Carmustine

Carmustine IV causes bone marrow suppression, primarily thrombocytopenia (which may lead to bleeding) and leukopenia (which may cause infection). Monitor blood counts weekly for at least 6 weeks following each dose. Adjust dosage based on nadir blood counts from prior dose for dosage adjustment. Do not administer a repeat course until blood counts recover. Hematologic toxicity is dose-limiting, may be severe, and is generally delayed and cumulative; thrombocytopenia is usually more severe than leukopenia. Myelosuppression generally occurs 4 to 6 weeks after administration; thrombocytopenia occurs at ~4 weeks and persists for 1 to 2 weeks; leukopenia occurs at 5 to 6 weeks and persists for 1 to 2 weeks. Anemia may occur (less common and less severe than leukopenia or thrombocytopenia). Platelet counts should be >100,000/mm3 and leukocytes should be >4,000/mm3 prior to a repeat course (repeat courses should not be administered more frequently than every 6 weeks).

Carmustine IV is associated with a moderate to high emetic potential (dose-related); antiemetics are recommended to prevent nausea and vomiting (Dupuis 2011; Hesketh 2017; Roila 2016).

Reversible increases in transaminases, bilirubin, and alkaline phosphatase have been reported (rare) with the IV formulation. Monitor liver function tests periodically during treatment.

Rapid infusions are associated with skin flushing and suffusion of the conjunctiva (onset: • Intracranial hypertension: Brain edema has been reported in patients with newly diagnosed glioma receiving wafer implants, including one report of intracranial mass effect unresponsive to corticosteroids that led to brain herniation. Monitor closely for intracranial hypertension related to brain edema, inflammation, or necrosis of brain tissue surrounding resection. Re-operation to remove wafers (or remnants) may be necessary for refractory cases.

Cases of meningitis have occurred in patients with recurrent glioma receiving wafer implants. Two cases were bacterial (one patient required removal of implants 4 days after implantation and the other developed meningitis following reoperation for recurrent tumor). Another case was determined to be chemical meningitis and resolved with corticosteroids. Monitor postoperatively for signs/symptoms of meningitis and CNS infection.

Investigational administration (intraarterial intracarotid route [not an approved route]) has been associated with ocular toxicity.

Carmustine IV is associated with dose-related pulmonary toxicity; patients receiving cumulative doses >1,400 mg/m2 are at significantly higher risk. Delayed onset of pulmonary fibrosis may occur years after treatment (may be fatal), particularly in children. Pulmonary toxicity has occurred in children and adolescents up to 17 years after treatment; this occurred in ages 1 to 16 for the treatment of intracranial tumors; cumulative doses ranged from 770 to 1,800 mg/m2 (in combination with cranial radiotherapy). Pulmonary toxicity is characterized by pulmonary infiltrates and/or fibrosis and has been reported from 9 days to 43 months after nitrosourea treatment (including carmustine). Although pulmonary toxicity generally occurs in patients who have received prolonged treatment, pulmonary fibrosis has been reported with cumulative doses below 1,400 mg/m2. Interstitial fibrosis at lower doses has occurred (rare). In addition to high cumulative doses, other risk factors for pulmonary toxicity include history of lung disease and baseline predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO) • Renal: Renal failure, progressive azotemia, and decreased kidney size have been reported in patients who have received large cumulative IV doses or prolonged IV treatment. Renal toxicity has also been reported in patients who have received lower cumulative doses. Monitor renal function tests periodically during treatment.

Long-term IV use is associated with the development of secondary malignancies (acute leukemias and bone marrow dysplasias).

Seizures occurred in patients who received carmustine wafer implants, including new or worsening seizures and treatment-emergent seizures. Just over half of treatment-emergent seizures occurred within 5 days of surgery; the median onset of first new or worsened post-operative seizure was 4 days. Optimal anti-seizure therapy should be initiated prior to surgery. Monitor (postoperatively) for seizures.

Impaired neurosurgical wound healing, including would dehiscence, delayed healing, and subdural, subgleal or wound effusions may occur with carmustine wafer implant treatment; cerebrospinal fluid leaks have also been reported. Monitor post-operatively for impaired neurosurgical wound healing. Disease related concerns:

May require dosage adjustment or discontinuation in patients with renal impairment. Do not administer carmustine IV in patients with compromised renal function. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Children are at higher risk of delayed pulmonary toxicity with the IV formulation. Dosage form specific issues:

Diluent contains ethanol.

Monitor closely for known craniotomy-related complications (seizure, intracranial infection, abnormal wound healing, brain edema). Wafer migration may occur; avoid communication between the resection cavity and the ventricular system to prevent wafer migration; communications larger than the wafer should be closed prior to implantation; wafer migration into the ventricular system may cause obstructive hydrocephalus. Monitor for signs/symptoms of obstructive hydrocephalus.