Didanosine

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. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

HIV-infected women are advised not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected. 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.

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.

A serious toxicity of didanosine is pancreatitis, which may be fatal. Other important toxicities include lactic acidosis/severe hepatomegaly with steatosis; retinal changes ans optic neuritis; and peripheral neuropathy.

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 pancreatitis and liver function abnormalities). Patients treated with didanosine in combination with stavudine may also be at increased risk for peripheral neuropathy.

Adults

Selected clinical adverse events that occurred in adult patients in clinical studies with didanosine are provided in Table 3 and Table 4.

Table 3. Selected Clinical Adverse Events from Monotherapy Studies:

Table 4. Selected Clinical Adverse Events from Combination Studies:

^a Data through a median of 32 weeks of treatment.
^b Data through 48 weeks of treatment.

Pancreatitis resulting in death was observed in one patient who received didanosine plus stavudine plus nelfinavir in Study AI454-148 and in one patient who received didanosine plus stavudine plus indinavir in the START 2 study. In addition, pancreatitis resulting in death was observed in 2 of 68 patients who received didanosine plus stavudine plus indinavir plus hydroxyurea in an ACTG clinical trial.

Selected laboratory abnormalities in clinical studies with didanosine are shown in Table 5, Table 6, and Table 7.

Table 5. Selected Laboratory Abnormalities from Monotherapy Studies:

ULN = upper limit of normal.

Table 6. Selected Laboratory Abnormalities from Combination Studies (Grades 3-4):

ULN = upper limit of normal.
NC=Not Collected
^a Data through a median of 32 weeks of treatment.
^b Data through 48 weeks of treatment.

Table 7. Selected Laboratory Abnormalities from Combination Studies (All Grades):

NC=Not Collected
^a Data through a median of 32 weeks of treatment.
^b Data through 48 weeks of treatment.

Observed during Clinical Practice

The following events have been identified during post approval use of 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 didanosine, or a combination of these factors.

Body as a Whole: alopecia, anaphylactoid reaction, asthenia, chills/fever, and pain.

Digestive Disorders: anorexia, dyspepsia, and flatulence.

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

Hematologic Disorders: anemia, leukopenia, and thrombocytopenia.

Liver: lactic acidosis and hepatic steatosis; hepatitis and liver failure.

Metabolic Disorders: diabetes mellitus, hypoglycemia, and hyperglycemia.

Musculoskeletal Disorders: myalgia (with or without increases in creatinine phosphokinase), rhabdomyolysis including acute renal failure and hemodialysis, arthralgia, and myopathy.

Ophthalmologic Disorders: Retinal depigmentation and optic neuritis.

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.