VA Class:AM800
Didanosine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).1, 3, 8, 30, 40, 72, 200
Didanosine is used in conjunction with other antiretroviral agents for treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, adolescents, and pediatric patients 2 weeks of age and older.1, 217
Didanosine usually is used in conjunction with another HIV nucleoside reverse transcriptase inhibitor (NRTI) (dual NRTIs) and either an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) or HIV protease inhibitor (PI) in NNRTI- or PI-based regimens.1, 201, 217
The most appropriate antiretroviral regimen cannot be defined for each clinical scenario and selection of specific antiretroviral agents for use in such regimens should be individualized based on information regarding antiretroviral potency, potential rate of development of resistance, known toxicities, and potential for pharmacokinetic interactions as well as virologic, immunologic, and clinical characteristics of the patient.200, 201, 202 For information on the general principles and guidelines for use of antiretroviral therapy, including specific recommendations for initial therapy in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, see the Antiretroviral Agents General Statement 8:18.08.
Antiretroviral-naive Adults and Adolescents
Didanosine is not recommended by the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents for initial treatment regimens in antiretroviral-naive adults and adolescents.200
A dual NRTI option of didanosine and lamivudine (or emtricitabine) is not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents because of inferior virologic efficacy, limited clinical trial experience in antiretroviral-naive patients, and didanosine toxicities (e.g., pancreatitis, peripheral neuropathy).200
A dual NRTI option of didanosine and tenofovir disoproxil fumarate (tenofovir DF) is not recommended at any time because of a high rate of early virologic failure, rapid selection of resistance mutations, potential for immunologic nonresponse or decline in CD4+ T-cell counts, and increased didanosine concentrations and serious didanosine toxicities.200 Clinicians caring for patients who are clinically stable on a regimen that contains didanosine and tenofovir DF should consider altering the NRTIs.200
A dual NRTI option of didanosine and stavudine should not be used at any time because of a high incidence of toxicities (e.g., peripheral neuropathy, pancreatitis, hyperlactatemia).1, 200, 202, 217 (See HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors [NRTIs] under Drug Interactions: Antiretroviral Agents and see Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
Safety and efficacy of an NNRTI-based regimen of efavirenz and the dual NRTI option of didanosine and emtricitabine was evaluated in a randomized multicenter study in treatment-naive adults (study 301A).218 In this study, 571 HIV-infected adults (mean age 36 years; 85% male; 52% white; 26% Hispanic; 16% African American; median baseline plasma HIV-1 RNA level 4.9 log10 copies/mL; mean baseline CD4+ T-cell count 318 cells/mm3) were randomized to receive efavirenz and didanosine in conjunction with either emtricitabine or stavudine.218 At week 48, 81 or 78% of adults receiving the regimen of efavirenz, didanosine, and emtricitabine had plasma HIV-1 RNA levels less than 400 or 50 copies/mL, respectively, and the mean increase in CD4+ T-cell count was 168 cells/mm3.218 Virologic failure (i.e., individuals who failed to achieve virologic suppression or experienced rebound after achieving virologic suppression) at week 48 occurred in 3% of patients receiving this regimen.218
A 3-drug NNRTI-based regimen of nevirapine, zidovudine, and didanosine was evaluated in a randomized, double-blind, placebo-controlled study in 151 antiretroviral-naive patients with mean baseline CD4+ T-cell counts of 200-600/mm3 (mean 376/mm3 and mean baseline plasma HIV-1 RNA levels of 4.41 log10 copies/mL [25,704 copies/mL] (study BI 1046; INCAS study).215 Patients received a 3-drug NNRTI-based regimen of nevirapine (200 mg daily for 2 weeks followed by 200 mg twice daily), zidovudine (200 mg 3 times daily), and didanosine (125 or 200 mg twice daily depending on body weight) or a 2-drug regimen of zidovudine and didanosine or zidovudine and nevirapine.215 The primary end point was the proportion of patients with HIV-1 RNA levels less than 400 copies/mL and not previously failed at 48 weeks.215 Results at 48 weeks indicated that the virologic responder rate was 45% in those treated with the 3-drug NNRTI-based regimen of nevirapine, zidovudine, and didanosine; 19% in those treated with the 2-drug regimen of zidovudine and didanosine; and 0% in those treated with the 2-drug regimen of nevirapine and zidovudine.215 At 1 year, there was a mean increase of 139 cells/mm3 above baseline CD4+ T-cell counts in those receiving the 3-drug regimen compared with a mean increase of 87 cells/mm3 above baseline in those receiving the 2-drug regimen of zidovudine and didanosine;215 there was a mean decrease of 6 cells/mm3 below baseline CD4+ T-cell counts in those receiving the 2-drug regimen of nevirapine and zidovudine.215
A 3-drug PI-based regimen of didanosine (200 mg twice daily), stavudine, and indinavir was compared with a 3-drug PI-based regimen of zidovudine, lamivudine, and indinavir in a multicenter, randomized, open-label study in 205 antiretroviral-naive adults (START 2 study).1 Both regimens resulted in similar decreases in plasma HIV-1 RNA levels and increases in CD4+ T-cell counts through 48 weeks of therapy.1
A 3-drug PI-based regimen of didanosine (400 mg once daily), stavudine (40 mg twice daily), and nelfinavir (750 mg 3 times daily) was compared with a 3-drug PI-based regimen of zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and nelfinavir (750 mg 3 times daily) in a multicenter, randomized, open-label study in 756 antiretroviral-naive patients with median CD4+ T-cell counts of 340/mm3 (range 80-1568/mm3) and median plasma HIV-1 RNA levels of 4.69 log10 copies/mL (range 2.6-5.9 log10 copies/mL) at baseline (study AI454-148).1 At 48 weeks, the median increase in CD4+ T-cell count was 188/mm3.1
Safety and efficacy of a once-daily regimen of didanosine delayed-release capsules have been evaluated in an open-label, randomized study in 511 antiretroviral-naive HIV-infected adults (study AI454-152).217 A 3-drug PI-based regimen of didanosine (400 mg once daily given as delayed-release capsules), stavudine (40 mg twice daily), and nelfinavir (750 mg 3 times daily) was compared with a 3-drug PI-based regimen of zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and nelfinavir (750 mg 3 times daily).217 At baseline, patients had mean CD4+ T-cell counts of 411/mm3 (range 39-1105/mm3) and mean plasma HIV-1 RNA levels of 4.71 log10 copies/mL (range 2.8-5.9 log10 copies/mL).217 The decrease in plasma HIV-1 RNA levels was similar with both regimens through 48 weeks of therapy.217
Antiretroviral-experienced Adults and Adolescents
Although monotherapy or 2-drug regimens that include only NRTIs are no longer recommended for treatment of HIV infection,200 early studies evaluating safety and efficacy of didanosine in antiretroviral-experienced (previously treated) patients compared use of a 2-drug regimen of didanosine and zidovudine with didanosine or zidovudine monotherapy.167, 170, 177 One of these early studies was the Delta trial designed to evaluate the comparative efficacy of zidovudine monotherapy (200 mg every 8 hours) and 2-drug regimens of zidovudine (200 mg every 8 hours) and didanosine (200 mg every 12 hours) or zalcitabine (0.75 mg every 8 hours; no longer commercially available in the US) in HIV-infected adults with CD4+ T-cell counts less than 350/mm3.170 Analysis of data on disease progression in the subgroup of 1083 patients who had received at least 3 months of prior zidovudine therapy (Delta 2) indicated that, after a median follow-up of 30 months, a change to a regimen that included didanosine and zidovudine improved survival.170
Study ACTG 241 was designed to evaluate safety and efficacy of a 3-drug NNRTI-based regimen of zidovudine, didanosine, and nevirapine and to determine whether addition of the third antiretroviral agent increased efficacy of zidovudine and didanosine in previously treated HIV-infected adults.177 Study ACTG 241 included 398 HIV-infected adults who had received at least 6 months of NRTI therapy (zidovudine, didanosine, and/or zalcitabine used in multiple-drug regimens or as sequential monotherapy) and had baseline CD4+ T-cell counts of 350/mm3 or less.177 Patients were randomized to receive a 3-drug regimen of zidovudine (200 mg every 8 hours), didanosine (200 mg every 12 hours), and nevirapine (200 mg daily for 2 weeks, then 200 mg every 12 hours) or a 2-drug regimen of zidovudine and didanosine with placebo.177 After 48 weeks of therapy, mean absolute CD4+ T-cell counts were higher in patients receiving the 3-drug NNRTI-based regimen than in those receiving the 2-drug regimen.177
For initial treatment of HIV infection in pediatric patients who are antiretroviral-naive, the HHS Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children recommends a PI or NNRTI in conjunction with 2 NRTIs (dual NRTIs).201 These experts state that didanosine and zidovudine or didanosine and either lamivudine or emtricitabine are alternative (not preferred) dual NRTI options for use in PI- or NNRTI-based regimens for initial treatment in antiretroviral-naive children 2 weeks of age and older.201
The dual NRTI option of didanosine and stavudine is not recommended for use in initial treatment regimens in children because the regimen has been associated with a high incidence of toxicities (e.g., neurotoxicity, pancreatitis, hyperlactatemia and lactic acidosis, lipodystrophy) compared with the dual NRTI option of zidovudine and lamivudine.201
The dual NRTI option of didanosine and abacavir is not recommended for use in initial antiretroviral regimens in antiretroviral-naive pediatric patients because of insufficient data.201
The dual NRTI option of didanosine and tenofovir DF is not recommended for use in initial antiretroviral regimens in antiretroviral-naive pediatric patients because of insufficient data and a high rate of virologic failure.201
A triple NRTI regimen of tenofovir DF, didanosine, and either lamivudine or emtricitabine should not be used at any time for treatment of HIV infection in pediatric patients because the regimen has been associated with a high rate of early virologic failure when used for initial treatment in antiretroviral-naive adults.201
For further information on treatment of HIV infection in pediatric patients, see Guidelines for Use of Antiretroviral Agents: Antiretroviral Therapy in Pediatric Patients, in the Antiretroviral Agents General Statement 8:18.08.
Although monotherapy or 2-drug regimens that include only NRTIs are no longer recommended for treatment of HIV infection,201 such regimens were used in early studies evaluating safety and efficacy of didanosine in pediatric patients, including several dose-ranging phase 1 or 2 studies and a phase 3 trial that included HIV-infected children 3 months to 18 years of age who were antiretroviral-naive (had not previously received antiretroviral therapy) or had previously received zidovudine monotherapy.1, 45, 173, 176, 188, 217 Study ACTG 152 was a randomized, double-blind controlled trial that compared zidovudine monotherapy (180 mg/m2 every 6 hours), didanosine monotherapy (120 mg/m2 every 12 hours), or a 2-drug regimen of zidovudine (120 mg/m2 every 6 hours) and didanosine (90 mg/m2 every 12 hours) in 831 HIV-infected children 3 months to 18 years of age (54% were younger than 30 months of age) who had only limited (less than 6 weeks) or no prior antiretroviral therapy.1, 188, 217 Most children (90%) had acquired HIV perinatally and were antiretroviral-naive (92%) prior to administration of the study drugs.188 Primary end point of the study was time to death or HIV progression; disease progression was defined as 2 or more new opportunistic infections, development of cancer, growth failure, or 2 or more CNS abnormalities (neurologic deterioration, decline in neurocognitive test scores, or brain-growth failure).188 Interim analysis (median follow-up 23 months) revealed that disease progression or death and adverse effects were significantly greater in children receiving zidovudine monotherapy than in those receiving the other regimens, and the zidovudine monotherapy treatment arm was discontinued.188 Results of study ACTG 152 indicated that didanosine monotherapy or a 2-drug regimen of didanosine and zidovudine was associated with lower rates of HIV progression or death compared with zidovudine monotherapy.1, 188, 217
Reconstitution and Administration
Didanosine is administered orally as delayed-release capsules containing enteric-coated pellets of the drug217 or as a buffered oral solution (i.e., pediatric oral solution admixed with antacid).1 The drug also has been given IV,36, 37, 38, 39, 41, 44, 45, 47, 61, 63 but a parenteral dosage form is not commercially available in the US.1
Because presence of food in the GI tract decreases the rate and extent of absorption of oral didanosine,1, 62 the drug should be administered without food on an empty stomach.1 Experts generally recommend that didanosine be administered 30 minutes before or 2 hours after a meal;200, 201 however, to improve adherence when used in children, some clinicians suggest that the drug can be administered without regard to meals.201
Delayed-release capsules containing enteric-coated pellets of didanosine should be administered without food.217 The capsules should be swallowed whole and should not be opened, crushed, chewed, or dissolved.217 The delayed-release capsules are used in adults and also can be used in children weighing at least 20 kg who can swallow capsules.217
The delayed-release capsules should only be administered in a once-daily regimen; data regarding more frequent dosing of this preparation are not available to date.217
Didanosine pediatric oral solution admixed with antacid should be administered at least 30 minutes before or 2 hours after a meal.1 The pediatric oral solution generally is used in children, but may be used in adults.1
In pediatric patients, didanosine pediatric oral solution admixed with antacid is administered in a twice-daily regimen.1, 201 If the pediatric oral solution admixed with antacid is used in adults and adolescents, a twice-daily regimen is preferred;1, 200 however, a once-daily regimen can be considered if needed.1
Didanosine pediatric powder for oral solution should be reconstituted and admixed with an antacid at the time of dispensing.1 The pediatric powder for oral solution should be reconstituted by adding 100 or 200 mL of water to the bottle labeled as containing 2 or 4 g of didanosine, respectively, to provide a solution containing 20 mg of the drug per mL.1 Immediately after reconstitution, the 20-mg/mL solution should be mixed with an equal amount of Mylanta® Maximum Strength oral suspension to provide a final admixture containing 10 mg of didanosine per mL.1 This final admixture should be shaken thoroughly prior to removing each dose.1
Dosage of didanosine in adults is based on weight of the patient; dosage in children is based on body surface area or weight.1, 217
For treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults, the usual dosage of didanosine given as delayed-release capsules containing enteric-coated pellets of the drug is 400 mg once daily for those weighing 60 kg or more and 250 mg once daily for those weighing 25 kg to less than 60 kg.217
If didanosine pediatric oral solution admixed with antacid is used for treatment of HIV infection in adults, the usual dosage is 200 mg twice daily for those weighing 60 kg or more or 125 mg twice daily for those weighing less than 60 kg.1 Alternatively, in adults whose management requires once-daily dosing of didanosine, the pediatric oral solution admixed with antacid can be given in a dosage of 400 mg once daily in those weighing 60 kg or more or 250 mg once daily in those weighing less than 60 kg.1
If didanosine delayed-release capsules or didanosine pediatric oral solution is used in conjunction with tenofovir disoproxil fumarate (tenofovir DF) (see Uses: Treatment of HIV Infection), the recommended dosage of didanosine in adults and adolescents is 250 mg once daily for those weighing 60 kg or more with creatinine clearances of 60 mL/minute or greater or 200 mg once daily for those weighing less than 60 kg with creatinine clearances of 60 mL/minute or greater.1, 217 If didanosine delayed-release capsules are used, didanosine and tenofovir DF may be taken at the same time with a light meal (less than 400 kcal, 20% fat) or in the fasted state.217 If didanosine is given as the pediatric oral solution, didanosine and tenofovir DF may be administered together in the fasted state; alternatively, tenofovir DF may be administered with food and the didanosine pediatric oral solution administered on an empty stomach (i.e., at least 30 minutes before or 2 hours after a meal).1 (See Tenofovir under Anti-infective Agents: HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors [NRTIs], in Drug Interactions.)
When didanosine pediatric oral solution admixed with antacid is used for treatment of HIV infection, the usual dosage in pediatric patients 2 weeks through 8 months of age is 100 mg/m2 twice daily and the usual dosage in pediatric patients older than 8 months of age is 120 mg/m2 twice daily.1 Based on pharmacokinetic considerations, some experts recommend that neonates and infants 2 weeks to less than 3 months of age receive a dosage of 50 mg/m2 every 12 hours.201 The manufacturer states that dosage recommendations for neonates younger than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in this age group are too variable to determine an appropriate dosage.1 Data are not available regarding use of once-daily dosing of didanosine pediatric oral solution in pediatric patients.1
When the delayed-release capsules are used for treatment of HIV infection in children and adolescents weighing 20 kg or more who can swallow capsules, those weighing 20 kg to less than 25 kg should receive a dosage of 200 mg once daily, those weighing 25 kg to less than 60 kg should receive 250 mg once daily, and those weighing 60 kg or more should receive 400 mg once daily.201, 217
Dosage in Renal and Hepatic Impairment
Modification of the usual dosage of didanosine is not necessary in patients with creatinine clearances of 60 mL/minute or greater.1
Creatinine Clearance (mL/minute) | Weighing less than 60 kg | Weighing 60 kg or more |
|---|---|---|
≥60 | 250 mg once daily | 400 mg once daily |
30-59 | 125 mg once daily | 200 mg once daily |
10-29 | 125 mg once daily | 125 mg once daily |
<10 | Not recommended; use alternative didanosine formulation | 125 mg once daily |
Hemodialysis or CAPD patients | Not recommended; use alternative didanosine formulation | 125 mg once daily; supplemental doses unnecessary after hemodialysis |
Creatinine Clearance (mL/minute) | Weighing less than 60 kg | Weighing 60 kg or more |
|---|---|---|
≥60 | 125 mg twice daily or 250 mg once daily | 200 mg twice daily or 400 mg once daily |
30-59 | 150 mg once daily or 75 mg twice daily | 200 mg once daily or 100 mg twice daily |
10-29 | 100 mg once daily | 150 mg once daily |
<10 | 75 mg once daily | 100 mg once daily |
Hemodialysis or CAPD patients | 75 mg once daily; supplemental doses unnecessary after hemodialysis | 100 mg once daily; supplemental doses unnecessary after hemodialysis |
The appropriate dosage of didanosine when given with tenofovir DF has not been established for patients with creatinine clearances less than 60 mL/minute.1, 217
The pharmacokinetics of didanosine may be altered in pediatric patients with impaired renal function.1, 217 Although data are insufficient to date to make specific dosage recommendations for pediatric patients with impaired renal function, the manufacturer states that dosage reduction should be considered.1, 217
Dosage adjustment of didanosine is not needed in patients with hepatic impairment.1, 217
The major toxicities of didanosine are potentially fatal pancreatitis, lactic acidosis and severe hepatomegaly with steatosis, peripheral neuropathy, and retinal changes and optic neuritis.1, 29, 34, 36, 37, 38, 39, 41, 44, 45, 47, 51, 111 The drug generally appears to be well tolerated in adults when oral dosages of 10 mg/kg or lower are given daily for 6-38 months or longer.29, 34, 36, 39, 44, 47, 51, 68, 82
Because many patients with human immunodeficiency virus (HIV) infection have serious underlying disease with multiple baseline symptomatology and clinical abnormalities and because many adverse effects that have been reported in patients receiving didanosine also occur in HIV-infected patients not receiving the drug, the causal relationship between didanosine and these adverse effects may not be clear.39, 41, 51, 66, 68 Didanosine (unlike zidovudine) does not appear to be associated with substantial myelosuppression.2, 23, 29, 31, 36, 37, 40, 47, 51, 64, 68
Pancreatitis, which has been fatal in some cases, is one of the most serious adverse effects reported in patients receiving didanosine.1, 29, 34, 36, 39, 41, 44, 47, 49, 69, 145 The frequency of pancreatitis is dose-related.1 In phase 3 studies, pancreatitis was reported in 1-7% of patients receiving the usually recommended dosage of didanosine and in 1-10% of patients receiving higher dosage of the drug.1 In studies in pediatric patients, pancreatitis has been reported in 3% of those receiving a dosage lower than 300 mg/m2 daily and in 13% of those receiving higher dosages.1 Fatal and nonfatal pancreatitis has been reported in patients receiving didanosine alone or in conjunction with other antiretrovirals in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression.1 In recent clinical studies evaluating regimens that included didanosine in conjunction with stavudine and either nelfinavir or indinavir, pancreatitis was reported in up to 1% of patients.1 Patients receiving didanosine in conjunction with stavudine may be at increased risk of pancreatitis;1, 217 there have been at least 2 fatalities related to pancreatitis228 in patients receiving didanosine concomitantly with stavudine, indinavir, and hydroxyurea.152, 228 There also has been at least one death related to pancreatitis in a patient receiving didanosine in conjunction with stavudine and nelfinavir.1
In early clinical studies evaluating didanosine, increased serum amylase concentrations (at least 1.4 times the upper limit of normal) were reported in 15-17% of patients receiving didanosine monotherapy.1 In more recent clinical studies evaluating regimens that included didanosine in conjunction with stavudine and either nelfinavir or indinavir, up to 31% of patients had increased serum amylase concentrations and 17-26% of patients had increased serum lipase concentrations.1 In these studies, up to 7 or 8% of patients receiving didanosine had serum lipase or amylase concentrations, respectively, that were increased to more than 2 times the upper limit of normal.1
Manifestations of pancreatitis generally become evident during the first 1-6 months of didanosine therapy29, 36, 47, 69, 145 and vary from mildly symptomatic hyperamylasemia to severe, hemorrhagic pancreatitis.29, 36, 39, 69 In most patients, pancreatitis begins with symptoms of vague abdominal pain, nausea, and vomiting.39, 44 Although the clinical importance is unclear, increases in serum triglyceride29, 34, 38, 44 or glucose concentrations69 have been reported in some patients prior to the onset of symptoms of pancreatitis.29, 44, 69 Pancreatitis generally resolves within 1-3 weeks following discontinuance of didanosine.29, 36, 38, 44 While manifestations of pancreatitis may not recur when didanosine is reinitiated at a lower dosage,29, 34, 36, 44 the manufacturer states that didanosine should be discontinued in patients with signs or symptoms of pancreatitis and should not be reinitiated in those with confirmed pancreatitis.1 (See Cautions: Precautions and Contraindications.)
The causal role of didanosine in the development of pancreatitis during therapy with the drug may be difficult to evaluate in some patients39, 41 since a substantial proportion of patients with HIV infection may exhibit pancreatic abnormalities in association with the infection.29, 82 In addition, several opportunistic infections that occur in patients with HIV infection also may result in adverse pancreatic effects (e.g., infections caused by cytomegalovirus, Cryptococcus , Toxoplasma , mycobacteria)29, 34, 39 and some other drugs frequently used in patients with HIV infection also have been associated with pancreatitis (e.g., co-trimoxazole, pentamidine).29, 34, 36, 41 A prior history of pancreatitis and/or use of high daily dosages of didanosine and resultant high steady-state plasma concentrations of the drug appear to be related to an increased risk of this adverse effect.1, 29, 34, 145 Other factors that may increase the risk of pancreatitis during didanosine therapy include a history of substantial alcohol ingestion1, 29, 34, 36, 39 or use of usual didanosine dosage in patients with impaired renal and/or hepatic function.1 (See Cautions: Precautions and Contraindications.)
Hepatic Effects and Lactic Acidosis
Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving didanosine and also have been reported in patients receiving other HIV nucleoside reverse transcriptase inhibitors (NRTIs).1, 65, 82, 129 Most reported cases have involved women; obesity and long-term therapy with NRTIs also may be risk factors.1 Fatal lactic acidosis has been reported in pregnant women who received an antiretroviral regimen that included didanosine and stavudine.1 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.) For further information on lactic acidosis and hepatomegaly in patients receiving NRTIs, see Cautions: Hepatic Effects and Lactic Acidosis in Zidovudine 8:18.08.20.
Safety and efficacy of didanosine have not been established in HIV-infected patients with substantial underlying liver disease.1, 217 Liver function abnormalities, including severe and potentially fatal hepatic events, have occurred in patients with preexisting hepatic dysfunction (e.g., chronic active hepatitis) receiving multiple-drug antiretroviral regimens.1, 217 Hepatotoxicity and hepatic failure resulting in death have been reported in HIV-infected patients receiving hydroxyurea in conjunction with other antiretroviral agents; fatal hepatic events occurred more often in patients receiving didanosine, stavudine, and hydroxyurea than in those receiving other regimens.1, 217
Increased serum concentrations of AST (SGOT),1, 37, 38, 44 ALT (SGPT),1, 37, 38, 44 alkaline phosphatase,1, 38γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP), and bilirubin1 have been reported in patients receiving didanosine.1 In early clinical studies evaluating didanosine, increased serum concentrations of AST, ALT, or alkaline phosphatase (exceeding 5 times the upper limit of normal) were reported in 1-9% of patients receiving didanosine monotherapy.1 In more recent clinical studies, the overall incidence of increased serum concentrations of AST, ALT, GGT, or bilirubin was 7-68% in patients receiving didanosine in conjunction with stavudine and either nelfinavir or indinavir.1 In these studies, 3-8% of patients receiving didanosine had serum AST, ALT, or GGT concentrations that were increased to more than 5 times the upper limit of normal and up to 16% of patients had serum bilirubin concentrations exceeding 2.6 times the upper limit of normal.1
Noncirrhotic Portal Hypertension
Noncirrhotic portal hypertension has been reported during postmarketing surveillance in patients receiving didanosine,1, 217, 268, 271 and the US Food and Drug Administration (FDA) has alerted healthcare professionals about this rare, but serious, adverse effect.268
As of April 2010, FDA had received reports of 42 postmarketing cases of noncirrhotic portal hypertension in patients 10-66 years of age receiving didanosine.268 Medical interventions included banding or ligation of esophageal varices (8 patients), transjugular intrahepatic portosystemic shunting (3 patients), and liver transplantation (3 patients).268 There were 4 deaths (2 deaths secondary to hemorrhage from esophageal varices, 1 death due to progressive liver failure, 1 death due to a combination of multiorgan failure, cerebral hemorrhage, sepsis, and lactic acidosis).268
In reported cases, the onset of signs and symptoms of noncirrhotic portal hypertension ranged from months to years following initiation of didanosine therapy;1, 217, 268, 271 common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.1, 217, 268, 271 Definitive cases of noncirrhotic portal hypertension were confirmed by liver biopsy and patients had no evidence of viral hepatitis or other alternative etiologies for such a diagnosis.1, 217, 268
Although a causal relationship is difficult to determine, after excluding other causes of portal hypertension (e.g., alcohol-related cirrhosis, hepatitis C virus [HCV] infection), the FDA concluded that there is an association between use of didanosine and development of noncirrhotic portal hypertension.268 However, the FDA states that the clinical benefits of the drug for some patients continue to outweigh potential risks and that the decision to use didanosine must be made on an individual basis.268
Patients receiving didanosine should be monitored for early signs of portal hypertension (e.g., thrombocytopenia, splenomegaly) and esophageal varices;1, 217, 268, 271 use of appropriate laboratory tests, including liver enzymes, serum bilirubin, albumin, complete blood count (CBC), international normalized ratio (INR), and ultrasonography, should be considered.1, 217, 271 Didanosine should be discontinued in patients with evidence of noncirrhotic portal hypertension.1, 217, 271 (See Cautions: Precautions and Contraindications.)
Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine.1 Peripheral neuropathy has been reported most frequently in patients with advanced HIV, patients with a history of neuropathy, or patients being treated with other neurotoxic drugs, including stavudine.1
In early clinical studies evaluating didanosine, peripheral neurologic symptoms or neuropathy were reported in 17-20% of patients receiving didanosine monotherapy.1 In more recent clinical studies, peripheral neurologic symptoms or neuropathy were reported in 21-26% of patients receiving didanosine in conjunction with stavudine and either nelfinavir or indinavir.1
Didanosine-associated peripheral neuropathy generally consists of tingling, burning, or aching in the hands or lower extremities, particularly in the soles of the feet, with intermittent, shooting “electrical” pain in the legs that generally lasts 1 hour or longer.36, 37, 38, 39, 41, 44, 82, 119 Symptoms may be more severe at night and, in more severe cases, may interfere with sleep and routine daily activities.37, 38, 44, 119 The frequency of peripheral neuropathy appears to be dose-related1 and the onset appears to be related to the daily didanosine dosage as well as the total cumulative dose of the drug.38, 39, 41, 44, 47 Peripheral neuropathy rarely occurs until after 2-6 months of didanosine therapy.41, 44, 47
The pathogenesis of the neuropathy is unknown, but clinical manifestations of the syndrome are similar to, but usually less severe than, those reported with zalcitabine (no longer commercially available in the US).29, 44 It has been suggested that the neuropathy may be related to inhibition of mitochondrial DNA synthesis.111 Nerve conduction studies have shown only minimal changes; most patients with didanosine-associated peripheral neuropathy have no measurable abnormalities in nerve conduction.38, 39, 41, 44 Generally, if didanosine is discontinued when the pain or tingling in the feet becomes mild to moderate in intensity, peripheral neuropathy subsides over the next 2-12 weeks;29, 36, 37, 38, 39, 41, 44 however, symptoms of the neuropathy may progress or worsen before they begin to improve following discontinuance of the drug.119 In some patients, symptoms may persist for several months.44, 47, 119
Retinal changes (including retinal depigmentation) and optic neuritis have been reported in adult or pediatric patients receiving didanosine.1, 82 Diplopia,66 dry eyes,1 optic atrophy,66 and blindness66 have been reported rarely in patients receiving didanosine. Although a causal relationship was not definitely established, bilateral optic retrobulbar neuritis with blurred vision and decreased visual acuity occurred in one patient who received didanosine in a dosage of 8 mg/kg daily for 6 weeks.66
Immune Reconstitution Syndrome
During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); this may necessitate further evaluation and treatment.1, 217
Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have been reported to occur in the setting of immune reconstitution; the time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1, 217
Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral agents, including didanosine.1, 217 The mechanism and long-term consequences of fat redistribution are unknown; a causal relationship has not been established.1, 217
Diarrhea, nausea, vomiting, and abdominal pain have been reported in patients receiving didanosine.1 In early clinical studies evaluating didanosine, diarrhea was reported in 19-28% and abdominal pain was reported in 7-13% of patients receiving didanosine monotherapy.1 In more recent clinical studies, diarrhea was reported in 45-70%, nausea in 28-53%, and vomiting in 12-30% of patients receiving didanosine in conjunction with stavudine and either nelfinavir or indinavir.1
Other GI effects reported in patients receiving didanosine include anorexia,1 constipation,36 dyspepsia,1 dry mouth,1 and flatulence.1 Xerostomia has been reported in some patients who had increased serum amylase concentrations; increased amylase concentrations in these patients were attributed to elevated levels of salivary rather than pancreatic amylase.29, 68
Asymptomatic increases in serum uric acid concentrations occur in some patients receiving didanosine.3, 29, 36, 37, 38, 39, 41, 44, 47, 68 In early clinical studies evaluating didanosine, increased serum uric acid concentrations (exceeding 12 mg/dL) were reported in 2-3% of patients receiving didanosine monotherapy.1 Increased serum uric acid concentrations have been reported most frequently in patients receiving high dosages of didanosine82 and presumably result from metabolism of didanosine to uric acid via purine metabolic pathways.3, 29, 36, 38, 39, 68
Dermatologic and Sensitivity Reactions
Rash1, 36, 47, 68 and pruritus1 have been reported in patients receiving didanosine. Transient morbilliform rash, as well as mild erythematous macular eruptions, have been reported.37, 68 In early clinical studies evaluating didanosine, rash or pruritus was reported in 7-9% of patients receiving didanosine monotherapy.1 In more recent clinical studies, rash was reported in 13-30% in patients receiving didanosine in conjunction with stavudine and either nelfinavir or indinavir.1 Alopecia also has been reported with didanosine.1
Anaphylactoid reaction has been reported rarely in patients receiving didanosine.1
Unlike zidovudine, didanosine does not appear to be myelosuppressive.2, 3, 23, 29, 31, 36, 47, 68 However, anemia, leukopenia, and thrombocytopenia have been reported in some patients receiving didanosine1, 37, 44, 83
Myalgia (with or without increases in creatine phosphokinase), rhabdomyolysis (including acute renal failure and hemodialysis), arthralgia, and myopathy have been reported in patients receiving didanosine.1
In mice and rats, but not dogs, dose-limiting skeletal muscle toxicity has occurred following long-term (i.e., longer than 3 months) didanosine therapy using dosages approximately 1.2-12 times the usual human dosage.1 The relationship between this adverse effect in animals and the potential of didanosine to cause myopathy in humans is unclear.1
Findings from a large observational study suggest that ongoing or recent use of didanosine (within the preceding 6 months) is associated with an increased risk for myocardial infarction.267
Other adverse nervous system effects reported in patients receiving didanosine include anxiety,68 headache,1, 3, 29, 39, 68 insomnia,3, 29, 39, 68 irritability,39 restlessness,3, 39 and seizures.39, 41, 68 In clinical studies evaluating didanosine used in conjunction with other antiretroviral agents (stavudine and either nelfinavir or indinavir), the overall incidence of headache was 21-46% in those receiving didanosine.1
Other adverse effects that have been reported with didanosine include asthenia,1, 217 cardiomyopathy,44 chills,1 fever,1 hypokalemia,67 pain,1 parotid gland enlargement,1 and sialadenitis.1 In addition, diabetes mellitus,1 hypoglycemia,1 and hyperglycemia1 have been reported.
Precautions and Contraindications
Didanosine is contraindicated in patients receiving concomitant allopurinol or ribavirin therapy.1, 217 (See Drug Interactions: Allopurinol and see Ribavirin under Drug Interactions: Anti-infective Agents.)
Patients should be informed about the clinical benefits and potential risks associated with didanosine therapy, including the risk of pancreatitis, peripheral neuropathy, lactic acidosis and severe hepatomegaly, noncirrhotic portal hypertension, hepatotoxicity (especially in those with preexisting hepatic dysfunction), retinal changes and optic neuritis, and adipogenic effects.1, 217, 268
Because fatal and nonfatal pancreatitis has been reported in patients receiving didanosine alone or in conjunction with other antiretroviral agents,1, 217 the possibility of pancreatitis should be considered whenever a patient receiving the drug develops abdominal pain and nausea, vomiting, or elevated biochemical markers (e.g., increased serum amylase or lipase concentrations).41, 68 The manufacturer states that didanosine should be suspended in patients with clinical and laboratory signs suggestive of pancreatitis and the patient carefully evaluated; the drug should be discontinued in those with confirmed pancreatitis.1 Didanosine should be used with extreme caution and with close monitoring and only if clearly needed in patients with factors known to increase the risk of pancreatitis, including advanced HIV infection, renal impairment, substantial alcohol ingestion, or elevated serum triglycerides.1, 29, 34, 82, 145 In addition, if treatment with other drugs known to be associated with pancreatic toxicity (e.g., pentamidine) is considered necessary in a patient receiving didanosine, the manufacturer of didanosine recommends that didanosine therapy be discontinued.1, 29, 34, 82 (See Drug Interactions: Drugs Associated with Pancreatitis.)
Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported rarely in patients receiving didanosine and also have been reported in patients receiving other NRTIs.1 Most reported cases have involved women; obesity and long-term therapy with NRTIs also may be risk factors.1 Didanosine should be used with caution in patient with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors.1 Didanosine therapy should be discontinued in any patient with clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations).1
Because noncirrhotic portal hypertension has been reported during postmarketing surveillance in patients receiving didanosine, including some cases resulting in liver transplantation or death (see Cautions: Noncirrhotic Portal Hypertension), 1, 217, 268, 271 patients receiving the drug should be monitored for early signs of portal hypertension (e.g., thrombocytopenia, splenomegaly) and esophageal varices1, 217, 268, 271 and appropriate laboratory tests, including liver enzymes, serum bilirubin, albumin, CBC, INR, and ultrasonography, should be considered.1, 217, 268, 271 Didanosine should be discontinued in patients with evidence of noncirrhotic portal hypertension.1, 217, 271
Hepatic toxicity has been reported in patients with underlying hepatic dysfunction receiving multiple-drug antiretroviral regimens; if worsening of liver disease occurs in these patients, temporary interruption or discontinuance of therapy should be considered.1, 217 Because an increased risk of potentially fatal hepatotoxicity may occur in patients receiving stavudine in conjunction with didanosine and hydroxyurea, concomitant use of didanosine, stavudine, and hydroxyurea should be avoided.1, 217
Because retinal changes and optic neuritis have been reported in adult and pediatric patients receiving didanosine, the manufacturer recommends that periodic retinal examinations be considered for patients receiving the drug.1 (See Cautions: Pediatric Precautions.)
Patients should be advised that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during didanosine therapy and usually occurs in patients with advanced HIV infection or a history of peripheral neuropathy.1, 217 If peripheral neuropathy occurs in a patient receiving didanosine, discontinuance of the drug should be considered.1, 217
Hyperuricemia has been reported in patients receiving didanosine.1, 217 The manufacturer of didanosine states that suspension of didanosine therapy may be needed if clinical measures to reduce serum uric acid concentrations are not effective.217
Patients receiving didanosine should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, and that the cause and long-term consequences of these adipogenic effects are not known.1, 217 (See Cautions: Adipogenic Effects.)
Didanosine in conjunction with other antiretroviral agents is not a cure for HIV infection, and patients receiving the drugs may continue to develop opportunistic infections and other complications associated with HIV disease.1, 217 Patients should be informed of the critical nature of compliance with HIV therapy and the importance of remaining under the care of a clinician.1, 217 Patients should be advised to take their antiretroviral regimen exactly as prescribed and to not alter or discontinue the regimen without consulting a clinician.1, 217
Patients should be advised that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Patients should continue to practice safer sex (e.g., use latex or polyurethane condoms to minimize sexual contact with body fluids), never share personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reuse or share needles.1, 200, 217
Patients with renal impairment (i.e., creatinine clearance less than 60 mL/minute) may be at increased risk of adverse effects during didanosine therapy because of decreased clearance or altered metabolism of the drug; a decrease in dosage is recommended in these patients.1, 111, 122 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.).
Safety and efficacy of didanosine pediatric oral solution admixed with antacid in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies in adult and pediatric patients.1 Use of delayed-release capsules containing enteric-coated pellets of didanosine in pediatric patients who weigh at least 20 kg is supported by pharmacokinetic studies.217
Didanosine generally is well tolerated in pediatric patients.35, 45, 131, 173, 174 Adverse effects reported in pediatric patients 2 weeks through 18 years of age are similar to those in adults and include pancreatitis, peripheral neuropathy, ophthalmic effects, GI effects, and hepatic effects.1, 35, 45, 131, 237
Pancreatitis has occurred in 3% of children (2 of 60) receiving didanosine in dosages less than 300 mg/m2 daily and in 13% of those (5 of 38) receiving higher dosages.1 In one study, pancreatitis was reported in less than 1% of pediatric patients receiving didanosine in a dosage of 90 mg/m2 every 12 hours in conjunction with zidovudine and was not reported in those receiving 120 mg/m2 every 12 hours without zidovudine.1 Didanosine should be suspended in pediatric patients with signs or symptoms of pancreatitis and should not be reinitiated if pancreatitis is confirmed.1
Although neuropathy has been reported only rarely in children receiving didanosine, signs and symptoms of neuropathy may be difficult to assess in children, and physicians should monitor children closely for this adverse effect.1
Retinal changes and optic neuritis have been reported in a few children receiving didanosine.1 The manufacturer recommends that all children receiving the drug receive dilated retinal examinations every 6 months and whenever a change in vision occurs.1, 82
Adverse hepatic effects, including increased serum concentrations of alkaline phosphatase and hepatic aminotransferases, have been reported rarely in children receiving didanosine.131 Although a definite causal relationship was not established, at least 2 fatalities associated with acute, fulminant hepatocellular failure have been reported in children receiving didanosine in a dosage of 120 or 270 mg/mm2 daily.131 In these cases, liver biopsy showed massive, diffuse hepatocyte necrosis with intranuclear inclusions.131
Clinical studies of didanosine have not included sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients.1, 217 In an expanded access program for patients with advanced HIV infection, there was a higher incidence of pancreatitis in adults 65 years of age or older (10%) than in younger adults (5%).1, 217 Didanosine is substantially eliminated by the kidneys, and the risk of toxic reactions may be greater in patients with impaired renal function.1, 217 Because of the greater frequency of decreased renal function observed in geriatric patients, dosage of didanosine should be carefully selected in these patients and renal function monitored and dosage adjustment made when indicated.1, 217 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
Mutagenicity and Carcinogenicity
Didanosine was not mutagenic in the Ames microbial ( Salmonella ) mutagen test or in vitro in a mutagenicity assay using Escherichia coli .1 However, in a mammalian mutagenicity assay using L5178Y/TK± mouse lymphoma cells, didanosine was weakly mutagenic at concentrations of 2000 mcg/mL or greater in the presence or absence of metabolic activation.1 At concentrations of 500 mcg/mL or greater, didanosine increased the frequency of cells bearing chromosomal aberrations in an in vitro cytogenic study in cultured human peripheral lymphocytes and produced chromosomal aberrations in Chinese hamster lung cells after 48 hours of exposure;1 no important elevation in the frequency of cells with chromosomal aberrations was evident when didanosine concentrations of 250 mcg/mL or less were used.1 In a BALB/c 3T3 in vitro transformation assay, didanosine was mutagenic at concentrations of 3000 mcg/mL or greater.1 There was no evidence of genotoxicity in rats or mice.1 Results of these studies suggest that didanosine is not mutagenic at biologically and pharmacologically relevant doses and that genotoxic effects occurring at higher doses are similar to those seen with natural nucleosides.1
In lifetime carcinogenicity studies conducted for 22 months in mice and 24 months in rats, didanosine induced no significant increase in neoplastic lesions at maximally tolerated dosages.1 Mice received initial dosages of 120, 800, and 1200 mg/kg daily; after 8 months, dosages were lowered to 120, 210, and 210 mg/kg daily for females and 120, 300, and 600 mg/kg daily for males.1 The 2 higher dosages in the female mice and the high dosage in male mice exceeded the maximally tolerated dosages in these animals.1 The low dosage in females represented 0.68-fold maximum human exposure and the intermediate dosage in males represented 1.7-fold maximum human exposure.1 Rats received initial dosages of 100, 250, and 1000 mg/kg daily; after 18 months, the high dosage was decreased to 500 mg/kg daily; the upper dosages represented threefold maximum human exposure.1
Pregnancy, Fertility, and Lactation
Reproduction studies in rats or rabbits using didanosine dosages up to 12 or 14.2 times the estimated human exposure (based on plasma concentrations), respectively, have not revealed evidence of harm to the fetus.1
There are no adequate and controlled studies to date using didanosine in pregnant women, and the drug should be used during pregnancy only if the potential benefits justify the potential risks.1
The US Department of Health and Human Services (HHS) Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission states that didanosine is not recommended for initial treatment regimens in antiretroviral-naive pregnant women because of toxicity.202 If didanosine is used during pregnancy, these experts state that it should not be used in a dual NRTI option that includes stavudine.202 (See HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors [NRTIs] under Drug Interactions: Antiretroviral Agents.)
Fatal lactic acidosis has been reported in pregnant women who received antiretroviral regimens that included both didanosine and stavudine.1, 202, 245 In 3 reported cases of fatal lactic acidosis, the women were either pregnant or postpartum and had received both didanosine and stavudine throughout gestation; in 2 of these cases, pancreatitis also occurred.245 The infants of 2 of these pregnancy-related cases of fatal lactic acidosis also died, one in utero at 32 weeks of gestation and one after emergency caesarian section at 36 weeks of gestation.245 Several cases of nonfatal pancreatitis, with and without lactic acidosis or hepatic failure, also have been reported in pregnant women receiving regimens that included both didanosine and stavudine.245 Women receiving NRTIs appear to be at increased risk of lactic acidosis and severe hepatomegaly with steatosis, and it is unclear whether pregnancy potentiates this risk.1, 245 The dual NRTI option of didanosine and stavudine should be used with caution in pregnant women and only if there are no other treatment options and potential benefits outweigh risks.1, 217 In addition, clinicians caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis and hepatitis steatosis syndrome.1
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including didanosine, an antiretroviral pregnancy registry was established; clinicians are encouraged to contact the registry at 800-258-4263 or [Web] to report cases of prenatal exposure to antiretroviral agents.1, 202, 217 Among first trimester exposures to didanosine reported to the registry, the prevalence of birth defects was 4.8%; the birth defect rate among pregnant women in the US reference population is 2.7%.202
There was no evidence of impaired fertility in reproduction studies in rats or rabbits using didanosine dosages up to 12 or 14.2 times, respectively, the estimated human exposure (based on plasma concentrations).1
It is not known whether didanosine is distributed into human milk;1, 202 the drug and/or its metabolites are distributed into milk in lactating rats.1
At dosages approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation.1 These rats showed reduced food intake and body weight gains, but the physical and functional development of the offspring was not impaired and there were no major changes in the F2 generation.1
The US Centers for Disease Control and Prevention (CDC) and other experts recommend that HIV-infected women (including those receiving antiretroviral therapy) not breast-feed infants.1, 202 Because of the potential for HIV transmission and the potential for serious adverse effects from didanosine in infants if the drug were distributed into milk, women should be instructed not to breast-feed while they are receiving didanosine.1
Drug interaction studies have been performed using buffered didanosine preparations (chewable/dispersible, buffered tablets [no longer commercially available in the US], pediatric oral solution admixed with antacid) or delayed-release capsules containing enteric-coated pellets of the drug.217 Although there are a few exceptions (e.g., ciprofloxacin, indinavir, ketoconazole),48, 217 results of drug interaction studies that used buffered didanosine preparations generally apply to the delayed-release capsules of the drug.217
Drugs Associated with Pancreatitis
Didanosine should be used with extreme caution and only if clearly indicated (e.g., when other alternatives are not available) in patients receiving other drugs that have been associated with pancreatic toxicity (e.g., pentamidine, co-trimoxazole) since concomitant use of these drugs could increase the risk of pancreatitis.1, 36, 39 The manufacturer of didanosine suggests that the drug be discontinued in patients who require life-sustaining treatment with other drugs known to cause pancreatitis.1
Some patients who have developed pancreatitis during didanosine therapy also were receiving pentamidine by oral inhalation;36, 44 however, the potential for drug interactions in patients receiving these drugs concomitantly has not been fully evaluated.36, 44, 45 Some clinicians suggest that because parenteral pentamidine has a long elimination half-life, didanosine therapy should not be reinitiated until one week after parenteral pentamidine therapy has been completed.82
Patients receiving didanosine in conjunction with stavudine, with or without hydroxyurea, may be at increased risk of pancreatitis;1 there have been at least 2 fatalities related to pancreatitis228 in patients receiving didanosine concomitantly with stavudine, indinavir, and hydroxyurea.152, 228 (See Drug Interactions: Hydroxyurea.) There also has been at least one death related to pancreatitis in a patient receiving didanosine in conjunction with stavudine and nelfinavir.1
Drugs Associated with Neurotoxicity
Because of an increased risk of neuropathy, the manufacturer states that didanosine should be used with caution in patients receiving neurotoxic drugs.1, 217
In 2 patients with renal impairment, concomitant use of allopurinol (300 mg daily) and a single 200-mg dose of buffered didanosine resulted in a 232% increase in peak plasma didanosine concentrations and a 312% increase in the area under the concentration-time curve (AUC) of didanosine.1 In 14 healthy adults who received a 7-day regimen of allopurinol (300 mg daily) and a single 400-mg dose of buffered didanosine, peak plasma didanosine concentrations were increased 69% and the AUC of didanosine was increased 113%.1
Concomitant use of allopurinol and didanosine is contraindicated since increased didanosine concentrations may be result in increased didanosine-associated toxicity.1, 217
Concomitant use of an oral antacid increases the oral bioavailability of didanosine.1, 2, 3, 38, 39, 62 Because didanosine is rapidly degraded at acidic pH, concomitant use of an oral antacid increases gastric pH and prevents inactivation of the drug by acidic gastric secretions.40 This effect is used to therapeutic advantage to maximize GI absorption of didanosine.1 Commercially available unbuffered didanosine pediatric powder for oral solution is reconstituted with water and admixed with equal parts of an oral antacid prior to administration to enhance GI absorption of the drug.1 (See Dosage and Administration: Reconstitution and Administration.) Additional antacids should be used with caution in patients receiving buffered didanosine (pediatric oral solution admixed with antacid), adverse effects of the antacids may be potentiated since this preparation is admixed with an antacid prior to administration.1
Concurrent oral administration of itraconazole and buffered didanosine preparations has resulted in decreased serum concentrations of the antifungal agent.1, 132 In at least one patient with human immunodeficiency virus (HIV) infection who was receiving itraconazole for maintenance treatment of cryptococcal meningitis, initiation of didanosine therapy apparently resulted in relapse of the meningitis because of decreased oral absorption of itraconazole.132 Therefore, some clinicians suggest that concurrent administration of didanosine and itraconazole should be avoided.132 To ensure adequate absorption of the antifungal agent, the manufacturer of didanosine recommends that itraconazole be administered at least 2 hours prior to buffered didanosine (pediatric oral solution admixed with antacid).1
Because GI absorption of ketoconazole is facilitated at acidic pH, ketoconazole should be administered at least 2 hours prior to buffered didanosine (pediatric oral solution admixed with antacid) to ensure adequate absorption of the antifungal agent.1 In a study in 12 HIV-infected individuals, 4 days of concomitant therapy with buffered didanosine (375 mg every 12 hours) and ketoconazole (200 mg daily given 2 hours before a didanosine dose) did not affect the AUC of didanosine and decreased the AUC of ketoconazole by 14%.1 Results of a study in healthy individuals indicate that concomitant use of a single 200-mg dose of ketoconazole and a single 400-mg dose of didanosine given as delayed-release capsules does not affect the pharmacokinetics of the antifungal agent.48, 217
Concomitant use of rifabutin and buffered didanosine results in slightly increased didanosine concentrations.1 Multiple-dose drug interaction studies have demonstrated that the pharmacokinetic interaction between rifabutin and didanosine is not clinically important.238
HIV Entry and Fusion Inhibitors
There is no in vitro evidence of antagonistic antiretroviral effects between maraviroc and didanosine.224
HIV Integrase Inhibitors (INSTIs)
In vitro studies indicate that additive to synergistic antiretroviral effects can occur between raltegravir and didanosine.225
HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
In vitro studies using some nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., delavirdine, efavirenz, nevirapine) indicate that the antiretroviral effects of didanosine and these drugs may be additive or synergistic against HIV-1.212, 213, 215 There is no in vitro evidence of antagonistic antiretroviral effects between didanosine and etravirine214 or rilpivirine.226
Results of a study in HIV-infected individuals indicate that concomitant use of delavirdine (a single 400-mg dose) and didanosine (125 or 250 mg every 12 hours) results in a 32% decrease in the AUC of delavirdine if doses of the drugs are administered simultaneously or a 20% increase in the AUC of delavirdine if didanosine is administered 1 hour after delavirdine.1 If delavirdine is used concomitantly with buffered didanosine (pediatric oral solution admixed with antacid), delavirdine should be given at least 1 hour before or 1 hour after didanosine.1, 212
Concomitant use of etravirine and didanosine does not have a clinically important effect on the plasma concentrations or AUC of either drug.214 Dosage adjustments are not needed if the drugs are used concomitantly.214
Concomitant use of nevirapine and didanosine does not appear to affect the pharmacokinetics of either drug.215
Pharmacokinetic interactions were not observed when didanosine given as delayed release capsules was administered 2 hours before rilpivirine.226
Although dosage adjustments are not needed if rilpivirine and didanosine are used concomitantly, the drugs have conflicting administration instructions regarding food.226 If the drugs are used concomitantly, didanosine should be administered (without food) at least 2 hours before or 4 hours after rilpivirine (with food).226
HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Results of in vitro studies indicate that the antiretroviral effects of didanosine and some other NRTIs (e.g., zidovudine) are additive to synergistic against HIV-1.70, 221, 222 Although some in vitro studies indicate that the antiretroviral activities of didanosine and stavudine are additive or synergistic against HIV-1,162, 189, 220 antagonism also has been reported.162 There is no in vitro evidence of antagonistic antiretroviral effects between didanosine and tenofovir.221
Results of multiple-dose studies have demonstrated that there are no clinically important pharmacokinetic interactions between stavudine and didanosine.1 However, concomitant use of stavudine and didanosine (with or without hydroxyurea) is associated with an increased risk of pancreatitis, peripheral neuropathy, and lactic acidosis.1, 200, 217, 220 Fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with stavudine used in conjunction with didanosine and hydroxyurea.1, 152, 217, 220, 228 Concomitant use of didanosine, stavudine, and hydroxyurea should be avoided.1, 217 (See Drug Interactions: Hydroxyurea.)
Although the manufacturers state that the dual NRTI option of stavudine and didanosine should be used with caution and is recommended during pregnancy only if potential benefits clearly outweigh potential risks,1, 217, 220 experts state that stavudine and didanosine should not be used concomitantly at any time, including during pregnancy, because of a high incidence of toxicities.200, 202 (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
Depending on the specific didanosine dosage used, concomitant use of buffered didanosine (Videx®) or delayed-release didanosine capsules (Videx® EC) and tenofovir disoproxil fumarate (tenofovir DF) results in substantially increased didanosine plasma concentrations and AUC,1, 217, 221 but does not affect tenofovir pharmacokinetics.1, 217, 221 The mechanism of this interaction is unknown.221 Concomitant use of the drugs potentially could potentiate didanosine-associated adverse effects (e.g., pancreatitis, lactic acidosis, neuropathy);200, 217, 221 concomitant use also has been associated with early virologic failure, rapid selection of resistant mutants, and immunologic nonresponse or decline in CD4+ T-cell count.1, 200, 217
Concomitant use of didanosine (Videx® 250 or 400 mg once daily) and tenofovir DF (300 mg once daily given 1 hour after didanosine) results in a 28% increase in peak plasma concentrations and a 44% increase in the AUC of didanosine.1 In a study using didanosine delayed-release capsules (Videx® EC), peak plasma concentrations and AUC of didanosine were increased 48% when didanosine (single 400-mg dose) was given in the fasting state 2 hours before tenofovir DF (300 mg once daily with a light meal); when this didanosine dose was given simultaneously with tenofovir DF (300 mg) and a light meal, peak plasma concentration and AUC of didanosine were increased 64 and 60%, respectively.217
Some experts state that didanosine and tenofovir DF should not be used concomitantly at any time.200 (See Dual NRTI Options under Treatment of HIV Infection: Antiretroviral-naive Adults and Adolescents, in Uses.) The manufacturers state that a reduced didanosine dosage can be used concomitantly with usual tenofovir DF dosage (see Treatment of HIV Infection under Dosage: Adult Dosage, in Dosage and Administration);1, 217, 221 caution is advised and patients should be monitored closely for didanosine-associated toxicities (e.g., pancreatitis, symptomatic hyperlactatemia/lactic acidosis, peripheral neuropathy) and clinical response.1, 217, 221 If signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop, didanosine should be discontinued.1, 217, 221
Concomitant use of buffered didanosine (200 mg every 12 hours for 3 days) and oral zidovudine (200 mg every 8 hours for 3 days) in HIV-infected patients decreased the peak plasma concentration and AUC of zidovudine by 17 and 10%, respectively, but did not affect the peak plasma concentration or AUC of didanosine.217 Results of a study in HIV-infected pediatric patients 3 months of age or older indicate that concomitant use of oral zidovudine and oral didanosine does not affect the AUC of either drug.259
Didanosine and some HIV protease inhibitors (PIs) (e.g., amprenavir [commercially available as fosamprenavir], indinavir, nelfinavir, ritonavir, saquinavir, tipranavir) are additive or synergistic against HIV-1 in vitro.186, 205, 206, 208, 209, 210, 211 There is no in vitro evidence of antagonistic antiretroviral effects between didanosine and atazanavir203 or darunavir.204
Administration of buffered didanosine and atazanavir at the same time results in substantially decreased plasma concentrations and AUC of atazanavir and decreased plasma concentrations and AUC of didanosine.203 Administration of didanosine delayed-release capsules and atazanavir at the same time and with food results in decreased plasma concentrations and AUC of didanosine,200, 203 but does not affect atazanavir concentrations.200
Atazanavir should be administered (with food) 2 hours before or 1 hour after buffered didanosine (pediatric oral solution admixed with antacid) or didanosine delayed-release capsules (without food).200, 203
Concomitant use of didanosine delayed-release capsules and ritonavir-boosted darunavir does not affect the pharmacokinetics of didanosine or darunavir.204 Dosage adjustments are not necessary, but didanosine doses should be given (without food) 1 hour before or 2 hours after ritonavir-boosted darunavir (with food).204
Simultaneous administration of a single 200-mg dose of buffered didanosine and a single 800-mg dose of indinavir decreased the peak plasma concentrations and AUC of indinavir by 82 and 84%, respectively, but did not affect peak plasma concentrations or AUC of didanosine.1 When the indinavir dose was administered 1 hour before the dose of buffered didanosine, peak plasma concentrations and AUC of indinavir were decreased by 4 and 11%, respectively, and peak plasma concentrations and AUC of didanosine were decreased 13 and 17%, respectively.1 Buffered didanosine preparations should be administered 1 hour after indinavir.1
Concomitant use of a single 400-mg dose of didanosine delayed-release capsules (Videx® EC) and a single 800-mg dose of indinavir did not affect peak plasma concentrations or AUC of indinavir.48, 217
Because of conflicting instructions regarding administration of didanosine and administration of the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) oral solution with meals, didanosine should be given without food 1 hour before or 2 hours after lopinavir/ritonavir oral solution (given with food).207 Lopinavir/ritonavir tablets can be taken at the same time as didanosine (without food).207
Administration of didanosine (single 200-mg dose in the fasting state) 1 hour before nelfinavir (single 750-mg dose with food) did not affect the AUC or peak plasma concentration of nelfinavir.208
Because didanosine should be administered in the fasting state and nelfinavir should be administered with food to optimize GI absorption, concomitant nelfinavir and didanosine therapy should involve administering didanosine (without food) 1 hour before or 2 hours after nelfinavir (with food).1, 208, 217
Concomitant use of oral didanosine (200 mg every 12 hours) and full-dose oral ritonavir (600 mg every 12 hours) for 4 days decreases peak plasma concentrations and AUC of didanosine by 13-16%, but does not result in a clinically important effect on the pharmacokinetics of ritonavir.1, 53, 209
Concomitant use of didanosine and ritonavir-boosted tipranavir may result in decreased didanosine concentrations,200, 211 but does not affect tipranavir concentrations.200 The clinical importance of this interaction is unknown.211 Didanosine doses should be administered at least 2 hours before or 2 hours after doses of ritonavir-boosted tipranavir.200, 211
Failure of dapsone to prevent Pneumocystis carinii pneumonia was reported in about 40% of patients with HIV infection who were receiving didanosine concomitantly.71 This failure rate was substantially higher than that reported in other studies in which dapsone was not administered with didanosine or that observed when didanosine was administered in patients receiving co-trimoxazole or aerosolized pentamidine for the prevention of pneumocystis pneumonia.71 Although the possibility of a pharmacokinetic interaction was not evaluated in these patients, it was suggested that buffers present in the didanosine preparation, which provide a pH of 7-8 to facilitate GI absorption of the antiviral agent, may interfere with GI absorption of dapsone.71 However, in a study in 6 healthy adults and 6 HIV-infected adults, the pharmacokinetics of dapsone was not affected when 100 mg of the drug was administered 5 minutes after a 200-mg dose of didanosine given as chewable/dispersible, buffered tablets (no longer commercially available in the US) in the patients, or 5 minutes after administration of placebo tablets containing the aluminum and magnesium buffer without didanosine, in the healthy individuals.181 It has been suggested that dapsone be administered at least 2 hours before didanosine,71 although some clinicians have observed prophylactic failure of dapsone despite such separation of dosing and therefore recommend that the drugs not be used concomitantly.82
Ganciclovir and Valganciclovir
Although the clinical importance is unknown, results of an in vitro study using H9 cells inoculated with HIV (strain HTLV-IIIB) indicate that ganciclovir antagonizes the antiretroviral activity of didanosine against HIV.115
Administration of buffered didanosine (200 mg) 2 hours before ganciclovir (1 g) has resulted in a 111% increase in the AUC of didanosine and a 21% decrease in the AUC of ganciclovir.1 Administration of didanosine (200 mg) with IV ganciclovir (5 mg/kg) has resulted in a 50-70% increase in the steady-state AUC (0-12 hours) of didanosine and a 36-49% increase in peak didanosine plasma concentrations with no change in the pharmacokinetic parameters of ganciclovir.250
There has been no evidence to date that concomitant didanosine potentiates the myelosuppressive effects of ganciclovir when the drugs are used concomitantly in patients with HIV infection and CMV disease, including CMV retinitis.133
The manufacturer of didanosine states that, if there is no suitable alternative to ganciclovir, then the drugs should be used concomitantly with caution and the patient monitored for didanosine toxicity.1, 217
Because valganciclovir is rapidly and completely converted to ganciclovir, the pharmacokinetic interaction reported with didanosine and ganciclovir is expected to occur with valganciclovir.251
Concomitant administration of loperamide (4 mg every 6 hours for 4 doses) and a single 300-mg dose of buffered didanosine resulted in a 23% decrease in peak plasma didanosine concentrations but did not affect the AUC of the drug.1
Concomitant administration of a single 10-mg dose of metoclopramide and a single 300-mg dose of buffered didanosine resulted in a 13% increase in peak plasma didanosine concentrations but did not affect the AUC of the drug.1
Concomitant administration of a single 150-mg dose of ranitidine 2 hours prior to a single 375-mg dose of buffered didanosine resulted in a 14% increase in the AUC of didanosine and a 16% decrease in the AUC of ranitidine.1
Clinically important interactions are not expected if simeprevir is used concomitantly with didanosine.187
Results of in vitro studies indicate that concomitant use of hydroxyurea and didanosine can result in a synergistic effect against HIV-1, including some didanosine-resistant strains.227, 229, 235, 274 The mechanism of the synergistic effect between hydroxyurea and NRTIs is not fully understood.235, 277 One postulated mechanism is that hydroxyurea, a potent inhibitor of the cellular enzyme ribonuclease reductase, depletes deoxynucleotide triphosphate (dNTP) pools and reduces competition between reverse transcriptase inhibitors and endogenous dNTPs for binding sites on HIV reverse transcriptase, which reduces the rate of HIV-1 DNA synthesis and results in inhibition of HIV replication.275, 276, 277 Hydroxyurea also may enhance the activation of reverse transcriptase inhibitors by blocking cells in the S phase of the cell cycle, when thymidine kinase, the cellular enzyme responsible for phosphorylation of reverse transcriptase inhibitors, is present in the highest concentrations.277 Based on analysis of clinical isolates from a limited number of patients receiving hydroxyurea and didanosine concomitantly, hydroxyurea does not appear to prevent emergence of didanosine-resistant strains of HIV-1.229
Because of in vitro evidence of synergism against HIV-1, use of hydroxyurea as an adjunct to antiretroviral therapy was evaluated in treatment-naive and previously treated HIV-infected patients.152, 227, 228, 229, 230, 231, 232, 233, 234, 272, 273, 274, 275, 276, 277, 278, 279 Although results of initial studies evaluating adjunctive use of hydroxyurea with didanosine (with or without stavudine) indicated that such a regimen results in a greater reduction in viral load than use of NRTI therapy alone,230, 232, 233, 235, 278, 279 the effect on CD4+ T-cells was inconsistent.230 In addition, an increased risk of serious adverse effects (e.g., neutropenia or other cytopenias, peripheral neuropathy, pancreatitis, hepatotoxicity) may occur in HIV-infected patients receiving hydroxyurea in conjunction with antiretroviral agents (e.g., stavudine with or without didanosine).1, 228, 217, 276, 277, 278 A randomized, controlled study (study ACTG 5025) evaluating use of a regimen of didanosine, stavudine, and indinavir with or without hydroxyurea (600 mg twice daily) was terminated152, 228 because the rate of discontinuance for drug toxicity was higher in those randomized to receive hydroxyurea and there were at least 2 fatalities related to pancreatitis in the hydroxyurea treatment arm.228
Concomitant use of didanosine, and hydroxyurea (with or without stavudine) should be avoided.1, 217
Concurrent administration of didanosine and clarithromycin in a limited number of HIV-infected adults did not affect the pharmacokinetics of didanosine.158
Opiates and Opiate Partial Agonists
Concomitant use of didanosine and buprenorphine does not result in clinically important pharmacokinetic interactions; dosage adjustments are not necessary if the drugs are used concomitantly.200
Concomitant use of methadone and buffered didanosine decreases plasma concentrations and AUC of didanosine.1, 217, 243 In a limited number of individuals, concomitant use of buffered didanosine and methadone resulted in a 66% decrease in the peak serum concentration and a 63% decrease in the AUC of didanosine; trough concentrations of methadone did not appear to be affected.243
Concomitant use of methadone and didanosine extended-release capsules does not result in a clinically important pharmacokinetic interaction.200
If concomitant use of didanosine and methadone is considered necessary, didanosine delayed-release capsules (not pediatric oral solution admixed with antacid) should be used and patients should be monitored closely for an adequate clinical response to the antiretroviral agent (e.g., monitored for changes in viral load).1, 217
Because oral absorption and plasma concentrations of fluoroquinolones may be decreased in the presence of antacids containing magnesium, calcium, or aluminum, concomitant use of buffered didanosine (pediatric oral solution admixed with antacid) and a fluoroquinolone may result in decreased concentrations of the fluoroquinolone.1, 262, 263, 264
Because oral absorption of ciprofloxacin may be decreased in the presence of antacids containing magnesium, calcium, or aluminum, the manufacturer of didanosine recommends that buffered didanosine (pediatric oral solution admixed with antacid) be administered at least 2 hours after or 6 hours before an oral dose of ciprofloxacin.1 In 8 HIV-infected patients, the steady-state AUC of ciprofloxacin was decreased an average of 26% when ciprofloxacin was administered 2 hours prior to a chewable/dispersible, buffered didanosine tablet (no longer commercially available in the US).1 The AUC of ciprofloxacin was on average 98% lower in healthy individuals who received ciprofloxacin and didanosine-placebo buffered tablets concomitantly.1
Results of a study in healthy individuals indicate that concomitant use of a single 750-mg dose of ciprofloxacin and a single 400-mg dose of didanosine given as delayed-release capsules does not affect the pharmacokinetics of ciprofloxacin.48, 217
Levofloxacin should be administered at least 2 hours before or 2 hours after buffered didanosine (pediatric oral solution admixed with antacid).262
Moxifloxacin should be administered at least 4 hours before or 8 hours after buffered didanosine (pediatric oral solution admixed with antacid).263
Ofloxacin should be administered at least 2 hours before or 2 hours after buffered didanosine (pediatric oral solution admixed with antacid). 264
Concomitant use of didanosine and ribavirin is contraindicated.1, 200, 217 Ribavirin has been shown in vitro to increase intracellular concentrations of an active triphosphate metabolite of didanosine and fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia and lactic acidosis, have been reported in patients receiving both didanosine and ribavirin.1, 200, 217
Results of in vitro tests in various cell cultures and peripheral blood lymphocytes indicate that ribavirin may potentiate the antiretroviral activity of didanosine against HIV.33, 73, 79 In vitro in MT-4 cells infected with HIV-1 (strain HTLV-IIIB), the EC50 (concentration of the drug required to suppress cytopathogenicity by 50%) of didanosine alone was 0.96 mcg/mL; when ribavirin was added at a concentration of 1.25 or 2.5 mcg/mL, the EC50 of didanosine decreased to 0.15 or 0.098 mcg/mL, respectively.33 In vitro in peripheral blood lymphocytes obtained from healthy adults and inoculated with HIV-1 (strain HTLV-IIIB), the EC50 of didanosine was 0.12 mcg/mL when the drug was used alone and 0.02 mcg/mL when the drug was combined with 5 mcg/mL of ribavirin.73 Ribavirin also appears to potentiate the antiretroviral effect of didanosine against Moloney murine sarcoma virus (MSV) in vitro and in vivo.33 In vitro in murine embryo fibroblast C3H/3T3 cells inoculated with MSV, ribavirin at a concentration of 0.25 or 1 mcg/mL decreased the EC50 of didanosine from 40 mcg/mL to 15 or 6 mcg/mL, respectively.33 When didanosine was administered alone (200 mg/kg daily) to MSV-infected newborn mice, only a slight delay in appearance of tumors resulted; however, administration of the same dose of didanosine in conjunction with ribavirin (40 mg/kg daily) resulted in a marked delay in tumor formation.33 Use of both antiviral agents did not significantly alter mortality associated with MSV infection in these newborn mice.33
Ribavirin appears to potentiate the antiretroviral effects of didanosine by promoting formation of dideoxyadenosine-5'-triphosphate (ddA-TP), the metabolically active metabolite of didanosine with antiviral activity.79 Ribavirin acts as an inhibitor of inosinate dehydrogenase (IMPD), which blocks the utilization of IMP for guanine nucleotide biosynthesis and results in increased intracellular concentrations of IMP; IMP is the preferred phosphate donor involved in the initial phosphorylation step that converts didanosine to ddA-TP.79
It has been suggested that concomitant use of ribavirin and NRTIs may increase the risk of mitochondrial dysfunction and associated toxicities (e.g., pancreatitis, lactic acidosis) reported with this group of antiretroviral agents.253, 254, 256 There have been several reports of lactic acidosis or pancreatitis occurring in HIV-infected patients coinfected with hepatitis C virus (HCV) who received antiretroviral therapy concomitantly with ribavirin and interferon alfa.253, 256 These patients had been receiving long-term therapy with combination antiretroviral regimens that included one or more NRTIs (abacavir, didanosine, stavudine, zidovudine) and were clinically stable until lactic acidosis or pancreatitis developed 4-6 months after a regimen ribavirin and interferon alfa was initiated for treatment of chronic HCV infection.253, 256 Because ribavirin also is a nucleoside analog, it has been suggested that concomitant use of ribavirin and NRTIs may result in an adverse additive effect on mitochondrial function; however, other clinicians suggest that ribavirin may have potentiated the effects of the NRTIs through some other mechanism or that the viral diseases themselves may have been partly responsible for mitochondrial dysfunction in these patients.253, 254, 255, 256
Concomitant use of tetracycline and buffered didanosine preparations (pediatric oral solution admixed with antacid) may result in decreased tetracycline concentrations.1 Some clinicians suggest that doses of didanosine pediatric oral solution be given 1-2 hours before or after a dose of tetracycline.82
Although the clinical importance is unclear, some patients with HIV infection receiving triazolam and didanosine reportedly became confused while the drugs were administered concomitantly; the confusion resolved when both drugs were discontinued and did not recur when didanosine therapy was reinitiated alone.82 Confusion can occur with benzodiazepine therapy alone, and additional study is needed to determine whether an interaction exists.
Limited information is available on the acute toxicity of didanosine in humans.1 In phase 1 studies in which didanosine was initially administered at dosages 10 times the currently recommended dosage, toxicities included pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction.1
There is no known antidote for didanosine overdosage.1 If acute overdosage of didanosine occurs, the stomach should be emptied by inducing emesis or by gastric lavage.82 Supportive and symptomatic treatment should be initiated, and the patient should be observed carefully.82 Although didanosine is removed to some extent by hemodialysis, the drug is not removed by peritoneal dialysis.1, 239
The complete mechanism(s) of antiviral activity of didanosine has not been fully elucidated.2, 8, 40, 185 Following conversion to a pharmacologically active metabolite, didanosine apparently inhibits replication of retroviruses, including human immunodeficiency virus (HIV), by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 18, 27, 29, 30, 34, 40, 43, 74 The drug, therefore, exerts a virustatic effect against retroviruses by acting as a reverse transcriptase inhibitor.1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 18, 27, 29, 30, 34, 40, 43, 72, 74
Like other HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., abacavir, lamivudine, stavudine, zidovudine) and other nucleoside antiviral agents (e.g., acyclovir, ganciclovir, ribavirin), the antiviral activity of didanosine appears to depend on intracellular conversion of the drug to a 5'-triphosphate metabolite; thus, dideoxyadenosine-5'-triphosphate (ddA-TP) and not unchanged didanosine appears to be the pharmacologically active form of the drug.1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 18, 27, 29, 30, 34, 40, 74 Substantial differences exist in the rates at which human cells phosphorylate various nucleoside-analog antiviral agents and in the enzymatic pathways involved.2, 3, 4, 1, 13, 29, 40 Enzymatic conversion of didanosine to ddA-TP appears to be complex, involving several steps and enzymes.2, 3, 8, 9, 29, 40 Didanosine is first converted to dideoxyinosine-5'-monophosphate (ddI-MP) by 5'-nucleotidase with inosine-5'-monophosphate as the phosphate donor.9, 29, 40 Subsequently, ddI-MP may be aminated to dideoxyadenosine-5'-monophosphate (ddA-MP) in a reaction catalyzed by adenylosuccinate synthetase/lyase and phosphorylated to dideoxyadenosine-5'-diphosphate (ddA-DP) and to ddA-TP via other enzymes (e.g., purine nucleoside monophosphate and purine diphosphate kinase).2, 9, 29, 40 Because phosphorylation of didanosine depends on cellular rather than viral enzymes, conversion of the drug to the active triphosphate derivative occurs in both virus-infected and uninfected cells4, 9, 15, 29, 34, 40
ddA-TP is a structural analog of 2'-deoxyadenosine-5'-triphosphate, the usual substrate for viral RNA-directed DNA polymerase.1, 2, 3, 4, 5, 10, 11, 12, 13, 14, 18, 21, 27, 29, 30 Although other mechanisms may be involved in the antiretroviral activity of the drug, ddA-TP appears to compete with 2'-deoxyadenosine-5'-triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA.1, 2, 3, 4, 5, 10, 11, 12, 13, 14, 18, 21, 27, 30 Following incorporation of ddA-TP into the viral DNA chain instead of 2'-deoxyadenosine-5'-triphosphate, DNA synthesis is prematurely terminated because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages.1, 2, 3, 4, 5, 10, 11, 12, 13, 14, 18, 21, 27, 29, 30
ddA-TP can bind to and inhibit some mammalian cellular DNA polymerases, particularly β- and γ-polymerases, in vitro.2, 4, 5, 10, 12, 15, 17, 18, 21, 27, 30, 32 However, ddA-TP and other dideoxynucleoside triphosphates appear to have much greater affinity for viral RNA-directed DNA polymerase than for mammalian DNA polymerases, particularly mammalian DNA α-polymerase, a DNA enzyme essential for cell division and cellular DNA repair.2, 4, 5, 10, 12, 15, 17, 18, 21, 27, 29, 30 This differential sensitivity of mammalian and viral DNA polymerases to dideoxynucleoside triphosphates may account, in part, for some of the antiviral selectivity of these drugs in cells that can phosphorylate them.2, 3, 4, 5, 12, 13, 17, 18, 27, 29, 30 However, inhibition of β- and γ-polymerases by these drugs may account, to some extent, for the toxic effects associated with didanosine and other dideoxynucleosides in humans.2, 4, 12, 14, 15, 18, 21, 29, 30
In vitro cell-growth assays have been used to assess the cytotoxicity of didanosine for various cell lines.1, 32 Results of these studies have shown that the drug has little cytogenic action and little effect on the growth of bone marrow progenitor cells.1, 3, 32 In cultured human bone marrow progenitor cells, the IC50 of didanosine (concentration of the drug required to inhibit cell growth by 50%) was greater than 20 mcg/mL.1
Results of in vitro studies evaluating the effects of didanosine on polymorphonuclear leukocytes (PMNs) obtained from healthy adults or adults with HIV infection indicate that didanosine concentrations of 0.04-10 mcg/mL had no effect on PMN viability, chemotaxis, phagocytosis of Candida albicans or Staphylococcus aureus , or superoxide production following stimulation by N -formylmethionylleucylphenylalanine.59 Although the clinical importance is unclear, exposure of PMNs to didanosine in vitro appeared to enhance killing of C. albicans and S. aureus ; it is not known whether this effect was the result of a direct interaction between didanosine and the PMNs or an indirect interaction that made the organisms more susceptible to PMN action.59 In studies using peripheral blood mononuclear cells (PBMC) isolated from healthy donors, didanosine (unlike zidovudine, ribavirin, and ganciclovir) had little, if any, effect on thymidine or leucine uptake.32 In addition, didanosine had little effect on mitogenesis of the cells and the PBMC response to Con A (a T-cell mitogen) was largely unaffected.32
Didanosine has a limited spectrum of antiviral activity.3 Following intracellular conversion to a pharmacologically active 5'-triphosphate metabolite, didanosine is active in vitro against many human and animal retroviruses, including human immunodeficiency viruses (HIV).1, 3, 4, 5, 6, 8, 10, 16, 17, 21, 30, 34, 40, 58, 70, 76 The drug also has some in vitro activity against hepatitis B virus.75
Various methods, including assays for cytopathic effect inhibition, plaque inhibition, viral RNA-directed DNA polymerase (reverse transcriptase) activity, or retroviral antigens such as p24 core antigen (p24 gag protein), have been used to test in vitro susceptibility of retroviruses to antiviral agents.3, 16, 17, 21, 58 The relationship between in vitro susceptibility of retroviruses to didanosine and inhibition of replication of these viruses in humans or clinical response to therapy with the drug has not been determined.1
A concentration of 1 mcg of didanosine per mL is approximately equivalent to 4.2 µmol/L.1
Didanosine is active in vitro against human retroviruses including HIV type 1 (HIV-1)1, 4, 5, 6, 8, 10, 16, 17, 21, 30, 34, 40, 58, 70, 76 and type 2 (HIV-2).1, 16, 34 The drug also is active in vitro against some animal retroviruses including feline leukemia virus,40 simian immunodeficiency virus,40 and Moloney murine sarcoma virus.4 Didanosine generally has been active in vitro against all types of retroviruses tested, provided the target cells used for in vitro testing could phosphorylate the drug to its active 5'-triphosphate metabolite.82 In vitro on a weight basis, didanosine is less active than zidovudine against susceptible HIV-1;70, 76 however, didanosine is active in vitro against some strains of HIV with in vitro resistance to zidovudine.29, 40, 46, 51, 54, 76, 111
In studies that evaluated the in vitro antiretroviral activity of didanosine using lymphoblastic cell lines and monocyte/macrophage cell cultures inoculated with HIV-1, the ID50 (concentration of the drug required to inhibit 50% of detectable HIV replication) of the drug ranged from 0.6-2.4 mcg/mL in lymphoblastic cell lines and from 0.002-0.02 mcg/mL in monocyte/macrophage cell cultures.1
In a study using human MT-2 cells that were inoculated with HIV in culture, the ID50 of didanosine was 0.2 mcg/mL for HIV-1 and 2 mcg/mL for HIV-2.16
Although the clinical importance is unclear, didanosine has some activity in vitro against hepatitis B virus.75 In cell culture using 2.2.15 (PR) cells derived from a human hepatoblastoma (HEP G2) cell line that continuously produces hepatitis B virus genome, the ID50 of didanosine was estimated to be 10-20 mcg/mL based on reduction in extrachromosomal hepatitis B virus DNA.75
Strains of human immunodeficiency virus (HIV) with decreased in vitro susceptibility to didanosine have been produced in vitro and have been isolated from patients who received didanosine.1, 156 For information on genotypic assays used to detect specific HIV-1 genetic variants (mutations), phenotypic assays used to measure HIV-1 drug resistance and recommendations regarding these assays, see In Vitro Resistance Testing under Guidelines for Use of Antiretroviral Agents: Laboratory Monitoring, in the Antiretroviral Agents General Statement 8:18.08.08.
Specific mutations of HIV RNA-directed DNA polymerase (reverse transcriptase) at critical codons on the pol gene fragment have been associated with decreased susceptibility to HIV nucleoside reverse transcriptase inhibitors (NRTIs).156, 157, 184, 185 Mutations that have been associated with decreased susceptibility to didanosine include K65R, L74V, and M184V.1, 156, 157, 183, 184 The mutation at codon 74 has been reported most frequently1 and appears to be the primary mutation responsible for didanosine resistance resulting in a 5- to 26-fold decrease in susceptibility to the drug.183, 184 In a study in HIV-infected patients who previously received zidovudine monotherapy, the L74V mutation was evident in 56% of patients after 24 weeks of didanosine therapy.183 This mutation can restore susceptibility to zidovudine, presumably by suppressing zidovudine resistance that results from a mutation at codon 215.183
Cross-resistance has been reported among the NRTIs.1, 112, 113, 114, 125, 126 In one study evaluating HIV-1 obtained from patients who had received zidovudine alone for a mean of 14.7 months (range: 0-53 months), all of the zidovudine-resistant isolates from these patients had decreased susceptibility to didanosine.155 HIV isolates with decreased susceptibility to didanosine, zidovudine, lamivudine, and stavudine have been isolated from patients who received zidovudine in conjunction with didanosine for up to 2 years.1, 182 Mutations identified in these isolates were A62V, V75I, F77L, F116Y, and Q151M.1
The pharmacokinetics of didanosine have been studied in adult1, 249 and pediatric patients1 with human immunodeficiency virus (HIV) infection and in individuals with renal or hepatic impairment.1, 217 The pharmacokinetics of the drug in adults 65 years of age or older have not been studied to date.1 The effects of gender on didanosine pharmacokinetics have not been studied.1
A concentration of 1 mcg of didanosine per mL is approximately equivalent to 4.2 µmol/L.1
The extent of absorption of oral didanosine is variable and depends on several factors including the dosage form administered, gastric pH, and presence of food in the GI tract.1, 37, 38, 39, 44, 61, 62, 63, 120, 217 There is considerable interindividual variation in peak plasma concentrations and areas under the plasma concentration-time curve (AUCs) of didanosine attained following oral administration.37, 38, 39, 44, 61, 62, 63, 120 It has been suggested that these differences in oral bioavailability of the drug, especially in patients with HIV infection, principally result from interindividual differences in gastric pH or the presence of disease conditions that affect GI motility and transit time.62, 63, 82
Because didanosine is rapidly degraded at acidic pH, gastric secretions may inactivate the drug following oral administration.1, 2, 3, 29, 34, 39, 40, 45, 61, 62, 63 To maximize GI absorption of intact drug, commercially available delayed-release capsules contain enteric-coated pellets of the drug217 and commercially available powder for oral solution must be admixed with antacids prior to administration.1, 39, 40, 62
In some studies described in the Pharmacokinetics section, didanosine was administered to adults, adolescents, and children as an oral solution prepared using a lyophilized formulation of the drug (not commercially available in the US) that is similar to the commercially available unbuffered pediatric powder for oral solution.37, 38, 39, 45, 61, 62, 63 When didanosine was administered as this oral solution, doses of the drug were given within 2 minutes after administration of a dose of oral antacid to maximize GI absorption of unchanged didanosine.37, 38, 39, 45, 61, 62, 63
Presence of food in the GI tract generally decreases the rate and extent of absorption of oral didanosine.1, 62, 217 If didanosine delayed-release capsules are administered with food, peak plasma concentrations and AUC of the drug are decreased approximately 46 and 19%, respectively.217 In one study, the bioavailability of chewable/dispersible, buffered tablets of didanosine (no longer commercially available in the US) administered up to 30 minutes prior to a meal was similar to the drug's bioavailability under fasting conditions.1 When the tablets were administered up to 2 hours after a meal, peak plasma concentrations and AUC of didanosine were decreased approximately 55%.1 (See Dosage and Administration: Reconstitution and Administration.)
Antacids increase the oral bioavailability of didanosine.1, 2, 3, 38, 39, 62 (See Drug Interactions: Antacids.)
Didanosine is rapidly, but incompletely, absorbed following oral administration.1, 37, 38, 44, 61, 62, 63 In fasting adults, peak plasma concentrations of the drug generally are attained within 0.25-1.5 hours following administration of a single dose of the drug given as chewable/dispersible, buffered tablets or buffered powder for oral solution (preparations no longer commercially available in the US).1, 249
Following administration of delayed-release capsules containing enteric-coated pellets of didanosine, peak plasma concentrations of the drug are approximately 40% lower than that reported following administration of chewable/dispersible, buffered tablets.217 In addition, the time to peak plasma concentrations following administration of the delayed-release capsules is 2 hours compared with approximately 0.67 hours with the tablets.217
Following administration of a single 400-mg dose of didanosine in individuals with moderate or severe hepatic impairment (Child-Pugh class B or C), mean peak plasma concentrations and AUC of the drug are increased 19 and 13%, respectively, compared with individuals without hepatic impairment.217
Following IV administration (parenteral dosage form not commercially available in the US) of a single 0.4-, 1-, 3-, or 5.1-mg/kg dose of didanosine infused over 1 hour in adults with symptomatic HIV infection, peak plasma concentrations averaged 0.31, 1.1, 2.8, or 5.1 mcg/mL, respectively.37, 63
Plasma concentrations of didanosine generally increase in proportion to dose over the dosage range of 50-400 mg.1 The pharmacokinetics of didanosine at steady state is similar to that reported after a single oral or IV dose of the drug;1, 37, 63 there is no evidence that the drug accumulates in plasma or urine following multiple oral or IV doses in adults.1, 37, 38, 44, 63
There are no clinically important changes in the pharmacokinetics of didanosine during pregnancy.202
Although didanosine is rapidly absorbed following oral administration in children and adolescents, there is considerable interindividual variation in oral bioavailability of the drug.45, 120, 131, 173 Oral bioavailability of didanosine averaged 25% in children 8 months to 19 years old.1 In a larger study in children 7 months to 18 years of age with asymptomatic or symptomatic HIV infection, oral bioavailability of the drug averaged only 19% but ranged from 2-89%.120
In children 3 months to 18 years of age who received a single 20- or 180-mg dose of didanosine given by IV infusion over 1 hour, mean peak plasma concentrations were 0.6 or 4.4 mcg/mL, respectively.45
Plasma didanosine concentrations increase in proportion to dosage over the oral dosage range of 80-180 mg/m2.1
In one limited study in HIV-infected pediatric patients (mean age: 4.8 years), bioavailability of didanosine administered as the pediatric oral solution admixed with antacid in a once-daily regimen (180 mg/m2 once daily for 45 days)† was compared with bioavailability of the same preparation of the drug given in a twice-daily regimen (90 mg/m2 every 12 hours for 45 days).240 Peak plasma concentrations, time to peak plasma concentrations, and plasma half-life were similar with both regimens, but mean AUCs were higher with the once-daily regimen and there was considerable interindividual and intraindividual variation in AUCs with both regimens.240 Therefore, although bioavailability of the once-daily regimen relative to that of the twice-daily regimen was 0.95 (range: 0.22-1.97) and suggests that bioavailability of these regimens is similar, the variability in AUCs resulted in the 90% confidence interval for the logarithmic transformed AUC (0.65-1.01) to be outside US Food and Drug Administration (FDA) regulatory limits for bioequivalence (0.8-125).240
The apparent volume of distribution of didanosine following IV administration averages 43.7 L/m2 in adult patients and 28 L/m2 in pediatric patients 8 months to 19 years of age.1
In vitro studies indicate that didanosine is less than 5% bound to plasma proteins.1
Didanosine is distributed into CSF following IV administration; CSF concentrations average 21% of concurrent plasma concentrations in samples obtained 1 hour after a dose of the drug.1, 39, 61 In one study in children and adolescents with HIV infection who received oral or IV didanosine, CSF concentrations were 46% (range: 12-85%) of concurrent plasma concentrations.1
Didanosine crosses the placenta and is distributed into cord blood and amniotic fluid.60 While it is not known whether didanosine is distributed into human milk, the drug and/or its metabolites are distributed into milk in rats.1
The metabolic fate of didanosine has not been fully evaluated in humans; however, because didanosine is an analog of inosine, a naturally occurring purine nucleoside, metabolism of the drug presumably would occur via the same pathways responsible for the elimination of endogenous purines.1
Intracellularly, didanosine is converted to dideoxyinosine-5'-monophosphate (ddI-MP) by cellular 5'-nucleotidase; the monophosphate derivative may then be aminated to dideoxyadenosine-5'-monophosphate (ddA-MP) in a reaction catalyzed by adenylosuccinate synthetase/lyase and phosphorylated to dideoxyadenosine-5'-diphosphate (ddA-DP) and to dideoxyadenosine-5'-triphosphate (ddA-TP) via other enzymes (e.g., purine nucleoside monophosphate, purine diphosphate kinase).2, 9, 29, 40 Intracellular (host cell) conversion of didanosine to the triphosphate derivative is necessary for the antiviral activity of the drug.29, 39, 40 The in vivo intracellular half-life of ddA-TP has not been determined to date; in vitro, the intracellular half-life of ddA-TP is 8-24 hours.2, 3, 40
In adults with HIV infection, the plasma half-life of didanosine averages 0.97-1.6 hours (range: 0.3-4.64 hours).1, 37, 44, 55, 63, 249 The plasma half-life following oral administration averages 0.8 hours in children 8 months to 19 years of age and 1.2 hours in neonates and children 2 weeks to 4 months of age.1
Total body clearance of didanosine averages 800 mL/minute (range: 412-1505 mL/minute) in adults and 490-532 mL/minute per m2 (range: 294-920 mL/minute per m2) in children and adolescents with HIV infection.45, 63 Following IV administration, systemic clearance of didanosine averages 526 mL/minute per m2 in adult patients and 516 mL/minute per m2 in pediatric patients 8 months to 19 years of age.1 Didanosine is eliminated in urine by glomerular filtration and active tubular secretion.63 Following either oral or IV in adults, the renal clearance of didanosine is approximately 50% of the total body clearance and averages 400 mL/minute (range: 95-860 mL/minute).63 Renal clearance following oral administration has been reported to average 5.5 mL/minute per kg in adult patients and 240 mL/minute per m2 in pediatric patients.1 Following oral or IV administration of a single dose of didanosine in adults with HIV infection, approximately 20% (range: 3-31%) or 55% (range: 27-98%) of the dose, respectively, is eliminated in urine.1, 55, 63 In pediatric patients, urinary recovery of didanosine averages 18% following oral administration.1
The apparent oral clearance of didanosine decreases and the terminal elimination half-life of the drug increases as creatinine clearance decreases.1 Following administration of a single oral didanosine dose, the mean half-life of the drug was 1.42 hours in patients with creatinine clearances of 90 mL/minute or greater or 1.59, 1.75, or 2 hours in those with creatinine clearances of 60-90, 30-59, or 10-29 mL/minute, respectively.1 In dialysis patients, the mean half-life was 4.1 hours.1
Didanosine is removed by hemodialysis.1, 122, 239 The amount of drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow rate).122 In a study in uremic adults with HIV infection, approximately 20% of a single 375-mg oral dose of didanosine was removed by a 4-hour period of hemodialysis.122 In patients with severe renal impairment, about 0.6-7.4% of an oral dose was recovered in hemodialysate over a 3-4-hour period.1 The absolute bioavailability of didanosine is not affected in patients requiring dialysis.1 Didanosine does not appear to be removed by peritoneal dialysis.1, 239
Didanosine, a synthetic antiretroviral agent,1, 2, 3, 8, 21, 30, 34, 36, 40, 44, 72 is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).30 The drug is a dideoxynucleoside reverse transcriptase inhibitor.30 Didanosine is an analog of inosine, a naturally occurring purine nucleoside.40 Didanosine differs structurally from inosine in that the 2'- and 3'-hydroxyl groups on the ribose moiety have been replaced with hydrogen atoms;40 the absence of the free 3'-hydroxyl group results in the inability of didanosine to form phosphodiester linkages at this position.40 Didanosine also is closely related to dideoxyadenosine (ddA), a prodrug of didanosine that is rapidly deaminated to didanosine by adenosine deaminase in plasma and various tissues.34, 40
Didanosine occurs as a white, nonhygroscopic, crystalline powder.1 The drug has a pKa of 9.13.40 The aqueous solubility of didanosine at pH 6 and 25°C is approximately 27.3 mg/mL.1
Didanosine is commercially available for oral administration as delayed-release capsules containing enteric-coated pellets217 and as an unbuffered pediatric powder for oral solution that is admixed with antacid.1
Didanosine is stable at neutral or slightly alkaline pH,40 but is unstable at acidic pH.1, 40, 61, 62 At pH less than 3, 10% of didanosine is hydrolyzed to hypoxanthine in less than 2 minutes at 37°C.1
Didanosine reportedly has only limited stability in vitro in whole blood samples; samples of whole blood should be kept on ice and plasma should be separated as soon as possible.82 In plasma or buffered urine samples in vitro, didanosine is stable when heated at 57°C for 3 hours and also is stable for at least 12 months when frozen at <20°C.55, 63
Delayed-release capsules containing enteric-coated pellets of didanosine should be stored in tight containers at 25°C, but may be exposed to temperatures ranging from 15-30°C.217
Didanosine unbuffered pediatric powder for oral solution should be stored at 15-30°C.1 Following reconstitution with water and admixture with a liquid antacid as directed, didanosine pediatric oral suspensions contain 10 mg of the drug per mL and are stable for 30 days when refrigerated at 2-8°C.1 Reconstituted and admixed pediatric oral suspensions of didanosine should be stored in tightly closed, flint-glass or plastic (HDPE, PET, PETG) bottles with child-resistant closures and refrigerated at 2-8°C.1 Unused portions of reconstituted and admixed pediatric didanosine oral suspension should be discarded after 30 days.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, delayed-release (containing enteric-coated pellets) | 125 mg* | Didanosine Delayed-release Capsules | |
Videx® EC | ||||
200 mg* | Didanosine Delayed-release Capsules | |||
Videx® EC | Bristol-Myers Squibb | |||
250 mg* | Didanosine Delayed-release Capsules | |||
Videx® EC | Bristol-Myers Squibb | |||
400 mg* | Didanosine Delayed-release Capsules | |||
Videx® EC | Bristol-Myers Squibb | |||
For solution | 2 g/bottle* | Didanosine for Oral Solution | ||
Videx® Pediatric | Bristol-Myers Squibb | |||
4 g/bottle* | Didanosine for Oral Solution | |||
Videx® Pediatric | Bristol-Myers Squibb |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Bristol-Myers Squibb. Videx® (didanosine) pediatric powder for oral solution prescribing information. Princeton, NJ; 2014 Aug.
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