These highlights do not include all the information needed to use VIDEX safely and effectively. See full prescribing information for VIDEX. VIDEX (didanosine, USP) Pediatric Powder for Oral SolutionInitial U.S. Approval: 1991

Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. VIDEX should be suspended in patients with suspected pancreatitis and discontinued in patients with confirmed pancreatitis [see Warnings and Precautions (5.1) ].

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Warnings and Precautions (5.2) ].

VIDEX (didanosine, USP), also known as ddI, in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14) ].

VIDEX should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating.

The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for patients whose management requires once-daily dosing of VIDEX [see Clinical Studies (14) ]. The recommended adult total daily dose is based on body weight (kg) (see Table 1).

Pediatric Patients (2 weeks old to 18 years old): The recommended dose of VIDEX (didanosine) in pediatric patients between 2 weeks old and 8 months old is 100 mg/m twice daily, and the recommended VIDEX dose for pediatric patients greater than 8 months old is 120 mg/m twice daily but not to exceed the adult dosing recommendation.

Dosing recommendations in patients less than 2 weeks of age cannot be made because the pharmacokinetics of didanosine in these children are too variable to determine an appropriate dose. There are no data on once-daily dosing of VIDEX in pediatric patients.

In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 2.

Urinary excretion is also a major route of elimination of didanosine in pediatric patients, therefore the clearance of didanosine may be altered in pediatric patients with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose should be considered (see Table 2).

For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance of less than 10 mL/min, shown in Table 2. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.

In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of VIDEX to 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) or 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) once daily is recommended. VIDEX and tenofovir disoproxil fumarate may be taken together in the fasted state. Alternatively, if tenofovir disoproxil fumarate is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). The appropriate dose of VIDEX coadministered with tenofovir disoproxil fumarate in patients with creatinine clearance of less than 60 mL/min has not been established. ([See Drug Interactions (7) and Clinical Pharmacology (12.3) ]; see the complete prescribing information for VIDEX EC (enteric-coated formulation of didanosine) for results of drug interaction studies of tenofovir disoproxil fumarate with reduced doses of the enteric-coated formulation of didanosine.)

No dose adjustment is required in patients with hepatic impairment [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3) ].

VIDEX (didanosine, USP) Pediatric Powder for Oral Solution is supplied in 4- and 8-ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.

These recommendations are based on either drug interaction studies or observed clinical toxicities.

Coadministration of didanosine and allopurinol is contraindicated because systemic exposures of didanosine are increased, which may increase didanosine-associated toxicity [see Clinical Pharmacology (12.3) ].

Coadministration of didanosine and ribavirin is contraindicated because exposures of the active metabolite of didanosine (dideoxyadenosine 5′-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin.

Fatal and nonfatal pancreatitis has occurred during therapy with VIDEX used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. VIDEX should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with VIDEX in combination with stavudine may be at increased risk for pancreatitis.

When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX should be used with extreme caution and only if clearly indicated. Patients with advanced HIV-1 infection, especially the elderly, are at increased risk of pancreatitis and should be followed closely. Patients with renal impairment may be at greater risk for pancreatitis if treated without dose adjustment. The frequency of pancreatitis is dose related. [See Adverse Reactions (6) .]

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk [see Use in Specific Populations (8.1) ]. Particular caution should be exercised when administering VIDEX to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIDEX should be suspended in any patient who develops clinical signs or symptoms with or without laboratory findings consistent with symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

The safety and efficacy of VIDEX have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. [See Adverse Reactions (6) .]

Postmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.

Patients receiving VIDEX should be monitored for early signs of portal hypertension (eg, thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. VIDEX should be discontinued in patients with evidence of non-cirrhotic portal hypertension.

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, in patients with a history of neuropathy, or in patients being treated with neurotoxic drug therapy, including stavudine. Discontinuation of VIDEX should be considered in patients who develop peripheral neuropathy. [See Adverse Reactions (6) .]

Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX [see Adverse Reactions (6) ].

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIDEX. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further eva luation and treatment.

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

The following adverse reactions are discussed in greater detail in other sections:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Selected clinical adverse reactions that occurred in adult patients in clinical studies with VIDEX are provided in Tables 3 and 4.

Pancreatitis resulting in death was observed in one patient who received VIDEX (didanosine) plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial [see Warnings and Precautions (5) ].

The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose.

Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 5-7.

In clinical trials, 743 pediatric patients between 2 weeks and 18 years of age have been treated with didanosine. Adverse reactions and laboratory abnormalities reported to occur in these patients were generally consistent with the safety profile of didanosine in adults.

In pediatric phase 1 studies, pancreatitis occurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m/day and in 5 of 38 (13%) patients treated at higher doses. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m every 12 hours in combination with zidovudine [see Clinical Studies (14) ].

Retinal changes and optic neuritis have been reported in pediatric patients.

The following adverse reactions have been identified during postapproval use of didanosine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to VIDEX, or a combination of these factors.

When didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and Precautions (5) ]. The combination of VIDEX and hydroxyurea, with or without stavudine, should be avoided.

Clinical recommendations based on the results of drug interaction studies are listed in Table 8. Pharmacokinetic results of drug interaction studies are shown in Tables 12 and 13 [see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3) ]. 

Exposure to didanosine is increased when coadministered with tenofovir disoproxil fumarate [Table 8 and see Clinical Pharmacokinetics (12.3, Table 12) ]. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop [see Dosage and Administration (2.3), Warnings and Precautions (5) ]. Suppression of CD4 cell counts has been observed in patients receiving tenofovir disoproxil fumarate with didanosine at a dose of 400 mg daily.

Predicted drug interactions with VIDEX are listed in Table 9.

Reproduction studies have been performed in rats and rabbits at doses up to 12 and 14.2 times the estimated human exposure (based upon plasma levels), respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to didanosine. At approximately 12 times the estimated human exposure, didanosine was slightly toxic to female rats and their pups during mid and late lactation. 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. A study in rats showed that didanosine and/or its metabolites are transferred to the fetus through the placenta. Animal reproduction studies are not always predictive of human response.

There are no adequate and well-controlled studies of didanosine in pregnant women. Didanosine should be used during pregnancy only if the potential benefit justifies the potential risk.

Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [see Warnings and Precautions (5.2) ]. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

To monitor maternal-fetal outcomes of pregnant women exposed to didanosine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. A study in rats showed that following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats. It is not known if didanosine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving didanosine.

Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of VIDEX in adult and pediatric patients [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14) ].

In an Expanded Access Program for patients with advanced HIV infection, patients aged 65 years and older had a higher frequency of pancreatitis (10%) than younger patients (5%) [see Warnings and Precautions (5.1) ]. Clinical studies of didanosine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.2) ].

Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance [see Clinical Pharmacology (12.3) ]. A dose reduction is recommended for these patients [see Dosage and Administration (2) ].

There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was initially administered at doses ten times the currently recommended dose, toxicities included: pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia, and hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis [see Clinical Pharmacology (12.3) ].

VIDEX is a brand name for didanosine, USP, a synthetic purine nucleoside analogue active against HIV-1.

Didanosine is available as VIDEX, a Pediatric Powder for Oral Solution [see How Supplied/Storage and Handling (16) ] and as VIDEX EC Delayed-Release Capsules, containing enteric-coated beadlets [consult prescribing information for VIDEX EC (didanosine)].

The chemical name for didanosine is 2′,3′-dideoxyinosine. The structural formula is:

Didanosine is a white crystalline powder with the molecular formula CHNO and a molecular weight of 236.2. The aqueous solubility of didanosine at 25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH less than 3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.

Didanosine is an antiviral agent [see Clinical Pharmacology (12.4) ].

The pharmacokinetic parameters of didanosine are summarized in Table 10. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (less than 5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.