Didanosine Information
Didanosine ()
Didanosine () Description
Didanosine () delayed-release capsules are an enteric-coated formulation of Didanosine () , (ddl), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). Didanosine () delayed-release capsules, containing enteric-coated pellets, are available for oral administration in the strengths of 200 mg, 250 mg, and 400 mg of Didanosine () . The inactive ingredients include croscarmellose sodium, hydroxypropyl cellulose, hypromellose, methacrylic acid copolymer dispersion, microcrystalline cellulose, polydextrose, polyethylene glycol, silicon dioxide, sodium hydroxide, talc, titanium dioxide, triacetin and triethyl citrate.The capsule shell contains FD&C blue no.1, gelatin, and titanium dioxide.The 200 mg capsule shell also contains D&C red no. 33, and FD&C yellow no. 6. The 250 mg capsule shell also contains D&C red no. 28. The 400 mg capsule shell also contains D&C red no.33, and FD&C yellow no. 6. The edible imprinting ink contains D&C yellow no. 10 aluminum lake, FD&C blue no. 1 aluminum lake, FD&C blue no. 2 aluminum lake, FD&C red no. 40 aluminum lake, iron oxide, propylene glycol and shellac glaze.
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
Didanosine () Clinical Pharmacology
The pharmacokinetic parameters of Didanosine () are summarized in . 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. 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 (
Comparisons of Didanosine () Formulations: In Didanosine () delayed-release capsules, the active ingredient Didanosine () , is protected against degradation by stomach acid by the use of an enteric coating on the pellets in the capsule. The enteric coating dissolves when the pellets empty into the small intestines, 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 concetration time curve (AUC) is equivalent for Didanosine () adminstered as the Didanosine () delayed-release formulation relative to a buffered tablet formulation. The peak plasma concentration (Cmax) of Didanosine () , administered as Didanosine () dleayed-release capsules, 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 hours for Didanosine () delayed-release capsules.
Effect of Food on Absorption of Didanosine () : In the presence of food, the Cmax and AUC for Didanosine () were reduced by approximately 46% and 19%, respectively, compared to the fasting state. Didanosine () should be taken on an empty stomach.
Renal Insufficiency: It is recommended that the Didanosine () dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see ). 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 ). 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 to 4 hour dialysis period. The absolute bioavailability of Didanosine () was not affected in patients requiring dialysis.
Pediatric Patients: The pharmacokinetics of Didanosine () administered as Didanosine () delayed-release capsules have not been studied in pediatric patients.
Geriatric Patients: Didanosine () pharmacokinetics have not been studied in patients over 65 years of age (see , ).
Gender: The effects of gender on Didanosine () pharmacokinetics have not been studied.
(See also , .)
Ribavirin has been shown in vitro to increase intracellular triphosphate levels of Didanosine () , which could cause or worsen clinical toxicities (see , ).
Didanosine () Delayed-Release Capsules: and summarize the effects on AUC and Cmax, with a 90% confidence interval (CI) when available, following coadministration of Didanosine () delayed-release capsules with a variety of drugs. Clinical recommendations based on drug interaction studies for drugs in bold font are included in , and .
Didanosine () Buffered Formulations: and 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. Except as noted in table footnotes, the results of these studies may be expected to apply to Didanosine () . For most of the listed drugs, no clinically significant pharmacokinetic interactions were noted. Clinical recommendations based on drug interaction studies for drugs in bold font are included in , and (for tenofovir).
Didanosine () Indications And Usage
Didanosine () delayed-release capsules in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults. (See .)
Study AI454-152 was a 48-week, randomized, open-label study comparing Didanosine () (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
○● Didanosine () + stavudine + nelfinavir, n= 258
∆▲ zidovudine/lamivudine + nelfinavir, n= 253
*Percent of patients at each time point who have HIV RNA
Didanosine () Contraindications
Didanosine () delayed-release capsules are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any component of the formulation.
Didanosine () Warnings
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 IMMUNOSUPPRESSION. Didanosine () SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH Didanosine () IN COMBINATION WITH STAVUDINE, WITH OR WITHOUT HYDROXYUREA, MAY BE AT INCREASED RISK FOR PANCREATITIS.
When treatment with life-sustaining drugs known to cause pancreatic toxicity is required, suspension of Didanosine () therapy is recommended. In patients with risk factors for pancreatitis, Didanosine () should be used with extreme caution and only if clearly indicated. Patients with advanced HIV 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. 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.
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.
PRECAUTIONS
Pregnancy, Reproduction and Fertility
Didanosine () Precautions
(See Patient Information Leaflet.)
Patients should be informed that a serious toxicity of Didanosine () , used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with Didanosine () . Patients should be counseled that peripheral neuropathy occures with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of Didanosine () may be required if toxicity develops. Patients 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, that may exacerbate Didanosine () toxicities. Didanosine () is not cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including oppurtunistic infection. Therefore, patients should remain under the care of a physician when using Didanosine () . Patients should be advised that Didanosine () therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of Didanosine () are unknown at this time. 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.
(see also , ):
Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in , ( and ). The clinical recommendatins based on the results of these studies are listed in .
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.
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 , ). 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 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.
Didanosine () Adverse Reactions
A SERIOUS TOXICITY OF Didanosine () IS PANCREATITIS, WHICH MAY BE FATAL (see ). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS. RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see and ).
When Didanosine () is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Didanosine () is used alone. Thus, patients treated with Didanosine () in combination with stavudine, with or without hydroxyurea, may be at increased risk for peripheral neuropathy (see ).
Selected clinical adverse events that occurred in a study of Didanosine () in combination with other antiretroviral agents are provided in .
Didanosine () 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 , ).
Didanosine () Dosage And Administration
Didanosine () should be administered on an empty stomach. Didanosine () delayed-release capsules should be swallowed intact.
The recommended daily dose is dependent on body weight and is adminstered as one capsule given on a once-daily schedule as outlined in .
Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. Didanosine () use should be discontinued in patients with confirmed pancreatitis (see and ,
). Based on data with buffered Didanosine () formulations, patients with symptoms of peripheral neuropathy may tolerate a reduced dose of Didanosine () after resolution of the symptoms of peripheral neuropathy upon drug interruption. If neuropathy recurs after resumption of Didanosine () , permanent discontinuation of Didanosine () should be considered.
Didanosine () How Supplied
Didanosine () Delayed-Release Capsules are available as:
250 mg: Two-piece hard gelatin capsule with blue opaque cap and white opaque body filled with white pellets. Imprinted in black ink stylized barr 589 over 250 mg. Available in unit dose packages of 30 (3x10) NDC 68084-431-21
400 mg: Two-piece hard gelatin capsule with red opaque cap and white opaque body filled with white pellets. Imprinted in black ink stylized barr 590 over 400 mg. Available in unit dose packages of 30 (3x10) NDC 68084-432-21.
Didanosine () Package/label Principal Display Panel
Didanosine () Package/label Principal Display Panel
