Carmustine

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

Warning(s)

  • Warning Information for IV Carmustine
  • Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.105

  • Risk of bone marrow suppression (e.g., thrombocytopenia, leukopenia), resulting in bleeding and infection.105 Bone marrow toxicity is delayed and cumulative.105 Monitor CBCs weekly during and for at least 6 weeks following each dose; do not administer more frequently than every 6 weeks.105 Adjust subsequent dosages based on nadir blood counts from previous dose.105 (See Dosage Modification for Toxicity under Dosage and Administration.)

  • Risk of dose-related pulmonary toxicity.105 Cumulative doses >1400 mg/m2 associated with substantially greater risk.105 Delayed pulmonary toxicity can occur years after treatment and result in death, particularly in patients treated during childhood.105

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

Slideshow: Flashback: FDA Drug Approvals 2013

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 alone114 116 or in combination therapy114 116 119 for palliative treatment of metastatic melanoma; however, low response rate and substantial toxicity limit this use of carmustine.117 122

Cutaneous T-cell Lymphoma

Used topically for palliative treatment of cutaneous T-cell lymphoma (mycosis fungoides).120 123 149 150

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 (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 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

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.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 (DLCO) <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

Interactions for Carmustine

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

Drug

Interaction

Comments

Cimetidine

Potentiation of neutropenic and thrombocytopenic effect of carmustined

Mitomycin

Possible changes in tear films, with subsequent damage of corneal and conjunctival epithelium146

Phenytoin

Possible decreased serum phenytoin concentrations147

Monitor serum phenytoin concentrations carefully and adjust dosage accordingly147

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

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

Parenteral

Solution CompatibilityHID

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

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.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.

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, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

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