Didanosine

Pronunciation: (dye-DAN-oh-seen)
Class: Nucleoside reverse transcriptase inhibitor

Trade Names

Videx
- Powder for oral solution 2 g
- Powder for oral solution 4 g

Videx EC
- Capsules, delayed release (with enteric-coated beadlets), oral 125 mg
- Capsules, delayed release (with enteric-coated beadlets), oral 200 mg
- Capsules, delayed release (with enteric-coated beadlets), oral 250 mg
- Capsules, delayed release (with enteric-coated beadlets), oral 400 mg

Pharmacology

Inhibits replication of HIV by interfering with DNA synthesis.

Pharmacokinetics

Absorption

T _max is 0.25 to 1.5 h (buffered formulation) and 2 h (delayed release). Bioavailability is approximately 42% (buffered formulation). Food decreased the C _max and AUC by approximately 55% when didanosine tablets were administered up to 2 h after a meal. C _max and AUC of the delayed-release capsules decreased by approximately 46% and 19%, respectively, in the presence of food. Didanosine should be taken on an empty stomach.

Distribution

Less than 5% protein bound. Vd is approximately 43.7 L/m ² (buffered formulation) and 308 L (delayed-release capsule).

Elimination

Half-life is approximately 1.5 h (buffered formulation). Approximately 18% is recovered in the urine (buffered formulation). Renal Cl is approximately 458 mL/min (buffered formulation) in patients with CrCl of at least 90 mL/min.

Special Populations

Renal Function Impairment

Half-life is increased and Cl is decreased.

Hepatic Function Impairment

Mean C _max and AUC were 19% and 13% higher, respectively.

Indications and Usage

Treatment of HIV-1 infection in combination with other antiretrovirals.

Contraindications

Coadministration with allopurinol or ribavirin.

Dosage and Administration

Delayed-Release Capsule
Adults and Children Patients weighing 20 kg to less than 25 kg

PO 200 mg once daily.

Patients weighing 25 kg to less than 60 kg

PO 250 mg once daily.

Patients weighing 60 kg or more

PO 400 mg once daily.

Powder for Oral Solution
Adults Patients weighing 60 kg or more

PO 200 mg twice daily. For patients who require once-daily dosing, administer 400 mg once daily.

Patients weighing less than 60 kg

PO 125 mg twice daily. For patients who require once-daily dosing, administer 250 mg once daily.

Patients weighing 60 kg or more

PO 400 mg once daily.

Children 2 wk to 8 mo of age

PO 100 mg/m ² twice daily, not to exceed the adult dosing recommendation.

Older than 8 mo

PO 120 mg/m ² twice daily, not to exceed the adult dosing recommendation.

Renal Function Impairment
Adults Delayed-release capsule CrCl 60 mL/min or more

PO For patients weighing at least 60 kg, administer 400 mg once daily; for patients weighing less than 60 kg, administer 250 mg once daily.

CrCl 30 to 59 mL/min

PO For patients weighing at least 60 kg, administer 200 mg once daily; for patients weighing less than 60 kg, administer 125 mg once daily.

CrCl 10 to 29 mL/min

PO 125 mg once daily.

CrCl less than 10 mL/min and patients requiring continuous ambulatory peritoneal dialysis or hemodialysis

PO For patients weighing at least 60 kg, administer 125 mg once daily; do not administer to patients weighing less than 60 kg.

Powder for oral solution CrCl 60 mL/min or more

PO For patients weighing at least 60 kg, administer 200 mg twice daily (or 400 mg once daily in patients who require once-daily dosing); for patients weighing less than 60 kg, administer 125 mg twice daily (or 250 mg once daily in patients who require once-daily dosing).

CrCl 30 to 59 mL/min

PO For patients weighing at least 60 kg, administer 200 mg once daily or 100 twice daily; for patients weighing less than 60 kg, administer 150 mg once daily or 75 mg twice daily.

CrCl 10 to 29 mL/min

PO For patients weighing at least 60 kg, administer 150 mg once daily; for patients weighing less than 60 kg, administer 100 mg once daily.

CrCl less than 10 mL/min and patients requiring continuous ambulatory peritoneal dialysis or hemodialysis

PO For patients weighing at least 60 kg, administer 100 mg once daily; for patients weighing less than 60 mg, administer 75 mg once daily.

Coadministration With Tenofovir Disoproxil Fumarate
Adults CrCl 60 mL/min or more and weighing at least 60 kg

PO Administer 250 mg once daily.

CrCl 60 mL/min or more and weighing less than 60 kg

PO Administer 200 mg once daily.

General Advice

Give on an empty stomach at least 30 min before or 2 h after eating.
Shake solution well before using.

Delayed-release capsule

Delayed-release capsule should be swallowed whole. Do not break, crush, or chew.
Patients with symptoms of peripheral neuropathy may tolerate a reduced dose after resolution of symptoms. If symptoms recur, consider permanently discontinuing treatment.
When coadministered with tenofovir disoproxil fumarate, administration with a light meal (400 kcal or less, 20% fat or less) or in the fasted state is recommended.

Powder for oral solution

Powder for oral solution is first mixed with purified water to obtain a concentration of 20 mg/mL, then mixed with an antacid to obtain a final concentration of 10 mg/mL.
When coadministered with tenofovir disoproxil fumarate, administer together on an empty stomach or administer didanosine on an empty stomach.

Storage/Stability

Powder for oral solution

Store powder between 59° and 86°F. Once mixed, store for up to 30 days in refrigerator between 36° and 46°F. Discard unused portion after 30 days.

Delayed-release capsule

Store between 59° and 86°F.

Drug Interactions

Allopurinol

Allopurinol may cause increased didanosine plasma levels. Coadministration is contraindicated.

Antacids

Aluminum- or magnesium-containing antacids may potentiate adverse reactions associated with the antacid component of didanosine powder. Use with caution.

Dapsone and other drugs whose absorption can be affected by gastric acidity

Plasma concentrations of these agents may be decreased. Administer at least 2 h before the buffered didanosine formulation.

Delavirdine, indinavir

Administer 1 h prior to didanosine to avoid decreasing plasma levels of delavirdine or indinavir.

Drugs that cause peripheral neuropathy or pancreatitis

Increased risk of these toxicities. If coadministration cannot be avoided, didanosine suspension is recommended. Use with extreme caution.

Food

Didanosine C _max and AUC were decreased by approximately 55% when didanosine tablets were administered up to 2 h after a meal. Administration of didanosine tablets up to 30 min before a meal did not result in a change in bioavailability. Food decreased the C _max and AUC of the delayed-release capsules 46% and 19%, respectively, compared with fasting. The delayed-release capsules should be taken on an empty stomach.

Fluoroquinolones, tetracyclines

Plasma concentrations of these agents may be decreased. If concurrent use cannot be avoided, give the fluoroquinolone at least 2 h before or 6 h after buffered didanosine formulations. Separate the administration times of tetracyclines and buffered didanosine formulations by 3 to 4 h.

Ganciclovir, valganciclovir

Didanosine plasma concentrations may be elevated, increasing the risk of toxicity. Monitor for clinical response and toxicity. Adjust the didanosine dose as needed.

Methadone

May decrease didanosine plasma levels. Do not administer methadone with didanosine powder because of decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the delayed-release capsules are recommended. Monitor the clinical response and adjust the didanosine dose as needed.

Nelfinavir

Nelfinavir plasma concentrations may be increased. The pharmacokinetics of nelfinavir are not altered to a clinically important degree when it is administered with a light meal 1 h after didanosine.

Ribavirin

Risk of didanosine toxicity may be increased. Coadministration is contraindicated.

Stavudine

Combination therapy of didanosine, stavudine, and other antiretrovirals has caused fatal lactic acidosis in women. Peripheral neuropathy has occurred more frequently in patients treated with neurotoxic drugs, including stavudine. The risk of fatal lactic acidosis may be increased in pregnant women. Close clinical monitoring is recommended.

Tenofovir disoproxil fumarate

Didanosine plasma concentrations may be increased, necessitating a dose reduction in didanosine.

Adverse Reactions

Incidences of the following adverse reactions were reported with didanosine monotherapy. When didanosine is used in combination with other agents with similar adverse reactions, the incidence of these reactions, including pancreatitis and hepatotoxicity, may be higher than with didanosine alone.

CNS

Peripheral neurologic symptoms/neuropathy (20%); asthenia (postmarketing).

Dermatologic

Rash/pruritus (9%); alopecia (postmarketing).

EENT

Dry eyes, optic neuritis, retinal depigmentation (postmarketing).

GI

Diarrhea (28%); abdominal pain (13%); pancreatitis (7%); anorexia, dry mouth, dyspepsia, flatulence, inflammation of the salivary gland (postmarketing).

Hematologic-Lymphatic

Anemia, leukopenia, thrombocytopenia (postmarketing).

Hepatic

Hepatitis, liver failure, noncirrhotic portal hypertension, symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (postmarketing).

Hypersensitivity

Anaphylactic reactions (postmarketing).

Lab Tests

Elevated serum amylase (17%); elevated ALT and AST (9%); elevated serum alkaline phosphatase (4%); elevated serum uric acid (3%); elevated serum GGT, hyperglycemia, hypoglycemia (postmarketing).

Metabolic-Nutritional

Diabetes mellitus, redistribution/accumulation of body fat (postmarketing).

Musculoskeletal

Arthralgia, myalgia, myopathy, rhabdomyolysis (postmarketing).

Miscellaneous

Chills/fever, pain, parotid gland enlargement (postmarketing).

Precautions

Warnings

Pancreatitis

Fatal and nonfatal pancreatitis have occurred during therapy regardless of the degree of immunosuppression. Withhold treatment in patients with suspected pancreatitis and discontinue in patients with confirmed pancreatitis.

Lactic acidosis and severe hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Fatal lactic acidosis has been reported in pregnant women receiving the combination of didanosine and stavudine with other antiretroviral agents.

Monitor

Patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver abnormalities, including severe and potentially fatal hepatic adverse reactions; monitor according to standard practice. Evidence of worsening liver disease may require interruption or discontinuation of treatment. Monitor patients for early signs of portal hypertension (eg, splenomegaly, thrombocytopenia) during routine medical visits. Consider appropriate laboratory testing, including liver enzymes, serum bilirubin, albumin, CBC, INR, and ultrasonography. Consider periodic retinal examination. Monitor patients, especially elderly patients, with advanced HIV infection closely for pancreatitis.

Pregnancy

Category B . The US Department of Health and Human Services guidelines recommend that HIV therapy, with the exception of efavirenz, be continued during pregnancy because the expected benefit to the HIV-positive mother outweighs the unknown risk to the fetus.

Lactation

Undetermined. HIV-infected women should not breast-feed infants.

Children

Safety and efficacy not established in children younger than 2 wk.

Elderly

Select dose with caution because of greater likelihood of decreased renal function.

Renal Function

Dosage reduction is recommended in patients with CrCl less than 60 mL/min.

Hepatic Function

Safety and efficacy have not been established in HIV-infected patients with significant underlying liver disease. Patients with preexisting liver dysfunction have an increased incidence of liver abnormalities, including severe and potentially fatal hepatic adverse events.

Fat redistribution

Redistribution/accumulation of body fat (eg, central obesity, dorsocervical fat enlargement [buffalo hump]) has been observed in patients receiving antiretroviral therapy.

Hepatotoxicity

Hepatotoxicity and hepatic failure resulting in death were reported in patients who were treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine; this combination should be avoided.

Immune reconstitution syndrome

Has been reported in patients receiving combination antiretroviral therapy, including didanosine. During the initial phase of treatment, patients may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium ), necessitating further evaluation and treatment.

Noncirrhotic portal hypertension

Has been reported postmarketing, including cases leading to liver transplantation or death. Common presenting features include elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.

Ophthalmic effects

Retinal changes and optic neuritis have been reported in adults and children.

Peripheral neuropathy

Has been reported and may occur more frequently in patients with advanced HIV, patients with a history of neuropathy, or patients treated with other neurotoxic drugs. Consider discontinuation in patients who develop peripheral neuropathy.

Overdosage

Symptoms

Diarrhea, hepatic dysfunction, hyperuricemia, pancreatitis, peripheral neuropathy.

Patient Information

Advise patient to take drug on empty stomach. Instruct patients to swallow capsules whole and to not open the capsules.
Inform patients that the preferred dosing frequency of the powder for oral solution is twice daily; once-daily dosing can be considered in adult patients whose management requires once-daily dosing of didanosine.
Inform patient that the drug does not completely eliminate HIV virus and, therefore, does not reduce the risk of transmitting HIV. Appropriate precautions must be continued.
Emphasize that the drug is not a cure for HIV infection, and patients may continue to develop HIV-associated illness, including opportunistic infections. Instruct patients to remain under the care of a health care provider.
Inform patients that pancreatitis, a serious toxicity of didanosine when used alone or in combination regimens, has been fatal.
Advise patients that peripheral neuropathy may develop during therapy with didanosine and occurs more frequently in patients with advanced HIV disease or a history of peripheral neuropathy. Discontinuation of therapy may be required if this toxicity occurs.
Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of didanosine alone or in combination with other antiretrovirals.
Inform patients that hepatoxicity, including fatal hepatic adverse events, were reported in patients with preexisting liver dysfunction.
Inform patients that noncirrhotic portal hypertension has been reported, including cases leading to liver transplantation or death.
Inform patients that retinal changes and optic neuritis have been reported.
Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Instruct patient to report these symptoms to health care provider: abdominal pain, diarrhea, fever, flu-like symptoms, nausea, sore throat, tingling pain or numbness in the hands or feet, vomiting.
Advise patient to avoid alcoholic beverages.
Advise patient not to take any medicine, vitamins, or herbal products without first checking with their health care provider.