DIDANOSINE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-The FDA-approved product labeling recommends administering on an empty stomach (i.e., at least 30 minutes before or 2 hours after eating). However, administration on an empty stomach may not be possible in frequently fed infants and it may decrease medication adherence. To improve adherence, some practitioners administer didanosine without regard to food. In a study comparing fed and fasting state administration in children (n = 106), overall systemic exposure (AUC) was similar between groups with slower absorption and prolonged elimination noted during the administration of food. Additionally, studies in adults suggest that didanosine may be given without regard to food.
Oral Solid Formulations
Delayed-release capsules
-Swallow whole. Do not crush, chew, or open.

Oral Liquid Formulations
Preparation of powder for oral solution
-Prior to dispensing, reconstitute 2 or 4 gram bottle by adding 100 or 200 ml Purified Water, USP, respectively, to produce a solution containing 20 mg/ml. Immediately after reconstitution, the 20 mg/ml solution should be mixed with an equal amount of any commercially available antacid that contains as active ingredients aluminum hydroxide (400 mg/5 ml), magnesium hydroxide (400 mg/5 ml), and simethicone (40 mg/5 ml) to produce a final admixture concentration of 10 mg/ml.
-Dispense final admixture in a flint-glass or plastic (HDPE, PET, or PETG) bottle.
-Shake well prior to administering each dose.
-Storage: Suspension is stable for 30 days when refrigerated at 2-8 degrees C (36-46 degrees F).

Adverse events and laboratory abnormalities in pediatric patients were generally consistent with the safety profile in adults.

Lactic acidosis (symptomatic hyperlactatemia) and severe hepatotoxicity (i.e., fatal cases of hepatomegaly with steatosis) have been reported with the use of nucleoside reverse transcriptase inhibitors, including didanosine. Many of these cases have occurred in women. In addition, deaths attributed to hepatotoxicity or hepatic failure have occurred with the combination of stavudine, didanosine, and hydroxyurea. Concurrent use of didanosine and stavudine is contraindicated. Discontinue didanosine if clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, with or without elevated hepatic enzymes, develop. There have been postmarketing reports of non-cirrhotic portal hypertension, including cases leading to liver transplantation or death; onset of signs and symptoms ranged from months to years after starting didanosine and symptoms included elevated hepatic enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. In a Phase III study of 34 children, 6 patients developed hepatic abnormalities with significant increases in hepatic enzymes. Two of these children died of fulminant hepatic failure. Elevated hepatic enzymes have been reported in 1% to 9% of adult patients in monotherapy trials and in 3% to 53% of adult patients in combination therapy trials. Hyperbilirubinemia was noted in up to 68% of adult patients in combination therapy trials. Hepatitis has been noted in postmarketing reports.

Fatal and non-fatal pancreatitis has occurred during therapy with didanosine when used alone or in combination regimens, regardless of the degree of immunosuppression exhibited by the patient. The incidence of pancreatitis is higher in children, patients with advanced HIV disease, those with a previous history of pancreatitis, and those with risk factors for pancreatitis. Fatal pancreatitis has occurred in fewer than 1% of patients. In pediatric patients, pancreatitis occurred in 3% of patients treated at doses less than 300 mg/m2/day and in 13% of patients treated at higher doses. Pancreatitis did not occur in pediatric patients in a study of a dose of 120 mg/m2 every 12 hours and it was reported in less than 1% of patients who received doses of 90 mg/m2 every 12 hours in combination with zidovudine. In studies of didanosine plus stavudine with or without hydroxyurea, deaths due to pancreatitis occurred in treatment-naive and treatment-experienced patients without significant immunosuppression and at the recommended didanosine and stavudine doses. Since 1998, the majority of reported cases have been in patients who were receiving stavudine with didanosine with or without hydroxyurea. Concurrent use of didanosine and stavudine is contraindicated. Pancreatitis generally appears within 1 to 6 months and can manifest as symptomatic hyperamylasemia or hemorrhagic pancreatitis. Elevated amylase occurred in 15% to 17% of adult patients in monotherapy trials. Hyperamylasemia has been reported in 8% to 31% of adult patients and increased lipase was noted in 5% to 26% of adult patients during combination therapy trials. Discontinue didanosine at the first sign of pancreatitis; symptoms may reverse 1 to 3 weeks after discontinuation. The manufacturer and the FDA request that all cases of pancreatitis be reported to Bristol-Meyers Squibb (800-721-5072) and the FDA via the MedWatch program (800-FDA-1088).

The most common adverse reaction associated with didanosine monotherapy in adults is diarrhea, occurring in 19% to 28% of patients, and in up to 70% during combination therapy trials. Other GI effects reported in adults include abdominal pain (7% to 13% monotherapy), nausea (24% to 53% combination therapy), and vomiting (12% to 30% combination therapy). These may or may not be associated with pancreatitis. Anorexia, dyspepsia, flatulence, and dry mouth (xerostomia) were noted in postmarketing reports.

In adults, peripheral neuropathy was reported in 17% to 20% of monotherapy patients and up to 26% of patients during combination therapy. It is manifested as burning, tingling, numbness, or shooting pains in a stocking-glove distribution and can be severe enough to discontinue therapy. Didanosine may be restarted at a lower dose after resolution of symptoms. Neurotoxicity is more common in patients with a history of peripheral neuropathies or who are receiving concurrent neurotoxic agents.

Anemia, leukopenia, and thrombocytopenia have been noted in post-marketing reports with didanosine.

Hyperuricemia has been reported in 2% to 3% of adult patients.

Retinal pigment changes (i.e., depigmentation) and optic neuritis have been reported during postmarketing surveillance in adults and pediatric patients receiving didanosine. Consider periodic retinal exams during treatment. Dry eyes (xerophthalmia) has also been noted during postmarketing reports.

Rash (unspecified) and pruritus have been reported in 7% to 9% of adult patients receiving didanosine monotherapy in trials. The incidence of rash has increased to up to 30% during combination therapy trials. Other adverse events noted during postmarketing reports include alopecia and anaphylactoid reactions.

Lipoatrophy (i.e., loss of subcutaneous fat in the face, limbs, and buttocks) has been reported in patients receiving didanosine. The incidence and severity of lipoatrophy are related to cumulative exposure, and often is nonreversible after treatment with didanosine is stopped. Lipodystrophy often accompanies other metabolic complications such as insulin resistance, dyslipidemia, and lactic acidosis. The prevalence of lipodystrophy in pediatric patients treated with HAART has ranged from approximately 20% to 50% in most clinical studies. Older age (preadolescents and adolescents vs. younger children) has also been shown to increase the risk of lipodystrophy. Unlike in adults, most studies in children have not found a higher incidence of lipodystrophy in girls vs. boys. The mechanism by which nucleoside analogs may cause body fat changes is not known. It has been suggested that nucleoside analogs may damage the mitochondria of adipocytes. Frequently monitor drug recipients for symptoms or signs of lipodystrophy. Consider switching to an alternative treatment regimen if lipoatrophy is observed.

Headache has been reported in 21% to 46% of adult patients during didanosine combination therapy trials. Other adverse reactions reported during postmarketing surveillance include asthenia, chills, fever, pain, sialadenitis, and parotid gland enlargement.

Diabetes mellitus, hypoglycemia, and hyperglycemia have been noted in postmarketing adverse event reports for didanosine.

Musculoskeletal adverse reactions noted during postmarketing reports for didanosine include myalgia (with or without increases in creatine kinase), arthralgia, myopathy, and rhabdomyolysis, including with acute renal failure (unspecified) and hemodialysis.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake, or drug non-availability. If short-term treatment interruption is necessary (i.e., less than 1 to 2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from less than 1 week to more than 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Pancreatitis has been reported less commonly in children as compared to adults. Didanosine should not be administered to patients with signs and symptoms of pancreatitis and should be discontinued in patients with confirmed pancreatitis. The incidence of didanosine-induced pancreatitis appears to be dose-related, and is higher in patients with advanced HIV-disease or with impairment of renal function. Medications that may increase the exposure to didanosine may also increase the risk of pancreatitis. Didanosine should be used with extreme caution, if at all, in these patients. If patients are treated with other drugs known to cause pancreatitis, it is recommended that didanosine therapy be discontinued.

The dose of didanosine should be adjusted in patients with renal impairment or renal failure. Patients receiving continuous ambulatory peritoneal dialysis (CAPD) require additional dosage reduction. Patients with renal impairment are at an increased risk of developing pancreatitis if treated without a dose reduction.

Fatalities associated with hepatotoxicity or lactic acidosis have been reported with use of antiretroviral agents alone or in combination, including didanosine. Adult females appear to be at high risk; it is not clear whether this increased risk also applies to pediatric females. Obesity and prolonged nucleoside exposure may be risk factors for lactic acidosis and severe hepatomegaly with steatosis during didanosine therapy. Clinicians need to be alert for early diagnosis of this syndrome. Didanosine should be used with caution in patients with hepatic disease or in those with known risk factors for liver disease; however, cases have been reported in patients with no known risk factors. Discontinue treatment in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactemia, lactic acidosis, or pronounced hepatotoxicity which may include hepatomegaly and steatosis even in the absence of marked increases in transaminases. It is not known if hepatic impairment affects the pharmacokinetics of didanosine; therefore, monitor these patients closely. Postmarketing cases of non-cirrhotic portal hypertension, including cases leading to liver transplantation or death, have been reported with didanosine when used long-term in adults. Onset of signs and symptoms ranged from months to years after starting didanosine. Symptoms include elevated hepatic enzymes, esophageal varices, hematemesis, ascites, and splenomegaly. Monitor patients for early signs of portal hypertension, by obtaining routine hepatic enzymes, serum bilirubin, albumin, complete blood count (CBC), and INR. Ultrasonography should be considered. Discontinue didanosine in patients with evidence of non-cirrhotic portal hypertension.

Patients with advanced HIV disease, pre-existing peripheral neuropathy, or who are receiving other drugs that cause peripheral neuropathies may be at increased risk for developing didanosine-induced peripheral neuropathy. Symptomatic patients may tolerate a reduced dose of didanosine after resolution of neuropathic symptoms upon discontinuation of didanosine. If neuropathies recur after restarting didanosine, permanent discontinuation of the didanosine should be considered.

The underlying risk of cardiac disease should be considered when prescribing antiretroviral therapies, including didanosine. Although the risk of cardiovascular events in pediatric patients is unknown, some data suggest an increased risk in adults taking didanosine, including some young adults in their early twenties. In a published prospective, observational, epidemiological study designed to investigate the rate of myocardial infarction in patients on combination antiretroviral therapy, the use of didanosine within the previous 6 months was correlated with an increased risk of myocardial infarction (MI) with the rate of MI decreasing within a few months after drug cessation. A second retrospective, observational study did not show increased risk of MI when assessing cardiovascular disease (CVD) risk factors.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when didanosine is used either alone or in combination with other agents. Monotherapy with didanosine is not recommended.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to didanosine therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop in the setting of immune reconstitution; the time to onset is variable and may occur months after treatment initiation.

Perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients 2 years and older receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, consider treatment for all children 3 years and older and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts more than 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Description: Didanosine (ddI) is a synthetic purine derivative oral nucleoside reverse transcriptase inhibitor (NRTI). It is an acid-labile drug and, hence, must be protected from stomach acids. The powder for oral solution contains buffering agents that, while improving didanosine bioavailability, are associated with several drug interactions. The delayed-release capsules contain enteric coated beads of didanosine that dissolve after entering the small intestine; this formulation is associated with fewer drug interactions than the buffered powder for oral solution. Fatal and nonfatal pancreatitis has been reported and is dose-related. Didanosine was originally approved specifically for the treatment of HIV infection in patients who failed therapy with zidovudine, and subsequently approved for use in combination with other antiretroviral agents for the treatment of HIV infection. Didanosine is FDA-approved for use in pediatric patients as young as 2 weeks of age, with the delayed-release capsules approved in pediatric patients 6 years of age and older weighing at least 20 kg.

NOTE: The HIV guidelines recommend that didanosine should never be used in pediatric patients due to the toxicity associated with this drug and the availability of safer agents; concurrent use with stavudine is contraindicated (due to increased toxicity risk).

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Didanosine is not recommended as part of an antiretroviral regimen in any patient due to an increased risk of serious toxicity.
-Refer to the HIV treatment guidelines for specific preferred and alternative regimens.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: hepatitis B virus
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
Oral dosage (powder for oral solution):
Neonates and Infants 2 weeks to 2 months: 50 mg/m2/dose PO every 12 hours is recommended in the HIV clinical guidelines. Although the FDA-approved dosage is 100 mg/m2/dose PO twice daily, pharmacokinetic data suggest increased toxicity if this dosage is used in infants younger than 3 months.
Infants 3 to 8 months: 100 mg/m2/dose PO every 12 hours.
Infants and Children 9 months to 12 years: 120 mg/m2/dose (range: 90 to 150 mg/m2/dose) PO every 12 hours (Max: 125 mg/dose for less than 60 kg; 200 mg/dose for 60 kg or more). Once daily regimens (240 mg/m2/dose PO once daily [Max: 250 mg/dose for less than 60 kg; 400 mg/dose for 60 kg or more]) have been used with effective viral suppression in treatment-naive children older than 3 years; however, once-daily regimens are not FDA-approved for pediatric patients.
Adolescents: 120 mg/m2/dose (range: 90 to 150 mg/m2/dose) PO every 12 hours (Max: 125 mg/dose for less than 60 kg; 200 mg/dose for 60 kg or more) for adolescents in early puberty. Once daily regimens (240 mg/m2/dose PO once daily [Max: 250 mg/dose for less than 60 kg; 400 mg/dose for 60 kg or more]) have been used with effective viral suppression; however, once-daily regimens are not FDA-approved for pediatric patients. For adolescents in late puberty (i.e., Sexual Maturity Rating (SMR) 4 or 5), refer to adult dosing schedules. Because of rapidly changing development during adolescence, monitor all patients for efficacy and toxicity.
Oral dosage (delayed-release capsules):
NOTE: Patients must be able to swallow capsules whole; otherwise, use the oral solution.
Children and Adolescents 6 to 17 years weighing 20 to 24 kg: 200 mg PO once daily.
Children and Adolescents 6 to 17 years weighing 25 to 59 kg: 250 mg PO once daily.
Children and Adolescents 6 to 17 years weighing 60 kg or more: 400 mg PO once daily.

Maximum Dosage Limits:
-Neonates
younger than 2 weeks: Safety and efficacy have not been established.
2 weeks and older: 200 mg/m2/day PO for oral solution is FDA-approved dosage; however, many limit dosage to 100 mg/m2/day in this age group to decrease toxicity; safety and efficacy of other formulations have not been established.
-Infants
younger than 3 months: 200 mg/m2/day PO for oral solution is FDA-approved dosage; however, many limit dosage to 100 mg/m2/day in this age group to decrease toxicity; safety and efficacy of other formulations have not been established.
3 to 8 months: 200 mg/m2/day PO for oral solution; safety and efficacy of other formulations have not been established.
9 months and older: 240 mg/m2/day PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day have been used off-label; safety and efficacy of other formulations have not been established.
-Children
1 to 6 years or less than 20 kg: 240 mg/m2/day PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day have been used off-label; safety and efficacy of delayed-release capsules have not been established.
6 to 12 years and 20 to 24 kg: 240 mg/m2/day PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day (Max: 250 mg/day) have been used off-label; 200 mg/day PO for delayed-release capsules.
6 to 12 years and 25 to 59 kg: 240 mg/m2/day (Max: 250 mg/day) PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day (Max: 250 mg/day) have been used off-label; 250 mg/day PO for delayed-release capsules.
6 to 12 years and 60 kg or more: 240 mg/m2/day (Max: 400 mg/day) PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day (Max: 400 mg/day) have been used off-label; 400 mg/day PO for delayed-release capsules.
-Adolescents
20 to 24 kg: 240 mg/m2/day PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day (Max: 250 mg/day) have been used off-label; 200 mg/day PO for delayed-release capsules.
25 to 59 kg: 240 mg/m2/day (Max: 250 mg/day) PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day (Max: 250 mg/day) have been used off-label; 250 mg/day PO for delayed-release capsules.
60 kg or more: 240 mg/m2/day (Max: 400 mg/day) PO for oral solution is FDA-approved dosage; however, doses as high as 300 mg/m2/day (Max: 400 mg/day) have been used off-label; 400 mg/day PO for delayed-release capsules.

Patients with Hepatic Impairment Dosing
The FDA-approved product labeling states that no dosage adjustments are needed in patients with hepatic impairment as a similar range and distribution of AUC and Cmax values were observed when compared to healthy controls in a small study (n = 12). If didanosine is used, monitor patients closely for associated drug toxicities and further hepatic decompensation.

Patients with Renal Impairment Dosing
Urinary excretion is a major route of elimination of didanosine in pediatric patients ; therefore, dose adjustments are recommended in patients with renal impairment.
Oral solution
The following renal dose adjustments are based on a usual dose of 100 mg/m2/dose every 12 hours in infants (2 weeks to 8 months) and 120 mg/m2/dose every 12 hours in children.
CrCl 30 to 50 mL/minute/1.73 m2: 75 mg/m2/dose PO every 12 hours (Max: 75 mg/dose for those weighing less than 60 kg and 100 mg/dose for those weighing 60 kg or more).
CrCl 10 to 29 mL/minute/1.73 m2: 90 mg/m2/dose PO every 24 hours (Max: 100 mg/dose for those weighing less than 60 kg and 150 mg/dose for those weighing 60 kg or more ).
CrCl less than 10 mL/minute/1.73 m2: 75 mg/m2/dose PO every 24 hours (Max: 75 mg/dose for those weighing less than 60 kg and 100 mg/dose for those weighing 60 kg or more).

Delayed-release capsules
Although the FDA-approved product labeling does not provide specific renal dosing guidelines in pediatric patients, the following adult renal dose adjustments may be considered for pediatric patients receiving the delayed-release capsules.
Patients weighing less than 60 kg:
CrCl 30 to 59 mL/minute: 125 mg PO once daily.
CrCl 10 to 29 mL/minute: 125 mg PO once daily.
CrCl less than 10 mL/minute: delayed-release capsules are not recommended in these patients.
Patients weighing 60 kg or more:
CrCl 30 to 59 mL/minute: 200 mg PO once daily.
CrCl 10 to 29 mL/minute: 125 mg PO once daily.
CrCl less than 10 mL/minute: 125 mg PO once daily.

Intermittent hemodialysis
Oral solution
75 mg/m2/dose PO every 24 hours (Max: 75 mg/dose for those weighing less than 60 kg and 100 mg/dose for those weighing 60 kg or more).
Delayed-release capsules
Although the FDA-approved product labeling does not provide specific renal dosing guidelines in pediatric patients, the following adult renal dose adjustments may be considered for pediatric patients receiving the delayed-release capsules.
patients weighing less than 60 kg: delayed-release capsules are not recommended in these patients.
patients weighing 60 kg or more: 125 mg PO every 24 hours.
It is not necessary to administer a supplemental dose of didanosine after hemodialysis.

Peritoneal dialysis
Oral solution
75 mg/m2/dose PO every 24 hours (Max: 75 mg/dose for those weighing less than 60 kg and 100 mg/dose for those weighing 60 kg or more).
Delayed-release capsules
Although the FDA-approved product labeling does not provide specific renal dosing guidelines in pediatric patients, the following adult renal dose adjustments may be considered for pediatric patients receiving the delayed-release capsules.
patients weighing less than 60 kg: delayed-release capsules are not recommended in these patients.
patients weighing 60 kg or more: 125 mg PO every 24 hours.

Continuous renal replacement therapy (CRRT)
Oral solution
75 mg/m2/dose PO every 12 hours (Max: 75 mg/dose for those weighing less than 60 kg and 100 mg/dose for those weighing 60 kg or more).

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Similar to zidovudine, didanosine inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity is dependent on intracellular conversion to the active triphosphorylated form. The rate of didanosine phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated didanosine, this action may nevertheless account for some of the drug's toxicity.

Pharmacokinetics: Didanosine is administered orally. Protein binding is less than 5%, which contributes to its extensive distribution. CSF concentrations reach 12% to 85% (mean 46%) of plasma concentrations.

Metabolism has not been well studied in humans, but it is assumed to follow normal purine metabolism and elimination. Renal clearance is 50% of total body clearance.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Oral Route
Didanosine is acid-labile and susceptible to degradation by stomach acid. Absorption from the GI tract varies among individuals and is also affected by the dosage form, presence of food, and gastric pH. The mean bioavailability in children and adolescents is 25% (+/- 20%). Because of this, the oral powder contains buffering agents. The delayed-release capsules contain enteric-coated beadlets that protect against degradation by stomach acid. The enteric coating dissolves when the beadlets empty into the small intestine. Didanosine should be given 1 hour before meals, on an empty stomach. Oral absorption is approximately 33% to 43% in the fasting state.

In a study comparing fed and fasting state administration of the buffered oral solution in children aged 3 months to 18 years (n = 77), overall systemic exposure (AUC) was highly variable between patients, but similar between the 2 groups. The fraction absorbed was lower in the presence of food (0.19 vs. 0.27, p less than 0.0001); however, the apparent half-life was increased from 0.93 hours to 1.39 hours with food. Therefore, the reduced fraction absorbed was offset by the absorption rate becoming rate limiting for drug elimination, which resulted in similar AUCs during the fed and fasting states. Overall, when administered with regular meals, lower maximum but more sustained plasma concentrations occurred over the 4 hours after the dose was administered to children. Additionally, studies in adults suggest that didanosine may be given without regard to food.

In pediatrics, body weight appears to be the primary factor associated with oral clearance. Dosing schedule and drug formulation do not affect clearance. Increases in plasma concentrations and AUC are dose proportional. Within all age groups, the AUC displays significant interpatient variability resulting in a wide range of AUCs at each dosage level.


-Special Populations
Pediatrics
Neonates older than 2 weeks and Infants younger than 8 months
The elimination half-life of didanosine in 1 day old infants (n = 10) is 2 hours (+/- 0.7 hours). In patients 2 weeks to 4 months (n = 60), the half-life is 1.2 hours (+/- 0.3 hours).

Infants 8 months and older, Children, and Adolescents
The elimination half-life of the oral powder in children 8 months to 19 years is 0.8 hours (+/- 0.3 hours) which is shorter than what is noted in adults (1.5 hours +/- 0.4 hours). However, when broken out by weight in studies with the delayed-release capsules, half-life increased as patients' weight increased. In pediatric patients weighing 20 to less than 25 kg, the half-life is 0.75 hours (+/- 0.13 hours). In patients weighing 25 to less than 60 kg, the half-life is 0.92 hours (+/- 0.09 hours). Once pediatric patients weigh at least 60 kg, the half-life of 1.26 hours (+/- 0.19 hours) more closely resembles that of adults of the same weight who have a half-life of 1.19 hours (+/- 0.21 hours). The apparent volume of distrubution (Vd) of didanosine oral powder in pediatric patients 8 months to 19 years is 28 L/m2 (+/- 15 L/m2) compared to an apparent Vd in adults of 43.7 L/m2 (+/- 8.9 L/m2). In studies with the delayed-release capsules, the Vd was listed by patient weight. For patients 20 to less than 25 kg, the Vd was 98.1 L (+/- 30.2 L). For patients 25 to less than 60 kg, the Vd was 154.7 L (+/- 55L). For patients weighing at least 60 kg, the Vd was 363 L (+/- 137.7 L) as compared to adults of the same weight who had a Vd of 308.3 L (+/- 164.3 L).

Hepatic Impairment
Pharmacokinetic data for didanosine are not available in pediatric patients with hepatic impairment. The pharmacokinetics of didanosine were studied in non-HIV-infected adult subjects with moderate to severe hepatic impairment (Child-Pugh Class B or C). After a single 400 mg oral dose, there were increases in the mean AUC and in the mean Cmax in those with hepatic impairment compared to matched healthy subjects. However, dosage adjustments are not needed.

Renal Impairment
Pharmacokinetic data for didanosine are not available in pediatric patients with renal impairment. However, a decrease in oral clearance of didanosine and an increase in terminal elimination half-life are seen in adult patients with renal impairment, necessitating dose reductions. The absolute bioavailability is not affected in patients requiring dialysis. Didanosine is not detectable in peritoneal dialysate fluid after oral administration of a single dose. After a 3 to 4 hour hemodialysis period, recovery of didanosine in hemodialysate ranged from 0.6% to 7.4% of a single oral dose. In a study comparing 6 adults with normal renal function, 6 adults receiving hemodialysis, and 6 adults receiving CAPD, hemodialysis removed approximately 30% of didanosine from the body while CAPD showed little effect on didanosine removal. The study stated that in anuric patients with chronic renal failure, clearance is decreased approximately 4-fold as compared to patients with normal renal function.