Didanosine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Delayed Release, Oral:

Videx EC: 125 mg, 200 mg, 250 mg, 400 mg [DSC]

Generic: 125 mg [DSC], 200 mg, 250 mg, 400 mg

Solution Reconstituted, Oral:

Videx: 2 g (100 mL); 4 g (200 mL [DSC])

Pharmacology

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.

Pharmacokinetics/Pharmacodynamics

Absorption

Subject to degradation by acidic pH of stomach; some formulations are buffered to resist acidic pH; ≤55% 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

Extensive intracellular distribution

CSF/plasma ratio: Infants 8 months to Adolescents 19 years: 46% (range: 12% to 85%); Adults: 21%

V_d (apparent):

Age-based:

Infants 8 months to Adolescents 19 years: 28 ± 15 L/m²

Adults: 43.7 ± 8.9 L/m²

Weight-based:

Children 20 kg to <25 kg: 98 ± 30 L

Children 25 kg to <60 kg: 155 ± 55 L

Children ≥60 kg: 363 ± 138 L

Adults ≥60 kg: 308 ± 164 L

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

Excretion

Unchanged drug excreted in urine

Infants 8 months to Adolescents 19 years: 18% ± 10%

Adults: 18% ± 8%

Time to Peak

Delayed release capsules: 2 hours; Powder for suspension: 0.25 to 1.5 hours

Half-Life Elimination

Plasma:

Newborns (1 day old): 2 ± 0.7 hours

Infants 2 weeks to 4 months: 1.2 ± 0.3 hours

Infants 8 months to Adolescents 19 years: 0.8 ± 0.3 hours

Adults with normal renal function: 1.5 ± 0.4 hours

Intracellular: Adults: 25 to 40 hours

Elimination: Increased as CrCl decreased

Children 20 kg to <25 kg: 0.75 ± 0.13 hours

Children 25 kg to <60 kg: 0.92 ± 0.09 hours

Children ≥60 kg: 1.26 ± 0.19 hours

Adults ≥60 kg: 1.19 ± 0.21 hours; 2 ± 0.3 hours (renal impairment [CrCl <30 mL/minute]); 4.1 ± 1.2 hours (dialysis)

Protein Binding

<5%

Use in Specific Populations

Special Populations: Renal Function Impairment

Half-life increased and clearance decreased as the CrCl decreased.

Special Populations: Hepatic Function Impairment

Mean C_max and AUC were 19% and 13% higher in patients with moderate to severe hepatic impairment.

Use: Labeled Indications

HIV infection: Treatment of HIV-1 infection in combination with other antiretroviral agents.

Contraindications

Coadministration with allopurinol, ribavirin, or stavudine

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to didanosine or any component of the formulation

Dosage and Administration

Dosing: Adult

Treatment of HIV-1 infection: Oral:

Dosing based on patient weight:

Pediatric powder for oral solution:

<60 kg: 125 mg twice daily (preferred) or 250 mg once daily

≥60 kg: 200 mg twice daily (preferred) or 400 mg once daily

Delayed-release capsule:

20 kg to <25 kg: 200 mg once daily

25 kg to <60 kg: 250 mg once daily

≥60 kg: 400 mg once daily

Dosage adjustment for concomitant therapy:

When taken with tenofovir:

<60 kg and CrCl ≥60 mL/minute: 200 mg once daily

≥60 kg and CrCl ≥60 mL/minute: 250 mg once daily

Dosing: Geriatric

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

Dosing: Pediatric

Note: Gene mutation and antiretroviral (ARV) resistance patterns should be evaluated (refer to www.iasusa.org for more information) when necessary.

HIV-1 infection, treatment: Oral: Note: Although FDA approved, didanosine is no longer recommended for use in children and adolescents due to higher rates of adverse effects than other nucleoside reverse transcriptase inhibitors (HHS [pediatric] 2018). If used, should be in combination with other ARV agents:

Infants 1 to 8 months (HHS [pediatric] 2018): Oral solution:

Infants 1 to <3 months: 50 mg/m²/dose every 12 hours. Note: Manufacturer's labeling not recommended (100 mg/m²/dose); pharmacokinetic data suggest toxicity may occur at this higher dose (HHS [pediatric] 2018).

Infants ≥3 to 8 months: 100 mg/m²/dose every 12 hours.

Infants >8 months, Children, and Adolescents:

Oral solution:

Twice-daily dosing: Infants >8 months, Children, and Adolescents: 120 mg/m²/dose (range: 90 to 150 mg/m²/dose) every 12 hours; do not exceed weight-based adult dose (HHS [pediatric] 2018; manufacturer labeling).

Once-daily dosing for treatment-naive patients: Children ≥3 year and Adolescents: 240 mg/m²/dose once daily; maximum dose: 400 mg/dose (HHS [pediatric] 2018).

Delayed-release capsule: Children ≥6 years weighing ≥20 kg who are able to swallow a capsule whole:

20 kg to <25 kg: 200 mg once daily.

25 kg to <60 kg: 250 mg once daily.

≥60 kg: 400 mg once daily.

Reconstitution

Pediatric powder for oral solution: Prior to dispensing, add 100 mL or 200 mL purified water, USP to the 2 g or 4 g container, respectively, to achieve a 20 mg/mL solution. Immediately mix the resulting solution with an equal volume of antacid that contains the active ingredients aluminum hydroxide (400 mg/5 mL), magnesium hydroxide (400 mg/5 mL) and simethicone (40 mg/5 mL) to achieve a final concentration of 10 mg/mL. Dispense in flint glass or plastic (eg, HDPE, PET or PETG) bottles with child resistant closures.

Administration

Oral: Pediatric powder for oral solution: Administer on an empty stomach at least 30 minutes before or 2 hours after eating. Shake well prior to use.

Oral: Videx EC: Administer on an empty stomach at least 30 minutes before or 2 hours after eating; swallow capsule whole.

Dietary Considerations

Take on an empty stomach; administer at least 30 minutes before or 2 hours after eating

Storage

Delayed release capsules should be stored in tightly closed bottles at controlled room temperature of 25°C (77°F). Unreconstituted powder should be stored at 15°C to 30°C (59°F to 86°F); reconstituted oral solution is stable for 30 days stored at 2°C to 8°C (36°F to 46°F).

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of Didanosine. Specifically, the risk of pancreatitis may be increased. Avoid combination

Allopurinol: May increase the serum concentration of Didanosine. Avoid combination

Antifungal Agents (Azole Derivatives, Systemic): Didanosine may decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Enteric coated didanosine capsules are not expected to affect these antifungals. Exceptions: Isavuconazonium Sulfate. Consider therapy modification

Atazanavir: Didanosine may decrease the serum concentration of Atazanavir. Specifically, the buffered formulation of didanosine may decrease atazanavir absorption. Atazanavir may decrease the serum concentration of Didanosine. Reported with enteric coated didanosine capsules. Management: To avoid therapeutic failure of atazanavir the drug should be administered 2 hours before or 1 hour after didanosine. This recommendation applies to both buffered didanosine products and enteric coated didanosine products. Consider therapy modification

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

Darunavir: May decrease the serum concentration of Didanosine. More specifically, this interaction is likely due to the effects of food (with which darunavir/ritonavir and darunavir/cobicistat are taken) on didanosine, which is supposed to be given on an empty stomach. Management: Didanosine should be administered 1 hour prior to or 2 hours after administration of darunavir/ritonavir or darunavir/cobicistat (which must be taken with food). Consider therapy modification

Febuxostat: May increase the serum concentration of Didanosine. Avoid combination

Ganciclovir-Valganciclovir: May increase the serum concentration of Didanosine. Monitor therapy

Hydroxyurea: Didanosine may enhance the adverse/toxic effect of Hydroxyurea. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Hydroxyurea may enhance the adverse/toxic effect of Didanosine. An increased risk of pancreatitis, hepatotoxicity and/or neuropathy may exist. Avoid combination

Indinavir: Didanosine may decrease the serum concentration of Indinavir. Management: Indinavir should be administered at least 1 hour apart from buffer-containing formulations of didanosine. Consider therapy modification

Levomethadone: May decrease the serum concentration of Didanosine. Monitor therapy

Lopinavir: May decrease the serum concentration of Didanosine. This interaction refers only to lopinavir/ritonavir oral solution, which must be taken with food, and is principally the result of a food-didanosine interaction. Management: Didanosine should be administered 1 hour prior to or 2 hours after administration of lopinavir/ritonavir oral solution (which must be taken with food). Didanosine and lopinavir/ritonavir tablets can be administered together. Consider therapy modification

Methadone: May decrease the serum concentration of Didanosine. Monitor therapy

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Quinolones: May decrease the serum concentration of Didanosine. Didanosine may decrease the serum concentration of Quinolones. Management: Administer oral quinolones at least 2 hours before or 6 hours after didanosine. Monitor for decreased therapeutic effects of quinolones, particularly if doses cannot be separated as recommended. This does not apply to unbuffered enteric coated didanosine. Exceptions: LevoFLOXacin (Oral Inhalation). Consider therapy modification

Ribavirin (Oral Inhalation): May enhance the adverse/toxic effect of Didanosine. Ribavirin (Oral Inhalation) may increase serum concentrations of the active metabolite(s) of Didanosine. Avoid combination

Ribavirin (Systemic): May enhance the adverse/toxic effect of Didanosine. Ribavirin (Systemic) may increase serum concentrations of the active metabolite(s) of Didanosine. Avoid combination

Rilpivirine: May decrease the absorption of Didanosine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Didanosine may decrease the absorption of Rilpivirine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Management: Administer didanosine on an empty stomach at least 2 hours before or 4 hours after rilpivirine, due to the requirement that rilpivirine be administered with food. Consider therapy modification

Stavudine: May enhance the adverse/toxic effect of Didanosine. The risk of lactic acidosis (possibly fatal), hepatomegaly, and pancreatitis may be increased with this combination. Avoid combination

Tenofovir Disoproxil Fumarate: May diminish the therapeutic effect of Didanosine. Tenofovir Disoproxil Fumarate may increase the serum concentration of Didanosine. Management: Avoid concomitant treatment with tenofovir disoproxil fumarate and didanosine. Consider altering even existing, stable treatment to avoid this combination. Avoid combination

Tipranavir: May decrease the serum concentration of Didanosine. Management: It is recommended that didanosine be administered at least 2 hours apart from tipranavir in order to minimize any potential dosage form-related interaction. Consider therapy modification

Adverse Reactions

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

>10%:

Central nervous system: Peripheral neuropathy (17% to 20%)

Endocrine & metabolic: Increased amylase (≥1.4 x ULN: 15% to 17%)

Gastrointestinal: Diarrhea (19% to 28%), abdominal pain (7% to 13%)

1% to 10%:

Dermatologic: Pruritus (≤9%), skin rash (≤9%)

Endocrine & metabolic: Increased uric acid (>12 mg/dL: 2% to 3%)

Gastrointestinal: Pancreatitis (6% to 7%)

Hepatic: Increased serum AST (>5 x ULN: 7% to 9%), increased serum ALT (>5 x ULN: 6% to 9%), increased serum alkaline phosphatase (>5 x ULN: 1% to 4%)

<1%, postmarketing, and/or case reports: Acute renal failure, alopecia, anaphylactoid reaction, anemia, anorexia, arthralgia, chills, diabetes mellitus, dyspepsia, fever, flatulence, hepatic failure, hepatitis, hyperglycemia, hypoglycemia, increased creatine phosphokinase, increased gamma-glutamyl transferase, lactic acidosis, leukopenia, lipoatrophy (buttocks, face, limbs), myalgia, myopathy, optic neuritis, pain, parotid gland enlargement, portal hypertension (noncirrhotic), retinal pigment changes (depigmentation), rhabdomyolysis, severe hepatomegaly with steatosis, sialadenitis, symptomatic hyperlactatemia, thrombocytopenia, weakness, xerophthalmia, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.
• Lactic acidosis/hepatomegaly: [US Boxed Warning]: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported, with nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. Risk may be increased with female gender, obesity, or prolonged exposure. Fatal lactic acidosis has been reported in pregnant individuals who received the combination of didanosine and stavudine with other antiretroviral agents. Use caution when administering to patients with known risk factors for liver disease. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).
• Lipoatrophy: May cause loss of subcutaneous fat, especially in the face, limbs, and buttocks. Lipoatrophy incidence and severity are related to cumulative exposure and may be only partially reversible. Monitor patients for signs of lipoatrophy and consider switching to a non-didanosine-containing regimen if lipoatrophy occurs.
• Noncirrhotic portal hypertension: Patients may develop noncirrhotic portal hypertension within months to years of starting didanosine therapy. Signs may include elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. Noncirrhotic portal hypertension may lead to liver failure and/or death. Discontinue use in patients with evidence of this condition.
• Ocular effects: Retinal changes (including retinal depigmentation) and optic neuritis have been reported in adults and children using didanosine; patients should undergo retinal examination periodically.
• Pancreatitis: [US Boxed Warning]: Pancreatitis (fatal and nonfatal) has been reported alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. Suspend use in patients with suspected pancreatitis and discontinue in patients with confirmed pancreatitis; frequency is dose related. In patients with risk factors for pancreatitis, use with extreme caution and only if clearly indicated. Patients with advanced HIV-1 infection, especially the elderly, are at increased risk and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment.
• Peripheral neuropathy: Peripheral neuropathy (numbness, tingling or pain in the hands or feet) has been reported, more frequently in patients with advanced HIV disease, in patients with a history of neuropathy or in patients being treated with a neurotoxic drug. Discontinue therapy if neuropathy occurs.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; safety and efficacy have not been established in patients with significant hepatic disease. Patients on combination antiretroviral therapy with hepatic impairment may be at increased risk of potentially severe and fatal hepatic toxicity; consider interruption or discontinuation of therapy if hepatic impairment worsens.
• Renal impairment: Use with caution in patients with renal impairment; dose reduction recommended for CrCl <60 mL/minute.

Concurrent drug therapy issues:

• Hydroxyurea and stavudine: Fatal cases of hepatotoxicity/lactic acidosis, pancreatitis, and/or severe peripheral neuropathy have been reported in HIV patients treated with didanosine with hydroxyurea and stavudine; avoid use with hydroxyurea; coadministration with stavudine is contraindicated.
• Tenofovir: Combined use may be associated with increased didanosine toxicity (eg, lactic acidosis, pancreatitis), immunologic nonresponse or CD4 cell decline despite viral suppression, early virologic failure and rapid resistance development; combined use is not recommended (HHS [adult], 2015); manufacturer labeling recommends a didanosine dose reduction if combination is used.
• Drug-drug interactions: Additional potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Delayed-release capsules: Didanosine delayed-release capsules are indicated for once-daily use.
• Powder for oral solution: Didanosine powder for oral solution is recommended for use in a twice daily regimen, as there is more efficacy evidence with twice daily administration.

Special populations:

Pediatric: Dosing recommendations for didanosine powder for oral solution in patients younger than 2 weeks cannot be made because the pharmacokinetics of didanosine in these infants are too variable to determine an appropriate dose. Delayed-release capsules may be used in pediatric patients who weigh at least 20 kg.

Monitoring Parameters

Serum potassium, uric acid, creatinine; hemoglobin, CBC with neutrophil and platelet count, CD4 cells; viral load; liver function tests, serum bilirubin, albumin, INR, amylase; weight gain; perform dilated retinal exam every 6 months, ultrasonography (if portal hypertension suspected)

Pregnancy

Pregnancy Considerations

[US Boxed Warning]: Fatal lactic acidosis has been reported in pregnant individuals using didanosine and stavudine in combination with other antiretroviral agents. The Health and Human Services (HHS) perinatal HIV guidelines do not recommend didanosine use in pregnant women due to toxicity, and women who are pregnant should be changed to a preferred or alternative therapy.

Didanosine crosses the human placenta.

Outcome information specific to didanosine use in pregnancy is no longer being reviewed and updated in the HHS perinatal guidelines. Maternal antiretroviral therapy (ART) may be associated with adverse pregnancy outcomes including preterm delivery, stillbirth, low birth weight, and small for gestational age infants. Actual risks may be influenced by maternal factors, such as disease severity, gestational age at initiation of therapy, and specific ART regimen, therefore close fetal monitoring is recommended. Because there is clear benefit to appropriate treatment, maternal ART should not be withheld due to concerns for adverse neonatal outcomes. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children without HIV but who were exposed to ART in utero and develop significant organ system abnormalities of unknown etiology (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction. Cases of lactic acidosis and hepatic steatosis have been reported in pregnant women with use of nucleoside reverse transcriptase inhibitors.

In general, ART is recommended for all pregnant females living with HIV to keep the viral load below the limit of detection and reduce the risk of perinatal transmission. Therapy should be individualized following a discussion of the potential risks and benefits of treatment during pregnancy. Monitoring of pregnant females is more frequent than in nonpregnant adults. ART should be continued postpartum for all females living with HIV and can be modified after delivery.

Health care providers are encouraged to enroll pregnant females exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or http://www.APRegistry.com). Health care providers caring for pregnant females living with HIV and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2019).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience headache, abdominal pain, nausea, vomiting, or diarrhea. Have patient report immediately to prescriber signs of lactic acidosis (fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), abdominal edema, severe dizziness, passing out, burning or numbness feeling, bruising, bleeding, vision changes, change in body fat, or signs of infection (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.