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Name:Didanosine
Manufacturer:American Health Packaging
Category:Prescription Marketed Drugs


Didanosine Delayed-Release Capsules (enteric-coated pellets)

DIDANOSINE - didanosine capsule, delayed release 
American Health Packaging

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Didanosine Delayed-Release Capsules (enteric-coated pellets)

WARNING:

FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH DIDANOSINE USED ALSONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION, DIDANOSINE SHOULD BE SUSPENDED IN PATIENTS WITH SUSPECTED PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS (see WARNINGS).

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. FATAL LACTIC ACIDOSIS HAS BEEN REPORTED IN PREGNANT WOMEN WHO RECEIVED THE COMBINATION OF DIDANSOINE AND STAVUDINE WITH OTHER ANTIRETROVIRAL AGENTS. THE COMBINATION OF DIDANOSINE AND STAVUDINE SHULD BE USED WITH CAUTION DURING PREGNANCY AND IS RECOMMENDED ONLY IF THE POTENTIAL BENEFIT CLEARLY OUTWEIGHS THE POTENTIAL RISK (SEE WARNINGS AND PRECAUTIONS, Pregnancy, Reproduction and Fertility),

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 structural formula

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 < 3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In didanosine delayed-release capsules, an enteric coating is used to protect didanosine from degradation by stomach acid.

MICROBIOLOGY

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.

In Vitro HIV Susceptibility

The in vitro 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. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not bee established.

Drug Resistance

HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. 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 vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established.

Cross-Resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been estabilished.

CLINICAL PHARMACOLOGY

Animal Toxicology

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.

Pharmacokinetics

The pharmacokinetic parameters of didanosine are summarized in 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. 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 (<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.

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.

Table 1: Pharmacokinetics Parameters for Didanosine in Adults
Parameter Mean ± SD n
Oral bioavailibilitya 42±12% 6
Apparent volume of distributionb 1.08±0.22 L/kg 6
CSF-plasma ratiob 21±0.03% 5
Systemic clearanceb 13±1.6 mL/min/kg 6
Renal clearancea 5.5±2.1 mL/min/kg 6
Elimination half-lifea 1.5±0.4 h 6
Urinary recovery of didanosinea 18±8% 6

CSF = cerebrospinal fluid
afollowing oral administration of a buffered formulation
bfollowing I.V. administration.
cmean ± SE.

Special Populations

Renal Insufficiency: It is recommended that the didanosine dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). 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 2). 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.

Table 2: Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose of a Buffered Formulation
ND = not determined due to anuria.
CLcr = creatinine clearance.
CL/F= apparent oral clearance.
CLR= renal clearance.
Creatinine Clearance (mL/min)
Parameter ≥ 90
n=12
60 to 90
n=6
30 to 59
n=6
10 to 29
n=3
Dialysis Patients
n=11
Clcr (mL/min) 112 ± 22 68 ± 8 46 ± 8 13 ± 5 ND
CL/F (mL/min) 2164 ± 638 1566 ± 833 1023 ± 378 628 ± 104 543 ± 174
CLR (mL/min) 458 ± 164 247 ± 153 100 ± 44 20 ± 8 <10
T1/2 (h) 1.42 ± 0.33 1.59 ± 0.13 1.75 ± 0.43 2 ± 0.3 4.1 ± 1.2

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 PRECAUTIONS, Geriatric use).

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

Drug Interactions

(See also PRECAUTIONS, Drug Interactions.)

Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine, which could cause or worsen clinical toxicities (see PRECAUTIONS, Drug Interactions).

Didanosine Delayed-Release Capsules: Table 3 and 4 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 PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION.

 

Table 3: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Coadministered Drug on Didanosine Plasma AUC and Cmax Valuesa
Drug Didanosine Dosage n AUC of Didanosine (90% CI) Cmax of Didanosine (90% CI)

tenofovir,b

300 mg once daily with a light mealc

400 mg single dose fasting 2 h before tenofovir 26

↑ 48%
(31, 67%)

↑ 48%
(25, 76%)

tenofovir,b

 300 mg once daily with a light mealc

400 mg single dose with tenofovir and a light meal 25

↑ 60%
(44, 79%)

↑ 64%
(41, 89%)

tenofovir,b

 300 mg once daily with a light mealc

200 mg single dose with tenofovir and a light meal

250 mg single dose with tenogovir and a light meal

325 mg single dose with tenofovir and a light meal

33

33

33

↑ 16%
(6, 27%)d

↔(-13, 5%)e

 

 ↑ 13%

(3, 24%)

↓ 12%
(-25, 3%)d

↓ 20%
(-32, -7%)e

↓ 11%
(-24, 4%)e

↑ indicates increase.

↓ indicates decrease.

↔ indicates no change, or mean increase or decrease of <10%.

a All studies conducted in healthy volunteers ≥60kg with creatinine clearance ≥60
mL/min.
b tenofovir disporoxil fumarate.
c 373 kcalories, 8.2 grams fat.
d Compared with didanosine delayed-release capsules 250 mg administered alone under
fasting coniditions.
e Compared with didanosine delayed-release capsules 400 mg administered alone under

fasting conditions.

Table 4: Results of Drug Interaction Studies with Didanosine Delayed-Release Capsules: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Valuesa
↔ Indicates no change, or mean increase or decrease of less than 10%.

* The 90% confidence intervals for the percent change in the pharmacokinetic parameter are displayed.

All studies conducted in healthy volunteers ≥ 60 kg with creatinine clearance ≥ 60 mL/min.

Tenofovir disoproxil fumarate.

§ 373 kcalories, 8.2 grams fat.

 

 

Drug

Didanosine Dosage

n

AUC of Coadministered Drug

Cmax of Coadministered Drug

ciprofloxacin,
750 mg single dose

indinavir,
800 mg single dose

ketoconazole,
200 mg single dose

tenofovir,
300 mg once daily
with a light meal§

tenofovir,
300 mg once daily
with a light meal§

400 mg single dose

400 mg single dose

400 mg single dose

400 mg single dose

fasting 2h before

tenofovir

400 mg single dose

with tenofovir and

a light meal

16

23

21

25

25

Didanosine Buffered Formulations: Table 5and 6 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 PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION (for tenofovir).

Table 5: Results of Drug Interaction Studies with Buggered Formulations of Didanosine: Effects of Coadministered Drug on Didanosine plasma AUC and Cmax Values
Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS, Drug Interactions )
Drug Didanosine Dosage n AUC 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 q8h, 2 h after didanosine 200 mg q12h 12 ↑111% NA
methadone, chronic maintenance dose 200 mg single dose 16, 10a ↓57% ↓66%
tenofovir,b 300 mg once daily 1 h after didanosine 250c or 400 mg once daily for 7 days 14 ↑44% (31, 59%)d ↔28% (11, 48%)d
No Clinically Significant Interactions Observed
ciprofloxacin, 750 mg q12h for 3 days, 2 h before didanosine 200 mg q12h for 3 days 8e ↓16% ↓28%
ininavir, 800 mg single dose simultaneous 200 mg single dose 16

1 h before didanosine 200 mg single dose 16 ↓17% (-27, -7%)d ↓13% (-28, 5%)d
ketoconazole, 200 mg/day for 4 days, 2 h before didanosine 375 mg q12h for 4 days 12e ↓12%
loperamide, 4 mg q6h for 1 day 300 mg single dose 12e ↓23%
metoclopramide, 10 mg single dose 300 mg single dose 12e ↑13%
ranitidine, 150 mg 2 h before didansine 375 mg single dose 12e ↑14% ↑13%
rifabutin, 300 or 600 mg/day for 12 days 167 or 250 mg q12h for 12 days 11 ↑13% (-1, 27%) ↑17% (-4, 38%)
ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 ↓13% (0, 23%) ↓16% (5, 26%)
stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8e
trimethoprim, 200 mg single dose 200 mg single dose 8e ↑17% (-23, 77%)
zidovudine, 200 mg q7h for 3 days 200 mg q12h for 3 days 8e

↑ indicates increase
↓ indicates decrease
↔ indicates no change, or mean increase or decrease of <10%.
a Parellel-group design; entries are subjects receiving combination and control regimens, respectively.
b tenogovir disoproxil fumarate
c patients <60 kg with creatinine clearance >60 mL/min.

d 90% CI
e HIV-infected patients
N/A Not available

Table 6: Results of Drug Interaction Studies with Buffered Formulations of Didanosine: Effects of Didanosine on Coadministered Drug Plasma AUC and Cmax Values
No Clinically Significant Interaction Observed
Drug Didanosine Dosage n AUC of Coadministered Drug (95% CI) Cmax of Coadministered Drug (95% CI)
dapsone, 100 mg single dose 200 mg q12h for 14 days 6a
delaviridine, 400 mg single dose simultaneous 125 or 200 mg q12h 12a ↓32%b ↓53%b
1 hr before didanosine 125 or 200 mg q12h 12a ↑20% ↑18%
ganciclovir, 1000 mg q8h, 2h after didanosine 200 mg q12h 12a ↓21% NA
nelfinavir, 750 mg single dose, 1 h after didanosine 200 mg single dose 10a ↑12%
ranitidine, 150 mg single dose, 2 h before didanosine 375 mg single dose 12a ↓16%
ritonavir, 600 mg q12h for 4 days 200 mg q12h for 4 days 12 
stavudine, 40 mg q12h for 4 days 100 mg q12h for 4 days 10a ↑17%
sulfamethoxazole, 1000 mg single dose 200 mg single dose 8a ↓11% (-17, -4%) ↓12% (-28, 8%)
tenofovir,C 300 mg once daily 1 h after didanosine 250d or 400 mg once daily for 7 days 14
trimethoprim, 200 mg single dose 200 mg single dose 8a ↑10% (-9, 34%) ↓22% (-59, 49%)
zidovudine, 200 mg q8h for 3 days 200 mg q12h for 3 days 6a ↓10% (-27, 11%) ↓16.5% (-53, 47%)

↑ indicates increase.

↓indicates decrease.

↔ indicates no change, or mean increase or decrease of <10%.
aHIV-infected patients.
bThis result is probably related to the bugger and is not expected to occur with didanosine delayed-release capsules.
ctenofovir disoproxil fumarate.
dpatients <60 kg with creatinine clearance >60 mL/min.

NA Not available

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 Clinical Studies.)

Clinical Studies

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 <400 and <50 copies/mL and outcomes of patients through 48 weeks are summarized in Figure 1 and Table 7, respectively.

Treatment Response Through week 48* chart

Figure 1 Treatment Response Through Week 48*, AI454-152

○● didanosine + stavudine + nelfinavir, n= 258

∆▲ zidovudine/lamivudine + nelfinavir, n= 253

*Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL and do not meet any criteria for treatment failure (eg, virologic failure or discontinuation for any reason).

Table 7: Outcomes of Randomized Treatment Through Week 48, AI454-152
Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
Outcome didanosine+
stavudine+
nelfinavir
n=258
zidovudine/
lamivudinea+
nelfinavir
n=253
Responderb, c 55% (33%) 56% (33%)
Virologic failured 22% (45%) 21% (43%)
Death or discontinued due to disease progression 1% (1%) 2% (2%)
Discontinued due to adverse event 6% (6%) 7% (7%)
Discontinued due to other reasonse 16% (16%) 15% (16%)
aZidovudine/lamivudine combination tablet.
bCorresponds to rates at Week 48 in Figure 1.s decision, never treated, and other reasons.
cSubjects achieved and maintained confirmed HIV RNA <400 copies/mL (<50 copies/mL)
dIncludes viral rebound at or before Week 48 and failure to achieve confirmed HIV RNA <400 copies/mL (<50 copies/mL) through Week 48.
eIncludes lost to follow-up, subject's withdrawal, discontinuation due to physician

CONTRAINDICATIONS

Didanosine delayed-release capsules are contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any component of the formulation.

WARNINGS

1. Pancreatitis:

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.

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. 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, Reproduction and Fertility). Particular caution should be exercised when administering didanosine 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 didanosine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

3. 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 didanosine (see ADVERSE REACTIONS.)

PRECAUTIONS

Dosing:

Didanosine should be administered once daily on an empty stomach.

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, including stavudine (see ADVERSE REACTIONS).

Fat Redistribution:

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushiongoid 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.

General

Patients with Renal Impairment:

Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION).

Patients with Hepatic Impairment:

It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity.

Hyperuricemia:

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

Information for patients

(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.

Drug Interactions:

(see also CLINICAL PHARMACOLOGY, Drug Interactions):

Drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY, Drug Interactions (Tables 3 and 6 ). The clinical recommendatins based on the results of these studies are listed in Table 8.

Table 8: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, Drug Interactions for Magnitude of Interaction)
Drug Effect Clinical Comment
allopurinol ↑didanosine concentration Coadministration not recommended
Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, Drug Interactions for Magnitude of Interaction
Drug Effect Clinical Comment
ganciclovir ↑didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established
methadone ↓didanosine concentration Appropriate doses for this combination, with respect to efficacy and safety, have not been established
tenofovir disoproxil fumarate ↑didanosine concentration A dose reduction of Didanosine Delayed-Release Capsules to 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 taken together with tenofovir and a light meal (≤400 kcalories and ≤20% fat) or in the fasted state is recommended. Patients should be monitored for didanosine-associated toxicities (see below).
↑ indicates increase ↓ indicates decrease

Coadministration of didanosine with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS, Pancreatitis). Predicted drug interactions with didanosine are listed in Table 9.

Table 9: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
Drug or Drug Class Effect Clinical Comment
Drugs that may cause pancreatic toxicity ↑risk of pancreatitis Use only with extreme caution.a
Neurotoxic drugs ↑risk of neuropathy Use with caution.b
Ribavirin ↑risk of toxicity Ribavirin has been shown in vitro to increase intracellular triphosphate levels of didanosine. Coadministration is not recommended (see below)
↑indicates increase.
aOnly if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended (see WARNINGS, Pancreatitis).
bSee PRECAUTIONS, Peripheral Neuropathy.

Nucleoside/nucleoside analogues:

Tenofovir disoproxil fumarate:

Exposure to didanosine is increase when coadministered with tenofovir (see Table 3, 5, and 8.) Inccreased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis,, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Coadministered of tenofovir with didanosine should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. Didanosine sholuld be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactemia, or lactic acidosis develop (see WARNINGS).Administration of reduced doses of didanosine with tenofovir and a light meal resulted in didanosine exposures (AUC) similar to the recommended doese of didanosine given alone in the fasted state (see Table 3). Therefore, when administered with tenofovir, a dose reduction of didanosine to 250 mg (adults weighing ≥60 kg with creatinine clearance ≥60 mL/min) or 200 mg (adults weighing <60 kg with creatinine clearance ≥60mL/min) once daily is recommended, and both drugs may be taken together with a light meal (≤400 kcalories, ≤20% fat) or in the fasted state (see DOSAGE AND ADMINISTRATION). 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.

Ribavirin:

Exposure to the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) is increased when didanosine is coadninstered with ribavirin (see Table 9). Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin. Coadministration of didanosine and ribavirin is not recommended.

Carcinogenesis and Mutagenesis:

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, Reproduction and Fertility

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, 2. 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. 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.

Nursing mothers

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

Pediatric use

The safety and efficacy of didanosine delayed-release capsules in pediatric patients have not been established. Please consult the complete prescribing information for didanosine chewable/dispersible buffered tablets and pediatric powder for oral solution for dosage and administration of didanosine to pediatric patients.

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). Clinical studies of didanosine, including those for didanosine delayed-release capsules, 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, Dose Adjustment).

ADVERSE REACTIONS

A SERIOUS TOXICITY OF DIDANOSINE IS PANCREATITIS, WHICH MAY BE FATAL (see WARNINGS). OTHER IMPORTANT TOXICITIES INCLUDE LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS. RETINAL CHANGES AND OPTIC NEURITIS; AND PERIPHERAL NEUROPATHY (see WARNINGS and PRECAUTIONS).

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 PRECAUTIONS).

Selected clinical adverse events that occurred in a study of didanosine in combination with other antiretroviral agents are provided in Table 10.

Table 10: Selected Clinical Adverse Events, Study AI454-152a
Percent of Patientsb
Adverse Events didanosine+ stavudine+ nelfinavir n=258 zidovudine/
lamivudinec+ 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) <1 *
aMedian duration of treatment was 62 weeks in the didansoine+stavudine+nelfinavir group and 61 weeks in the zidovudine/lamivudine+nelfinavir group.
bPercentages based on treated patients.
cZidovudine/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 patietns 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 didanosine plus stavudine plus hydroxyurea plus ritonavir plus indinavir plus efavirenz (see WARNINGS).

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 didanosine in combination with other antiretroviral agents are shown in Table 11.

Table 11: Selected Laboratory Abnormalities, Study AI454-152a
Percent of Patientsb

didanosine+ stavudine+ nelfinavir

n=258

zidovudine/lamivudinec+ nelfinavir n=253
Parameter Grades 3 to 4d All Grades Grades 3 to 4d All Grades
SGOT (AST) 5 46 5 19
SGPT (ALT) 6 44 5 22
Lipase 5 23 2 13
Bilirubin <1 9 <1 3

aMedian duration of treatment was 62 weeks in the didanosine+stavudine+nelfinavir group and 61 weeks in the zidovudine/lamivudine+nelfinavir group.

bPercentages based on treated patients.

cZidovudine/lamivudine combination tablet.

d>5 x ULN for SGOT and SGPT, ≥2.1 x ULN for lipase, and ≥2.6 x ULN for bilirubin (ULN = upper limit of normal).

Observed During Clinical Practice:

The following events have been identified during postapproval use of didanosine beffered 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.

Body as a Whole: abdominal pain, alopecia, anaphylactoid reaction, asthenia, chills/fever, pain, and redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution).

Digestive Disorders: anorexia, dyspepsia, and flatulence.

Exocrine Gland Disorders: pancreatitis (including fatal cases) (see WARNINGS), sialoadenitis, parotid gland enlargement, dry mouth, and dry eyes.

Hematologic Disorders: anemia, leukopenia, and thrombocytopenia.

Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure.

Metabolic Disorders: diabete melitus, 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 creatinine kinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.

Ophthalmologic Disorders: retinal depigmentation and optic neuritis (see WARNINGS).

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, Pharmacokinetics).

DOSAGE AND ADMINISTRATION

Adults:

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 Table 12.

Table 12: Dosing of Didanosine Delayed-Release Capsules
Patient Weight Dosage
≥60 kg 400 mg once daily
<60 kg 250 mg once daily

Pediatric Patients

Didanosine delayed-release capsules have not been studied in pediatric patients. Please consult the complete prescribing information for didanosine chewable/dispersible buffered tablets and pediatric powder for oral solution for dosage and administration of didanosine to pediatric patients.

Dose Adjustment:

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 WARNINGS and PRECAUTIONS, Drug Interactions

). 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.

Concomitant Therapy:

Tenofovir disoproxil fumarate. A dose reduction of didanosine delayed-release capsules to 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 taken daily together with tenofovir and a light meal (≤400 kcalories, ≤20% fat) or in the fasted state is recommended. The appropriate dose of didanosine delayed-release capsules coadministered with tenofovir in patients with creatinine clearance <60 mL/min has not been established. (See CLINICAL PHARMACOLOGY, Drug Interactions and PRECAUTIONS, Drug Interactions.)

Renal Impairment:

Dosing recommendations for didanosine delayed-release capsules and didanosine buffered formulations are different for patients with renal impairment. Please consult the complete prescribing information on administration of didanosine buffered formulations to patients with renal impairment. In adult patients with impaired renal function, the dose of didanosine should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of didanosine in adult patients with renal insufficiency are presented in Table 13.

Table 13: Recommended Dosage of Didanosine in Renal Impairment by Body Weighta
Dosage (mg)
Creatinine Clearance (mL/min) ≥ 60 kg < 60 kg
60 400 once daily 250 once daily
30 to 59 200 once daily 125 once daily
10 to 29 125 once daily 125 once daily
<10 125 once ddaily b

aBased on studies using a buffered formulation of didanosine

bNot suitable for use in patients <60 kg with CLCR <10 mL/min. An alternate formulation of didanosine should be used.

Patients Requiring Continuous Ambulatory Peritoneal Dialysis (CAPD) or Hemodialysis:

For patients requiring CAPD or hemodialysis, follow dosing recommendations for patients with creatinine clearance less than 10 mL/min, shown in Table 13. It is not necessary to administer a supplement dose of didanosine following hemodialysis.

Hepatic Impairment:

(See WARNINGS and PRECAUTIONS.)

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 62584-046-21

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 62584-048-21.

HANDLING AND DISPOSAL:

Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

PATIENT INFORMATION

Rx only

Didanosine Delayed-Release Capsules Enteric-Coated Pellets

What is didanosine?

Didanosine is a prescription medicine used in combination with other drugs to treat children and adults who are infected with HIV (the human immunodeficiency virus, the virus that causes AIDS). Didanosine belongs to a class of drugs called nucleoside analogues. By reducing the growth of HIV, didanosine helps your body maintain its supply of CD4 cells, which are important for fighting HIV and other infections.

Didanosine will not cure your HIV infection. At present there is no cure for HIV infection. Even while taking didanosine, you may continue to have HIV-related illnesses, including infections with other disease-producing organisms. Continue to see your doctor regularly and report any medical problems that occur.

Didanosine does not prevent a patient infected with HIV from passing the virus to other people. To protect others, you must continue to practice safe sex and take precautions to prevent others from coming in contact with your blood and other body fluids.

There is limited information on the antiviral response of long-term use of didanosine.

In didanosine, an enteric coating is used to protect the medicine while it is in your stomach since stomach acids can break it down. The enteric coating dissolves when the medicine reaches your small intestine.

Who should not take didanosine?

Do not take didanosine if you are allergic to any of its ingredients, including its active ingredient, didanosine, and the inactive ingredients. (See Inactive Ingredients at the end of this leaflet.) Tell your doctor if you think you have had an allergic reaction to any of these ingredients. Because it has only been studied in adults, didanosine is not recommended for children.

How should I take didanosine?/How should I store it?

Didanosine should only be taken once daily. Your doctor will determine your dose based on your body weight, kidney and liver function, other medicines you are taking, and any side effects that you may have had with didanosine or other medicines. Take didanosine on an empty stomach. Do not take didanosine with food. Swallow the capsule whole; do not open it. Try not to miss a dose, but if you do, take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule.

Store capsules in a tightly closed container at room temperature away from heat and out of the reach of children and pets.

If you have kidney disease: If your kidneys are not working properly, your doctor will need to do regular tests to check how they are working while you take didanosine. Your doctor may also lower your dosage of didanosine.

What should I do if someone takes an overdose of didanosine?

If someone may have taken an overdose of didanosine, get medical help right away. Contact their doctor or a poison control center.

What should I avoid while taking didanosine?

Alcohol. Do not drink alcohol while taking didanosine since alcohol may increase your risk of pancreatitis (pain and inflammation of the pancreas) or liver damage.

Other medicines. Other medicines, including those you can buy without a prescription, may interfere with the actions of didanosine or may increase the possibility or severity of side effects. Do not take any medicine, vitamin supplement, or other health preparation without first checking with your doctor.

Pregnancy. It is not known if didanosine can harm a human fetus. Also, pregnant women have experienced serious side effects when taking didanosine in combination with ZERIT (stavudine), also known as d4T, and other HIV medicines. Didanosine should be used during pregnancy only after discussion with your doctor. Tell your doctor if you become pregnant or plan to become pregnant while taking didanosine.

Nursing. Studies have shown didanosine is in the breast milk of animals getting the drug. It may also be in human breast milk. The Centers for Disease Control and Prevention (CDC) recommends that HIV-infected mothers not breast-feed. This should reduce the risk of passing HIV infection to their babies and the potential for serious adverse reactions in nursing infants. Therefore, do not nurse a baby while taking didanosine.

What are the possible side effects of didanosine?

Pancreatitis. Pancreatitis is a dangerous inflammation of the pancreas that may cause death. Tell your doctor right away if you or a child taking didanosine develop stomach pain, nausea, or vomiting.These can be signs of pancreatitis. Before starting didanosine therapy, let your doctor know if you or a child for whom it has been prescribed have ever had pancreatitis. This condition is more likely to happen in people who have had it before. It is also more likely in people with advanced HIV disease. However, it can occur at any stage of HIV disease. It may be more common in patients with kidney problems, those who drink alcohol, and those who are also treated with stavudine. If you get pancreatitis, your doctor will tell you to stop taking didanosine.

Lactic acidosis, severe liver enlargement, and liver failure, including deaths, have been reported among patients taking didanosine (including pregnant women). Symptoms that may indicate a liver problem are:

• feeling very weak, tired, or uncomfortable

• unusual or unexpected stomach discomfort

• feeling cold

• feeling dizzy or lightheaded

• suddenly developing a slow or irregular heartbeat

Lactic acidosis is a medical emergency that must be treated in a hospital.

If you notice any of these symptoms or if your medical condition changes, stop taking didanosine and call your doctor right away. Women, overweight patients, and those who have been treated for a long time with other medicines used to treat HIV infection are more likely to develop lactic acidosis. Your doctor should check your liver function periodically while you are taking didanosine. You should be especially careful if you have a history of heavy alcohol use or a liver problem.

Vision changes. Didanosine may affect the nerves in your eyes. Because of this, you should have regular eye examinations. You should also report any changes in vision to your doctor right away. This includes, for example, seeing colors abnormally or blurred vision.

Peripheral neuropathy. This is a problem with the nerves in your hands or feet. The nerve problem may be serious. Tell your doctor right away if you have continuing numbness, tingling, or pain in the feet or hands.

Before starting didanosine therapy, let your doctor know if you have ever had peripheral neuropathy. This condition is more likely to happen in people who have had it before. It is also more likely in patients taking medicines that affect the nerves and in people with advanced HIV disease. However, it can occur at any stage of HIV disease. If you get peripheral neuropathy, your doctor will tell you to stop taking didanosine. After stopping didanosine, the symptoms may get worse for a short time and then get better. Once symptoms of peripheral neuropathy go away completely, you and your doctor should decide if starting didanosine again is right for you. If so, you might be started at a lower dose.

Special note about other medicines. If you take didanosine along with other medicines with similar side effects, you may increase the chance of having these side effects. For example, using didanosine in combination with other medicines that may cause pancreatitis, peripheral neuropathy, or liver problems (including stavudine) may increase your chance of having these side effects.

Other side effects: The most common side effects in adults taking didanosine in combination with other HIV drugs included diarrhea, nausea, headache, vomiting, and rash.

Changes in body fat have been seen in some patients taking antiretroviral therapy. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long term health effects of these conditions are not known at this time.

Inactive Ingredients:

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.

This medicine was prescribed for your particular condition. Do not use didanosine for another condition or give it to others. Keep didanosine and all medicines out of the reach of children. w Throw away didanosine when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.

This summary does not include everything there is to know about didanosine. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. If you have questions or concerns, or want more information about didanosine, your physician and pharmacist have the complete prescribing information upon which this leaflet is based. You may want to read it and discuss it with your doctor or other healthcare professional. Remember, no written summary can replace careful discussion with your doctor.

This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.

Zerit is a registered trademark of Bristol-Myers Squibb Company.

Manufactured by:
Barr Laboratories, Inc.
Pomona, NY 10970

Repackaged by
American Health Packaging
Columbus, Ohio 43217

8004621/0804

PRINCIPAL DISPLAY PANEL

Didanosine Delayed-Release Capsules (enteric-coated pellets) 250 mg label

Label Text

NDC 62584-046-21

Didanosine
Delayed-Release Capsules
(enteric-coated pellets)

250 mg

30 Capsules (3x10)

Each capsule contains 250 mg of didanosine as
enteric-coated pellets.
Usual Dosage: See package insert.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled
Room Temperature].
Pharmacist: Dispense the enclosed Patient
Information Leaflet with the drug product.

Rx only

Didanosine Delayed-Release Capsules (enteric-coated pellets) 400 mg label

Label Text

NDC 62584-048-21

Didanosine
Delayed-Release Capsules
(enteric-coated pellets)

400 mg

30 Capsules (3x10)

Each capsule contains 400 mg of didanosine as
enteric-coated pellets.
Usual Dosage: See package insert.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled
Room Temperature].
Pharmacist: Dispense the enclosed Patient
Information Leaflet with the drug product.

Rx only


DIDANOSINE 
didanosine capsule, delayed release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62584-046(NDC:0555-0589)
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DIDANOSINE (DIDANOSINE) DIDANOSINE 250 mg
Inactive Ingredients
Ingredient Name Strength
CROSCARMELLOSE SODIUM  
HYDROXYPROPYL CELLULOSE  
HYPROMELLOSE  
METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1)  
CELLULOSE, MICROCRYSTALLINE  
POLYDEXTROSE  
POLYETHYLENE GLYCOL  
SILICON DIOXIDE  
SODIUM HYDROXIDE  
TALC  
TITANIUM DIOXIDE  
TRIACETIN  
TRIETHYL CITRATE  
FD&C BLUE NO. 1  
GELATIN  
D&C RED NO. 28  
D&C YELLOW NO. 10  
FD&C BLUE NO. 2  
FD&C RED NO. 40  
FERROSOFERRIC OXIDE  
PROPYLENE GLYCOL  
SHELLAC  
Product Characteristics
Color BLUE (opaque) Score no score
Shape CAPSULE Size 23mm
Flavor Imprint Code barr;250mg;589
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:62584-046-21 3 BLISTER PACK ( BLISTER PACK) in 1 CARTON contains a BLISTER PACK (62584-046-11)
1 NDC:62584-046-11 10 CAPSULE, DELAYED RELEASE ( CAPSULE) in 1 BLISTER PACK This package is contained within the CARTON (62584-046-21)

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077167 12/08/2009

DIDANOSINE 
didanosine capsule, delayed release
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62584-048(NDC:0555-0590)
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DIDANOSINE (DIDANOSINE) DIDANOSINE 400 mg
Inactive Ingredients
Ingredient Name Strength
CROSCARMELLOSE SODIUM  
HYDROXYPROPYL CELLULOSE  
HYPROMELLOSE  
METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1)  
CELLULOSE, MICROCRYSTALLINE  
POLYDEXTROSE  
POLYETHYLENE GLYCOL  
SILICON DIOXIDE  
SODIUM HYDROXIDE  
TALC  
TITANIUM DIOXIDE  
TRIACETIN  
TRIETHYL CITRATE  
FD&C BLUE NO. 1  
GELATIN  
D&C RED NO. 33  
FD&C YELLOW NO. 6  
D&C YELLOW NO. 10  
FD&C BLUE NO. 2  
FD&C RED NO. 40  
FERROSOFERRIC OXIDE  
PROPYLENE GLYCOL  
SHELLAC  
Product Characteristics
Color RED (opaque) Score no score
Shape CAPSULE Size 23mm
Flavor Imprint Code barr;400mg;590
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:62584-048-21 3 BLISTER PACK ( BLISTER PACK) in 1 CARTON contains a BLISTER PACK (62584-048-11)
1 NDC:62584-048-11 10 CAPSULE, DELAYED RELEASE ( CAPSULE) in 1 BLISTER PACK This package is contained within the CARTON (62584-048-21)

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077167 12/08/2009

Labeler - American Health Packaging (007914906)

Revised: 12/2009 American Health Packaging



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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