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<!--FDA-Labeled Indications and Dosage (Adult)--> | <!--FDA-Labeled Indications and Dosage (Adult)--> | ||
|fdaLIADAdult=====Indication==== | |fdaLIADAdult=====Indication==== | ||
* | * Carmustine is indicated for the treatment of patients with: | ||
:* newly-diagnosed high-grade malignant [[glioma]] as an adjunct to [[surgery]] and radiation, and recurrent [[glioblastoma multiforme]] as an adjunct to [[surgery]]. | :* newly-diagnosed high-grade malignant [[glioma]] as an adjunct to [[surgery]] and radiation, and recurrent [[glioblastoma multiforme]] as an adjunct to [[surgery]]. | ||
====Dosage==== | ====Dosage==== | ||
=====Recommended Dose===== | =====Recommended Dose===== | ||
* The recommended dose of | * The recommended dose of carmustine is eight 7.7 mg wafers for a total of 61.6 mg implanted intracranially. The safety and effectiveness of repeat administration have not been studied. | ||
=====Insertion Instructions===== | =====Insertion Instructions===== | ||
* Following maximal [[tumor]] resection, confirmation of tumor pathology and establishment of [[hemostasis]], place up to a maximum of eight | * Following maximal [[tumor]] resection, confirmation of tumor pathology and establishment of [[hemostasis]], place up to a maximum of eight carmustines to cover as much of the resection cavity as possible. Should the size and shape of the resected cavity not accommodate eight wafers, place the maximum number of wafers feasible within the cavity. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but discard wafers broken in more than two pieces. Oxidized regenerated cellulose (Surgicel®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, irrigate the resection cavity and close the dura in a water-tight fashion. | ||
=====Preparation and Safe Handling===== | =====Preparation and Safe Handling===== | ||
* | * Carmustines contain a cytotoxic drug. Follow applicable special handling and disposal procedures.1 | ||
* Each wafer is packaged within two nested aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outside surface of the outer laminated aluminum foil pouch is a peelable overwrap and is not sterile. | * Each wafer is packaged within two nested aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outside surface of the outer laminated aluminum foil pouch is a peelable overwrap and is not sterile. | ||
* Deliver | * Deliver carmustines to the operating room in their outer aluminum foil pouch, unopened. Do not open the pouch until the wafers are ready to be implanted. Carmustines in unopened outer foil pouches are stable at room temperature for six hours at a time for up to three cycles within a 30-day period. | ||
* Exposure to carmustine can cause severe burning and [[hyperpigmentation]] of the skin. Use double gloves when handling | * Exposure to carmustine can cause severe burning and [[hyperpigmentation]] of the skin. Use double gloves when handling carmustines. Discard the outer gloves into a biohazard waste container after use. Use a dedicated surgical instrument for wafer implantation. If repeat neurosurgical intervention is indicated, handle residual wafers or wafer remnants as potential cytotoxic agents. | ||
* Instructions for Opening Pouch Containing | * Instructions for Opening Pouch Containing carmustine | ||
* Read all steps of the instructions prior to opening the pouch. | * Read all steps of the instructions prior to opening the pouch. | ||
[[File:Carmu Dosage and admin.png|thumb|none|400px|This image is provided by the National Library of Medicine.]] | [[File:Carmu Dosage and admin.png|thumb|none|400px|This image is provided by the National Library of Medicine.]] | ||
| Line 54: | Line 54: | ||
<!--Warnings--> | <!--Warnings--> | ||
|warnings======Seizures===== | |warnings======Seizures===== | ||
* Seizures occurred in 37% of patients treated with | * Seizures occurred in 37% of patients treated with carmustines for recurrent glioma in Study 2. New or worsening (treatment emergent) seizures occurred in 20% of patients; 54% of treatment emergent [[seizures]] occurred within the first 5 post-operative days. The median time to onset of the first new or worsened post-operative seizure was four days. Institute optimal anti-seizure therapy prior to [[surgery]]. | ||
* Monitor patients for seizures postoperatively. | * Monitor patients for seizures postoperatively. | ||
=====Intracranial Hypertension===== | =====Intracranial Hypertension===== | ||
* Brain edema occurred in 23% of patients with newly diagnosed [[glioma]] treated with | * Brain edema occurred in 23% of patients with newly diagnosed [[glioma]] treated with carmustines in Study 1. Additionally, one GLIADEL-treated patient experienced [[intracerebral mass]] effect unresponsive to [[corticosteroids]] which led to [[brain herniation]]. Monitor patients closely for [[intracranial hypertension]] related to [[brain edema]], [[inflammation]], or [[necrosis of the brain]] tissue surrounding the resection. In refractory cases, consider re-operation and removal of carmustines or Wafer remnants. | ||
=====Impaired Neurosurgical Wound Healing===== | =====Impaired Neurosurgical Wound Healing===== | ||
* Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and [[subdural]], subgleal, or wound effusions occur with | * Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and [[subdural]], subgleal, or wound effusions occur with carmustine treatment. In Study 1, 16% of carmustine-treated patients with newly diagnosed glioma experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In Study 2, 14% of carmustine-treated patients with recurrent glioma experienced wound healing abnormalities [see ADVERSE REACTIONS (6.1)]. Monitor patients post-operatively for impaired neurosurgical wound healing. | ||
=====Meningitis===== | =====Meningitis===== | ||
* [[Meningitis]] occurred in 4% of patients with recurrent [[glioma]] receiving | * [[Meningitis]] occurred in 4% of patients with recurrent [[glioma]] receiving carmustines in Study 2. Two cases of meningitis were bacterial; one patient required removal of the Wafers four days after implantation; the other developed meningitis following reoperation for recurrent tumor. One case was diagnosed as chemical meningitis and resolved following steroid treatment. In one case the cause was unspecified, but meningitis resolved following antibiotic treatment. Monitor postoperatively for signs of meningitis and central nervous system infection. | ||
=====Wafer Migration===== | =====Wafer Migration===== | ||
* | * Carmustine migration can occur. To reduce the risk of [[obstructive hydrocephalus]] due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation. Monitor patients for signs of obstructive hydrocephalus. | ||
=====Embryo-Fetal Toxicity===== | =====Embryo-Fetal Toxicity===== | ||
* | * Carmustines can cause fetal harm when administered to a [[pregnant]] woman. Carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to the exposure at the recommended human dose on a mg/m2 basis. Advise females of reproductive potential to avoid pregnancy after implantation of carmustines. If the patient becomes pregnant after carmustine implantation, warn the patient about the potential hazard to the [[fetus]]. | ||
|clinicalTrials=* Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. | |clinicalTrials=* Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. | ||
=====Newly-Diagnosed High-Grade Malignant Glioma===== | =====Newly-Diagnosed High-Grade Malignant Glioma===== | ||
* The safety of | * The safety of carmustines was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 240 adult patients with newly-diagnosed high-grade malignant [[glioma]] who received up to eight carmustines or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 1). | ||
* The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of [[glioblastoma multiforme]] as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. | * The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of [[glioblastoma multiforme]] as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. | ||
* Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving | * Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving carmustines compared to 2 (2%) of patients receiving placebo. Deaths on the GLIADEL arm resulted from cerebral hematoma/edema (n=3), pulmonary embolism (n=1) and acute coronary event (n=1). Deaths on the placebo arm resulted from sepsis (n=1) and malignant disease (n=1). | ||
* The incidence of common adverse reactions in | * The incidence of common adverse reactions in carmustine-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2. | ||
: [[File:Carmu Adverse effects.png|thumb|none|600px|This image is provided by the National Library of Medicine.]] | : [[File:Carmu Adverse effects.png|thumb|none|600px|This image is provided by the National Library of Medicine.]] | ||
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label. | |postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label. | ||
|FDAPregCat=D | |FDAPregCat=D | ||
|useInPregnancyFDA======Risk Summary===== | |useInPregnancyFDA======Risk Summary===== | ||
* | * Carmustine can cause fetal harm when administered to a [[pregnant]] woman. There have been no studies with carmustine; however, carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to exposures at the recommended human dose on a mg/m2 basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. | ||
=====Animal Data===== | =====Animal Data===== | ||
* There are no studies assessing the reproductive toxicity of | * There are no studies assessing the reproductive toxicity of carmustine; however, carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at intraperitoneal doses of 0.5mg/kg/day or greater when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 0.12 the recommended human dose, eight wafers of 7.7 mg carmustine/wafer, on a mg/m2 basis). Carmustine was embryotoxic in rabbits at intravenous doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes. | ||
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category''' | |useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category''' | ||
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant. | There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant. | ||
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery. | |useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery. | ||
|useInNursing=* It is not known if carmustine, the active component of | |useInNursing=* It is not known if carmustine, the active component of carmustine, is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from carmustine, a decision should be made whether to discontinue nursing or not to administer the drug, taking into account the importance of the drug to the mother. | ||
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients. | |useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients. | ||
|useInGeri=Clinical trials of | |useInGeri=Clinical trials of carmustine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. | ||
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations. | |useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations. | ||
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations. | |useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations. | ||
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<!--Pharmacokinetics--> | <!--Pharmacokinetics--> | ||
|PK=* Carmustine concentrations delivered by | |PK=* Carmustine concentrations delivered by carmustine in human [[brain]] tissue have not been determined. | ||
* Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m2, the average terminal half-life, clearance and steady-state volume of distribution were 22 minutes, 56 mL/min/kg and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200-mg/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2. Carmustine degrades both spontaneously and metabolically. The relevance of these data to elimination of intracranial implant-delivered carmustine are unknown. | * Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m2, the average terminal half-life, clearance and steady-state volume of distribution were 22 minutes, 56 mL/min/kg and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200-mg/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2. Carmustine degrades both spontaneously and metabolically. The relevance of these data to elimination of intracranial implant-delivered carmustine are unknown. | ||
* | * Carmustines are biodegradable when implanted into the human brain. Wafer remnants may be observed on brain imaging scans or at re-operation. Wafer remnants were visible in 11 of 18 patients on CT scans obtained 49 days after implantation of carmustine. More than 70% of the copolymer degrades within three weeks. Wafer remnants have been present at re-operation and autopsy up to 232 days after carmustine implantation, and consisted mostly of water and monomeric components with minimal detectable carmustine present. | ||
|nonClinToxic=There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label. | |nonClinToxic=There is limited information regarding <i>Nonclinical Toxicology</i> of {{PAGENAME}} in the drug label. | ||
<!--Clinical Studies--> | <!--Clinical Studies--> | ||
|clinicalStudies=[[File:Carmu Clinicl studies.png|thumb|none|500px]] | |clinicalStudies=[[File:Carmu Clinicl studies.png|thumb|none|500px]] | ||
|howSupplied=* | |howSupplied=* Carmustine is supplied in a single dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7 mg of carmustine and is packaged in two aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outer pouch is a peelable overwrap. The outside surface of the outer pouch is not sterile. | ||
* NDC for single dose treatment box: 24338-050-08 | * NDC for single dose treatment box: 24338-050-08 | ||
|storage=* Store | |storage=* Store carmustine at or below -20ºC (-4ºF). | ||
* Do not keep unopened foil pouches at ambient room temperature for more than six hours at a time for up to three cycles within a 30-day period. | * Do not keep unopened foil pouches at ambient room temperature for more than six hours at a time for up to three cycles within a 30-day period. | ||
* | * Carmustine is a cytotoxic drug and special handling and disposal procedures should be considered.1 | ||
|packLabel=[[File:Carmu 01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]] | |packLabel=[[File:Carmu 01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]] | ||
[[File:DailyMed GLIADEL carmustine wafer.png|thumb|none|400px|This image is provided by the National Library of Medicine.]] | [[File:DailyMed GLIADEL carmustine wafer.png|thumb|none|400px|This image is provided by the National Library of Medicine.]] | ||
| Line 131: | Line 131: | ||
* Meningitis: Advise patients to report symptoms of meningitis such as fever or stiff neck. | * Meningitis: Advise patients to report symptoms of meningitis such as fever or stiff neck. | ||
* Embryo-Fetal Toxicity: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use effective [[contraception]] during treatment with GLIADEL. | * Embryo-Fetal Toxicity: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use effective [[contraception]] during treatment with GLIADEL. | ||
* Nursing Infants: Advise nursing mothers to discontinue nursing after | * Nursing Infants: Advise nursing mothers to discontinue nursing after carmustine [[implantation]]. | ||
|alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. | |alcohol=* Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. | ||
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}} | }} | ||
{{PillImage | {{PillImage | ||
<!--Pill Image--> | <!--Pill Image--> | ||
<!--Label Display Image--> | <!--Label Display Image--> | ||
<!--Category--> | <!--Category--> | ||
[[Category:Drug]] | [[Category:Drug]] | ||
[[Category:Chemotherapy]] | |||
[[Category:Chemotherapeutic agents]] | |||
[[Category:Alkylating agents]] | |||
[[Category:Nitrosoureas]] | |||
Latest revision as of 18:41, 18 August 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
Overview
Carmustine (implant) is an alkylationg agent that is FDA approved for the treatment of high-grade malignant glioma, glioblastoma multiforme. Common adverse reactions include headache, nausea and vomiting.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indication
- Carmustine is indicated for the treatment of patients with:
- newly-diagnosed high-grade malignant glioma as an adjunct to surgery and radiation, and recurrent glioblastoma multiforme as an adjunct to surgery.
Dosage
Recommended Dose
- The recommended dose of carmustine is eight 7.7 mg wafers for a total of 61.6 mg implanted intracranially. The safety and effectiveness of repeat administration have not been studied.
Insertion Instructions
- Following maximal tumor resection, confirmation of tumor pathology and establishment of hemostasis, place up to a maximum of eight carmustines to cover as much of the resection cavity as possible. Should the size and shape of the resected cavity not accommodate eight wafers, place the maximum number of wafers feasible within the cavity. Slight overlapping of the wafers is acceptable. Wafers broken in half may be used, but discard wafers broken in more than two pieces. Oxidized regenerated cellulose (Surgicel®) may be placed over the wafers to secure them against the cavity surface. After placement of the wafers, irrigate the resection cavity and close the dura in a water-tight fashion.
Preparation and Safe Handling
- Carmustines contain a cytotoxic drug. Follow applicable special handling and disposal procedures.1
- Each wafer is packaged within two nested aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outside surface of the outer laminated aluminum foil pouch is a peelable overwrap and is not sterile.
- Deliver carmustines to the operating room in their outer aluminum foil pouch, unopened. Do not open the pouch until the wafers are ready to be implanted. Carmustines in unopened outer foil pouches are stable at room temperature for six hours at a time for up to three cycles within a 30-day period.
- Exposure to carmustine can cause severe burning and hyperpigmentation of the skin. Use double gloves when handling carmustines. Discard the outer gloves into a biohazard waste container after use. Use a dedicated surgical instrument for wafer implantation. If repeat neurosurgical intervention is indicated, handle residual wafers or wafer remnants as potential cytotoxic agents.
- Instructions for Opening Pouch Containing carmustine
- Read all steps of the instructions prior to opening the pouch.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carmustine (implant) in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carmustine (implant) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Carmustine (implant) in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Carmustine (implant) in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Carmustine (implant) in pediatric patients.
Contraindications
- Condition1
Warnings
Seizures
- Seizures occurred in 37% of patients treated with carmustines for recurrent glioma in Study 2. New or worsening (treatment emergent) seizures occurred in 20% of patients; 54% of treatment emergent seizures occurred within the first 5 post-operative days. The median time to onset of the first new or worsened post-operative seizure was four days. Institute optimal anti-seizure therapy prior to surgery.
- Monitor patients for seizures postoperatively.
Intracranial Hypertension
- Brain edema occurred in 23% of patients with newly diagnosed glioma treated with carmustines in Study 1. Additionally, one GLIADEL-treated patient experienced intracerebral mass effect unresponsive to corticosteroids which led to brain herniation. Monitor patients closely for intracranial hypertension related to brain edema, inflammation, or necrosis of the brain tissue surrounding the resection. In refractory cases, consider re-operation and removal of carmustines or Wafer remnants.
Impaired Neurosurgical Wound Healing
- Impaired neurosurgical wound healing including wound dehiscence, delayed wound healing, and subdural, subgleal, or wound effusions occur with carmustine treatment. In Study 1, 16% of carmustine-treated patients with newly diagnosed glioma experienced impaired intracranial wound healing and 5% had cerebrospinal fluid leaks. In Study 2, 14% of carmustine-treated patients with recurrent glioma experienced wound healing abnormalities [see ADVERSE REACTIONS (6.1)]. Monitor patients post-operatively for impaired neurosurgical wound healing.
Meningitis
- Meningitis occurred in 4% of patients with recurrent glioma receiving carmustines in Study 2. Two cases of meningitis were bacterial; one patient required removal of the Wafers four days after implantation; the other developed meningitis following reoperation for recurrent tumor. One case was diagnosed as chemical meningitis and resolved following steroid treatment. In one case the cause was unspecified, but meningitis resolved following antibiotic treatment. Monitor postoperatively for signs of meningitis and central nervous system infection.
Wafer Migration
- Carmustine migration can occur. To reduce the risk of obstructive hydrocephalus due to wafer migration into the ventricular system, close any communication larger than the diameter of a Wafer between the surgical resection cavity and the ventricular system prior to Wafer implantation. Monitor patients for signs of obstructive hydrocephalus.
Embryo-Fetal Toxicity
- Carmustines can cause fetal harm when administered to a pregnant woman. Carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to the exposure at the recommended human dose on a mg/m2 basis. Advise females of reproductive potential to avoid pregnancy after implantation of carmustines. If the patient becomes pregnant after carmustine implantation, warn the patient about the potential hazard to the fetus.
Adverse Reactions
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Newly-Diagnosed High-Grade Malignant Glioma
- The safety of carmustines was evaluated in a multicenter, randomized (1:1), double-blind, placebo controlled trial of 240 adult patients with newly-diagnosed high-grade malignant glioma who received up to eight carmustines or matched placebo implanted against the resection surfaces after maximal tumor resection (Study 1).
- The population in Study 1 was 67% male and 97% White, and the median age was 53 years (range: 21-72). Eighty-seven percent had a Karnofsky performance status ≥ 70 and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma multiforme as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; an additional 11% received no radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy.
- Deaths occurred within 30 days of wafer implantation in 5 (4%) of patients receiving carmustines compared to 2 (2%) of patients receiving placebo. Deaths on the GLIADEL arm resulted from cerebral hematoma/edema (n=3), pulmonary embolism (n=1) and acute coronary event (n=1). Deaths on the placebo arm resulted from sepsis (n=1) and malignant disease (n=1).
- The incidence of common adverse reactions in carmustine-treated patients is listed in Table 1. The incidence of local adverse reactions is shown in Table 2.
This image is provided by the National Library of Medicine.
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Carmustine (implant) in the drug label.
Drug Interactions
There is limited information regarding Carmustine (implant) Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Risk Summary
- Carmustine can cause fetal harm when administered to a pregnant woman. There have been no studies with carmustine; however, carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at exposures less than the exposure at the recommended human dose on a mg/m2 basis and embryotoxic in rabbits at exposures similar to exposures at the recommended human dose on a mg/m2 basis. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Animal Data
- There are no studies assessing the reproductive toxicity of carmustine; however, carmustine, the active component of carmustine, is embryotoxic and teratogenic in rats at intraperitoneal doses of 0.5mg/kg/day or greater when given on gestation days 6 through 15. Carmustine caused fetal malformations (anophthalmia, micrognathia, omphalocele) at 1.0 mg/kg/day (about 0.12 the recommended human dose, eight wafers of 7.7 mg carmustine/wafer, on a mg/m2 basis). Carmustine was embryotoxic in rabbits at intravenous doses of 4.0 mg/kg/day (about 1.2 times the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths, reduced numbers of litters, and reduced litter sizes.
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Carmustine (implant) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Carmustine (implant) during labor and delivery.
Nursing Mothers
- It is not known if carmustine, the active component of carmustine, is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from carmustine, a decision should be made whether to discontinue nursing or not to administer the drug, taking into account the importance of the drug to the mother.
Pediatric Use
There is no FDA guidance on the use of Carmustine (implant) with respect to pediatric patients.
Geriatic Use
Clinical trials of carmustine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
Gender
There is no FDA guidance on the use of Carmustine (implant) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Carmustine (implant) with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Carmustine (implant) in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Carmustine (implant) in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Carmustine (implant) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Carmustine (implant) in patients who are immunocompromised.
Administration and Monitoring
Administration
Monitoring
There is limited information regarding Monitoring of Carmustine (implant) in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Carmustine (implant) in the drug label.
Overdosage
There is limited information regarding Carmustine (implant) overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Carmustine (implant) Pharmacology in the drug label.
Mechanism of Action
- Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross-resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins.
Structure
- The structural formula is:
Pharmacodynamics
There is limited information regarding Pharmacodynamics of Carmustine (implant) in the drug label.
Pharmacokinetics
- Carmustine concentrations delivered by carmustine in human brain tissue have not been determined.
- Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m2, the average terminal half-life, clearance and steady-state volume of distribution were 22 minutes, 56 mL/min/kg and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200-mg/m2 dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2. Carmustine degrades both spontaneously and metabolically. The relevance of these data to elimination of intracranial implant-delivered carmustine are unknown.
- Carmustines are biodegradable when implanted into the human brain. Wafer remnants may be observed on brain imaging scans or at re-operation. Wafer remnants were visible in 11 of 18 patients on CT scans obtained 49 days after implantation of carmustine. More than 70% of the copolymer degrades within three weeks. Wafer remnants have been present at re-operation and autopsy up to 232 days after carmustine implantation, and consisted mostly of water and monomeric components with minimal detectable carmustine present.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Carmustine (implant) in the drug label.
Clinical Studies
How Supplied
- Carmustine is supplied in a single dose treatment box containing eight individually pouched wafers. Each wafer contains 7.7 mg of carmustine and is packaged in two aluminum foil laminate pouches. The inner pouch is sterile and is designed to maintain product sterility and protect the product from moisture. The outer pouch is a peelable overwrap. The outside surface of the outer pouch is not sterile.
- NDC for single dose treatment box: 24338-050-08
Storage
- Store carmustine at or below -20ºC (-4ºF).
- Do not keep unopened foil pouches at ambient room temperature for more than six hours at a time for up to three cycles within a 30-day period.
- Carmustine is a cytotoxic drug and special handling and disposal procedures should be considered.1
Images
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Patient Counseling Information
- Seizures: Advise patients to report any new or change in their seizure activity.
- Intracranial Hypertension: Advise patients to report severe headaches, nausea, vomiting or new onset visual disturbances.
- Impaired Neurosurgical Wound Healing: Advise patients to report any evidence of wound dehiscence, fever or cerebrospinal fluid leak.
- Meningitis: Advise patients to report symptoms of meningitis such as fever or stiff neck.
- Embryo-Fetal Toxicity: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use effective contraception during treatment with GLIADEL.
- Nursing Infants: Advise nursing mothers to discontinue nursing after carmustine implantation.
Precautions with Alcohol
- Alcohol-Carmustine (implant) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
- GLIADEL®[1]
Look-Alike Drug Names
There is limited information regarding Carmustine (implant) Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.
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