These highlights do not include all the information needed to use VIDEX EC safely and effectively. See full prescribing information for VIDEX EC. VIDEX EC (didanosine, USP) Delayed-Release Capsules         Enteric-Coated Beadlets Initial U.S

Fatal and nonfatal pancreatitishas occurred during therapy with didanosine used alone or in combination regimensin both treatment-naive and treatment-experienced patients, regardless ofdegree of immunosuppression. VIDEX EC should be suspended in patients withsuspected pancreatitis and discontinued in patients with confirmed pancreatitis [see Warnings and Precautions (5.1) ].

Lacticacidosis and severe hepatomegaly with steatosis, including fatal cases, havebeen reported with the use of nucleoside analogues alone or in combination,including didanosine and other antiretrovirals. Fatal lactic acidosis hasbeen reported in pregnant women who received the combination of didanosineand stavudine with other antiretroviral agents. The combination of didanosineand stavudine should be used with caution during pregnancy and is recommendedonly if the potential benefit clearly outweighs the potential risk [seeWarnings and Precautions (5.2) ].

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

VIDEX EC should beadministered on an empty stomach. VIDEX EC Delayed-Release Capsules shouldbe swallowed intact.

The recommendedtotal daily dose is based on body weight and is administered as one capsulegiven on a once-daily schedule as outlined in Table 1.

Therecommended total daily dose to be administered once daily to pediatric patientsweighing at least 20 kg who can swallow capsules is based on body weight (kg),consistent with the recommended adult dosing guidelines (see Table 1). Please consult the complete prescribing information for VIDEX (didanosine)Pediatric Powder for Oral Solution for dosage and administration of didanosineto pediatric patients weighing less than 20 kg or who can not swallow capsules.

Dosing recommendations for VIDEX ECand VIDEX Pediatric Powder for Oral Solution are different for patients withrenal impairment. Please consult the complete prescribing information on administrationof VIDEX (didanosine) Pediatric Powder for Oral Solution to patients withrenal impairment.

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

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

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

In patients who are also taking tenofovirdisoproxil fumarate, a dose reduction of VIDEX EC to 250 mg (adults weighingat 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 60mL/min) once daily taken together with tenofovir disoproxil fumarate and alight meal (400 kcalories or less, 20% fat or less) or in the fasted stateis recommended. The appropriate dose of VIDEX EC coadministered with tenofovirdisoproxil fumarate in patients with creatinine clearance of less than 60mL/min has not been established [see Drug Interactions (7) and ClinicalPharmacology (12.3) ].

No dose adjustmentis required in patients with hepatic impairment [see Warnings andPrecautions (5.3) and ClinicalPharmacology (12.3) ].

VIDEXEC (didanosine, USP) Delayed-Release Capsules are white, opaque capsules asdescribed below:

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 pancreatitishas occurred during therapy with didanosine used alone or in combination regimensin both treatment-naive and treatment-experienced patients, regardless ofdegree of immunosuppression. VIDEX EC should be suspended in patients withsigns or symptoms of pancreatitis and discontinued in patients with confirmedpancreatitis. Patients treated with VIDEX EC in combination with stavudinemay be at increased risk for pancreatitis.

Whentreatment with life-sustaining drugs known to cause pancreatic toxicity isrequired, suspension of VIDEX EC (didanosine) therapy is recommended. In patientswith risk factors for pancreatitis, VIDEX EC should be used with extreme cautionand only if clearly indicated. Patients with advanced HIV-1 infection, especiallythe elderly, are at increased risk of pancreatitis and should be followedclosely. Patients with renal impairment may be at greater risk for pancreatitisif treated without dose adjustment. The frequency of pancreatitis is doserelated. [See Adverse Reactions (6) .]

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

The safety and efficacy of VIDEX EChave not been established in HIV-infected patients with significant underlyingliver disease. During combination antiretroviral therapy, patients with preexistingliver dysfunction, including chronic active hepatitis, have an increased frequencyof liver function abnormalities, including severe and potentially fatal hepaticadverse events, and should be monitored according to standard practice. Ifthere is evidence of worsening liver disease in such patients, interruptionor discontinuation of treatment must be considered.

Hepatotoxicity and hepatic failure resulting in death were reportedduring postmarketing surveillance in HIV-infected patients treated with hydroxyureaand other antiretroviral agents. Fatal hepatic events were reported most oftenin 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 EC 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 EC should be discontinued in patients with evidence of non-cirrhotic portal hypertension.

Peripheral neuropathy, manifested bynumbness, tingling, or pain in the hands or feet, has been reported in patientsreceiving didanosine therapy. Peripheral neuropathy has occurred more frequentlyin 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 EC should be considered in patients who develop peripheral neuropathy. [See Adverse Reactions (6) .]

Retinal changes and optic neuritishave been reported in patients taking didanosine. Periodic retinal examinationsshould be considered for patients receiving VIDEX EC [see AdverseReactions (6) ].

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

Redistribution/accumulation of bodyfat 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 mechanismand long-term consequences of these events are currently unknown. A causalrelationship has not been established.

The following adverse reactions arediscussed in greater detail in other sections:

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

Study Al454-152 was a 48-week, randomized,open-label study comparing VIDEX EC (400  mg once daily)plus stavudine (40 mg twice daily) plus nelfinavir (750 mg three times daily)to zidovudine (300 mg) plus lamivudine (150 mg) combination tablets twicedaily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients.Selected clinical adverse reactions that occurred in combination with otherantiretroviral agents are provided in Table 3.

In clinical trials using a buffered formulation of didanosine,pancreatitis resulting in death was observed in one patient who received didanosineplus stavudine plus nelfinavir, one patient who received didanosine plus stavudineplus indinavir, and 2 of 68 patients who received didanosine plus stavudineplus indinavir plus hydroxyurea. In an early access program, pancreatitisresulting in death was observed in one patient who received VIDEX EC plusstavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz [seeWarnings and Precautions (5) ].

Thefrequency of pancreatitis is dose related. In phase 3 studies with bufferedformulations of didanosine, incidence ranged from 1% to 10% with doses higherthan are currently recommended and 1% to 7% with recommended dose.

Selectedlaboratory abnormalities that occurred in a study of VIDEX EC in combinationwith other antiretroviral agents are shown in Table 4.

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

In pediatric phase 1 studies, pancreatitisoccurred in 2 of 60 (3%) patients treated at entry doses below 300 mg/m/dayand 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 didanosine120 mg/m every 12 hours and in less than 1% ofthe 274 pediatric patients who received didanosine 90 mg/m every12 hours in combination with zidovudine [see Clinical Studies (14) ].

Retinalchanges and optic neuritis have been reported in pediatric patients.

The following adverse reactions havebeen identified during postapproval use of didanosine. Because they are reportedvoluntarily from a population of unknown size, estimates of frequency cannotbe made. These reactions have been chosen for inclusion due to their seriousness,frequency of reporting, causal connection to didanosine, or a combinationof these factors.

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

Clinical recommendations based onthe results of drug interaction studies are listed in Table 5. Pharmacokineticresults of drug interaction studies are shown in Tables 9-12 [see Contraindications (4.1 and 4.2), Clinical Pharmacology (12.3) ].

Exposure to didanosine is increased when coadministeredwith tenofovir disoproxil fumarate [Table 5 and see Clinical Pharmacokinetics (12.3, Tables 9 and 10)].Increased exposure may cause or worsen didanosine-related clinical toxicities,including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheralneuropathy. Coadministration of tenofovir disoproxil fumarate with VIDEX ECshould be undertaken with caution, and patients should be monitored closelyfor didanosine-related toxicities and clinical response. VIDEX EC should besuspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia,or lactic acidosis develop [see Dosage and Administration (2.3),Warnings and Precautions (5) ]. Suppressionof CD4 cell counts has been observed in patients receiving tenofovir disoproxilfumarate with didanosine at a dose of 400 mg daily.

Predicted drug interactions with VIDEXEC are listed in Table 6.

Reproduction studies have been performedin 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 ofimpaired fertility or harm to the fetus due to didanosine. At approximately12 times the estimated human exposure, didanosine was slightly toxic to femalerats and their pups during mid and late lactation. These rats showed reducedfood intake and body weight gains but the physical and functional developmentof the offspring was not impaired and there were no major changes in the F2generation. A study in rats showed that didanosine and/or its metabolitesare transferred to the fetus through the placenta. Animal reproduction studiesare not always predictive of human response.

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

Fatal lactic acidosis has beenreported in pregnant women who received the combination of didanosine andstavudine with other antiretroviral agents. It is unclear if pregnancy augmentsthe risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnantindividuals receiving nucleoside analogues [see Warnings and Precautions (5.2) ]. The combination of didanosineand stavudine should be used with caution during pregnancy and is recommendedonly if the potential benefit clearly outweighs the potential risk. Healthcareproviders caring for HIV-infected pregnant women receiving didanosine shouldbe alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

To monitor maternal-fetal outcomesof pregnant women exposed to didanosine and other antiretroviral agents, anAntiretroviral Pregnancy Registry has been established. Physicians are encouragedto register patients by calling 1-800-258-4263.

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

Use of didanosine in pediatric patientsfrom 2 weeks of age through adolescence is supported by evidence from adequateand well-controlled studies of didanosine in adult and pediatric patients[see Dosage and Administration (2),Adverse Reactions (6.1), Clinical Pharmacology (12.3) , and Clinical Studies (14) ]. Additional pharmacokinetic studiesin pediatric patients support use of VIDEX EC in pediatric patients who weighat least 20 kg.

In an Expanded Access Program usinga buffered formulation of didanosine for the treatment of 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, including those for VIDEX EC, did not includesufficient numbers of subjects aged 65 years and over to determine whetherthey respond differently than younger subjects. Didanosine is known to besubstantially excreted by the kidney, and the risk of toxic reactions to thisdrug may be greater in patients with impaired renal function. Because elderlypatients are more likely to have decreased renal function, care should betaken in dose selection. In addition, renal function should be monitored anddosage adjustments should be made accordingly [see Dosage and Administration (2.2) ].

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

There is no known antidote for didanosineoverdosage. In phase 1 studies, in which buffered formulations of didanosinewere 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 ECis the brand name for an enteric-coated formulation of didanosine, USP, asynthetic purine nucleoside analogue active against HIV-1. VIDEX EC Delayed-ReleaseCapsules, containing enteric-coated beadlets, are available for oral administrationin strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredientsin the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate,methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, andtalc. The capsule shells contain gelatin and titanium dioxide. The capsulesare imprinted with edible inks.

Didanosine is alsoavailable in a powder formulation. Please consult the prescribing informationfor VIDEX (didanosine) Pediatric Powder for Oral Solution for additional information.

Thechemical name for didanosine is 2′,3′-dideoxyinosine. The structural formulais:

Didanosine is a whitecrystalline powder with the molecular formula CHNO and a molecular weight of 236.2. The aqueous solubility of didanosine at25° C and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidicsolutions. For example, at pH less than 3 and 37° C, 10% of didanosine decomposesto hypoxanthine in less than 2 minutes. In VIDEX EC, an enteric coating isused to protect didanosine from degradation by stomach acid.

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

The pharmacokinetic parameters ofdidanosine in HIV-infected adult and pediatric patients are summarized in Table 7, by weight ranges that correspond to recommended doses (Table 1). Didanosine is rapidly absorbed, with peak plasma concentrationsgenerally observed from 0.25 to 1.50 hours following oral dosing with a bufferedformulation. Increases in plasma didanosine concentrations were dose proportionalover the range of 50 to 400 mg. In adults, the mean (± standard deviation) oral bioavailabilityfollowing single oral dosing with a buffered formulation is 42 (±12)%. Afteroral administration, the urinary recovery of didanosine is approximately 18(±8)% of the dose. The CSF-plasma ratio following IV administration is 21(±0.03)%. Steady-state pharmacokinetic parameters did not differ significantlyfrom values obtained after a single dose. Binding of didanosine to plasmaproteins in vitro was low (less than 5%). Based on data from in vitro andanimal studies, it is presumed that the metabolism of didanosine in man occursby the same pathways responsible for the elimination of endogenous purines.

In VIDEX EC, the active ingredient,didanosine, is protected against degradation by stomach acid by the use ofan enteric coating on the beadlets in the capsule. The enteric coating dissolveswhen the beadlets empty into the small intestine, the site of drug absorption.With buffered formulations of didanosine, administration with antacid providesprotection from degradation by stomach acid.

In healthyvolunteers, as well as subjects infected with HIV-1, the AUC is equivalentfor didanosine administered as the VIDEX EC formulation relative to a bufferedtablet formulation. The peak plasma concentration (C)of didanosine, administered as VIDEX EC, is reduced approximately 40% relativeto didanosine buffered tablets. The time to the peak concentration (T)increases from approximately 0.67 hours for didanosine buffered tablets to2.0 hours for VIDEX EC.

In the presence of food, the C andAUC for VIDEX EC were reduced by approximately 46% and 19%, respectively,compared to the fasting state [see Dosage and Administration (2) ]. VIDEX EC should be taken on an emptystomach.

Renal Insufficiency: Datafrom two studies using a buffered formulation of didanosine indicated thatthe apparent oral clearance of didanosine decreased and the terminal eliminationhalf-life increased as creatinine clearance decreased (see Table 8). Following oral administration, didanosine was not detectable inperitoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailabilityof didanosine was not affected in patients requiring dialysis. [SeeDosage and Administration (2.2) .]

Hepatic Impairment: The pharmacokineticsof didanosine have been studied in 12 non-HIV-infected subjects with moderate(n=8) to severe (n=4) hepatic impairment (Child-Pugh Class B or C). Mean AUCand C values following a single 400 mg dose of didanosinewere approximately 13% and 19% higher, respectively, in patients with hepaticimpairment compared to matched healthy subjects. No dose adjustment is needed,because a similar range and distribution of AUC and C valueswas observed for subjects with hepatic impairment and matched healthy controls.[See Dosage and Administration (2.3) .]

PediatricPatients: The pharmacokinetics of didanosine have been eva luatedin HIV-exposed and HIV-infected pediatric patients from birth to adulthood.

Apopulation pharmacokinetic analysis was conducted on pooled didanosine plasmaconcentration data from 9 clinical trials in 106 pediatric (neonate to 18years of age) and 45 adult patients (greater than 18 years of age). Resultsshowed that body weight is the primary factor associated with oral clearance.Based on the data analyzed, dosing schedule (once versus twice daily) andformulation (powder for oral solution, tablet, and delayed-release capsule)did not have an effect on oral clearance. Didanosine exposure similar to thatat recommended adult doses can be achieved in pediatric patients with a weight-baseddosing scheme [see Dosage and Administration (2) ].

GeriatricPatients: Didanosine pharmacokinetics have not been studied inpatients over 65 years of age [see Use in Specific Populations (8.5) ].

Gender: The effects of gender on didanosine pharmacokinetics have not been studied.

Tables9 and 10 summarize the effects on AUC and C, witha 90% confidence interval (CI) when available, following coadministrationof VIDEX EC with a variety of drugs. For clinical recommendations based ondrug interaction studies for drugs in bold font, see Dosage and Administration (2.3) and Drug Interactions (7.1) .

Didanosine Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and C, witha 90% or 95% CI when available, following coadministration of buffered formulationsof didanosine with a variety of drugs. The results of these studies may be expected to apply to VIDEX EC. For mostof the listed drugs, no clinically significant pharmacokinetic interactionswere noted. For clinical recommendations based on drug interaction studiesfor drugs in bold font, see Dosage and Administration (2.3 forConcomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4.1), and DrugInteractions (7.1) .

Manufacturer

Bristol-Myers Squibb Company

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011