Carmustine

Pronunciation: CAR-muss-teen
Class: Nitrosourea

Trade Names

BiCNU
- Powder for injection 100 mg

Gliadel
- Wafer 7.7 mg

Pharmacology

Carmustine alkylates DNA and RNA and also inhibits several enzymes by carbamoylation of amino acids in proteins. Antineoplastic and toxic activities may be caused by metabolites.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

IV

Vd is 3.25 L/kg. Crosses the blood-brain barrier.

Elimination

IV

The t ½ is 22 min. Cl is 56 mL/min/kg. Approximately 60% is excreted in the urine; 6% is expired as CO 2 .

Indications and Usage

Brain tumors, multiple myeloma, Hodgkin and non-Hodgkin lymphomas; adjunct to surgery and radiation in newly diagnosed high-grade malignant glioma patients and as an adjunct in recurrent glioblastoma multiforme patients (wafer).

Unlabeled Uses

Mycosis fungoides.

Contraindications

Standard considerations.

Dosage and Administration

Brain Tumors, Multiple Myeloma, Hodgkin and Non-Hodgkin Lymphomas (Single Agent in Previously Untreated Patients)
Adults

IV 150 to 200 mg/m 2 every 6 wk, as a single dose or divided into 2 successive daily infusions.

Dosage Reduction
Adults

IV Compromised bone marrow function or therapy with other myelosuppressive drugs requires a reduction in dose. Do not administer repeat courses until acceptable leukocyte and platelet counts have recovered (usually greater than 4,000/mm 3 and 100,000/mm 3 , respectively). Subsequent doses are determined by the clinical and hematologic tolerance of the previous dose. The following leukocyte and platelet counts refer to the levels reached at nadir after prior dose. Give 100% of the prior dose given if the leukocytes are greater than 3000 cells/mm 3 and the platelets are greater than 75,000 cells/mm 3 . Give 70% of the prior dose given if the leukocytes are 2000 to 2999 cells/mm 3 and the platelets are 25,000 to 74,999 cells/mm 3 . Give 50% of the prior dose given if the leukocytes are less than 2000 cells/mm 3 and the platelets are less than 25,000 cells/mm 3 .

Adjunct To Surgery And Radiation In Newly Diagnosed High-Grade Malignant Glioma Patients And As An Adjunct In Recurrent Glioblastoma Multiforme Patients
Adults

Wafer for implantation 8 wafers placed in the resection cavity, for a total dose of 61.6 mg. If the cavity size and shape will not accommodate this, use the greatest number of wafers that will fit.

General Advice

  • Administer by IV infusion or intracranial implantation.
  • Follow procedures for proper handling and disposal of chemotherapy drugs. Wear gloves and avoid skin exposure and inhalation of fumes.
  • IV
  • The reconstituted solution is administered by IV drip over 1 to 2 h. Shorter infusion times may produce intense pain and burning at the site of injection.
  • Dissolve 1 vial with 3 mL of the dehydrated alcohol diluent, followed by 27 mL of sterile water for injection for a final concentration of 3.3 mg/mL in 10% alcohol. This solution may be further diluted with 5% dextrose for a concentration of 0.2 mg/mL in glass containers.
  • Accidental contact of carmustine with skin can cause temporary severe burning and hyperpigmentation; wear gloves when handling. Double gloving is recommended.
  • When administered with polyvinyl chloride tubing, longer infusion times may result in unacceptable drug loss. To avoid drug loss, polyethylene tubing, such as nitroglycerin tubing, can be utilized for infusions of carmustine.
  • Wafer
  • Open the foil pouches containing the wafer in the operating room immediately prior to implantation.
  • Unopened foil pouches are stable at room temperature for up to 6 h at a time.
  • Wafers may be used if broken in half. Do not use if broken in more than 2 pieces; dispose of as a hazardous chemical waste.
  • Use a dedicated surgical instrument for handling the wafers during implantation.

Storage/Stability

IV

Store the unopened vials in a refrigerator (2° to 8°C; 3° to 46°F). After reconstitution, store at room temperature (25°C; 77°F) for up to 8 h. Protect from light.

Wafer

Store at or below –20°C (–4°F). Unopened foil pouches may be kept at room temperature for up to 6 h.

Drug Interactions

Cimetidine

Cimetidine may enhance the myelosuppressive effects of carmustine.

Digoxin, phenytoin

Digoxin and phenytoin serum levels may be reduced by carmustine.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Wafer

Deep thrombophlebitis (10%); pulmonary embolus (8%); hemorrhage (7%).

CNS

Wafer

Depression (16%); intracranial hypertension (9%); anxiety, facial paralysis (7%); ataxia, hypesthesia (6%); dizziness, hallucinations, seizures (5%); headache (28%); meningitis; abscess; asthenia; confusion; somnolence; brain edema; intracranial infection.

Dermatologic

Rash (wafer) (12%); local burning pain at the injection site; intense flushing of the skin.

GI

Constipation (19%); abdominal pain, diarrhea (5%), (wafer); nausea (22%); vomiting (21%).

Genitourinary

UTI (8%; wafer); amenorrhea; male infertility.

Hematologic

Bone marrow suppression; myelosuppression.

Hepatic

Transient LFT elevations; hepatic necrosis and veno-occlusive disease after bone marrow transplantation.

Metabolic

Diabetes mellitus (wafer).

Renal

Dose-related, delayed-onset, progressive renal failure.

Respiratory

Early pulmonary toxicity; delayed pulmonary fibrosis.

Special Senses

Retinitis; optic neuritis; suffusion of the conjunctiva.

Miscellaneous

Wafer

Surgical wound healing abnormalities (16%); fever (12%); back pain, pain (7%); face edema (6%); abscess, chest pain (5%); CSF leak; subdural fluid collection; subgaleal or wound effusion; wound breakdown.

Precautions

Warnings

Bone marrow suppression (notably thrombocytopenia and leukopenia)

May contribute to bleeding and infections. Toxicity is cumulative, thus adjust dose based on nadir counts from prior doses. Do not repeat doses more frequently than every 6 wk. Perform weekly complete blood cell counts for 6 wk postdose.

Hematologic

The most frequent and serious toxic effect of injectable carmustine is delayed myelosuppression.

Pulmonary fibrosis

Delayed onset pulmonary fibrosis has occurred up to 17 yr after treatment and has been reported in patients who received injectable carmustine in childhood and early adolescence.

Pulmonary toxicity

Pulmonary toxicity from injectable carmustine appears to be dose-related. Patients receiving more than 1400 mg/m 2 cumulative dose are at significantly higher risk than those receiving less. Other risk factors include history of lung disease and duration of treatment. Cases of fatal pulmonary toxicity have occurred.


Monitor

Liver/Renal function tests

Monitor liver and renal function tests periodically.

Pulmonary function tests

Conduct baseline pulmonary function studies and frequent pulmonary function tests during treatment. Patients with a baseline less than 70% of predicted forced vital capacity (FVC) or carbon monoxide diffusing capacity (DL co ) are at particular risk.


Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Mutagenesis

Long-term use of nitrosoureas has been reported to be associated with the development of secondary malignancies.

Fertility

There have been reports of persistent testicular damage causing infertility with injectable carmustine.

Brain edema

Brain edema was noted in 4% of patients treated with the wafer.

Brain herniation

Cases of intracerebral mass effect unresponsive to corticosteroids have been described in patients treated with the wafer.

GI

Nausea and vomiting after IV administration. This dose-related toxicity appears within 2 h of dosing and lasts 4 to 6 h.

Healing abnormalities

The majority of these events were mild to moderate in severity.

Hepatic toxicity

Reversible hepatic toxicity, manifested by increased transaminase, alkaline phosphatase, and bilirubin levels, has occurred in a small percentage of patients using injectable carmustine.

Intracranial infection

Intracranial infection (eg, meningitis, abscess) occurred in 4% to 5% of patients treated with the wafer.

Obstructive hydrocephalus

Avoid communication between the surgical resection cavity and the ventricular system to prevent the wafers from migrating into the ventricular system and causing obstructive hydrocephalus.

Ocular

Toxicity manifested as nerve fiber-layer infarcts and retinal hemorrhages has been associated with high dose injectable carmustine therapy.

Renal toxicity

Decrease in kidney size, progressive azotemia, and renal failure have occurred in patients.

Seizures

The majority of seizures in the placebo vs wafer study were mild or moderate in severity.

Wafer remnants

Remnants of implanted wafers may be observed on brain imaging scans or during later operations even though all components are extensively degraded. Remnants removed from 2 patients after 64 and 92 days contained less than 0.0004% and 0.034%, respectively, of the original carmustine content. Remnants may persist for up to 232 days after implantation.

Patient Information

  • Contraceptive measures are recommended during therapy.

Copyright © 2009 Wolters Kluwer Health.

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