.2 fold higher than the background at 10 mg/plate, the maximum possible drug concentration. Formulated pentostatin was clastogenic in the in vivo mouse bone marrow micronucleus assay at 20, 120, and 240 mg/kg. Pentostatin was not mutagenic to V79 Chinese hamster lung cells at the HGPRT locus exposed 3 hours to concentrations of 1 to 3 mg/mL, with or without metabolic activation. Pentostatin did not significantly increase chromosomal aberrations in V79 Chinese hamster lung cells exposed 3 hours to 1 to 3 mg/mL in the presence or absence of metabolic activation.
Impairment of Fertility: No fertility studies have been conducted in animals; however, in a 5-day intravenous toxicity study in dogs, mild seminiferous tubular degeneration was observed with doses of 1 and 4 mg/kg. The possible adverse effects on fertility in humans have not been determined.
Pregnancy
Pregnancy Category D: (See WARNINGS )
Nursing Mothers
It is not known whether NIPENT is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from pentostatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of NIPENT to the mother.
Pediatric Use
Safety and effectiveness in children or adolescents have not been established.
ADVERSE REACTIONS
Most patients treated for hairy cell leukemia in the five NCI-sponsored Phase 2 and the Phase 3 SWOG study experienced an adverse event. The following table lists the most frequently occurring adverse events in patients treated with NIPENT (both frontline and IFN-refractory patients) compared with IFN (frontline only), regardless of drug association. The drug association of some adverse events is uncertain as they may be associated with the disease itself (eg, infection, hematologic suppression), but other events, such as the gastrointestinal symptoms, rashes, and abnormal liver function tests, can in many cases be attributed to the drug. Most adverse events that were asssessed for severity were either mild or moderate, and diminished in frequency with continued therapy.
The total incidence for all types of infections is considerably higher for both treatment groups in the SWOG 8691 study than is listed in the table above. An intent-to-treat analysis of infections found that 38% of patients treated with NIPENT and 34% of patients treated with IFN averaged 2.4 and 1.9 documented infections during treatment, respectively. The following table lists the different types of infections that were reported as adverse events during the initial phase of the SWOG study. There were no apparent differences in the types of infection between the 2 treatment groups, with the possible exception of herpes zoster which was reported more frequently for NIPENT (8%) than for IFN (1%).
The drug relatedness of the adverse events listed below cannot be excluded. The following adverse events occurred in 3% to 10% of NIPENT-treated patients in the initial phase of the SWOG study:
Body as a Whole --Chest Pain, Death, Face Edema, Peripheral Edema
Cardiovascular System --Hemorrhage, Hypotension
Digestive System --Dental Abnormalities, Dyspepsia, Flatulence, Gingivitis
Hemic and Lymphatic System --Agranulocytosis
Laboratory Deviations --Elevated Creatinine
Musculoskeletal System --Arthralgia
Nervous System --Confusion, Dizziness, Insomnia, Paresthesia, Somnolenc |
