lopurinol did not appear to produce a higher incidence of skin rashes than observed with Nipent alone. There has been a report of one patient who received both drugs and experienced a hypersensitivity vasculitis that resulted in death. It was unclear whether this adverse event and subsequent death resulted from the drug combination.
Biochemical studies have demonstrated that pentostatin enhances the effects of vidarabine, a purine nucleoside with antiviral activity. The combined use of vidarabine and Nipent may result in an increase in adverse reactions associated with each drug. The therapeutic benefit of the drug combination has not been established.
The combined use of Nipent and fludarabine phosphate is not recommended because it may be associated with an increased risk of fatal pulmonary toxicity (see WARNINGS).
Acute pulmonary edema and hypotension, leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of the ablative regimen for bone marrow transplant.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: No animal carcinogenicity studies have been conducted with pentostatin.
Mutagenesis: Pentostatin was nonmutagenic when tested in Salmonella typhimurium strains TA-98, TA-1535, TA-1537, and TA-1538. When tested with strain TA-100, a repeatable statistically significant response trend was observed with and without metabolic activation. The response was 2.1 to 2.2 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 studies 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 sy
