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.
These recommendations are based on either drug interaction studies or observed clinical toxicities.
AllopurinolCoadministration of didanosine and allopurinol is contraindicated because systemic exposures of didanosine are increased, which may increase didanosine-associated toxicity.
RibavirinCoadministration of didanosine and ribavirin is contraindicated because exposures of the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin.
The following adverse reactions are discussed in greater detail in other sections:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
AdultsStudy 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 AI454-152a
| Adverse Reactions | Percent of Patientsb,c | |
| VIDEX EC + stavudine + nelfinavir n=258 |
zidovudine/lamivudined +nelfinavir
n=253 |
|
| Diarrhea | 57 | 58 |
| Peripheral Neurologic Symptoms/Neuropathy | 25 | 11 |
| Nausea | 24 | 36 |
| Headache | 22 | 17 |
| Rash | 14 | 12 |
| Vomiting | 14 | 19 |
| Pancreatitis (see below) | less than 1 | * |
| a 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. |
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.
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 AI454-152a
| Parameter | Percent of Patientsb | |||
| VIDEX EC + stavudine+ nelfinavir n=258 |
zidovudine/lamivudinec +nelfinavir n=253 |
|||
| Grades 3-4d | All Grades | Grades 3-4d | All Grades | |
| SGOT (AST) | 5 | 46 | 5 | 19 |
| SGPT (ALT) | 6 | 44 | 5 | 22 |
| Lipase | 5 | 23 | 2 | 13 |
| Bilirubin | less than 1 | 9 | less than 1 | 3 |
| a 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 x ULN for SGOT and SGPT, at least 2.1 x ULN for lipase, and at least 2.6 x ULN for bilirubin (ULN = upper limit of normal). |
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.
Retinal changes and optic neuritis have been reported in pediatric patients.
Postmarketing ExperienceThe 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, and redistribution/accumulation of body fat.
Digestive Disorders - anorexia, dyspepsia, and flatulence.
Exocrine Gland Disorders - pancreatitis (including fatal cases) , sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.
Hepatobiliary Disorders - symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis ; non-cirrhotic portal hypertension ; 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 .
Use with Stavudine- and Hydroxyurea-Based RegimensWhen didanosine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when didanosine is used alone. Thus, patients treated with VIDEX EC in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy. The combination of VIDEX EC and hydroxyurea, with or without stavudine, should be avoided.
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.
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
Patients
| Parametera | Pediatrics | Adults | ||
| 20 kg to less than 25 kg n=10 |
25 kg to less than 60 kg n=17 |
At least 60 kg n=7 |
At least 60 kg n=44 |
|
| Apparent clearance (L/h) | 89.5 ± 21.6 | 116.2 ± 38.6 | 196.0 ± 55.8 | 174.5 ± 69.7 |
| Apparent volume of distribution (L) | 98.1 ± 30.2 | 154.7 ± 55.0 | 363 ± 137.7 | 308.3 ± 164.3 |
| Elimination half-life (h) | 0.75 ± 0.13 | 0.92 ± 0.09 | 1.26 ± 0.19 | 1.19 ± 0.21 |
| Steady-state AUC (mg•h/L) | 2.38 ± 0.66 | 2.36 ± 0.70 | 2.25 ± 0.89 | 2.65 ± 1.07 |
| a The pharmacokinetic parameters (mean ± standard deviation) of didanosine were determined by a population pharmacokinetic model based on combined clinical studies. |
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 FoodIn the presence of food, the Cmax and AUC for VIDEX EC were reduced by approximately 46% and 19%, respectively, compared to the fasting state. VIDEX EC should be taken on an empty stomach.
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 . The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy RegistryTo 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.
VIDEX EC (didanosine, USP) Delayed-Release Capsules are white, opaque capsules as described below:
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 Capsules
| 125 mg capsule imprinted with “BMS 125 mg 6671” in Tan | |
| NDC No. 0087-6671-17 | 30 capsules/bottle |
| 200 mg capsule imprinted with “BMS 200 mg 6672” in Green | |
| NDC No. 0087-6672-17 | 30 capsules/bottle |
| 250 mg capsule imprinted with “BMS 250 mg 6673” in Blue | |
| NDC No. 0087-6673-17 | 30 capsules/bottle |
| 400 mg capsule imprinted with “BMS 400 mg 6674” in Red | |
| NDC No. 0087-6674-17 | 30 capsules/bottle |
The 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).
Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Rev November 2011
Included as part of the PRECAUTIONS section.
PRECAUTIONS PancreatitisFatal 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.
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.
Lactic Acidosis/Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. 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).
Hepatic ToxicityThe 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. This combination should be avoided.
Non-cirrhotic Portal HypertensionPostmarketing cases of non-cirrhotic portal hypertension have been reported, including cases leading to liver transplantation or death. Cases of didanosine-associated non-cirrhotic portal hypertension were confirmed by liver biopsy in patients with no evidence of viral hepatitis. Onset of signs and symptoms ranged from months to years after start of didanosine therapy. Common presenting features included elevated liver enzymes, esophageal varices, hematemesis, ascites, and splenomegaly.
Patients receiving VIDEX EC should be monitored for early signs of portal hypertension (eg, thrombocytopenia and splenomegaly) during routine medical visits. Appropriate laboratory testing including liver enzymes, serum bilirubin, albumin, complete blood count, and international normalized ratio (INR) and ultrasonography should be considered. VIDEX EC should be discontinued in patients with evidence of non-cirrhotic portal hypertension.
Peripheral NeuropathyPeripheral 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, including stavudine. Discontinuation of
VIDEX EC should be considered in patients who develop peripheral neuropathy.
Retinal Changes and Optic NeuritisRetinal changes and optic neuritis have been reported in patients taking didanosine. Periodic retinal examinations should be considered for patients receiving VIDEX EC.
Immune Reconstitution SyndromeImmune 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.
Fat RedistributionRedistribution/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.
Patient Counseling InformationSee Medication Guide.
PancreatitisPatients should be informed that a serious toxicity of didanosine, used alone and in combination regimens, is pancreatitis, which may be fatal.
Peripheral NeuropathyPatients should be informed that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX EC (didanosine). Patients should be counseled 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.
Lactic Acidosis and Severe Hepatomegaly with SteatosisPatients should be informed 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.
Hepatic ToxicityPatients should be informed that hepatotoxicity including fatal hepatic adverse events were 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.
Non-cirrhotic Portal HypertensionPatients should be informed that non-cirrhotic portal hypertension has been reported in patients taking VIDEX EC, including cases leading to liver transplantation or death.
Retinal Changes and Optic NeuritisPatients should be informed that retinal changes and optic neuritis have been reported in adult and pediatric patients.
Fat RedistributionPatients 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.
Concomitant TherapyPatients should be informed that when didanosine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when didanosine is used alone. These patients should be followed closely.
Patients should be cautioned about the use of medications or other substances, including alcohol, which may exacerbate VIDEX EC toxicities.
General InformationVIDEX EC is not a cure for HIV-1 infection, and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Therefore, patients should remain under the care of a physician when using VIDEX EC.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
Patients should be instructed to swallow the capsule as a whole and to not open the capsule.
Patients should be instructed to not miss a dose but if they do, patients should take VIDEX EC as soon as possible. Patients should be told that if it is almost time for the next dose, they should skip the missed dose and continue with the regular dosing schedule.
Patients should be instructed to contact a poison control center or emergency room right away in case of an overdose.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of FertilityLifetime 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.
Use In Specific Populations Pregnancy Pregnancy Category BReproduction 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 . The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy RegistryTo 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.
Nursing MothersThe 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.
Pediatric UseUse 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. Additional pharmacokinetic studies in pediatric patients support use of VIDEX EC in pediatric patients who weigh at least 20 kg.
Geriatric UseIn 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%). 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.
Renal ImpairmentPatients 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 . A dose reduction is recommended for these patients.
VIDEX EC should be administered on an empty stomach. VIDEX EC Delayed-Release Capsules should be swallowed intact.
Recommended Dosage (Adult and Pediatric Patients)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 Weight | Dose |
| 20 kg to less than 25 kg | 200 mg once daily |
| 25 kg to less than 60 kg | 250 mg once daily |
| at least 60 kg | 400 mg once daily |
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 PatientsIn 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 Weighta
| Creatinine Clearance (mL/min) | Dosage (mg) | |
| at least 60 kg | less than 60 kg | |
| at least 60 | 400 once daily | 250 once daily |
| 30-59 | 200 once daily | 125 once daily |
| 10-29 | 125 once daily | 125 once daily |
| less than 10 | 125 once daily | b |
| a 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. |
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 HemodialysisFor 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.
Dose Adjustment Concomitant Therapy with Tenofovir Disoproxil FumarateIn 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 kcalories 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.
Hepatic ImpairmentNo dose adjustment is required in patients with hepatic impairment.
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 and DRUG INTERACTIONS.
Table 9: Results of Drug Interaction Studies with VIDEX EC:
Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Values
| Drug | Didanosine Dosage | n | % Change of Didanosine Pharmacokinetic Parametersa | |
| AUC of Didanosine (90% CI) | Cmax of Didanosine (90% CI) | |||
| tenofovirb,c,300 mg once daily with a light meald |
400 mg single dose fasting 2 hours before tenofovir |
26 | ↑48% (31, 67%) |
↑48% (25, 76%) |
tenofovirb,c,300 mg once daily with a light meald |
400 mg single dose with tenofovir and a light meal |
25 | ↑60% (44, 79%) |
↑64% (41, 89%) |
tenofovirb,c,300 mg once daily with a light meald |
200 mg single dose with tenofovir and a light meal |
33 | ↑16% (6, 27%)e |
↓12% (-25, 3%)e |
| 250 mg single dose with tenofovir and a light meal |
33 | ↔ (-13, 5%)f |
↓20% (-32, -7%)f |
|
| 325 mg single dose with tenofovir and a light meal |
33 | ↑13% (3, 24%)f |
↓11% (- 24,4%)f |
|
| methadone, chronic maintenance dose |
400 mg single dose | 15, 16g | ↓17% (-29, -2%) |
↓ 16% (-33, 4%) |
| ↑ 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 kcalories, 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. |
Table 10: Results of Drug Interaction Studies with VIDEX
EC: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
| Drug | Didanosine Dosage | n | % Change of Coadministered Drug Pharmacokinetic Parameters a,b | |
| AUC of Coadministered Drug (90% CI) | Cmax of Coadministered Drug (90% CI) | |||
| ciprofloxacin, 750 mg single dose | 400 mg single dose | 16 | ↔ | ↔ |
| indinavir, 800 mg single dose | 400 mg single dose | 23 | ↔ | ↔ |
| ketoconazole, 200 mg single dose | 400 mg single dose | 21 | ↔ | ↔ |
| tenofovir,c 300 mg once daily with a light meald | 400 mg single dose fasting 2 hours before tenofovir | 25 | ↔ | ↔ |
| tenofovir,c 300 mg once daily with a light meald | 400 mg single dose with tenofovir and a light meal | 25 | ↔ | ↔ |
| ↔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 kcalories, 8.2 grams fat. |
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, and DRUG INTERACTIONS
Table 11: Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Coadministered Drug on Didanosine Plasma
AUC and Cmax Values
| Drug | Didanosine Dosage | n | % Change of Didanosine Pharmacokinetic Parametersa | |
| AUC of Didanosine (95% CI) | Cmax of Didanosine (95% CI) | |||
| allopurinol, renally impaired, 300 mg/day | 200 mg single dose | 2 | ↑312% | ↑232% |
| healthy volunteer, 300 mg/day for 7 days | 400 mg single dose | 14 | ↑113% | ↑69% |
| ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine | 200 mg every 12 hours | 12 | ↑111% | NA |
| ciprofloxacin, 750 mg every 12 hours for 3 days, 2 hours before didanosine | 200 mg every 12 hours for 3 days | 8c | ↓16% | ↓28% |
| indinavir, 800 mg single dose simultaneous | 200 mg single dose | 16 | ↔ | ↔ |
| 1 hour before didanosine | 200 mg single dose | 16 | ↓17% (-27, -7%)b | ↓13% (-28, 5%)b |
| ketoconazole, 200 mg/day for 4 days, 2 hours before didanosine | 375 mg every 12 hours for 4 days | 12c | ↔ | ↓12% |
| loperamide, 4 mg every 6 hours for 1 day | 300 mg single dose | 12c | ↔ | ↓23% |
| metoclopramide, 10 mg single dose | 300 mg single dose | 12c | ↔ | ↑13% |
| ranitidine, 150 mg single dose, 2 hours before didanosine | 375 mg single dose | 12c | ↑14% | ↑13% |
| rifabutin, 300 mg or 600 mg/day for 12 days | 167 mg or 250 mg every 12 hours for 12 days | 11 | ↑13%(-1, 27%) | ↑17%(-4, 38%) |
| ritonavir, 600 mg every 12 hours for 4 days | 200 mg every 12 hours for 4 days | 12 | ↓13% (0, 23%) | ↓16% (5, 26%) |
| stavudine, 40 mg every 12 hours for 4 days | 100 mg every 12 hours for 4 days | 10 | ↔ | ↔ |
| sulfamethoxazole, 1000 mg single dose | 200 mg single dose | 8c | ↔ | ↔ |
| trimethoprim, 200 mg single dose | 200 mg single dose | 8c | ↔ | ↑17% (-23, 77%) |
| zidovudine, 200 mg every 8 hours for 3 days | 200 mg every 12 hours for 3 days | 6c | ↔ | ↔ |
| ↑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. |
Table 12: Results of Drug Interaction Studies with Buffered
Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma
AUC and Cmax Values
| Drug | Didanosine Dosage | n | % Change of Coadministered Drug Pharmacokinetic Parametersa | |
| AUC of Coadministered Drug (95% CI) | Cmax of Coadministered Drug (95% CI) | |||
| dapsone, 100 mg single dose | 200 mg every 12 hours for 14 days | 6b | ↔ | ↔ |
| ganciclovir, 1000 mg every 8 hours, 2 hours after didanosine | 200 mg every 12 hours | 12b | ↓21% | NA |
| nelfinavir, 750 mg single dose, 1 hour after didanosine | 200 mg single dose | 10b | ↑12% | ↔ |
| ranitidine, 150 mg single dose, 2 hours before didanosine | 375 mg single dose | 12b | ↓16% | ↔ |
| ritonavir, 600 mg every 12 hours for 4 days | 200 mg every 12 hours for 4 days | 12 | ↔ | ↔ |
| stavudine, 40 mg every 12 hours for 4 days | 100 mg every 12 hours for 4 days | 10b | ↔ | ↑17% |
| sulfamethoxazole, 1000 mg single dose | 200 mg single dose | 8b | ↓11% (-17, -4%) | ↓12% (-28, 8%) |
| trimethoprim, 200 mg single dose | 200 mg single dose | 8b | ↑10% (-9, 34%) | ↓22% (-59, 49%) |
| zidovudine, 200 mg every 8 hours for 3 days | 200 mg every 12 hours for 3 days | 6b | ↓10% (-27, 11%) | ↓16.5% (-53, 47%) |
| ↑ 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. |
