Carmustine

Drug class: Antineoplastic Agents

Usage of Carmustine

Brain Tumors: Conventional Chemotherapy

Adjunct to radiation therapy following surgery for palliative treatment of malignant glioma (i.e., astrocytoma, ependymoma, medulloblastoma, brainstem glioma) and metastatic brain tumors.

Among several preferred chemotherapeutic regimens for anaplastic astrocytoma and glioblastoma multiforme. Has not been shown to increase survival time, but a trend toward a higher long-term survival rate (e.g., at 18 months) has been observed.

Adjuvant or salvage therapy for oligodendroglioma.

Surgery with or without radiation therapy currently considered standard treatment for ependymoma and medulloblastoma. Radiation therapy considered standard treatment for brainstem glioma.

Brain Tumors: Intracranial Wafer Implant

Adjunct to surgery and radiation for treatment of newly diagnosed high-grade malignant glioma. Among several preferred chemotherapeutic regimens for anaplastic astrocytoma and glioblastoma multiforme.

Adjunct to surgery for treatment of recurrent glioblastoma multiforme.

Multiple Myeloma

Carmustine-containing regimens considered alternative therapy for palliative treatment of multiple myeloma.

Hodgkin’s Disease

Used in combination with other agents as secondary therapy for treatment of refractory or relapsed Hodgkin’s disease.

Combination regimens containing other agents currently are preferred as initial or alternative therapy for this cancer.

Non-Hodgkin’s Lymphoma

Used in combination with other agents as secondary therapy for treatment of refractory or relapsed non-Hodgkin’s lymphomas.

Combination regimens containing other agents currently are preferred as initial or alternative therapy for these cancers.

Melanoma

Has been used alone or in combination therapy for palliative treatment of metastatic melanoma† [off-label]; however, low response rate and substantial toxicity limit this use of carmustine.

Cutaneous T-cell Lymphoma

Used topically† [off-label] for palliative treatment of cutaneous T-cell lymphoma (mycosis fungoides)† [off-label].

Relate drugs

How to use Carmustine

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics.

    • Administration

    Administer by IV infusion or intracranially as wafer implants.

    Has been administered by intra-arterial† [off-label] (into the carotid artery) route; however, such administration has been associated with ocular toxicity (blindness), fatal encephalopathy, and inferior survival.

    Has been administered topically† [off-label] as a 0.05–0.4% hydroalcoholic solution or as an ointment, but dosage forms for such use are not commercially available in US; consult specialized references.

    IV Administration

    For solution and drug compatibility information, see Compatibility under Stability.

    Vials are for single use only.

    Use glass containers for administration.

    Handle cautiously (e.g., use gloves); avoid exposure during handling of powder and preparation of IV solution.

    If skin or mucosal contact occurs, immediately wash affected area(s) thoroughly with soap and water.

    Reconstitution

    Add 3 mL of diluent provided by manufacturer (sterile dehydrated [absolute] alcohol) to vial containing 100 mg of carmustine; then add 27 mL of sterile water for injection. Resulting solution contains 3.3 mg/mL carmustine in 10% ethanol.

    Dilution

    Dilute with 5% Dextrose injection.

    Rate of Administration

    Administer by IV infusion over 1–2 hours. More rapid administration associated with adverse effects. (See Local Effects under Cautions.)

    Intracranial Wafer Implant

    Handle with care (cytotoxic material); use double surgical gloves and discard outer gloves into biohazard waste container after use.

    Wafers broken in half may be used; discard in biohazard container if broken in >2 pieces.

    Deliver aluminum foil laminate pouches containing wafer to operating room; do not open until ready to implant. Outside surface of outer foil pouch is not sterile.

    Use surgical instrument dedicated to handling carmustine wafers to implant the wafers.

    Implant intracranially in the resection cavity following surgical resection of brain tumor.

    Place oxidized regenerated cellulose (Surgicel) over wafers to secure them against surface of resection cavity. Following placement of wafers, irrigate resection cavity and close dura in a watertight fashion to minimize risk of CSF leak.

    Dosage

    Adults

    Brain Tumors IV

    As monotherapy in previously untreated patients, 150–200 mg/m2 administered as a single dose or in divided doses (e.g., 75–100 mg/m2 on 2 successive days) at intervals of at least 6 weeks.

    Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.

    Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).

    Intracranial Wafer Implant

    Up to 8 wafers (total carmustine dose: 61.6 mg) intracranially to cover as much of the resection cavity as possible (slight overlapping permissible). If size and shape of cavity will not allow placement of 8 wafers, use maximum possible number.

    Do not place >8 wafers intracranially per surgical procedure.

    In clinical trials, chemotherapy was withheld for at least 4 weeks (6 weeks for nitrosoureas) prior to and 2 weeks after surgery; external beam radiation therapy was administered no sooner than 3 weeks after surgery.

    Multiple Myeloma IV

    As monotherapy in previously untreated patients, 150–200 mg/m2 administered as a single dose or in divided doses (e.g., 75–100 mg/m2 on 2 successive days) at intervals of at least 6 weeks.

    Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.

    Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).

    Hodgkin’s Disease IV

    As monotherapy in previously untreated patients, 150–200 mg/m2 administered as a single dose or in divided doses (e.g., 75–100 mg/m2 on 2 successive days) at intervals of at least 6 weeks.

    Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.

    Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).

    Non-Hodgkin’s Lymphoma IV

    As monotherapy in previously untreated patients, 150–200 mg/m2 administered as a single dose or in divided doses (e.g., 75–100 mg/m2 on 2 successive days) at intervals of at least 6 weeks.

    Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.

    Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).

    Cutaneous T-cell Lymphoma† Topical

    Usual topical dosage is 10 mg once daily for 7–14 weeks (maximum: 17 weeks). If response is inadequate, after a rest interval of 6 weeks, administer second course of topical therapy with 20 mg once daily for 4–8 weeks, as tolerated.

    Topical dosage form not commercially available in US; consult specialized references for specific information on topical use.

    Dosage Modification for Toxicity

    Conventional Chemotherapy

    Do not administer repeat courses until leukocyte count >4000/mm3, platelet count >100,000/mm3, and an adequate number of neutrophils is present on peripheral blood smear.

    Bone marrow toxicity is cumulative; adjust subsequent dosages based on nadir blood counts from previous dose.

    Table 1. Dosage Adjustments for Hematologic Toxicities Based on Nadir After Prior Dose (manufacturer’s recommendations)

    Leukocytes (cells/mm3)

    Platelets (cells/mm3)

    Percentage of Prior Dose to be Given

    >4000

    >100,000

    100%

    3000–3999

    75,000–99,999

    100%

    2000–2999

    25,000–74,999

    70%

    <2000

    <25,000

    50%

    Alternatively, to avoid potential overdosage associated with manufacturer’s suggested modifications, some clinicians recommend reducing subsequent dosage by 25% when platelet nadirs are 50,000–74,999/mm3; by 50% for nadirs of 25,000–49,999/mm3; and by 75% for nadirs <25,000/mm3.

    Prescribing Limits

    Adults

    Brain Tumors Intracranial Wafer Implant

    Maximum 8 wafers per surgical procedure.

    Special Populations

    Geriatric Patients

    Select IV dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. (See Geriatric Use under Cautions.)

    Warnings

    Contraindications

  • Known hypersensitivity to carmustine or any ingredient in the formulations.

    • Warnings/Precautions

    Warnings

    Hematologic Effects

    Risk of myelosuppression (e.g., thrombocytopenia, leukopenia) following IV carmustine; effects are delayed and cumulative. (See Boxed Warning.) Thrombocytopenia generally more severe than leukopenia but both considered dose-limiting toxicities. Anemia reported less frequently and is less severe.

    Following IV administration, thrombocytopenia and leukopenia occur at approximately 4 and 5–6 weeks, respectively, and persist for 1–2 weeks.

    Repeated dosing associated with more severe and more prolonged myelosuppression.

    Use with caution in patients with depressed platelet, leukocyte, or erythrocyte counts.

    Pulmonary Effects

    With IV carmustine, risk of dose-related, sometimes fatal, pulmonary toxicity (characterized by pulmonary infiltrates and/or fibrosis). (See Boxed Warning.) Risk factors include prolonged therapy (with cumulative doses >1400 mg/m2) and history of lung disease.

    Risk of delayed-onset pulmonary fibrosis (occurred up to 17 years after treatment during childhood and early adolescence); possible reduction of pulmonary function or death. (See Pediatric Use under Cautions.)

    Perform pulmonary function tests prior to initiation of and frequently during therapy. Patients with baseline forced vital capacity (FVC) or pulmonary diffusion capacity for carbon monoxide (DLCO) <70% of predicted value are particularly at risk.

    Secondary Malignancies

    Risk of secondary malignancies following long-term use of nitrosoureas.

    Intracranial Implant Complications

    Intracerebral mass effect unresponsive to corticosteroids reported, including one case leading to brain herniation. Brain edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate reoperation and, in some cases, removal of wafer or wafer remnants.

    Risk of seizures; median time to onset is 3.5 days.

    Formation of tumor bed cyst unresponsive to high-dose corticosteroids reported; required reoperation for drainage following implantation of carmustine wafers.

    Monitor patients closely for potential complications of craniotomy (e.g., seizures, intracranial infections, abnormal wound healing, brain edema).

    Fetal/Neonatal Morbidity and Mortality

    Possible fetal harm; teratogenicity and embryotoxicity demonstrated in animals. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

    Major Toxicities

    Local Effects

    Rapid IV infusion may result in intensive flushing of the skin and suffusion of the conjunctiva; these effects occur within 2 hours and persist for 4 hours after IV administration. Also associated with intense pain and burning at injection site; thrombosis is rare.

    With intracranial wafer implant, wound dehiscence; delayed wound healing; subdural, subgaleal, or wound effusions; and CSF leak reported.

    Infectious Complications

    With intracranial wafer implant, abscess, meningitis, and pneumonia reported. Sepsis reported but causal relationship not established.

    GI Effects

    With IV carmustine, dose-related nausea and vomiting reported within 2 hours and persisting for 4–6 hours. Premedication with antiemetics may diminish or prevent.

    Hepatic Effects

    After IV therapy, reversible increases in serum transaminase, alkaline phosphatase, and bilirubin concentrations reported. Possible hepatic dysfunction. Monitor hepatic function periodically.

    Renal Effects

    After prolonged IV therapy (with large cumulative doses), progressive azotemia, decrease in kidney size, and renal failure reported. Kidney damage reported occasionally in patients receiving lower total doses. Monitor renal function periodically.

    General Precautions

    IV Therapy

    Evaluate carmustine benefits against possible risks. Most adverse effects are reversible if detected early with appropriate management (e.g., dosage reduction, discontinuance, appropriate corrective measures). Reinstitute with caution, considering risks and benefits.

    Risk of transient hyperpigmentation of skin with accidental dermal exposure; immediately wash exposed skin or mucosa.

    Intracranial Wafer Implant

    Risk of wafer migration from surgical resection cavity into ventricular system, leading to obstructive hydrocephalus. If communication between surgical resection cavity and ventricular system is larger than diameter of wafers, close such communication prior to implantation.

    Enhancement in brain tissue surrounding resection cavity (demonstrated by CT scan or MRI) following intracranial implantation may represent edema and inflammation caused by wafer or tumor progression.

    Therapy Monitoring

    With IV therapy, monitor CBCs weekly during and for at least 6 weeks following each dose. Also monitor pulmonary, hepatic, and renal function tests periodically during treatment.

    Specific Populations

    Pregnancy

    Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

    Lactation

    Not known whether carmustine is distributed into milk. Discontinue nursing because of potential risk to nursing infants. Not known whether constituents of polifeprosan 20 copolymer (i.e., carboxyphenoxypropane, sebacic acid) intracranial wafer are distributed into milk.

    Pediatric Use

    Safety and efficacy of IV carmustine not established in children. Fatal pulmonary fibrosis reported with delayed onset up to 17 years following IV treatment of brain tumors during childhood or adolescence. Extremely high risk of fatal pulmonary toxicity, particularly in children <5 years of age at initial treatment; carefully weigh benefits and risks of therapy in pediatric patients.

    Safety and efficacy of intracranial wafer implant not established in pediatric patients.

    Geriatric Use

    Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

    Systemic carmustine substantially eliminated by kidneys; monitor renal function periodically since geriatric patients are more likely to have decreased renal function.

    Common Adverse Effects

    For IV carmustine, pulmonary infiltrates and/or fibrosis, thrombocytopenia, leukopenia, anemia, nausea, vomiting, hepatic and renal toxicity. (See Warnings/Precautions under Cautions.)

    For intracranial wafer, hemiplegia, seizures, confusion, brain edema, headache, asthenia, nausea, vomiting, constipation, infection, fever, aphasia, abnormal healing, depression, pain, rash, somnolence, speech disorder, deep thrombophlebitis, alopecia.

    What other drugs will affect Carmustine

    Intracranial Wafer

    No formal drug interaction studies to date. In clinical trials, chemotherapy was withheld for at least 4 weeks (6 weeks for nitrosoureas) prior to and 2 weeks after surgery. Implantation in conjunction with radiotherapy does not appear to have any short-term or chronic toxicities; in clinical trials, external beam radiation therapy was administered >3 weeks after surgery.

    Specific Drugs

    Drug

    Interaction

    Comments

    Cimetidine

    Potentiation of neutropenic and thrombocytopenic effect of carmustine

    Mitomycin

    Possible changes in tear films, with subsequent damage of corneal and conjunctival epithelium

    Phenytoin

    Possible decreased serum phenytoin concentrations

    Monitor serum phenytoin concentrations carefully and adjust dosage accordingly

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