DESCRIPTION

VIDEX® (didanosine) is a brand name for didanosine (ddI), a synthetic purine nucleoside analogue active against the Human Immunodeficiency Virus (HIV).

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® 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 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.

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.

HIV Susceptibility in Cell Culture

The anti-HIV-1 activity of didanosine was eva luated 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.

Resistance

HIV-1 isolates with reduced sensitivity to didanosine have been selected in cell culture 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 cell culture 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 cell culture. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. In data from clinical studies, the presence of thymidine analogue mutations (M41L, D67N, L210W, T215Y, K219Q) has been shown to decrease the response to didanosine.

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 nucleosideanalogues.

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.

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 in adults 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.

Pediatric Patients: The pharmacokinetics of didanosine have been eva luated in HIV-exposed and -infected pediatric patients from birth to 19 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients are similar to those of didanosine in adults. Didanosine plasma concentrations appear to increase in proportion to oral doses ranging from 25 to 120 mg/m2 in pediatric patients less than 5 months old and from 80 to 180 mg/m2 in children above 8 months old. For information on controlled clinical studies in pediatric patients, see INDICATIONS AND USAGE: Clinical Studies and PRECAUTIONS: Pediatric Use.

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

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

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).

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 (didanosine) 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 and DOSAGE AND ADMINISTRATION (for tenofovir).

INDICATIONS AND USAGE

VIDEX (didanosine) in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection (see Clinical Studies).

Clinical Studies

Combination Therapy

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.

Monotherapy

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 (ACTG 116B/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 3 months to 18 years of age 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

1. 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 phase 1 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. In study ACTG 152, pancreatitis occurred in none of the 281 pediatric patients who received didanosine 120 mg/m2 q12h and in <1% of the 274 pediatric patients who received didanosine 90 mg/m2 q12h in combination with zidovudine. VIDEX (didanosine) use should be suspended in pediatric patients with signs or symptoms of pancreatitis and discontinued in pediatric patients with confirmed pancreatitis.

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 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 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 adult and pediatric patients. Periodic retinal examinations should be considered for patients receiving VIDEX. (See ADVERSE REACTIONS.)

4. Hepatic Impairment and Toxicity

It is unknown if hepatic impairment significantly affects didanosine pharmacokinetics. Therefore, these patients should be monitored closely for evidence of didanosine toxicity. The safety and efficacy of VIDEX have notbeen established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

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

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

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including VIDEX. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further eva luation and treatment.

General

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).

Hyperuricemia: 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.

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 6.

Coadministration of VIDEX with drugs that are known to cause pancreatitis may increase the risk of this toxicity (see WARNINGS: Pancreatitis). Because VIDEX is mixed with an antacid 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 7.

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