VIDEX EC (Page 4 of 8)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to VIDEX EC during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Fatal lactic acidosis has been reported in pregnant individuals 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 and Precautions (5.2) ]. Coadministration of VIDEX EC and stavudine is contraindicated [see Contraindications (4) ].

Based on APR reports, congenital malformations were reported when administered during pregnancy. The prevalence of birth defects was 4.7% in the first trimester compared with 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) and 4.2% in the Texas Birth Defects Registry (TBDR) (see Data). No pattern of defects was identified by the APR. Based on these findings, the clinical relevance is uncertain.

The rate of miscarriage is not reported in the APR. In the U.S. general population, the estimated background risks of miscarriage in clinically recognized pregnancies is 15 to 20%, respectively.

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with didanosine at systemic exposures (AUC) up to 12 (rats) and 14 (rabbits) times the exposure in humans at the recommended daily human dose of VIDEX EC (see Data).

Clinical Considerations

Maternal Adverse Reactions

Cases of lactic acidosis syndrome, sometimes fatal, have occurred in pregnant individuals using VIDEX EC in combination with stavudine. VIDEX EC is associated with an increased risk of lactic acidosis syndrome/hepatic steatosis syndrome [see Warnings and Precautions (5.2) ]

Data

Human Data

Based on prospective reports to the APR of exposure to didanosine-containing regimens during pregnancy (including 427 exposed in the first trimester and 462 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.7% (95% CI: 2.9% to 7.1%) with first trimester exposure to didanosine-containing regimens and 4.3% (95% CI: 2.7% to 6.6%) with the second/third trimester exposure to didanosine-containing regimens compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP and 4.2% in the TBDR.

Prospective reports from the APR of overall major birth defects in pregnancies exposed to VIDEX EC is compared with a U.S.background major birth defect rate. Methodological limitations of the APR include the use of MACDP and TBDR as the external comparator groups. Limitations of using external comparators include differences in methodology and populations, as well as confounding due to the underlying disease.

Animal Data

Didanosine was administered orally at up to 1000 mg per kg daily to pregnant rats and at up to 600 mg per kg daily to pregnant rabbits on gestation Days 7 to 17 and 6 to 18, respectively, and also to rats 14 days before mating through weaning. No adverse effects on embryo-fetal development (rats and rabbits) were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to didanosine were up to 12 (rats) and 14.2 (rabbits) times the estimated human exposure at the recommended daily human dose. Didanosine and/or its metabolites are transferred to the fetus through the placenta. In the rat pre/postnatal development study, didanosine administered to pregnant rats reduced food intake and body weight gains in pups at a maternally toxic exposure (approximately 12 times the exposure at the recommended human dose).

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether didanosine is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, didanosine was present in milk (see Data).

Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving VIDEX EC.

Data

Didanosine and its metabolites were excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 14, with milk concentrations 5 times that of maternal plasma concentrations at 8 and 24 hours post-dose.

8.4 Pediatric Use

Use of didanosine in pediatric patients from 2 weeks of age through adolescence is supported by evidence from adequate and well-controlled studies of didanosine in adult and pediatric patients [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Additional pharmacokinetic studies in pediatric patients support use of VIDEX EC in pediatric patients who weigh at least 20 kg.

8.5 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 and Precautions (5.1) ]. Clinical studies of didanosine, including those for VIDEX EC, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently than younger subjects. Didanosine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. In addition, renal function should be monitored and dosage adjustments should be made accordingly [see Dosage and Administration (2.2) ].

8.6 Renal Impairment

Patients with renal impairment (creatinine clearance of less than 60 mL/min) may be at greater risk of toxicity from didanosine due to decreased drug clearance [see Clinical Pharmacology (12.3) ]. A dose reduction is recommended for these patients [see Dosage and Administration (2) ].

10 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 (12.3) ].

11 DESCRIPTION

VIDEX® EC is the brand name for an enteric-coated formulation of didanosine, USP, a synthetic purine nucleoside analogue active against HIV-1. VIDEX EC Delayed-Release Capsules, containing enteric-coated beadlets, are available for oral administration in strengths of 125, 200, 250, and 400 mg of didanosine. The inactive ingredients in the beadlets include carboxymethylcellulose sodium 12, diethyl phthalate, methacrylic acid copolymer, sodium hydroxide, sodium starch glycolate, and talc. The capsule shells contain gelatin and titanium dioxide. The capsules are imprinted with edible inks.

Didanosine is also available in a powder formulation. Please consult the prescribing information for VIDEX (didanosine) Pediatric Powder for Oral Solution for additional information.

The chemical name for didanosine is 2′,3′-dideoxyinosine. The structural formula is:

didanosine-structure.jpg
(click image for full-size original)

Didanosine is a white crystalline powder with the molecular formula C10 H12 N4 O3 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 less than 3 and 37° C, 10% of didanosine decomposes to hypoxanthine in less than 2 minutes. In VIDEX EC, an enteric coating is used to protect didanosine from degradation by stomach acid.

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