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Carmustine

Class: Antineoplastic Agents
- Alkylating Agents
VA Class: AN100
CAS Number: 154-93-8
Brands: BiCNU, Gliadel Wafer

Medically reviewed by Drugs.com. Last updated on Jul 22, 2020.

Warning

    Warning Information for IV Carmustine
  • Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.

  • Risk of bone marrow suppression (e.g., thrombocytopenia, leukopenia), resulting in bleeding and infection. Bone marrow toxicity is delayed and cumulative. Monitor CBCs weekly during and for at least 6 weeks following each dose; do not administer more frequently than every 6 weeks. Adjust subsequent dosages based on nadir blood counts from previous dose. (See Dosage Modification for Toxicity under Dosage and Administration.)

  • Risk of dose-related pulmonary toxicity. Cumulative doses >1400 mg/m2 associated with substantially greater risk. Delayed pulmonary toxicity can occur years after treatment and result in death, particularly in patients treated during childhood.

Introduction

Antineoplastic agent; a nitrosourea-derivative alkylating agent.

Uses for 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; however, low response rate and substantial toxicity limit this use of carmustine.

Cutaneous T-cell Lymphoma

Used topically for palliative treatment of cutaneous T-cell lymphoma (mycosis fungoides).

Carmustine Dosage and Administration

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 (into the carotid artery) route; however, such administration has been associated with ocular toxicity (blindness), fatal encephalopathy, and inferior survival.

Has been administered topically 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.)

Cautions for Carmustine

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.

Interactions for 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

Carmustine Pharmacokinetics

Absorption

Bioavailability

Intracranial wafer: Plasma concentrations following intracranial implantation not determined in humans; not detectable in plasma of rabbits undergoing surgical implantation of 3.85% carmustine wafers.

Absorption of biodegradable copolymer from wafers has not been evaluated in humans.

Distribution

Extent

Readily crosses the blood-brain barrier (due to high lipid solubility); concentrations of radioactivity in CSF are ≥50% of concurrent plasma concentrations.

Not known whether carmustine is distributed into milk.

Intracranial wafer: Concentration achieved in brain tissue not determined. Not detectable in CSF of rabbits undergoing surgical implantation of 3.85% carmustine wafers.

Distribution of biodegradable copolymer from wafers has not been evaluated in humans.

Elimination

Metabolism

Rapidly metabolized and cleared from plasma following IV administration; no intact drug detectable after 15 minutes.

Antineoplastic and toxic effects believed to be caused by active metabolites.

Intracranial wafer: Carmustine is released and diffuses into brain tissue after hydrolysis of anhydride bonds in implant copolymer. Metabolism of copolymer not evaluated in humans; 2 monomers (carboxyphenoxypropane and sebacic acid) are released.

Elimination Route

Excreted principally in urine as metabolites.

Following IV administration, about 30 or 60–70% of radioactivity excreted within 24 or 96 hours, respectively. About 6–10% of radioactivity excreted as respiratory carbon dioxide.

Intracranial wafer: Biodegradable in human brain. In animal studies, >70% of polifeprosan 20 copolymer degrades into monomers within 3 weeks of implantation. Carboxyphenoxypropane is eliminated renally; sebacic acid is metabolized in liver and expired as carbon dioxide.

Half-life

22 minutes following IV infusion.

In humans, wafer remnants have been observed on brain imaging scans or located during subsequent surgical procedures up to 8 months following intracranial implantation. Wafer remnants retrieved from 2 patients approximately 2–3 months after implantation consisted mostly of water and monomers with minimal carmustine.

Stability

Storage

Parenteral

Powder for Injection

2–8°C; discard after 3 years. Lyophilized powder decomposes to an oily liquid at temperatures ≥30.5°C. Upon receipt, inspect vials that may not have been refrigerated adequately by holding them up to bright light. Discard if an oily film is present. If dry flakes or a dry, congealed mass is present, vial is suitable for use; refrigerate immediately.

Store reconstituted solution in glass container at 25°C; protect from light. Discard after 8 hours.

Store diluted solution in glass container at 25°C; protect from light. Discard after 8 hours.

Intracranial

Implants

≤−20°C. Do not open aluminum foil laminate pouches containing wafer until immediately prior to implantation in the operating room.

May keep unopened foil pouches at ambient room temperature for up to 6 hours.

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution CompatibilityHID

Compatible for 8 hours at 25°C; use within 8 hours.

Compatible

Sodium chloride 0.9%

Variable

Dextrose 5% in water

Drug Compatibility
Admixture CompatibilityHID

Incompatible

Sodium bicarbonate

Y-Site CompatibilityHID

Compatible

Amifostine

Aztreonam

Cefepime HCl

Etoposide phosphate

Filgrastim

Fludarabine phosphate

Gemcitabine HCl

Granisetron HCl

Melphalan HCl

Ondansetron HCl

Piperacillin sodium–tazobactam sodium

Sargramostim

Teniposide

Thiotepa

Vinorelbine tartrate

Incompatible

Allopurinol sodium

Actions

  • Alkylates DNA and RNA. May inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. Overall result is thought to be the inhibition of both DNA and RNA synthesis.

  • Cytotoxic effect of wafer depends on release of sufficient amounts of carmustine in the tumor cavity to achieve tumoricidal concentrations.

Advice to Patients

  • Risk of myelosuppression or pulmonary toxicity with conventional chemotherapy. Importance of adherence to laboratory appointment schedules. Notify clinician if fever, sore throat, or unusual bleeding or bruising occurs.

  • Risk of post-implantation complications with wafers.

  • Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Importance of women informing their clinician if they are or plan to become pregnant or to breast-feed. Importance of women avoiding pregnancy during therapy. Advise pregnant women of risk to the fetus.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Carmustine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Local

For injection, for IV infusion

100 mg

BiCNU (with 3 mL dehydrated [absolute] alcohol diluent)

Bristol-Myers Squibb

Local

Implants

7.7 mg (of carmustine per wafer)

Gliadel Wafer (with polifeprosan 20)

Guilford

AHFS DI Essentials™. © Copyright 2021, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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