Carmustine (Monograph)

Brand names: BiCNU, Gliadel Wafer
Drug class: Antineoplastic Agents
- Alkylating Agents
VA class: AN100
CAS number: 154-93-8

Medically reviewed by Drugs.com on Jul 24, 2023. Written by ASHP.

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.^{105 120 125}

Among several preferred chemotherapeutic regimens for anaplastic astrocytoma and glioblastoma multiforme.^{120 125} 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.^{126 127}

Adjuvant or salvage therapy for oligodendroglioma.^{120 127 128}

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

Brain Tumors: Intracranial Wafer Implant

Adjunct to surgery and radiation for treatment of newly diagnosed high-grade malignant glioma.^{124 135} Among several preferred chemotherapeutic regimens for anaplastic astrocytoma and glioblastoma multiforme.¹²⁰

Adjunct to surgery for treatment of recurrent glioblastoma multiforme.^{120 124 135 137}

Multiple Myeloma

Carmustine-containing regimens considered alternative therapy for palliative treatment of multiple myeloma.^{105 120 138}

Hodgkin’s Disease

Used in combination with other agents as secondary therapy for treatment of refractory or relapsed Hodgkin’s disease.¹⁰⁵

Combination regimens containing other agents currently are preferred as initial or alternative therapy for this cancer.^{120 141}

Non-Hodgkin’s Lymphoma

Used in combination with other agents as secondary therapy for treatment of refractory or relapsed non-Hodgkin’s lymphomas.¹⁰⁵

Combination regimens containing other agents currently are preferred as initial or alternative therapy for these cancers.^{120 144}

Melanoma

Has been used alone^{114 116} or in combination therapy^{114 116 119} for palliative treatment of metastatic melanoma^{† [off-label]}; however, low response rate and substantial toxicity limit this use of carmustine.^{117 122}

Cutaneous T-cell Lymphoma

Used topically^{† [off-label]} for palliative treatment of cutaneous T-cell lymphoma (mycosis fungoides)^{† [off-label]}.^{120 123 149 150}

Related/similar drugs

Carvykti, methotrexate, Keytruda, rituximab, cyclophosphamide, Avastin, pembrolizumab

Carmustine Dosage and Administration

General

• Consult specialized references for procedures for proper handling and disposal of antineoplastics.^{105 124}

Administration

Administer by IV infusion¹⁰⁵ or intracranially as wafer implants.¹²⁴

Has been administered by intra-arterial^{† [off-label]} (into the carotid artery) route; however, such administration has been associated with ocular toxicity¹⁰⁵ (blindness), fatal encephalopathy, and inferior survival.¹³²

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.^{100 120 149 150}

IV Administration

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

Vials are for single use only.¹⁰⁵

Use glass containers for administration.¹⁰⁵

Handle cautiously (e.g., use gloves); avoid exposure during handling of powder and preparation of IV solution.¹⁰⁵

If skin or mucosal contact occurs, immediately wash affected area(s) thoroughly with soap and water.¹⁰⁵

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.¹⁰⁵ Resulting solution contains 3.3 mg/mL carmustine in 10% ethanol.¹⁰⁵

Dilution

Dilute with 5% dextrose injection.¹⁰⁵

Rate of Administration

Administer by IV infusion over 1–2 hours.¹⁰⁵ More rapid administration associated with adverse effects.¹⁰⁵ (See Local Effects under Cautions.)

Intracranial Wafer Implant

Handle with care (cytotoxic material);¹²⁴ use double surgical gloves and discard outer gloves into biohazard waste container after use.¹²⁴

Wafers broken in half may be used; discard in biohazard container if broken in >2 pieces.¹²⁴

Deliver aluminum foil laminate pouches containing wafer to operating room; do not open until ready to implant.¹²⁴ Outside surface of outer foil pouch is not sterile.¹²⁴

Use surgical instrument dedicated to handling carmustine wafers to implant the wafers.¹²⁴

Implant intracranially in the resection cavity following surgical resection of brain tumor.¹²⁴

Place oxidized regenerated cellulose (Surgicel) over wafers to secure them against surface of resection cavity.¹²⁴ Following placement of wafers, irrigate resection cavity and close dura in a watertight fashion to minimize risk of CSF leak.¹²⁴

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.¹⁰⁵

Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.¹⁰⁵

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).¹⁰⁵

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).¹²⁴ If size and shape of cavity will not allow placement of 8 wafers, use maximum possible number.¹²⁴

Do not place >8 wafers intracranially per surgical procedure.¹²⁴

In clinical trials, chemotherapy was withheld for at least 4 weeks (6 weeks for nitrosoureas) prior to and 2 weeks after surgery;¹²⁴ external beam radiation therapy was administered no sooner than 3 weeks after surgery.¹⁵¹

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.¹⁰⁵

Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.¹⁰⁵

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).¹⁰⁵

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.¹⁰⁵

Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.¹⁰⁵

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).¹⁰⁵

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.¹⁰⁵

Reduce dosage if used in combination with other myelosuppressive drugs or in patients with compromised bone marrow function.¹⁰⁵

Adjust subsequent dosages based on nadir blood counts from preceding dose (see Dosage Modification for Toxicity under Dosage and Administration).¹⁰⁵

Cutaneous T-cell Lymphoma†

Topical

Usual topical dosage is 10 mg once daily for 7–14 weeks (maximum: 17 weeks).^{149 150} 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.^{149 150}

Topical dosage form not commercially available in US; consult specialized references for specific information on topical use.^{149 150}

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.¹⁰⁵

Bone marrow toxicity is cumulative; adjust subsequent dosages based on nadir blood counts from previous dose.¹⁰⁵

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.^d

Prescribing Limits

Adults

Brain Tumors

Intracranial Wafer Implant

Maximum 8 wafers per surgical procedure.¹²⁴

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.^{105 148} (See Geriatric Use under Cautions.)

Cautions for Carmustine

Contraindications

• Known hypersensitivity to carmustine or any ingredient in the formulations.^{105 124}

Warnings/Precautions

Warnings

Hematologic Effects

Risk of myelosuppression (e.g., thrombocytopenia, leukopenia) following IV carmustine; effects are delayed and cumulative.¹⁰⁵ (See Boxed Warning.) Thrombocytopenia generally more severe than leukopenia but both considered dose-limiting toxicities.¹⁰⁵ Anemia reported less frequently and is less severe.¹⁰⁵

Following IV administration, thrombocytopenia and leukopenia occur at approximately 4 and 5–6 weeks, respectively, and persist for 1–2 weeks.¹⁰⁵

Repeated dosing associated with more severe and more prolonged myelosuppression.¹⁰⁵

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

Pulmonary Effects

With IV carmustine, risk of dose-related, sometimes fatal, pulmonary toxicity (characterized by pulmonary infiltrates and/or fibrosis).¹⁰⁵ (See Boxed Warning.) Risk factors include prolonged therapy (with cumulative doses >1400 mg/m²) and history of lung disease.¹⁰⁵

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.¹⁰⁵ (See Pediatric Use under Cautions.)

Perform pulmonary function tests prior to initiation of and frequently during therapy.¹⁰⁵ Patients with baseline forced vital capacity (FVC) or pulmonary diffusion capacity for carbon monoxide (DL_CO) <70% of predicted value are particularly at risk.¹⁰⁵

Secondary Malignancies

Risk of secondary malignancies following long-term use of nitrosoureas.¹⁰⁵

Intracranial Implant Complications

Intracerebral mass effect unresponsive to corticosteroids reported, including one case leading to brain herniation.¹²⁴ 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.¹²⁴

Risk of seizures; median time to onset is 3.5 days.¹²⁴

Formation of tumor bed cyst unresponsive to high-dose corticosteroids reported; required reoperation for drainage following implantation of carmustine wafers.¹³⁶

Monitor patients closely for potential complications of craniotomy (e.g., seizures, intracranial infections, abnormal wound healing, brain edema).¹²⁴

Fetal/Neonatal Morbidity and Mortality

Possible fetal harm; teratogenicity and embryotoxicity demonstrated in animals.¹⁰⁵ Avoid pregnancy during therapy.¹⁰⁵ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.^{105 124}

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.¹⁰⁵ Also associated with intense pain and burning at injection site; thrombosis is rare.¹⁰⁵

With intracranial wafer implant, wound dehiscence; delayed wound healing; subdural, subgaleal, or wound effusions; and CSF leak reported.¹²⁴

Infectious Complications

With intracranial wafer implant, abscess, meningitis, and pneumonia reported.¹²⁴ Sepsis reported but causal relationship not established.¹²⁴

GI Effects

With IV carmustine, dose-related nausea and vomiting reported within 2 hours and persisting for 4–6 hours.¹⁰⁵ Premedication with antiemetics may diminish or prevent.¹⁰⁵

Hepatic Effects

After IV therapy, reversible increases in serum transaminase, alkaline phosphatase, and bilirubin concentrations reported.¹⁰⁵ Possible hepatic dysfunction.¹⁰⁵ Monitor hepatic function periodically.¹⁰⁵

Renal Effects

After prolonged IV therapy (with large cumulative doses), progressive azotemia, decrease in kidney size, and renal failure reported.¹⁰⁵ Kidney damage reported occasionally in patients receiving lower total doses.¹⁰⁵ Monitor renal function periodically.¹⁰⁵

General Precautions

IV Therapy

Evaluate carmustine benefits against possible risks.¹⁰⁵ Most adverse effects are reversible if detected early with appropriate management (e.g., dosage reduction, discontinuance, appropriate corrective measures).¹⁰⁵ Reinstitute with caution, considering risks and benefits.¹⁰⁵

Risk of transient hyperpigmentation of skin with accidental dermal exposure; immediately wash exposed skin or mucosa.¹⁰⁵

Intracranial Wafer Implant

Risk of wafer migration from surgical resection cavity into ventricular system, leading to obstructive hydrocephalus.¹²⁴ If communication between surgical resection cavity and ventricular system is larger than diameter of wafers, close such communication prior to implantation.¹²⁴

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.¹²⁴

Therapy Monitoring

With IV therapy, monitor CBCs weekly during and for at least 6 weeks following each dose.¹⁰⁵ Also monitor pulmonary, hepatic, and renal function tests periodically during treatment.¹⁰⁵

Specific Populations

Pregnancy

Category D.^{105 124} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether carmustine is distributed into milk.^{105 124} Discontinue nursing because of potential risk to nursing infants.^{105 124} Not known whether constituents of polifeprosan 20 copolymer (i.e., carboxyphenoxypropane, sebacic acid) intracranial wafer are distributed into milk.¹²⁴

Pediatric Use

Safety and efficacy of IV carmustine not established in children.¹⁰⁵ Fatal pulmonary fibrosis reported with delayed onset up to 17 years following IV treatment of brain tumors during childhood or adolescence.¹⁰⁵ 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.¹⁰⁵

Safety and efficacy of intracranial wafer implant not established in pediatric patients.¹²⁴

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹⁰⁵ Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.^{105 148}

Systemic carmustine substantially eliminated by kidneys; monitor renal function periodically since geriatric patients are more likely to have decreased renal function.^{105 148}

Common Adverse Effects

For IV carmustine, pulmonary infiltrates and/or fibrosis, thrombocytopenia, leukopenia, anemia, nausea, vomiting, hepatic and renal toxicity.¹⁰⁵ (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.¹²⁴

Drug Interactions

Intracranial Wafer

No formal drug interaction studies to date.¹²⁴ In clinical trials, chemotherapy was withheld for at least 4 weeks (6 weeks for nitrosoureas) prior to and 2 weeks after surgery.¹²⁴ Implantation in conjunction with radiotherapy does not appear to have any short-term or chronic toxicities;¹²⁴ in clinical trials, external beam radiation therapy was administered >3 weeks after surgery.¹²⁴

Specific Drugs

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.¹²⁴

Absorption of biodegradable copolymer from wafers has not been evaluated in humans.¹²⁴

Distribution

Extent

Readily crosses the blood-brain barrier (due to high lipid solubility); concentrations of radioactivity in CSF are ≥50% of concurrent plasma concentrations.¹⁰⁵

Not known whether carmustine is distributed into milk.^{105 124}

Intracranial wafer: Concentration achieved in brain tissue not determined.¹²⁴ Not detectable in CSF of rabbits undergoing surgical implantation of 3.85% carmustine wafers.¹²⁴

Distribution of biodegradable copolymer from wafers has not been evaluated in humans.¹²⁴

Elimination

Metabolism

Rapidly metabolized and cleared from plasma following IV administration; no intact drug detectable after 15 minutes.¹⁰⁵

Antineoplastic and toxic effects believed to be caused by active metabolites.¹⁰⁵

Intracranial wafer: Carmustine is released and diffuses into brain tissue after hydrolysis of anhydride bonds in implant copolymer.¹²⁴ Metabolism of copolymer not evaluated in humans; 2 monomers (carboxyphenoxypropane and sebacic acid) are released.¹²⁴

Elimination Route

Excreted principally in urine as metabolites.¹⁰⁵

Following IV administration, about 30 or 60–70% of radioactivity excreted within 24³⁸ or 96 hours, respectively.^{105 124} About 6–10% of radioactivity excreted as respiratory carbon dioxide.^{105 124}

Intracranial wafer: Biodegradable in human brain.¹²⁴ In animal studies, >70% of polifeprosan 20 copolymer degrades into monomers within 3 weeks of implantation.¹²⁴ Carboxyphenoxypropane is eliminated renally; sebacic acid is metabolized in liver and expired as carbon dioxide.¹²⁴

Half-life

22 minutes following IV infusion.¹²⁴

In humans, wafer remnants have been observed on brain imaging scans or located during subsequent surgical procedures up to 8 months following intracranial implantation.¹²⁴ Wafer remnants retrieved from 2 patients approximately 2–3 months after implantation consisted mostly of water and monomers with minimal carmustine.¹²⁴

Stability

Storage

Parenteral

Powder for Injection

2–8°C; discard after 3 years.¹⁰⁵ Lyophilized powder decomposes to an oily liquid at temperatures ≥30.5°C.¹⁰⁵ Upon receipt, inspect vials that may not have been refrigerated adequately by holding them up to bright light.¹⁰⁵ Discard if an oily film is present.¹⁰⁵ If dry flakes or a dry, congealed mass is present, vial is suitable for use; refrigerate immediately.¹⁰⁵

Store reconstituted solution in glass container at 25°C; protect from light.^{101 105} Discard after 8 hours.¹⁰⁵

Store diluted solution in glass container at 25°C; protect from light.¹⁰⁵ Discard after 8 hours.¹⁰⁵

Intracranial

Implants

≤-20°C.¹²⁴ Do not open aluminum foil laminate pouches containing wafer until immediately prior to implantation in the operating room.¹²⁴

May keep unopened foil pouches at ambient room temperature for up to 6 hours.¹²⁴

Compatibility

Parenteral

Solution CompatibilityHID

Compatible for 8 hours at 25°C;¹⁰¹ use within 8 hours.¹⁰⁵

Drug Compatibility

Actions

• Alkylates DNA and RNA.^{105 124} May inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.¹⁰⁵ Overall result is thought to be the inhibition of both DNA and RNA synthesis.^d

• Cytotoxic effect of wafer depends on release of sufficient amounts of carmustine in the tumor cavity to achieve tumoricidal concentrations.¹²⁴

Advice to Patients

• Risk of myelosuppression or pulmonary toxicity with conventional chemotherapy.¹⁰⁵ Importance of adherence to laboratory appointment schedules.¹⁰⁵ Notify clinician if fever, sore throat, or unusual bleeding or bruising occurs.^d

• Risk of post-implantation complications with wafers.¹²⁴

• 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.^{105 124}

• Importance of women informing their clinician if they are or plan to become pregnant or to breast-feed.^{105 124} Importance of women avoiding pregnancy during therapy.^{105 124} Advise pregnant women of risk to the fetus.^{105 124}

• 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.

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