FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX 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 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 WARNINGS AND PRECAUTIONS: PREGNANCY.)

DESCRIPTION

VIDEX (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV). VIDEX Chewable/Dispersible Buffered Tablets are available for oral administration in strengths of 25, 50, 100, 150, and 200 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. VIDEX tablets also contain aspartame, sorbitol, microcrystalline cellulose, polyplasdone, mandarin-orange flavor, and magnesium stearate. VIDEX Buffered Powder for Oral Solution is supplied for oral administration in single- dose packets containing 100, 167, or 250 mg of didanosine. Packets of each product strength also contain a citrate-phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. VIDEX Pediatric Powder for Oral Solution is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine, respectively. Didanosine is also available as an enteric-coated formulation (VIDEX(r) EC Delayed- Release Capsules). Please consult the prescribing information for VIDEX EC (didanosine). 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 25degC and pH of approximately 6 is 27.3 mg/mL. Didanosine is unstable in acidic solutions. For example, at pH <3 and 37degC, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes.

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.

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% (IC50) ranged from 2.5 to 10 uM (1 uM = 0.24 ug/mL) in lymphoblastic cell lines and 0.01 to 0.1 uM 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 been 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 mutation 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 established.

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 VIDEX (didanosine) to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of VIDEX 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. 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.

Table 1: Mean +- SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients

following IV administration in adults and IV or oral administration in pediatric patients

Effect of Food on Absorption of Didanosine: Didanosine peak plasma concentrations (CMAX) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when VIDEX tablets were administered up to 2 hours after a meal. Administration of VIDEX tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating. (See DOSAGE AND ADMINISTRATION.)

Special Populations

Renal Insufficiency: It is recommended that the VIDEX (didanosine) dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION). Data from two studies 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 3-4 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

Pediatric Patients: The pharmacokinetics of didanosine have been evaluated in HIV-infected pediatric patients from 0.7 to 18.9 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients greater than 0.7 years of age are similar to those of didanosine in adults. Didanosine plasma concentrations increased in proportion to oral doses ranging from 80 to 180 mg/m2. For information on controlled clinical studies in pediatric patients, see PRECAUTIONS: Pediatric Use and Clinical Studies.

Didanosine pharmacokinetics have not been studied in patients over 65 years of age.

Drug Interactions: Tables 3 and 4 summarize the effects on AUC and CMAX, with a 90% or 95% confidence interval (CI) when available, following coadministration of VIDEX with a variety of drugs. For most of the listed drugs, no clinically significant pharmacokinetic interactions were observed. Clinical recommendations based on drug interaction studies for drugs in bold font are included in PRECAUTIONS: Drug Interactions.

Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)

renally impaired, 300 mg/day 200 mg single dose 2 |312% |232% healthy volunteer, 300 mg/day

Table 4: Results of Drug Interaction Studies: Effects of Didanosine on Coadministered Drug Plasma AUC and CMAX Values

Drugs With Clinical Recommendations Regarding Coadministration (see PRECAUTIONS: Drug Interactions)

trimethoprim, 200 mg single dose 200 mg single dose 8a |10% (-9, 34%) |22% (-59, 49%)

Clinical Studies

START 2 was a multicenter, randomized, open-label study comparing VIDEX (200 mg twice daily)/stavudine/indinavir to zidovudine/lamivudine/indinavir in 205 treatment-naive patients. Both regimens resulted in a similar magnitude of suppression of HIV RNA levels and increases in CD4 cell counts through 48 weeks. Study A1454-148 was a randomized, open-label, multicenter study comparing treatment with VIDEX (400 mg once daily) plus stavudine (40 mg twice daily) and nelfinavir (750 mg three times daily) versus zidovudine (300 mg twice daily) plus lamivudine (150 mg twice daily) and nelfinavir (750 mg three times daily) in 756 treatment-naive patients, with a median CD4 cell count of 340 cells/mm3 (range 80 to 1568 cells/mm3) and a median plasma HIV-1 RNA of 4.69 log10 copies/mL (range 2.6 to 5.9 log10 copies/mL) at baseline. Median CD4 cell count increases at 48 weeks were 188 cells/mm3 in both treatment groups. Treatment response and outcomes through 48 weeks are shown in Figure 1 and Table 5.

* Percent of patients at each time point who have HIV RNA <400 or <50 copies/mL, are on their original study medication (except stavudine- zidovudine switches), and have not experienced an AIDS-defining event.

<0.05 for the differences between treatment groups, by Cochran-Mantel-Haenszel test.

Percent of Patients with HIV RNA <400 copies/mL (<50 copies/mL)
Week 48 Status	VIDEX/stavudine/nelfinavir n=503	lamivudine/zidovudine/nelfinavir n=253
Responder a	50 * (34 *)	59 (47)
Virologic failure b	36 (57)	32 (48)
Death or disease progression	<1 (<1)	1 (<1)
Discontinued due to adverse events	4 (2)	2 (<1)
Discontinued due to other reasons c	6 (3)	4 (2)
Never initiated treatment	4 (4)	2 (2)

The efficacy of VIDEX was demonstrated in two randomized, double-blind studies comparing VIDEX, given on a twice-daily schedule, to zidovudine, given three times daily, in 617 (ACTG 116A, conducted 1989-1992) and 913 (ACTG116B/117, conducted 1989-1991) patients with symptomatic HIV infection or AIDS who were treated for more than one year. In treatment-naive patients (ACTG 116A), the rate of HIV disease progression or death was similar between the treatment groups; mortality rates were 26% for patients receiving VIDEX and 21% for patients receiving zidovudine. Of the patients who had received previous zidovudine treatment (ACTG 116B/117), those treated with VIDEX had a lower rate of HIV disease progression or death (32%) compared to those treated with zidovudine (41%); however, survival rates were similar between the treatment groups. Efficacy in pediatric patients was demonstrated in a randomized, double-blind, controlled study (ACTG 152, conducted 1991-1995) involving 831 patients treated for more than 1.5 years with zidovudine (180 mg/m2 q6h), VIDEX (120 mg/m2 q12h), or zidovudine (120 mg/m2 q6h) plus VIDEX (90 mg/m2 q12h). Patients treated with VIDEX or VIDEX plus zidovudine had lower rates of HIV disease progression or death compared with those treated with zidovudine alone. Studies have demonstrated that the clinical benefit of monotherapy with antiretrovirals, including VIDEX, was time limited.

CONTRAINDICATION

VIDEX (didanosine) is contraindicated in patients with previously demonstrated clinically significant hypersensitivity to any of the components of the formulations.

WARNINGS

Pancreatitis

FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WITH VIDEX USED ALONE OR IN COMBINATION REGIMENS IN BOTH TREATMENT-NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION. VIDEX SHOULD BE SUSPENDED IN PATIENTS WITH SIGNS OR SYMPTOMS OF PANCREATITIS AND DISCONTINUED IN PATIENTS WITH CONFIRMED PANCREATITIS. PATIENTS TREATED WITH VIDEX 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 VIDEX (didanosine) therapy is recommended. In patients with risk factors for pancreatitis, VIDEX 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, incidence ranged from 1% to 10% with doses higher than are currently recommended and 1% to 7% with recommended dose. In pediatric studies, pancreatitis occurred in 3% (2/60) of patients treated at entry doses below 300 mg/m2/day and in 13% (5/38) of patients treated at higher doses. VIDEX use should be suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis.

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. PRECAUTIONS: Pregnancy

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

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

Retinal Changes and Optic Neuritis

Retinal changes and optic neuritis have been reported in adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.)

PRECAUTIONS

Frequency of Dosing

The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see Clinical Studies).

VIDEX should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating.

Peripheral Neuropathy

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving VIDEX 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 "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.

General

VIDEX Chewable/Dispersible Buffered Tablets contain the following quantities of phenylalanine:

VIDEX Buffered Powder for Oral Solution: Each single-dose packet of VIDEX Buffered Powder for Oral Solution contains 1380 mg sodium.

Patients with Renal Impairment: Patients with renal impairment (creatinine clearance <60 mL/min) may be at greater risk of toxicity from VIDEX due to decreased drug clearance (see CLINICAL PHARMACOLOGY). A dose reduction is recommended in these patients (see DOSAGE AND ADMINISTRATION). The magnesium content of each buffered tablet of VIDEX is 8.6 mEq. This may present an excessive load of magnesium to patients with significant renal impairment, particularly after prolonged dosing.

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

VIDEX 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 VIDEX used alone and in combination regimens, is pancreatitis, which may be fatal. Patients should be informed that the preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing frequency. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX. Patients should also be aware that peripheral neuropathy, manifested by numbness, tingling, or pain in hands or feet, may develop during therapy with VIDEX. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients with advanced HIV disease or a history of peripheral neuropathy, and that dose modification and/or discontinuation of VIDEX may be required if toxicity develops. Patients should be informed that when VIDEX is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when VIDEX 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 VIDEX toxicities. Patients should be advised that to ensure proper acid neutralization in the stomach they must take at least two of the appropriate strength VIDEX tablets at each dose. To reduce the risk of gastrointestinal side effects from excess antacid, patients should take no more than four VIDEX tablets at each dose. VIDEX (didanosine) is not a cure for HIV infection, and patients may continue to develop HIV-associated illnesses, including opportunistic infection. Therefore, patients should remain under the care of a physician when using VIDEX. Patients should be advised that VIDEX 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 VIDEX 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 4). The clinical recommendations based on the results of these studies are listed in Table 7.

Coadministration Not Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)

Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY: Drug Interactions for Magnitude of Interaction)

ciprofloxacin | ciprofloxacin concentration Administer VIDEX at least 2 hours after or

delavirdine | delavirdine concentration Administer VIDEX 1 hour after delavirdine.

nelfinavir No interaction 1 hour after didanosine Administer nelfinavir 1 hour after VIDEX.

Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis).

Because VIDEX formulations either contain buffers or are mixed with antacids before administration, interactions may be anticipated with drugs whose absorption can be affected by the level of acidity in the stomach and with drugs that have been demonstrated to interact with antacids containing magnesium, calcium, or aluminum. Predicted drug interactions with VIDEX are listed in Table 8.

Use caution with VIDEX Chewable/Dispersible Buffered Tablets and Pediatric Powder for Oral Solution.

Use with Caution, Plasma Concentrations May Be Decreased by Coadministration with VIDEX

Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX.

Tetracycline antibiotics | antibiotic concentration Consult package insert of the tetracycline.

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: Lactic Acidosis/Severe Hepatomegaly with Steatosis). The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV- infected pregnant women receiving didanosine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

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. mothers should be instructed not to breast-feed if they are receiving VIDEX

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,

Pediatric Use

Use of VIDEX in pediatric patients is supported by evidence from adequate and well- controlled studies of VIDEX in adults and pediatric patients (see Clinical Studies, CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).

Geriatric Use

In an Expanded Access Program for patients with 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 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 VIDEX (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 VIDEX is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when VIDEX is used alone. Thus, patients treated with VIDEX in combination with stavudine, with or without hydroxyurea, may be at increased risk for pancreatitis, which may be fatal, and hepatotoxicity WARNINGS). Patients treated with VIDEX in combination with stavudine may also be at increased risk for peripheral neuropathy (PRECAUTIONS).

(see

see

Adults:

Selected clinical adverse events that occurred in adult patients in clinical studies with VIDEX are provided in Tables 9 and 10.

Table 9: Selected Clinical Adverse Events from Monotherapy Studies

Percent of Patients

ACTG 116A ACTG 116B/117
Adverse Events	VIDEX n=197	zidovudine n=212	VIDEX n=298	zidovudine n=304
Diarrhea	19	15	28	21
Peripheral Neurologic Symptoms/Neuropathy	17	14	20	12
Rash/Pruritus	7	8	9	5
Abdominal Pain	13	8	7	8
Pancreatitis	7	3	6	2

Table 10: Selected Clinical Adverse Events from Combination Studies

Percent of Patientsa

AI454-148b START 2b
	VIDEX + stavudine + nelfinavir	zidovudine + lamivudine + nelfinavir	VIDEX + stavudine + indinavir	zidovudine + lamivudine + indinavir
Adverse Events	n=482	n=248	n=102	n=103
Diarrhea	70	60	45	39
Nausea	28	40	53	67
Headache	21	30	46	37
Peripheral Neurologic Symptoms/Neuropathy	26	6	21	10
Rash	13	16	30	18
Vomiting	12	14	30	35
Pancreatitis (see below	) 1	*	<1	*

Percentages based on treated subjects.
Median duration of treatment 48 weeks.

This event was not observed in this study arm.

Pancreatitis resulting in death was observed in one patient who received VIDEX plus stavudine plus nelfinavir in Study Al454-148 and in one patient who received VIDEX plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received VIDEX plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial (WARNINGS).

see

The frequency of pancreatitis is dose related. In phase 3 studies, incidence ranged from 1% to 10% with doses higher than are currently recommended and from 1% to 7% with recommended dose. Selected laboratory abnormalities in clinical studies with VIDEX are shown in Tables 11-13.

Table 11: Selected Laboratory Abnormalities from Monotherapy Studies

Percent of Patients

Table 11: Selected Laboratory Abnormalities from Monotherapy Studies

ACTG 116A ACTG 116B/117

VIDEX zidovudine VIDEX zidovudine

Parameter n=197 n=212 n=298 n=304

SGOT (AST) (>5 x ULN)	9	4	7	6
SGPT (ALT) (>5 x ULN)	9	6	6	6
Alkaline phosphatase (>5 x ULN)	4	1	1	1
Amylase ( 3 1.4 x ULN)	17	12	15	5
Uric acid (>12 mg/dL)	3	1	2	1

ULN = upper limit of normal.

Table 12: Selected Laboratory Abnormalities from Combination Studies (Grades 3-4)

Percent of Patientsa

AI454-148b START 2b

stavudine + nelfinavir

zidovudine + lamivudine + nelfinavir

VIDEX +

stavudine + indinavir

zidovudine + lamivudine + indinavir

Bilirubin (>2.6 x ULN)	<1	<1	16	8
SGOT (AST) (>5 x ULN)	3	2	7	7
SGPT (ALT) (>5 x ULN)	3	3	8	5
GGT (>5 x ULN)	NC	NC	5	2
Lipase (>2 x ULN)	7	2	5	5
Amylase (>2 x ULN)	NC	NC	8	2
ULN = upper limit of normal. NC=Not Collected

Parameter n=482 n=248 n=102 n=103

Percentages based on treated subjects.
Median duration of treatment 48 weeks.

Table 13: Selected Laboratory Abnormalities from Combination Studies (All Grades)

Percent of Patientsa

I454-148b START 2b
	VIDEX + stavudine + nelfinavir	zidovudine + lamivudine + nelfinavir	VIDEX + stavudine + indinavir	zidovudine + lamivudine + indinavir
Parameter	n=482	n=248	n=102	n=103
Bilirubin	7	3	68	55
SGOT (AST)	42	23	53	20
SGPT (ALT)	37	24	50	18
GGT	NC	NC	28	12
Lipase	17	11	26	19
Amylase	NC	NC	31	17
NC = Not Collected

Percentages based on treated subjects.
Median duration of treatment 48 weeks.

Observed during Clinical Practice:

The following events have been identified during postapproval use of VIDEX (didanosine). 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 VIDEX, or a combination of these factors.

Body as a Whole - 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 - lactic acidosis and hepatic steatosis (see WARNINGS); hepatitis and liver failure.

Metabolic Disorders

- diabetes mellitus, hypoglycemia, and hyperglycemia.

Musculoskeletal Disorders

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

Ophthalmologic Disorders - Retinal depigmentation and optic neuritis (see WARNINGS).

Pediatric Patients:

Adverse events and laboratory abnormalities reported to occur in the pediatric patients in ACTG 152 were generally similar to adverse events and laboratory abnormalities reported in adult patients.

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. Retinal changes and optic neuritis have been reported in pediatric patients.

OVERDOSAGE

There is no known antidote for VIDEX (didanosine) overdosage. In phase 1 studies, in which VIDEX was 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

Dosage

All VIDEX formulations should be administered on an empty stomach, at least 30 minutes before or 2 hours after eating. For either a once-daily or twice-daily regimen, patients must take at least two of the appropriate strength tablets at each dose to provide adequate buffering and prevent gastric acid degradation of didanosine. Because of the need for adequate buffering, the 200-mg strength tablet should only be used as a

component of a once-daily regimen. To reduce the risk of gastrointestinal side effects, patients should take no more than four tablets at each dose.

Adults: The preferred dosing frequency of VIDEX is twice daily because there is more evidence to support the effectiveness of this dosing regimen. Once-daily dosing should be considered only for adult patients whose management requires once-daily dosing of VIDEX (see Clinical Studies). The daily dose in adult patients is dependent on weight as outlined in Table 14.

The 200-mg strength tablet should only be used as a component of a once- daily regimen.

Patient Weight VIDEX Tabletsa VIDEX Buffered Powderb
Preferred dosing 3 60 kg	200 mg twice daily	250 mg twice daily
< 60 kg	125 mg twice daily	167 mg twice daily
Dosing for patients whose management requires once-daily frequency
3 60 kg	400 mg once daily	b
< 60 kg	250 mg once daily	b

Pediatric Patients: The recommended dose of VIDEX (didanosine) in pediatric patients is 120 mg/m2 twice daily. There are no data on once-daily dosing of VIDEX in pediatric patients.

Dose Adjustment

Clinical and laboratory signs suggestive of pancreatitis should prompt dose suspension and careful evaluation of the possibility of pancreatitis. VIDEX use should be discontinued in patients with confirmed pancreatitis (WARNINGS).

Patients with symptoms of peripheral neuropathy may tolerate a reduced dose of VIDEX after resolution of the symptoms of peripheral neuropathy upon drug discontinuation. If neuropathy recurs after resumption of VIDEX, permanent discontinuation of VIDEX should be considered.

In adult patients with impaired renal function, the dose of VIDEX should be adjusted to compensate for the slower rate of elimination. The recommended doses and dosing intervals of VIDEX in adult patients with renal insufficiency are presented in Table 15.

VIDEX Chewable/Dispersible Buffered Tablet. Two VIDEX tablets must be taken with each dose; different strengths of tablets may be combined to yield the recommended dose.

c 400 mg once daily (360 kg) or 250 mg once daily (<60 kg) for patients whose management requires once- daily frequency of administration. Urinary excretion is also a major route of elimination of didanosine in pediatric patients; therefore, the clearance of didanosine may be altered in children with renal impairment. Although there are insufficient data to recommend a specific dose adjustment of VIDEX in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.

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

15. It is not necessary to administer a supplemental dose of VIDEX following hemodialysis.

Method of Preparation

Adult Dosing: To provide adequate buffering, at least two of the appropriate strength tablets, but no more than four tablets, should be thoroughly chewed or dispersed in at least 1 ounce of water prior to consumption (see PRECAUTIONS: Information for Patients). To disperse tablets, add 2 tablets to at least 1 ounce of drinking water. Stir until a uniform dispersion forms, and drink the entire dispersion immediately. If additional flavoring is desired, the dispersion may be diluted with one ounce of clear apple juice. Stir the further diluted dispersion just prior to consumption. The dispersion with clear apple juice is stable at room temperature, 62deg to 73degF (17deg to 23degC), for up to one hour.

Open packet carefully and pour contents into a container with approximately 4 ounces of drinking water. Do not mix with fruit juice or other acid-containing liquid. Stir until the powder completely dissolves (approximately 2 to 3 minutes). Drink the entire solution immediately.

Prior to dispensing, the pharmacist must constitute dry powder with Purified Water, USP, to an initial concentration of 20 mg/mL and immediately mix the resulting solution with antacid to a final concentration of 10 mg/mL as follows:

Constitute the product to 20 mg/mL by adding 100 mL or 200 mL of Purified Water, USP, to the 2 g or 4 g of VIDEX powder, respectively, in the product bottle.

10 mg/mL Final Admixture: 1. Immediately mix one part of the 20 mg/mL initial solution with one part of either Mylanta(r) Double Strength Liquid, Extra Strength Maalox(r) Plus Suspension, or Maalox(r) TC Suspension for a final dispensing concentration of 10 mg Mylanta(r) is a registered trademark of Johnson & Johnson-Merck Consumer Pharmaceuticals Company. Maalox(r) is a registered trademark of Novartis Consumer Health, Inc. VIDEX per mL. For patient home use, the admixture should be dispensed in appropriately sized, flint-glass or plastic (HDPE, PET, or PETG) bottles with child-resistant closures. This admixture is stable for 30 days under refrigeration, 36deg to 46deg F (2deg to 8deg C). 2. Instruct the patient to shake the admixture thoroughly prior to use and to store the tightly closed container in the refrigerator, 36deg to 46deg F (2deg to 8deg C), up to 30 days.

HOW SUPPLIED

are round, off white to light orange/yellow with a mottled appearance, orange-flavored, tablets embossed with "VIDEX" on one side and the product strength on the other. The tablets are available in the following strengths of VIDEX: 25, 50, 100, 150, and 200 mg. Sixty tablets are packaged in bottles with child-resistant closures.

The tablets should be stored in tightly closed bottles at 59deg to 86deg F (1 5 deg to 30 deg C ). If dispersed in water, the dose may be held for up to 1 hour at ambient temperature.

is supplied in single-dose, child-resistant foil packets in the following strengths of VIDEX: 100, 167, or 250 mg. Each product strength provides a sweetened, buffered solution of VIDEX.

The packets should be stored at 59deg to 86deg F (15deg to 30deg C). After dissolving in water, the solution may be stored at ambient room temperature for up to 4 hours.

is supplied in 4- and 8- ounce glass bottles containing 2 g or 4 g of VIDEX, respectively.

The bottles of powder should be stored at 59deg to 86deg F (15deg to 30deg C). The VIDEX admixture may be stored up to 30 days in a refrigerator, 36deg to 46deg F (2deg to 8degC). Discard any unused portion after 30 days. The NDC numbers for the previously described VIDEX products are:

HANDLING AND DISPOSAL

Spill, Leak, and Disposal Procedure

Avoid generating dust during clean-up of powdered products; use wet mop or damp sponge. Clean surface with soap and water as necessary. Containerize larger spills. There is no single preferred method of disposal of containerized waste. Disposal options include incineration, landfill, or sewer as dictated by specific circumstances and relevant national, state, and local regulations.

Parameter	3 90 (n=12)	60-90 (n=6)	30-59 (n=6)	10-29 (n=3)
CL cr (mL/min) CL/F (mL/min)	112 +- 22 2164 +- 638	68 +- 8 1566 +- 833	46 +- 8 1023 +- 378	13 +- 5 628 +- 104
CL R (mL/min) T 1/2 (h)	458 +- 164 1.42 +- 0.33	247 +- 153 1.59 +- 0.13	100 +- 44 1.75 +- 0.43	20 +- 8 2.0 +- 0.3

WARNING

DESCRIPTION

MICROBIOLOGY

Mechanism of Action

Drug Resistance

Cross-resistance

CLINICAL PHARMACOLOGY

Animal Toxicology

Pharmacokinetics

Special Populations

INDICATIONS AND USAGE

Clinical Studies

CONTRAINDICATION

WARNINGS

Pancreatitis

Lactic Acidosis/Severe Hepatomegaly with Steatosis

Retinal Changes and Optic Neuritis

PRECAUTIONS

Frequency of Dosing

Peripheral Neuropathy

Fat Redistribution

General

Information for Patients (See Patient Information Leaflet.)

Drug Interactions (see also CLINICAL PHARMACOLOGY: Drug Interactions)

Carcinogenesis and Mutagenesis

Pregnancy, Reproduction, and Fertility

Nursing Mothers

Pediatric Use

Geriatric Use

ADVERSE REACTIONS

OVERDOSAGE

DOSAGE AND ADMINISTRATION

Dosage

Dose Adjustment

Method of Preparation

HOW SUPPLIED

HANDLING AND DISPOSAL

Spill, Leak, and Disposal Procedure