The most frequent and most serious toxicityof CeeNU is delayed myelosuppression. It usually occurs 4 to 6 weeks afterdrug administration and is dose related. Thrombocytopenia occurs at about4 weeks postadministration and persists for 1 to 2 weeks. Leukopenia occursat 5 to 6 weeks after a dose of CeeNU and persists for 1 to 2 weeks. Approximately65% of patients receiving 130 mg/m2 develop whiteblood counts below 5000 wbc/mm3. Thirty-six percentdeveloped white blood counts below 3000 wbc/mm3.Thrombocytopenia is generally more severe than leukopenia. However, both maybe dose-limiting toxicities.
CeeNU may producecumulative myelosuppression, manifested by more depressed indices or longerduration of suppression after repeated doses.
Theoccurrence of acute leukemia and bone marrow dysplasias have been reportedin patients following long-term nitrosourea therapy.
Anemiaalso occurs, but is less frequent and less severe than thrombocytopenia orleukopenia.
Pulmonary toxicity characterized by pulmonaryinfiltrates and/or fibrosis has been reported rarely with CeeNU. Onset oftoxicity has occurred after an interval of 6 months or longer from the startof therapy with cumulative doses of CeeNU usually greater than 1100 mg/m2.There is 1 report of pulmonary toxicity at a cumulative dose of only 600 mg.
Delayedonset pulmonary fibrosis occurring up to 17 years after treatment has beenreported in patients who received related nitrosoureas in childhood and earlyadolescence (1-16 years) combined with cranial radiotherapy for intracranialtumors. There appeared to be some late reduction of pulmonary function ofall long-term survivors. This form of lung fibrosis may be slowly progressiveand has resulted in death in some cases. In this long-term study of carmustine,all those initially treated at less than 5 years of age died of delayed pulmonaryfibrosis.
Nausea and vomiting may occur 3 to 6hours after an oral dose and usually last less than 24 hours. Prior administrationof antiemetics is effective in diminishing and sometimes preventing this sideeffect. Nausea and vomiting can also be reduced if CeeNU is administered tofasting patients.
A reversible type of hepatic toxicity,manifested by increased transaminase, alkaline phosphatase and bilirubin levels,has been reported in a small percentage of patients receiving CeeNU.
Renal abnormalities consisting of progressiveazotemia, decrease in kidney size, and renal failure have been reported inpatients who received large cumulative doses after prolonged therapy withCeeNU. Kidney damage has also been reported occasionally in patients receivinglower total doses.
Stomatitis, alopecia, optic atrophy,and visual disturbances, such as blindness, have been reported infrequently.
Neurologicalreactions, such as disorientation, lethargy, ataxia, and dysarthria have beennoted in some patients receiving CeeNU. However, the relationship to medicationin these patients is unclear.