Videx EC

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, the area under the plasma concentration time curve (AUC) is equivalent for didanosine administered as the VIDEX EC formulation relative to a buffered tablet formulation. The peak plasma concentration (C_max ) of didanosine, administered as VIDEX EC, is reduced approximately 40% relative to didanosine buffered tablets. The time to the peak concentration (T_max) increases from approximately 0.67 hours for didanosine buffered tablets to 2.0 hours for VIDEX EC.

VIDEX EC should be taken on an empty stomach, at least 1.5 hours before or 2 hours after a meal. Compared to the fasting condition, the administration of VIDEX EC capsules with a high-fat meal significantly decreased the didanosine C_max (46%) and AUC (19%). Coadministering VIDEX EC capsules with a light meal, 1.5 hours before a light meal, or 2 hours after a light meal resulted in significant decrease in both C_max (22%, 15%, and 15% respectively) and AUC of didanosine (27%, 24%, and 10% respectively) compared to the fasting condition. Administration of VIDEX EC capsules 1.5, 2 or 3 hours before a light meal resulted in equivalent C_max and AUC values compared to those obtained under fasting conditions. Compared to the intact capsule administered in the fasting condition, coadministration of VIDEX EC beadlets with yogurt or apple sauce resulted in a significant decrease in C_max (30% and 24% respectively) and AUC of didanosine (20% and 18% respectively).

Coadministration of VIDEX EC with drugs that are known to cause peripheral neuropathy or pancreatitis may increase the risk of these toxicities (see Warnings, Pancreatitis, Peripheral Neuropathy) and should be done only with extreme caution.

Methadone: When VIDEX tablets were administered to opiate-dependent patients (n=16) chronically treated with methadone, didanosine exposure, as measured by AUC, was decreased by 57% compared to untreated controls (n=10). There was no clinically significant impact on methadone exposure. No studies have been conducted with VIDEX EC.

Tenofovir disoproxil fumarate: Exposure to VIDEX EC is increased when coadministered with tenofovir. When VIDEX EC was administered (in the fasting state) 2 hours before tenofovir disoproxil fumarate with a light meal, the AUC of didanosine increased by 48% relative to VIDEX EC alone in the fasted state. When VIDEX EC was administered together with tenofovir disoproxil fumarate and a light meal, the AUC of didanosine increased by 60% relative to VIDEX EC alone in the fasted state. Administration of reduced doses of VIDEX EC with tenofovir and a light meal resulted in didanosine exposures (AUC) similar to the recommended doses of VIDEX EC given alone in the fasted state. Therefore, a dose reduction of VIDEX EC is recommended when coadministered with tenofovir (see Dosage, Concomitant Therapy). Caution should be used when coadministering reduced-dose didanosine, tenofovir, and an NNRTI in treatment-naive patients with high viral loads at baseline since such use has been associated with reports of a high rate of virologic failure and emergence of resistance at an early stage. Increased exposure may cause or worsen didanosine-related clinical toxicities including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. All patients receiving tenofovir disoproxil fumarate and didanosine concomitantly should be closely monitored for didanosine-related adverse events and clinical response (see Warnings).

Allopurinol: The AUC of didanosine was increased about 4-fold when allopurinol at 300 mg/day was coadministered with a single 200-mg dose of didanosine to two patients with renal impairment (CL_cr=15 and 18 mL/min). In 14 healthy volunteers, the mean AUC of didanosine increased approximately 2-fold when a 300-mg dose of allopurinol (daily for 7 days) was given with a single 400 mg dose of VIDEX. Thus, the risk of dose-related toxicities, such as pancreatitis (see Warnings), may be increased if allopurinol and didanosine are administered together. It is recommended that these two drugs not be administered together.

Quinolone Antibiotics: VIDEX EC capsules do not contain an antacid component and therefore can be coadministered with tetracycline or quinolone anti-infective agents.

Ganciclovir: Administration of VIDEX (tablets or the powder) two hours prior to, or concurrent with, ganciclovir was associated with a mean increase of 111% in the steady state AUC of didanosine. A minor decrease (21%) in the steady state AUC of ganciclovir was seen when VIDEX (tablets or the powder) was administered 2 hours prior to ganciclovir, but not when both drugs were given simultaneously. It is not known if these changes are clinically significant. There were no changes in the renal clearance of either drug. There is no evidence that VIDEX EC potentiates the myelosuppressive effects of ganciclovir.

Ribavirin: Based on in vitro data, ribavirin increases the intracellular triphosphate levels of didanosine. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving didanosine and ribavirin with or without stavudine. The administration of didanosine and ribavirin should be avoided unless the potential benefit outweighs the risk. Patients should be monitored for didanosine-related toxicities.

Interactions with Other Antiretroviral Drugs: There is no drug-drug interaction between VIDEX EC capsules and indinavir, therefore, these two products can be given together.

Drugs whose absorption can be affected by the level of acidity in the stomach (e.g., ketoconazole, dapsone, itraconazole): VIDEX EC capsules can be coadministered with these drugs, due to the absence of the antacid component in the VIDEX EC capsule formulation.

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). 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, Dose Adjustment).

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate evaluation and treatment.

HIV-Infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether VIDEX is excreted in human milk. A study in rats showed that, following oral administration, didanosine and/or its metabolites were excreted into the milk of lactating rats.

The VIDEX EC capsule formulation does not contain sucrose.

VIDEX EC capsules have not been studied in pediatric patients.

Ingestion of VIDEX EC with food significantly reduces the amount of didanosine absorbed. VIDEX EC should be administered at least 1.5 hours before or 2 hours after eating (see Dosage).

There are no adequate and well-controlled studies of didanosine in pregnant women. VIDEX EC 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 not known if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see Warnings, Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

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.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Patients with renal impairment (serum creatinine >1.5 mg/dL or creatinine clearance <60 mL/min) may be at greater risk for toxicity from VIDEX EC due to decreased drug clearance. The risk of pancreatitis (see Warnings), may be increased if allopurinol and didanosine are administered together in this patient population; it is recommended that these 2 drugs not be administered together (see Drug Interactions).

The elimination half-life of didanosine is increased in anuric patients requiring hemodialysis (see Pharmacokinetics, Pharmacology). Because of the potential for drug removal, VIDEX EC should be administered after dialysis. Dose reductions should be considered in patients with renal impairment (see Warnings and Dosage).

Patients with hepatic impairment may be at greater risk for toxicity related to VIDEX EC treatment due to altered metabolism (see Warnings and Dosage).

Didanosine has been associated with asymptomatic hyperuricemia; treatment suspension may be necessary if clinical measures aimed at reducing uric acid levels fail.

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

VIDEX EC Capsules: Sodium contents are minimal, 0.53 mg for the 125-mg capsule formulation, 0.85 mg for the 200-mg capsules formulation, 1.06 mg for the 250-mg capsule formulation, and 1.70 mg for the 400-mg formulation.

VIDEX EC should only be administered once daily. There are no data on the use of VIDEX EC dosed more frequently than once daily.

VIDEX EC is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses including opportunistic infections. Therefore, patients should be informed to remain under the care of a physician when using VIDEX EC.

The major toxicity of VIDEX EC is pancreatitis, which has been fatal in some patients.

Symptoms of pancreatitis include abdominal pain, and nausea and vomiting. Peripheral neuropathy occurs in patients treated with VIDEX EC. Symptoms of peripheral neuropathy include tingling, burning, pain or numbness in the hands or feet. Patients should be advised to report these symptoms to their physician. The above toxicities of VIDEX EC occur with the greatest frequency in patients with a history of these events and dose modification and/or discontinuation of VIDEX EC may be required if toxicity develops. There are other medications including alcohol which may exacerbate VIDEX EC toxicity. Patients should be advised to consult their physician about such medications.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.

Patients should also be informed that the long-term effects of VIDEX EC are unknown at this time. VIDEX EC therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.

Each white, opaque enteric coated beadlet capsule, printed in green with “BMS 200 mg” and “6672”, contains: didanosine 200 mg. Nonmedicinal ingredients: carboxymethylcellulose sodium, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate and talc; capsule shell: gelatin, sodium lauryl sulfate and titanium dioxide. Capsules are imprinted with edible ink. Bottles of 30. Store in tightly closed bottles at room temperature (15 to 30°C).

Each white, opaque, enteric coated beadlet capsule, printed in blue with “BMS 250 mg” and “6673”, contains: didanosine 250 mg. Nonmedicinal ingredients: carboxymethylcellulose sodium, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate and talc; capsule shell: gelatin, sodium lauryl sulfate and titanium dioxide. Capsules are imprinted with edible ink. Bottles of 30. Store in tightly closed bottles at room temperature (15 to 30°C).

Each white, opaque enteric coated beadlet capsule, printed in tan with “BMS 125 mg” and “6671”, contains: didanosine 125 mg. Nonmedicinal ingredients: carboxymethylcellulose sodium, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate and talc; capsule shell: gelatin, sodium lauryl sulfate and titanium dioxide. Capsules are imprinted with edible ink. Bottles of 30. Store in tightly closed bottles at room temperature (15 to 30°C).

Each white, opaque, enteric coated beadlet capsule, printed in red with “BMS 400 mg” and “6674”, contains: didanosine 400 mg. Nonmedicinal ingredients: carboxymethylcellulose sodium, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate and talc; capsule shell: gelatin, sodium lauryl sulfate and titanium dioxide. Capsules are imprinted with edible ink. Bottles of 30. Store in tightly closed bottles at room temperature (15 to 30°C).

Patients receiving VIDEX EC or any antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection, and therefore should remain under close clinical observation by physicians experienced in the treatment of patients with HIV-associated diseases.

Fatal and nonfatal pancreatitis have occurred during therapy with didanosine used alone or in combination regimens in both treatment-naive and treatment-experienced patients, regardless of degree of immunosupression. VIDEX EC should be suspended in patients with signs or symptoms of pancreatitis and discontinued in patients with confirmed pancreatitis. Suspension of treatment should also be considered when biochemical markers of pancreatitis have increased to clinically significant levels, even in the absence of symptoms. Patients treated with VIDEX EC in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis.

Positive relationships have been found between the risk of pancreatitis and daily dose. Pancreatitis is also a complication of HIV infection alone.

Signs or symptoms of pancreatitis include abdominal pain and nausea, vomiting, or elevated biochemical markers for pancreatitis.

When treatment with other drugs known to cause pancreatic toxicity is required (for example, IV pentamidine), or known to increase exposure or activity of didanosine (e.g., hydroxyurea or allopurinol), suspension of didanosine therapy is recommended. Allopurinol was observed to increase exposure to didanosine in renally impaired patients and healthy volunteers and may increase the risk of dose-related toxicities such as pancreatitis. It is recommended that these two drugs not be administered together (see Precautions, Drug Interactions).

VIDEX should be used with caution in patients with risk factors for pancreatitis. For example, the following patients may be at increased risk for developing pancreatitis and should be followed closely for signs and symptoms of pancreatitis: patients with advanced HIV infection, patients with a history of pancreatitis, elevated triglycerides, or alcohol consumption; elderly patients and patients with renal impairment if treated with unadjusted doses; and patients treated with didanosine in combination with stavudine, with or without hydroxyurea.

Peripheral neuropathy occurs in patients treated with didanosine and the frequency appears to be related to dose and/or stage of disease. Lower rates were seen in patients with less advanced disease. Patients should be monitored for the development of a neuropathy that is usually characterized by bilateral symmetrical distal numbness, tingling, and pain in feet and, less frequently, hands. In controlled clinical trials, neuropathy has occurred more frequently in patients with a history of neuropathy or neurotoxic drug therapy, including stavudine, and these patients may be at increased risk of neuropathy during didanosine therapy.

Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine, with or without stavudine.

Neuropathy has been reported rarely in children treated with didanosine. However, because signs and symptoms of neuropathy are difficult to assess in children, physicians should be alerted to the possibility of this event.

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

The safety and efficacy of VIDEX EC have not been established in patients with significant underlying liver disorders. 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, discontinuation of treatment must be considered. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products (see Precautions and Dosage).

There have been rare (<1%) reports of retinal depigmentation and optic neuritis in adult patients (see Adverse Effects). Periodic retinal examinations should be considered for patients receiving didanosine. Consideration should be given to modifying treatment based on the physician's assessment of benefit to risk.

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 antiretroviral agents. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk (see Precautions, Pregnancy). 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 or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Liver failure, of unknown etiology, has occured in patients receiving didanosine and may be fatal. Patients should be observed for liver enzyme elevations and didanosine should be suspended if enzymes rise to a clinically significant level. Rechallenge should be considered only if the potential benefits clearly outweigh the potential risks.

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

Selected Laboratory Abnormalities, AI454-152^a

anorexia, dyspepsia, and flatulence.

abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, and pain, redistribution/accumulation of body fat (see Precautions, Fat Redistribution).

lactic acidosis and hepatic steatosis (see Warnings and Precautions); hepatitis and liver failure.

Retinal depigmentation and optic neuritis (see Warnings).

anemia, leukopenia, granulocytopenia and thrombocytopenia.

pancreatitis (including fatal cases) (see Warnings), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.

diabetes mellitus, elevated serum alkaline phosphatase level, elevated serum amylase level, elevated serum gamma-glutamyltransferase level, elevated serum uric acid level, hypoglycemia, and hyperglycemia.

myalgia (with or without increases in creatine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.

Although no data with didanosine are available, activated charcoal should be administered to aid in the removal of unabsorbed drug, as recommended in American College of Emergency Physicians guidelines. General supportive measures are also recommended.

There is no known antidote for didanosine overdosage. Experience in the Phase I studies in which didanosine was initially administered at doses ten times the currently recommended doses indicates that the complications of chronic overdosage would include pancreatitis, peripheral neuropathy, diarrhea, hyperuricemia and, hepatic dysfunction. Didanosine is not dialyzable by peritoneal dialysis, although there is some clearance by hemodialysis. The fractional removal of didanosine during an average hemodialysis session of 3 to 4 hours is approximately 20-35% of the amount present in the body at the start of dialysis.

See Symptoms.

There were no substantial alterations in didanosine pharmacokinetics in patients with moderate or severe (Child-Pugh class B or C) hepatic impairment compared with healthy subjects. No dose adjustment of VIDEX EC is necessary for patients with moderate (Child-Pugh class B) hepatic impairment. There is insufficient data to recommend a specific dose of adjustment in patients with severe (Child-Pugh class C) hepatic impairment.

During treatment with VIDEX EC, patients should be observed for liver enzyme elevations and VIDEX EC suspended if enzymes rise to a clinically significant level (see Warnings and Precautions).

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 adjustment should be made accordingly.

Children: The safety and efficacy of VIDEX EC in pediatric patients have not been established. Please consult the complete prescribing information for VIDEX (didanosine) buffered formulations and Pediatric Powder for Oral Solution for dosage and administration of didanosine to pediatric patients.

For patients undergoing dialysis, the daily dose of VIDEX EC should be administered after dialysis. It is not necessary to administer a supplemental dose of VIDEX EC following hemodialysis.

Tenofovir disoproxil fumarate: A dose reduction of VIDEX EC is recommended when coadministered with tenofovir (see Precautions, Drug Interactions).

VIDEX EC: 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60 mL/min) once daily together with tenofovir and a light meal (≤400 kcalories, ≤20% fat).

The appropriate dose of VIDEX EC coadministered with tenofovir in patients with creatinine clearance <60 mL/min has not been established.