mg, 100 mg, 150 mg, 200 mg [all strengths contain phenylalanine 36.5 mg/tablet; orange flavor]

References

Balis FM, Pizzo PA, Butler KM, et al, "Clinical Pharmacology of 2', 3'-Dideoxyinosine in Human Immunodeficiency Virus-Infected Children,"J Infect Dis, 1992, 165(1):99-104.

Bissuel F, Cotte L, Cruneel F, et al, "Didanosine-Induced Fulminant Hepatitis," 10th Internal Conference on AIDS, Abstract, 1994, 2:204.

Bouvet E, Casalino E, Prevost MH, et al, "Fatal Case of 2',3'-Dideoxyinosine-Associated Pancreatitis,"Lancet, 1990, 336(8729):1515.

Brouillette MJ, Chouinard G, and Lalonde R, "Didanosine-Induced Mania in HIV Infection,"Am J Psychiatry, 1994, 151(12):1839-40.

Butler KM, Husson RN, Balis FM, et al, "Dideoxyinosine in Children With Symptomatic Human Immunodeficiency Virus Infection,"N Engl J Med, 1991, 324(3):137-44.

Chidiac C, Alfandari S, Caron J, et al, "Diabetes Mellitus Following Treatment of AIDS With Didanosine,"AIDS, 1995, 9(2):215-6.

Faulds D and Brogden RN, "Didanosine: A Review of Its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Potential in Human Immunodeficiency Virus Infection,"Drugs, 1992, 44(1):94-116.

"Guidelines for the Use of Antiretroviral Agents in HIV-infected Adults and Adolescents. Panel on Clinical Practices for Treatment of HIV Infection," March 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed June 1, 2004.

Hilts AE and Fish DN, "Dosage Adjustment of Antiretroviral Agents in Patients With Organ Dysfunction,"Am J Health Syst Pharm, 1998, 55:2528-33.

Hirsch MS and D'Aquila RT, "Therapy for Human Immunodeficiency Virus Infection,"N Engl J Med, 1993, 328(23):1686-95.

Knupp CA, Hak LJ, Coakley DF, et al, "Disposition of Didanosine in HIV-Seropositive Patients With Normal Renal Function of Chronic Renal Failure: Influence of Hemodialysis and Continuous Ambulatory Peritoneal Dialysis,"Clin Pharmacol Ther, 1996, 60(5):535-42.

Lafeuillade A, Hittinger G, and Chadapaud S, "Increased Mitochondrial Toxicity With Ribavirin in HIV/HCV Coinfection,"Lancet, 2001, 357(9252):280-1.

Longhurst HJ, and Pinching AJ, "Pancreatitis Associated With Hydroxyurea in Combination with Didanosine,"Br Med J, 2001, 322:81.

May DB, Drew RH, Yedinak KC, et al, "Effect of Simultaneous Didanosine Administration on Itraconazole Absorption in Healthy Volunteers,"Pharmacotherapy, 1994, 14(5):509-13.

Morse GD, Shelton MJ, and O'Donnell AM, "Comparative Pharmacokinetics of Antiviral Nucleoside Analogues,"Clin Pharmacokinet, 1993, 24(2):101-23.

Pelucio MT, Rothenhaus T, Smith M, et al, "Fatal Pancreatitis as a Complication of Therapy for HIV Infection,"J Emerg Med, 1995, 13(5):633-7.

Perry CM and Balfour JA, "Didanosine. An Update on Its Antiviral Activity, Pharmacokinetic Properties, and Therapeutic Efficacy in the Management of HIV Disease,"Drugs, 1996, 52(6):928-62.

"Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV-1 Transmission in the United States," June 23, 2004. Available at: http://www.aidsinfo.nih.gov. Accessed July 1, 2004.

Rathbun RC and Martin ES 3d, "Didanosine Therapy in Patients Intolerant of or Failing Zidovudine Therapy,"Ann Pharmacother, 1992, 26(11):1347-51.

Salmon-Ceron D, Chauvelot-Moachon L, Abad S, et al, "Mitochondrial Toxic Effects and Ribavirin,"Lancet, 2001, 357(9270):1803-4.

Sande MA, Carpenter CC, Cobbs CG, et al, "Antiretroviral Therapy for Adult HIV-Infected Patients,"JAMA, 1993, 270(21):2583-9.

Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, "Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection," March 1, 1999. Available at: http://www.aidsinfo.nih.gov.

International Brand Names

Aso DDI® (AR); Bristol-Videx® (CO); Cipladinex® (CO); DDI Biocrom® (AR); D.D.I. Delta® (AR); DDI Filaxis® (AR); DDI Martian® (AR); Dibistic® (AR); Didanisin® (AR); Didanosina® (BR); Didanosina Richmond® (AR); Megavir® (AR); Ronvir® (AR); Viden® (CO); Videx® (AR, AT, AU, BE, BR, CA, CH, CL, CN, CZ, DE, DK, EC, ES, FI, FR, GB, HR, HU, ID, IE, IL, IT, LU, MX, NL, NO, NZ, PL, PT, RO, RU, SE, SG, TH, TR, YU, ZA); Videx® EC (CA)