NDC 0087-6672 Videx Ec

Didanosine

NDC Product Code 0087-6672

NDC CODE: 0087-6672

Proprietary Name: Videx Ec What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Didanosine What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • This drug is used with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better. This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life. Didanosine belongs to a class of drugs known as nucleoside reverse transcriptase inhibitors-NRTI. Didanosine is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, do all of the following: (1) continue to take all HIV medications exactly as prescribed by your doctor, (2) always use an effective barrier method (latex or polyurethane condoms/dental dams) during all sexual activity, and (3) do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.

Product Characteristics

Color(s):
WHITE (C48325 - OPAQUE)
Shape: CAPSULE (C48336)
Size(s):
16 MM
18 MM
Imprint(s):
BMS;125;MG;6671
BMS;200;MG;6672
Score: 1

NDC Code Structure

  • 0087 - Bristol-myers Squibb Company

NDC 0087-6672-17

Package Description: 30 CAPSULE, DELAYED RELEASE in 1 BOTTLE

NDC Product Information

Videx Ec with NDC 0087-6672 is a a human prescription drug product labeled by Bristol-myers Squibb Company. The generic name of Videx Ec is didanosine. The product's dosage form is capsule, delayed release and is administered via oral form.

Labeler Name: Bristol-myers Squibb Company

Dosage Form: Capsule, Delayed Release - A solid dosage form in which the drug is enclosed within either a hard or soft soluble container made from a suitable form of gelatin, and which releases a drug (or drugs) at a time other than promptly after administration. Enteric-coated articles are delayed release dosage forms.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Videx Ec Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • DIDANOSINE 200 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • CARBOXYMETHYLCELLULOSE SODIUM (UNII: K679OBS311)
  • DIETHYL PHTHALATE (UNII: UF064M00AF)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TALC (UNII: 7SEV7J4R1U)
  • GELATIN (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • CARBOXYMETHYLCELLULOSE SODIUM (UNII: K679OBS311)
  • DIETHYL PHTHALATE (UNII: UF064M00AF)
  • METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)
  • TALC (UNII: 7SEV7J4R1U)
  • GELATIN (UNII: 2G86QN327L)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor - [EPC] (Established Pharmacologic Class)
  • Nucleoside Analog - [EXT]
  • Nucleoside Reverse Transcriptase Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Bristol-myers Squibb Company
Labeler Code: 0087
FDA Application Number: NDA021183 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 10-31-2000 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 10-31-2021 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Didanosine

Didanosine is pronounced as (dye dan' oh seen)

Why is didanosine medication prescribed?
Didanosine is used along with other medications to treat human immunodeficiency virus (HIV) infection. Didanosine is in a class of medications called nucleoside reverse t...
[Read More]

* Please review the disclaimer below.

Videx Ec Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Pancreatitis, Lactic Acidosis And Hepatomegaly With Steatosis

Fatal and nonfatal pancreatitis has occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. VIDEX EC 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. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. Coadministration of VIDEX EC and stavudine is contraindicated because of increased risk of serious and/or life-threatening events [see Contraindications (4) and Warnings and Precautions (5.2)]. Suspend treatment if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occurs.

1 Indications And Usage

VIDEX® EC (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)].

2 Dosage And Administration

VIDEX EC should be administered on an empty stomach. VIDEX EC Delayed-Release Capsules should be swallowed intact.

The recommended total daily dose is based on body weight and is administered as one capsule given on a once-daily schedule as outlined in Table 1.The recommended total daily dose to be administered once daily to pediatric patients weighing 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 didanosine to pediatric patients weighing less than 20 kg or who can not swallow capsules.Table 1: Recommended Dosage (Adult and Pediatric Patients)Body WeightDose20 kg to less than 25 kg200 mg once daily25 kg to less than 60 kg250 mg once dailyat least 60 kg400 mg once daily

2.2 Renal Impairment

Dosing recommendations for VIDEX EC and VIDEX Pediatric Powder for Oral Solution are different for patients with renal impairment. Please consult the complete prescribing information on administration of VIDEX (didanosine) Pediatric Powder for Oral Solution to patients with renal impairment.

Adult Patients

In adult patients with impaired renal function, the dose of VIDEX EC should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX EC in adult patients with renal insufficiency are presented in Table 2.Table 2: Recommended Dosage in Patients with Renal Impairment by Body WeightaCreatinine Clearance(mL/min)Dosage (mg)at least 60 kgless than 60 kga   Based on studies using a buffered formulation of didanosine.b  Not suitable for use in patients less than 60 kg with CLcr less than 10 mL/min. An alternate formulation of didanosine should be used.at least 60400 once daily250 once daily30-59200 once daily125 once daily10-29125 once daily125 once dailyless than 10125 once dailyb

Pediatric Patients

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 EC in this patient population, a reduction in the dose should be considered (see Table 2).

Patients Requiring Continuous Ambulatory Peritoneal Dialysis (Capd) Or Hemodialysis

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 didanosine following hemodialysis.

Concomitant Therapy With Tenofovir Disoproxil Fumarate

In patients who are also taking tenofovir disoproxil fumarate, a dose reduction of VIDEX EC 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 taken together with tenofovir disoproxil fumarate and a light meal (400 kilocalories or less, 20% fat or less) or in the fasted state is recommended. The appropriate dose of VIDEX EC 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)].

Hepatic Impairment

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

3 Dosage Forms And Strengths

  • VIDEX EC (didanosine, USP) Delayed-Release Capsules are white, opaque capsules as described below: •125 mg capsule imprinted with “BMS 125 mg 6671” in Tan •200 mg capsule imprinted with “BMS 200 mg 6672” in Green •250 mg capsule imprinted with “BMS 250 mg 6673” in Blue •400 mg capsule imprinted with “BMS 400 mg 6674” in Red

Contraindications

  • Ribavirin- 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.

5.1 Pancreatitis

Fatal and nonfatal pancreatitis has occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. VIDEX EC should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Patients treated with VIDEX EC in combination with stavudine may be at increased risk for pancreatitis; the coadministration of VIDEX EC and stavudine is contraindicated [see Contraindications (4)].When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of VIDEX EC (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX EC 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)].

5.2 Lactic Acidosis/Severe Hepatomegaly With Steatosis

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. Coadministration of VIDEX EC and stavudine is contraindicated [see Contraindications (4) and see Use in Specific Populations (8.1)]. Particular caution should be exercised when administering VIDEX EC 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 EC 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).

5.3 Hepatic Toxicity

The safety and efficacy of VIDEX EC 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. Coadministration of VIDEX EC and stavudine is contraindicated; the combination of VIDEX EC and hydroxyurea should be avoided. [see Contraindications (4) and Drug Interactions (7.2)].

5.4 Non-Cirrhotic Portal Hypertension

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 (e.g., 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.

5.5 Peripheral Neuropathy

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving didanosine 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. Discontinuation of VIDEX EC should be considered in patients who develop peripheral neuropathy. [see Contraindications (4), Adverse Reactions (6) and Drug Interactions (7.2)].

5.6 Retinal Changes And Optic Neuritis

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

5.7 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIDEX EC. 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 evaluation and treatment.Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.8 Lipoatrophy

Treatment with VIDEX EC has been associated with loss of subcutaneous fat, which is most evident in the face, limbs, and buttocks. The incidence and severity of lipoatrophy are related to cumulative exposure, and is often not reversible when VIDEX EC treatment is stopped. Patients receiving VIDEX EC should be frequently examined and questioned for signs of lipoatrophy, and if feasible therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.

6 Adverse Reactions

  • The following adverse reactions are discussed in greater detail in other sections: •Pancreatitis [see Boxed Warning, Warnings and Precautions (5.1)] •Lactic acidosis/severe hepatomegaly with steatosis [see Boxed Warning, Warnings and Precautions (5.2)] •Hepatic toxicity [see Warnings and Precautions (5.3)] •Non-cirrhotic portal hypertension [see Warnings and Precautions (5.4)] •Peripheral neuropathy [see Warnings and Precautions (5.5)] •Retinal changes and optic neuritis [see Warnings and Precautions (5.6)]

6.1 Clinical Trials Experience

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.

Clinical Trials Experience In Adult Subjects

Study AI454-152 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 twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients. Selected clinical adverse reactions that occurred in combination with other antiretroviral agents are provided in Table 3. Table 3: Selected Clinical Adverse Reactions, Study AI454-152aAdverse ReactionsPercent of Patientsb,cVIDEX EC + stavudine+ nelfinavirn=258zidovudine/lamivudined+ nelfinavirn=253a  Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group.b  Percentages based on treated patients.c  The incidences reported included all severity grades and all reactions regardless of causality.d  Zidovudine/lamivudine combination tablet.*  This event was not observed in this study arm.Diarrhea5758Peripheral Neurologic Symptoms/Neuropathy2511Nausea2436Headache2217Rash1412Vomiting1419Pancreatitis (see below)less than 1*In clinical trials using a buffered formulation of didanosine, pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir, one patient who received didanosine plus stavudine plus indinavir, and 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea. In an early access program, pancreatitis resulting in death was observed in one patient who received VIDEX EC plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz [see Warnings and Precautions (5)].The frequency of pancreatitis is dose related. In phase 3 studies with buffered formulations of didanosine, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose.Selected laboratory abnormalities that occurred in a study of VIDEX EC in combination with other antiretroviral agents are shown in Table 4.Table 4: Selected Laboratory Abnormalities, Study AI454-152aPercent of PatientsbVIDEX EC + stavudine+ nelfinavirn=258zidovudine/lamivudinec+ nelfinavirn=253ParameterGrades 3-4dAll GradesGrades 3-4dAll Gradesa  Median duration of treatment was 62 weeks in the VIDEX EC + stavudine + nelfinavir group and 61 weeks in the zidovudine/lamivudine + nelfinavir group.b  Percentages based on treated patients.c  Zidovudine/lamivudine combination tablet.d  Greater than 5 × ULN for SGOT and SGPT, at least 2.1 × ULN for lipase, and at least 2.6 × ULN for bilirubin (ULN = upper limit of normal).SGOT (AST)546519SGPT (ALT)644522Lipase523213Bilirubinless than 19less than 13

Clinical Trials Experience In Pediatric Patients

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/m2/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/m2 every 12 hours and in less than 1% of the 274 pediatric patients who received didanosine 90 mg/m2 every 12 hours in combination with zidovudine [see Clinical Studies (14)].Retinal changes and optic neuritis have been reported in pediatric patients.

6.2 Postmarketing Experience

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 didanosine, or a combination of these factors.Blood and Lymphatic System Disorders - anemia, leukopenia, and thrombocytopenia.Body as a Whole - abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain.Digestive Disorders - anorexia, dyspepsia, and flatulence.Exocrine Gland Disorders - pancreatitis (including fatal cases) [see Warnings and Precautions (5.1)], sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.Hepatobiliary Disorders - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.2)]; non cirrhotic portal hypertension [see Warnings and Precautions (5.4)]; hepatitis and liver failure.Metabolic Disorders - diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia.Musculoskeletal Disorders - myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.Ophthalmologic Disorders - retinal depigmentation and optic neuritis [see Warnings and Precautions (5.6)].

7.1 Established Drug Interactions

  • Clinical recommendations based on the results of drug interaction studies are listed in Table 5. Pharmacokinetic results of drug interaction studies are shown in Tables 9-12 [see Contraindications (4), Clinical Pharmacology (12.3)].Table 5: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX ECDrugEffectClinical Comment↑ Indicates increase.↓ Indicates decrease.a  Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.ganciclovir↑ didanosine concentrationIf there is no suitable alternative to ganciclovir, then use in combination with VIDEX EC with caution. Monitor for didanosine-associated toxicity.methadone↓ didanosine concentrationIf coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations.nelfinavirNo interaction 1 hour after didanosineAdminister nelfinavir 1 hour after VIDEX EC.tenofovir disoproxil fumarate↑ didanosine concentrationA dose reduction of VIDEX EC to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kilocalories or less and 20% fat or less) or in the fasted state is recommended.a250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min)200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min)Patients should be monitored for didanosine-associated toxicities and clinical response.Exposure to didanosine is increased when coadministered with 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 peripheral neuropathy. Coadministration of tenofovir disoproxil fumarate with VIDEX EC should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities and clinical response. VIDEX EC 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.

7.2 Predicted Drug Interactions

Predicted drug interactions with VIDEX EC are listed in Table 6.Table 6: Predicted Drug Interactions with VIDEX ECDrug or Drug ClassEffectClinical Comment↑ Indicates increase.a  Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended [see Warnings and Precautions (5.1)].b  [see Warnings and Precautions (5.6)].Drugs that may cause pancreatic toxicity↑ risk of pancreatitisUse only with extreme caution.aNeurotoxic drugs↑ risk of neuropathyUse with caution.bHydroxyurea↑ risk of pancreatitis,fatal hepatotoxicity, andsevere peripheral neuropathyUse should be avoided.

Pregnancy Category B

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)]. Coadministration of VIDEX EC and stavudine is contraindicated [see Contraindications (4)]. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

Antiretroviral Pregnancy Registry

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.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed 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 breastfeed if they are receiving didanosine.

8.4 Pediatric Use

Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and 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 studies in pediatric patients support use of VIDEX EC in pediatric patients who weigh at least 20 kg.

8.5 Geriatric Use

In an Expanded Access Program using a 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 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)].

8.6 Renal Impairment

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)].

10 Overdosage

There is no known antidote for didanosine overdosage. In phase 1 studies, in which buffered formulations of didanosine were 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)].

11 Description

VIDEX® EC is the brand name for an enteric-coated formulation of didanosine, USP, a synthetic purine nucleoside analogue active against HIV-1. VIDEX EC Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain gelatin and titanium dioxide. The capsules are imprinted with edible inks.Didanosine is also available in a powder formulation. Please consult the prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for additional information.The chemical name for didanosine is 2′,3′-dideoxyinosine. The structural formula is:Didanosine is a white crystalline powder with the molecular formula C10H12N4O3 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. In VIDEX EC, an enteric coating is used to protect didanosine from degradation by stomach acid.

12.1 Mechanism Of Action

Didanosine is an antiretroviral drug [see Microbiology (12.4) ].

12.3 Pharmacokinetics

The pharmacokinetic parameters of didanosine 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 concentrations generally observed from 0.25 to 1.50 hours following oral dosing with a buffered formulation. Increases in plasma didanosine concentrations were dose proportional over the range of 50 to 400 mg. In adults, the mean (± standard deviation) oral bioavailability following single oral dosing with a buffered formulation is 42 (±12)%. After oral 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 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.Table 7: Pharmacokinetic Parameters for Didanosine in HIV-infected Patientsa  The pharmacokinetic parameters (mean ± standard deviation) of didanosine were determined by a population pharmacokinetic model based on combined clinical studies.ParameteraPediatricsAdults20 kg to less than 25 kgn=1025 kg to less than 60 kgn=17At least 60 kgn=7At least 60 kgn=44Apparent clearance (L/h)89.5 ± 21.6116.2 ± 38.6196.0 ± 55.8174.5 ± 69.7Apparent volume of distribution (L)98.1 ± 30.2154.7 ± 55.0363 ± 137.7308.3 ± 164.3Elimination half-life (h)0.75 ± 0.130.92 ± 0.091.26 ± 0.191.19 ± 0.21Steady-state AUC (mg•h/L)2.38 ± 0.662.36 ± 0.702.25 ± 0.892.65 ± 1.07

Comparison Of Didanosine Formulations

In VIDEX EC, the active ingredient, didanosine, is protected against degradation by stomach acid by the use of an enteric coating on the beadlets in the capsule. The enteric coating dissolves when the beadlets empty into the small intestine, the site of drug absorption. With buffered formulations of didanosine, administration with antacid provides protection from degradation by stomach acid.In healthy volunteers, as well as subjects infected with HIV-1, the AUC is equivalent for didanosine administered as the VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma concentration (Cmax) of didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (Tmax) increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for VIDEX EC.

Effect Of Food

In the presence of food, the Cmax and AUC 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 empty stomach.

Special Populations

Renal Insufficiency: Data from two studies using a buffered formulation of didanosine indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 8). Following oral administration, didanosine was not detectable in peritoneal 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 bioavailability of didanosine was not affected in patients requiring dialysis. [See Dosage and Administration (2.2)].Table 8: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered FormulationParameterCreatinine Clearance (mL/min)Dialysis Patientsn=11at least 90n=1260-90n=630-59n=610-29n=3ND = not determined due to anuria.CLcr = creatinine clearance.CL/F = apparent oral clearance.CLR = renal clearance.CLcr (mL/min)112 ± 2268 ± 846 ± 813 ± 5NDCL/F (mL/min)2164 ± 6381566 ± 8331023 ± 378628 ± 104543 ± 174CLR (mL/min)458 ± 164247 ± 153100 ± 4420 ± 8less than 10T½ (h)1.42 ± 0.331.59 ± 0.131.75 ± 0.432.0 ± 0.34.1 ± 1.2Hepatic Impairment: The pharmacokinetics of 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 AUC and Cmax values following a single 400 mg dose of didanosine were approximately 13% and 19% higher, respectively, in patients with hepatic impairment compared to matched healthy subjects. No dose adjustment is needed, because a similar range and distribution of AUC and Cmax values was observed for subjects with hepatic impairment and matched healthy controls. [see Dosage and Administration (2.3)].Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-exposed and HIV-infected pediatric patients from birth to adulthood.A population pharmacokinetic analysis was conducted on pooled didanosine plasma concentration data from 9 clinical trials in 106 pediatric (neonate to 18 years of age) and 45 adult patients (greater than 18 years of age). Results showed that body weight is the primary factor associated with oral clearance. Based on the data analyzed, dosing schedule (once versus twice daily) and formulation (powder for oral solution, tablet, and delayed-release capsule) did not have an effect on oral clearance. Didanosine exposure similar to that at recommended adult doses can be achieved in pediatric patients with a weight-based dosing scheme [see Dosage and Administration (2)].Geriatric Patients: Didanosine pharmacokinetics have not been studied in patients over 65 years of age [see Use in Specific Populations (8.5)].Gender: The effects of gender on didanosine pharmacokinetics have not been studied.

Drug Interactions

Tables 9 and 10 summarize the effects on AUC and Cmax, with a 90% confidence interval (CI) when available, following coadministration of VIDEX EC with a variety of drugs. For clinical recommendations based on drug interaction studies for drugs in bold font, [see Dosage and Administration (2.3) and Drug Interactions (7.1)].Table 9: Results of Drug Interaction Studies with VIDEX EC: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values% Change of DidanosinePharmacokinetic ParametersaDrugDidanosine DosagenAUC of Didanosine(90% CI)Cmax of Didanosine(90% CI)↑ Indicates increase.↓ Indicates decrease.↔ Indicates no change, or mean increase or decrease of less than 10%.a  The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.b  All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.c  Tenofovir disoproxil fumarate.d  373 kilocalories, 8.2 grams fat.e  Compared with VIDEX EC 250 mg administered alone under fasting conditions.f  Compared with VIDEX EC 400 mg administered alone under fasting conditions.g  Comparisons are made to historical controls (n=148, pooled from 5 studies) conducted in healthy subjects. The number of subjects evaluated for AUC and Cmax is 15 and 16, respectively.tenofovir,b,c 300 mg  once daily with a light meald400 mg single dose fasting2 hours before tenofovir26↑ 48%(31, 67%)↑ 48%(25, 76%)tenofovir,b,c 300 mg  once daily with a light meald400 mg single dosewith tenofovir and a light meal25↑ 60%(44, 79%)↑ 64%(41, 89%)tenofovir,b,c 300 mg  once daily with a light meald200 mg single dosewith tenofovir and a light meal33↑ 16%(6, 27%)e↓ 12%(-25, 3%)e250 mg single dosewith tenofovir and a light meal33↔ (-13, 5%)f↓ 20%(-32, -7%)f325 mg single dosewith tenofovir and a light meal33↑ 13%(3, 24%)f↓ 11%(-24, 4%)fmethadone, chronic maintenance dose400 mg single dose15, 16g↓ 17%(-29, -2%)↓ 16%(-33, 4%)Table 10: Results of Drug Interaction Studies with VIDEX EC: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values% Change of Coadministered DrugPharmacokinetic Parametersa,bDrugDidanosine DosagenAUC of Coadministered Drug(90% CI)Cmax of Coadministered Drug(90% CI)↔ Indicates no change, or mean increase or decrease of less than 10%.a  The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.b  All studies conducted in healthy volunteers at least 60 kg with creatinine clearance of at least 60 mL/min.c  Tenofovir disoproxil fumarate.d  373 kilocalories, 8.2 grams fat.ciprofloxacin, 750 mg  single dose400 mg single dose16↔↔indinavir, 800 mg   single dose400 mg single dose23↔↔ketoconazole, 200 mg   single dose400 mg single dose21↔↔tenofovir,c 300 mg  once daily with a light meald400 mg single dosefasting 2 hours before tenofovir25↔↔tenofovir,c 300 mg   once daily with a light meald400 mg single dosewith tenofovir and a light meal25↔↔Didanosine Buffered Formulations: Tables 11 and 12 summarize the effects on AUC and Cmax, with a 90% or 95% CI when available, following coadministration of buffered formulations of didanosine with a variety of drugs. The results of these studies may be expected to apply to VIDEX EC. For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. For clinical recommendations based on drug interaction studies for drugs in bold font, [(see Dosage and Administration, 2.3 for Concomitant Therapy with Tenofovir Disoproxil Fumarate), Contraindications (4), and Drug Interactions (7.1)].Table 11: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values% Change of DidanosinePharmacokinetic ParametersaDrugDidanosine DosagenAUC of Didanosine (95% CI)Cmax of Didanosine(95% CI)↑ Indicates increase.↓ Indicates decrease.↔ Indicates no change, or mean increase or decrease of less than 10%.a  The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.b  90% CI.c  HIV-infected patients.NA = Not available.allopurinol,renally impaired, 300 mg/day200 mg single dose2↑ 312%↑ 232%healthy volunteer, 300 mg/dayfor 7 days400 mg single dose14↑ 113%↑ 69%ganciclovir, 1000 mg every 8 hours,2 hours after didanosine200 mg every 12 hours12↑ 111%NAciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before didanosine200 mg every 12 hoursfor 3 days8c↓ 16%↓ 28%indinavir, 800 mg single dose  simultaneous200 mg single dose16↔↔  1 hour before didanosine200 mg single dose16↓ 17%(-27, -7%)b↓ 13%(-28, 5%)bketoconazole, 200 mg/day for 4 days,  2 hours before didanosine375 mg every 12 hoursfor 4 days12c↔↓ 12%loperamide, 4 mg every 6 hours for 1 day300 mg single dose12c↔↓ 23%metoclopramide, 10 mg single dose300 mg single dose12c↔↑ 13%ranitidine, 150 mg single dose,  2 hours before didanosine375 mg single dose12c↑ 14%↑ 13%rifabutin, 300 mg or 600 mg/day for 12 days167 mg or 250 mg every 12 hoursfor 12 days11↑ 13%(-1, 27%)↑ 17%(-4, 38%)ritonavir, 600 mg every 12 hours for 4 days200 mg every 12 hoursfor 4 days12↓ 13%(0, 23%)↓ 16%(5, 26%)stavudine, 40 mg every 12 hours for 4 days100 mg every 12 hoursfor 4 days10↔↔sulfamethoxazole, 1000 mg single dose200 mg single dose8c↔↔trimethoprim, 200 mg single dose200 mg single dose8c↔↑ 17%(-23, 77%)zidovudine, 200 mg every 8 hours for 3 days200 mg every 12 hoursfor 3 days6c↔↔Table 12: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values% Change of Coadministered DrugPharmacokinetic ParametersaDrugDidanosine DosagenAUC of Coadministered Drug(95% CI)Cmax of Coadministered Drug(95% CI)↑ Indicates increase.↓ Indicates decrease.↔ Indicates no change, or mean increase or decrease of less than 10%.a  The 95% confidence intervals for the percent change in the pharmacokinetic parameter are displayed. b  HIV-infected patients.NA = Not available.dapsone, 100 mg single dose200 mg every 12 hours for 14 days6b↔↔ganciclovir, 1000 mg every 8 hours,2 hours after didanosine200 mg every 12 hours12b↓ 21%NAnelfinavir, 750 mg single dose,1 hour after didanosine200 mg single dose10b↑ 12%↔ranitidine, 150 mg single dose,2 hours before didanosine375 mg single dose12b↓ 16%↔ritonavir, 600 mg every 12 hours for 4 days200 mg every 12 hoursfor 4 days12↔↔stavudine, 40 mg every 12 hours for 4 days100 mg every 12 hoursfor 4 days10b↔↑ 17%sulfamethoxazole, 1000 mg single dose200 mg single dose8b↓ 11%(-17, -4%)↓ 12%(-28, 8%)trimethoprim, 200 mg single dose200 mg single dose8b↑ 10%(-9, 34%)↓ 22%(-59, 49%)zidovudine, 200 mg every 8 hours for 3 days200 mg every 12 hoursfor 3 days6b↓ 10%(-27, 11%)↓ 16.5%(-53, 47%)

Mechanism Of Action

Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3′-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5′-triphosphate. Dideoxyadenosine 5′-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5′-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.

Antiviral Activity In Cell Culture

The anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (EC50) ranged from 2.5 to 10 μM (1 μM = 0.24 μg/mL) in lymphoblastic cell lines and 0.01 to 0.1 μM in monocyte/macrophage cell cultures.

Resistance

HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed amino acid substitutions K65R, L74V, and M184V in reverse transcriptase. The L74V substitution was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in cell culture compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine resistance-associated substitutions.

Cross-Resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with didanosine and zidovudine exhibited decreased susceptibility to didanosine, lamivudine, stavudine, and zidovudine in cell culture. These isolates harbored five substitutions (A62V, V75I, F77L, F116Y, and Q151M) in reverse transcriptase. In data from clinical studies, the presence of thymidine analogue mutation substitutions (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime carcinogenicity studies were conducted in mice and rats for 22 and 24 months, respectively. In the mouse study, initial doses of 120, 800, and 1200 mg/kg/day for each sex were lowered after 8 months to 120, 210, and 210 mg/kg/day for females and 120, 300, and 600 mg/kg/day for males. The two higher doses exceeded the maximally tolerated dose in females and the high dose exceeded the maximally tolerated dose in males. The low dose in females represented 0.68-fold maximum human exposure and the intermediate dose in males represented 1.7-fold maximum human exposure based on relative AUC comparisons. In the rat study, initial doses were 100, 250, and 1000 mg/kg/day, and the high dose was lowered to 500 mg/kg/day after 18 months. The upper dose in male and female rats represented 3-fold maximum human exposure.Didanosine induced no significant increase in neoplastic lesions in mice or rats at maximally tolerated doses.Didanosine was positive in the following genetic toxicology assays: 1) the Escherichia coli tester strain WP2 uvrA bacterial mutagenicity assay; 2) the L5178Y/TK+/- mouse lymphoma mammalian cell gene mutation assay; 3) the in vitro chromosomal aberrations assay in cultured human peripheral lymphocytes; 4) the in vitro chromosomal aberrations assay in Chinese Hamster Lung cells; and 5) the BALB/c 3T3 in vitro transformation assay. No evidence of mutagenicity was observed in an Ames Salmonella bacterial mutagenicity assay or in rat and mouse in vivo micronucleus assays.

13.2 Animal Toxicology And/Or Pharmacology

Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues.

14.1 Adult Patients

Study AI454-152 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 twice daily plus nelfinavir (750 mg three times daily) in 511 treatment-naive patients, with a mean CD4 cell count of 411 cells/mm3 (range 39 to 1105 cells/mm3) and a mean plasma HIV-1 RNA of 4.71 log10 copies/mL (range 2.8 to 5.9 log10 copies/mL) at baseline. Patients were primarily males (72%) and Caucasian (53%) with a mean age of 35 years (range 18 to 73 years). The percentages of patients with HIV-1 RNA less than 400 and less than 50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 13, respectively.Table 13: Outcomes of Randomized Treatment Through Week 48, AI454-152OutcomePercent of Patients with HIV-1 RNA less than 400 copies/mL(less than 50 copies/mL)VIDEX EC + stavudine+ nelfinavirn=258zidovudine/lamivudinea+ nelfinavirn=253a  Zidovudine/lamivudine combination tablet.b  Corresponds to rates at Week 48 in Figure 1.c  Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.d  Includes viral rebound at or before Week 48 and failure to achieve confirmed HIV-1 RNA less than 400 copies/mL (less than 50 copies/mL) through Week 48.e  Includes lost to follow-up, subject’s withdrawal, discontinuation due to physician’s decision, never treated, and other reasons.Responderb,c55% (33%)56% (33%)Virologic failured22% (45%)21% (43%)Death or discontinued due to disease progression1% (1%)2% (2%)Discontinued due to adverse event6% (6%)7% (7%)Discontinued due to other reasonse16% (16%)15% (16%)

14.2 Pediatric Patients

Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients 3 months to 18 years of age treated for more than 1.5 years with zidovudine (180 mg/m2 every 6 hours), didanosine (120 mg/m2 every 12 hours), or zidovudine (120 mg/m2 every 6 hours) plus didanosine (90 mg/m2 every 12 hours). Patients treated with didanosine or didanosine plus zidovudine had lower rates of HIV-1 disease progression or death compared with those treated with zidovudine alone.

16 How Supplied/Storage And Handling

VIDEX EC (didanosine, USP) Delayed-Release Capsules are white, opaque capsules that are packaged in bottles with child-resistant closures as described in Table 14.Table 14: VIDEX EC Delayed-Release Capsules125 mg capsule imprinted with “BMS 125 mg 6671” in TanNDC No. 0087-6671-1730 capsules/bottle200 mg capsule imprinted with “BMS 200 mg 6672” in GreenNDC No. 0087-6672-1730 capsules/bottle250 mg capsule imprinted with “BMS 250 mg 6673” in BlueNDC No. 0087-6673-1730 capsules/bottle400 mg capsule imprinted with “BMS 400 mg 6674” in RedNDC No. 0087-6674-1730 capsules/bottle

Storage And Handling

StorageThe capsules should be stored in tightly closed containers at 25° C (77° F). Excursions between 15° C and 30° C (59° F and 86° F) are permitted (see USP Controlled Room Temperature).

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Other

PancreatitisInform patients that a serious toxicity of VIDEX EC, used alone and in combination regimens, is pancreatitis, which may be fatal. [see Warnings and Precautions (5.1)].Lactic Acidosis and Severe Hepatomegaly with SteatosisInform patients that 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. [see Warnings and Precautions (5.2)].Hepatic ToxicityInform patients that hepatotoxicity including fatal hepatic adverse events has been reported in patients with preexisting liver dysfunction. The safety and efficacy of VIDEX EC have not been established in HIV-infected patients with significant underlying liver disease. [see Warnings and Precautions (5.3)].Non-cirrhotic Portal HypertensionInform patients that non-cirrhotic portal hypertension has been reported in patients taking VIDEX EC, including cases leading to liver transplantation or death. [see Warnings and Precautions (5.4)].​Peripheral NeuropathyInform patients that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX EC (didanosine). Instruct patients that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV-1 disease or a history of peripheral neuropathy, and that discontinuation of VIDEX EC may be required if toxicity develops [see Warnings and Precautions (5.5)].​Retinal Changes and Optic NeuritisInform patients that retinal changes and optic neuritis, which may result in blurred, have been reported in adult and pediatric patients. Advise patients to have regular eye exams while taking VIDEX EC [see Warnings and Precautions (5.6)].​Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.7)].LipoatrophyInform patient that loss of body fat (e.g., from arms, legs, or face) may occur in individuals receiving antiretroviral therapy including VIDEX EC. Monitor patients receiving VIDEX EC to monitor for clinical signs and symptons of lipoatrophy. Patients should be routinely questioned about body changes related to lipoatrophy [see Warnings and Precautions (5.8)].​Drug InteractionsVIDEX EC may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription of non-prescription medication or herbal products, including alcohol, which may exacerbate VIDEX EC toxicities. Patients should avoid alcohol with VIDEX EC [see Contraindications (4), Drug Interactions (7)].Pregnancy RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnancy women exposed to VIDEX EC [seeUse in Specific Populations (8.1)].LactationInform patients that it is not known if VIDEX EC can be passed to the baby by breast milk and whether it could harm the baby. Advise mothers with HIV-1 not breastfeed because HIV-1 can be passed to the baby in breast milk. [seeUse in Specific Populations (8.3)].Dosing InformationInstruct patients to swallow the capsule whole on an empty stomach and to not open the capsule.Instruct patients not to miss a dose but if they do, patients should take VIDEX EC as soon as possible. Inform patients that it is important to take VIDEX EC on a regular dosing schedule.

Spl Medguide

  • Medication GuideVIDEX EC (VY-dex Ee-see)(didanosine, USP)Delayed-Release CapsulesEnteric-Coated BeadletsWhat is the most important information I should know about VIDEX EC?VIDEX EC may cause serious side effects, including:Inflammation of your pancreas (pancreatitis) can happen in people who take VIDEX EC and can lead to death. People who take VIDEX EC in combination with the medicine stavudine may be at an increased risk for pancreatitis. Do not take VIDEX EC with stavudine.Call your healthcare provider right away if you have any of the following symptoms of pancreatitis:severe stomach (abdomen) painnausea and vomitingswelling of your stomachfeverBuild-up of an acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take VIDEX EC or similar medicines (nucleoside analogues). Lactic acidosis is a serious medical emergency that can lead to death. There have been deaths reported in pregnant women who get lactic acidosis after taking VIDEX EC and ZERIT (stavudine). Do not take VIDEX EC with stavudine.Call your healthcare provider right away if you have any of the following symptoms which could be signs of lactic acidosis: feel weak or tired feel cold, especially in your arms and legs have unusual (not normal) muscle pain feel dizzy or light-headed have trouble breathing have a fast or irregular heartbeat have stomach pain with nausea and vomiting weight lossSevere liver problems, including liver failure, can happen in people who take VIDEX EC. Your liver may become large (hepatomegaly), you may develop fat in the liver (steatosis), or you may have high blood pressure in the large vein of the liver (portal hypertension). Severe liver problems can lead to liver transplantation or death in some people taking VIDEX EC. Taking VIDEX EC with medicines that contain hydroxyurea or stavudine may increase your risk for liver problems.You may be more likely to get lactic acidosis or severe liver problems if you are a female, are very overweight (obese), or have been taking nucleoside analogue medicines for a long time.Call your healthcare provider right away if you have any of the following symptoms of severe liver problems:yellowing of your skin or the white of your eyes (jaundice)dark or "tea-colored" urinelight colored stools (bowel movements)loss of appetitenauseapain, aching, or tenderness on the right side of your stomach areaFor more information about side effects, see "What are the possible side effects of VIDEX EC?."What is VIDEX EC?VIDEX EC is a prescription medicine that is used with other antiretroviral medicines to treat Human Immunodeficiency Virus (HIV)-1 infection.HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).Do not take VIDEX EC if you take: allopurinol ribavirin stavudineBefore you take VIDEX EC, tell your healthcare provider about all of your medical conditions, including if you:have or had problems with your pancreashave or had kidney problemshave or had liver problems, including hepatitishave or had numbness, tingling, or pain in the hands or feet (peripheral neuropathy)are receiving dialysisdrink alcoholic beveragesare pregnant or plan to become pregnant. It is not known if VIDEX EC will harm your unborn baby. Pregnancy Registry: There is a pregnancy registry for women who take antiretroviral medicines, including VIDEX EC during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.are breastfeeding or plan to breastfeed. Do not breastfeed if you take VIDEX EC. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.      It is not known if VIDEX EC can pass into your breast milk and if it could harm your baby.      Talk with your healthcare provider about the best way to feed your baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.Some medicines interact with VIDEX EC. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.You can ask your healthcare provider or pharmacist for a list of medicines that interact with VIDEX EC.Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take VIDEX EC with other medicines.How should I take VIDEX EC?Take VIDEX EC exactly as your healthcare provider tells you to take it.Your healthcare provider will tell you how much VIDEX EC to take and when to take it.Take VIDEX EC on an empty stomach.Take VIDEX EC capsules whole. If you cannot swallow VIDEX EC capsules whole, tell your healthcare provider. You may need a different medicine.Your healthcare provider may change your dose. Do not change your dose of VIDEX EC without talking to your healthcare provider.Do not miss a dose of VIDEX EC. If you miss a dose of VIDEX EC, take it as soon as possible.It is important to take VIDEX EC on a regular schedule. The virus in your blood may increase and the virus may become harder to treat if you miss doses.Your healthcare provider may lower your dosage of VIDEX EC if your kidneys are not working well.If you take too much VIDEX EC, go to the nearest emergency room right away.What are the possible side effects of VIDEX EC?VIDEX EC can cause serious side effects, including:See "What is the most important information I should know about VIDEX EC?"Numbness, tingling, or pain in your hands or feet (peripheral neuropathy). Peripheral neuropathy is common during treatment with VIDEX EC and can be severe. Peripheral neuropathy happens more often in people who have advanced HIV-1 disease, have a history of peripheral neuropathy, or in people who are being treated with medicines that can cause neurologic problems. Tell your healthcare provider if you get numbness, tingling, or pain in your hands or feet during treatment with VIDEX EC.Vision changes. Call your healthcare provider if you have changes in vision, such as blurred vision. You should have regular eye exams while taking VIDEX EC.Changes in your immune system (immune reconstitution syndrome). Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new or worse symptoms of infection after you start taking HIV medicine.Loss of body fat (lipoatrophy) can happen with VIDEX use. These changes may include less fat in your legs, arms, face.The most common side effects of VIDEX EC include: diarrhea rash nausea vomiting headacheThese are not all the possible side effects of VIDEX EC.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1 800-FDA-1088.How should I store VIDEX EC?Store VIDEX EC capsules in a tightly closed container between 59° F to 86° F (15° C to 30° C)Keep VIDEX EC and all medicines out of the reach of children.General information about the safe and effective use of VIDEX EC.Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VIDEX EC for a condition for which it was not prescribed. Do not give VIDEX EC to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for information about VIDEX EC that is written for health professionals. What are the ingredients in VIDEX EC?Active Ingredients: didanosine, USPInactive Ingredients: carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talcCapsule shell: gelatin, and titanium dioxide.VIDEX® EC is a registered trademark of Bristol-Myers Squibb Company. Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USAFor more information, go to www.bms.com/products/Pages/prescribing.aspx or call 1-800-321-1335. This Medication Guide has been approved by the U.S. Food and Drug Administration.[Print code]Revised January 2018

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