Carmustine Implant - Indication, Dosage, Precautions, Side Effects, and Warnings and Precautions

Overview:

Recent decades have seen progress in high-grade glioma (HGG) treatment, but it remains a highly malignant brain tumor with a poor prognosis. Despite advanced surgery, HGG's deep infiltration makes it nearly incurable, often leading to recurrence near the original site. Carmustine implants act as a bridge between surgery and chemo-radiotherapy, though their use is debated due to cost and potential trial impact. Long-term studies show improved survival with Carmustine wafer implantation in newly diagnosed HGG. This meta-analysis examines its impact on overall and progression-free survival compared to standard surgery. The Food and Drug Administration approved Carmustine implant insertion inside the patients’ skull at the time of HGG surgery in 2003.

Description and Drug Group of the Implant:

Carmustine implant is a medical implant designed for use inside the brain. It contains Carmustine, a type of medication that belongs to the nitrosourea alkylating agents. The implant also includes polifeprosan, a biodegradable material that helps control the release of Carmustine. This implant is a small, sterile, off-white to pale yellow disk, about 1.45 cm (centimeter) in diameter and 1 mm (millimeter) thick. Each disk contains 7.7 mg (milligram) of Carmustine and 192.3 mg of biodegradable material, which is a copolymer called polifeprosan 20. The copolymer is made up of specific chemicals (poly [bis (p-carboxyphenoxy)] propane and sebacic acid) in a particular ratio (20:80). Carmustine is evenly distributed within this copolymer matrix.

Available Doses and Dosage Forms:

The Carmustine implant is a circular, off-white to pale yellow tablet. Each wafer has 7.7 mg of Carmustine in it.

For Patients

What Is Diagnosed as High-Grade Glioma?

High-grade gliomas are fast-growing tumors that develop from glial cells in the brain and spinal cord. These tumors spread rapidly through the brain tissue, making them challenging to treat. High-grade gliomas are classified as either grade three or four, signifying that they are more aggressive and grow faster.

How Does Carmustine Implant Work?

The Carmustine implant is a type of Carmustine enclosed in a wafer. The wafer has a coating that dissolves gradually, releasing Carmustine directly into the region where the tumor was taken out. This form may be more effective and cause fewer side effects for brain tumors compared to other Carmustine forms.

What Is the Dosage of Carmustine Implant?

The suggested amount of Carmustine implant is eight wafers, each containing 7.7 mg, making a total of 61.6 mg implanted into the brain. It is important to note that using it again has not been studied for safety and effectiveness.

What Are the Things to Inform the Doctor Before Taking Carmustine Implant?

• Inform the doctor and pharmacist about any allergies to Carmustine or its components in the Carmustine implant.

• Ask the pharmacist for a list of the ingredients in the Carmustine implant.

• Share with the doctor and pharmacist the medications (prescription and over-the-counter), vitamins, and supplements a person is taking or planning to take.

• If the person is pregnant or planning to become pregnant, inform the doctor.

• If the person becomes pregnant while using the Carmustine implant, contact the doctor promptly, as Carmustine may harm the fetus.

• Let the doctor know if the person is breastfeeding.

How Is Carmustine Implant Inserted?

After removing the tumor as much as possible and confirming the type of tumor, up to eight Carmustine implants can be placed to cover the emptied space. If the cavity is not large enough for eight, use as many as will fit, even if they slightly overlap. It is okay to use half-wafers, but discard those broken into more than two pieces. An oxidized regenerated cellulose (surgicel) can be used to secure the wafers against the cavity surface. Once the wafers are in place, clean the cavity and close the protective layer around the brain tightly.

What Are the Side Effects of Carmustine Implant?

The possible side effects include:

• Seizures.

• Nausea.

• Vomiting.

• Constipation.

• Diarrhea.

• Rash.

• Confusion.

• Depressed mood.

• Pain.

• Drowsiness or sleepiness.

• Extreme tiredness or weakness.

• Impaired speech.

• Severe bleeding.

• Chest pain.

• Increased pressure inside the head (intracranial hypertension).

• Problems with healing after brain surgery (Impaired Neurosurgical Wound Healing).

• Inflammation of the membranes surrounding the brain and spinal cord (Meningitis).

Dietary Considerations:

Some medications may not be suitable when taken with or close to meals, or with specific types of food. Additionally, consuming alcohol or tobacco while on certain medications can lead to interactions. It is important to consult with the healthcare provider about how to take the medication about food, alcohol, or tobacco.

Storage:

• Carmustine implant comes in a box with a one-time treatment containing eight separate wafers. Each wafer has 7.7 mg of Carmustine and is sealed in two aluminum foil pouches.

• The inner pouch is sterile, keeping the product clean and safe from moisture, while the outer pouch is a peelable cover. The outside of the outer pouch is not sterile.

• To preserve the Carmustine implant's effectiveness, store it at or below -20ºC (Celsius) (-4ºF (Fahrenheit)). It is essential not to leave unopened foil pouches at room temperature for more than six hours at a time, and this can be done for up to three cycles within 30 days.

• Since Carmustine implant is a potent drug, it requires special care in handling and disposal.

For Doctors

Indication:

• Carmustine implant is for treating brain tumors.

• It helps newly diagnosed high-grade gliomas when used with surgery and radiation.

• It is recommended for patients with recurrent glioblastoma as an additional treatment after surgery.

Dose:

The recommended dose of Carmustine implant is eight wafers, each containing 7.7 mg of Carmustine, totaling 61.6 mg implanted into the brain. The safety and effectiveness of administering Carmustine implants repeatedly have not been investigated.

Dosing Considerations:

After completing the maximum tumor removal, verifying tumor pathology, and ensuring hemostasis, place up to eight Carmustine implants to cover as much of the resection cavity as possible. If the cavity size does not permit eight wafers, use the maximum feasible number. Overlapping the wafers slightly is acceptable. Wafers broken in half can be used, but discard those broken into more than two pieces. Oxidized regenerated cellulose can be used over the wafers to secure them against the cavity surface. After placing the wafers, irrigate the resection cavity and close the dura securely to prevent water leakage.

Carmustine implants contain a cytotoxic drug, so follow specific handling and disposal procedures. Each wafer is double-packaged in sterile aluminum foil pouches, with the inner pouch maintaining sterility and protecting it from moisture. The outer surface of the outer pouch is not sterile. Keep Carmustine implants in their unopened outer pouches when delivering to the operating room. Do not open the pouch until ready to implant the wafers. Unopened outer pouches are stable at room temperature for six hours at a time, up to three cycles within 30 days.

Handling a Carmustine implant requires precautions due to the potential skin effects of Carmustine. Use double gloves, discarding the outer gloves into a biohazard waste container after use. Utilize a dedicated surgical instrument for wafer implantation. If repeat neurosurgical intervention is necessary, treat residual wafers or wafer remnants as potential cytotoxic agents.

Instructions for Opening the Pouch Containing The GLIADEL Wafer:

• Slowly pull the folded corner of the sterile inner pouch outward to remove it from the outer pouch.

• Do not pull downward or roll knuckles over the pouch to avoid exerting pressure on the wafer.

• The inner pouch is a multi-layered, silver-colored foil laminate. Remove it by grabbing the crimped edge with a sterile instrument and pulling it upward.

• To open the inner pouch, gently cut in an arc-like fashion around the wafer while holding the crimped edge.

• Grasp the wafer with forceps and place it on a designated sterile field.

Pharmacological Aspects of Carmustine Implant

Pharmacodynamics:

Carmustine, a nitrosourea, is recommended for palliative treatment either as a sole agent or in conjunction with approved chemotherapy for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. While its primary mechanism involves the alkylation of DNA (deoxyribonucleic acid) and RNA (ribonucleic acid), Carmustine differs from other alkylators in terms of cross-resistance. Additionally, it may impede vital enzymatic processes by carbonylation amino acids in proteins, aligning with the characteristics of nitrosoureas.

Mechanism:

Carmustine implant's effectiveness stems from the controlled release of cytotoxic levels of Carmustine, an agent that alkylates DNA and RNA, into the cavity left after tumor removal. When in contact with the fluid environment of the resection cavity, the anhydride bonds in the copolymer undergo hydrolysis. This process releases Carmustine, along with carboxyphenoxy propane and sebacic acid, into the adjacent brain tissue.

Pharmacokinetics:

The concentrations of Carmustine delivered by Carmustine implants in human brain tissue have not been established. After administering Carmustine intravenously in doses ranging from 30 to 170 mg/m² (milligram per meter square), the average terminal half-life, clearance, and steady-state volume of distribution were 22 minutes, 56 mL/min/kg (milliliter per minute per kilogram), and 3.25 L/kg (liter per kilogram), respectively. Following a 200-mg/m² intravenous dose of 14C-Carmustine, approximately 60 % was excreted in urine over 96 hours, and 6 % was expired as CO2 (carbon dioxide). Carmustine undergoes spontaneous and metabolic degradation. The relevance of these findings to the elimination of intracranial implant-delivered Carmustine is uncertain.

Carmustine implant biodegrades when implanted in the human brain. Remnants may be visible on brain imaging or during re-operation. On CT scans taken 49 days after Carmustine implant placement, remnants were observed in 11 of 18 patients. Over 70 % of the copolymer degrades within three weeks. Remnants have been present up to 232 days post-implantation, primarily composed of water and monomeric components, with minimal detectable Carmustine.

Toxicity:

The Carmustine implant has not undergone studies for its potential to cause cancer, genetic mutations, or affect fertility. However, studies conducted on Carmustine, the active ingredient in Carmustine implant, have shown that Carmustine can cause cancer in rats and mice, even at doses lower than those used in Carmustine implant. Carmustine has also demonstrated mutagenic effects in laboratory tests and caused damage to genetic material both in test tubes and in animals. Additionally, in male rats, Carmustine led to testicular issues at doses higher than the recommended human dose.

Clinical Studies:

Due to varying conditions in clinical trials, adverse reaction rates observed in one drug's trials cannot be directly compared to another. These rates may not reflect real-world observations.

Newly-Diagnosed High-Grade Glioma:

• The safety of Carmustine implant was assessed in a double-blind trial involving 240 adults with newly diagnosed high-grade glioma.

• Carmustine implant or a placebo was implanted after maximal tumor resection.

• Deaths within 30 days occurred in 4 % of Carmustine implant treated patients, primarily due to cerebral hematoma or edema.

Adverse Reactions in Newly-Diagnosed High-Grade Glioma:

• Common adverse reactions (Carmustine implant vs. Placebo) included nausea (22 % vs. 17 %), vomiting (21 % vs. 16 %), and wound healing abnormalities (16 % vs. 12 %).

Recurrent High-Grade Glioma:

• A double-blind trial with 222 patients assessed Carmustine implants' safety in recurrent high-grade glioma after maximal tumor resection.

• Adverse reactions, including meningitis, were reported more in Carmustine implant-treated patients.

• Seizure incidence and other neurologic reactions were noted.

Adverse Reactions in Recurrent High-Grade Glioma:

• Notable adverse reactions (Carmustine implant vs placebo) included fever (12 % vs 8 %) and urinary tract infections (21 % vs17 %).

Seizure Incidence:

• Seizures occurred in 37 % of Carmustine implant-treated patients compared to 29 % with a placebo.

• New or worsening seizures were observed in 20 % of Carmustine implant-treated patients.

• The mean time to onset of new or worsening seizures was significantly shorter in Carmustine implant-treated patients.

Hydrocephalus and Cerebral Edema:

• Carmustine implant-treated patients had higher incidences of hydrocephalus (5 % vs 2 %) and cerebral edema (4 % vs 1 %) compared to the placebo group.

• These findings provide insights into the safety profile of Carmustine implants in these specific clinical settings.

Contraindications of Carmustine Implant:

Carmustine can induce a significant reduction in bone marrow blood cell counts, elevating the susceptibility to severe infections or bleeding.

Warnings and Precautions:

• Seizures: About 37 % of patients treated with Carmustine implant for recurrent glioma experienced seizures. New or worsening seizures occurred in 20 percent of patients, with 54 percent happening within the first 5 postoperative days. Optimal anti-seizure therapy is recommended before surgery, and postoperative monitoring for seizures is crucial.

• Intracranial Hypertension: Brain edema occurred in 23 percent of newly diagnosed glioma patients treated with Carmustine implants. One patient experienced intracerebral mass effect unresponsive to corticosteroids, leading to brain herniation. Close monitoring for intracranial hypertension is essential, with consideration for re-operation and wafer removal in refractory cases.

• Impaired Neurosurgical Wound Healing: Carmustine implant treatment may lead to impaired neurosurgical wound healing, including dehiscence, delayed healing, and effusions. In newly diagnosed glioma patients, 16 percent experienced impaired intracranial wound healing, and five percent had cerebrospinal fluid leaks. Postoperative monitoring is advised for impaired neurosurgical wound healing.

• Meningitis: Meningitis occurred in four percent of recurrent glioma patients receiving Carmustine implant. Two cases were bacterial, with one requiring wafer removal after four days; the other developed meningitis post-reoperation. Monitoring for postoperative signs of meningitis and central nervous system infection is recommended.

• Wafer Migration: Carmustine implant migration may happen, risking obstructive hydrocephalus. Closing any communication larger than a wafer's diameter between the resection cavity and ventricular system before implantation is advised. Regular monitoring for signs of obstructive hydrocephalus in patients is essential.

• Embryo-Fetal Toxicity: Carmustine implants pose a risk of fetal harm in pregnant women. Carmustine, the active component, is embryotoxic and teratogenic in rats at exposures less than the recommended human dose. Patients should be informed of fetal risks, and females of reproductive potential should use contraception for six months after wafer implantation. Males with reproductive partners should use contraception for three months after implantation.

Drug Interactions of Carmustine Implant

Certain medications may have interactions, and the doctor may need to adjust doses or take precautions. Inform the healthcare professional about the medicines the person is using. Some medications, like live vaccines for measles or varicella, are not recommended alongside this medicine. The doctor may choose not to administer this medication or may adjust other medicines. Additionally, there may be considerations for using this medicine with others, such as vaccines (adenovirus, influenza) or drugs like Cimetidine or Phenobarbital. In such cases, the doctor might modify doses or frequency. Always keep the healthcare provider informed about the complete medication history.

Specific Considerations:

• Pregnancy: Carmustine implants pose a risk of fetal harm when administered during pregnancy.

• Lactation: Due to potentially serious adverse reactions in breastfed infants, women are advised not to breastfeed after Carmustine implant placement for at least seven days.

• Females and Males of Reproductive Potential: Pregnancy status should be verified in females before Carmustine implant placement. Contraception is crucial due to the risk of fetal harm: females should use effective contraception for six months post-implantation, and males with reproductive partners should do so for three months. Males are informed about the potential risk of infertility based on the mechanism of action.

• Pediatric Use: The safety and effectiveness of Carmustine implants in pediatric patients have not been established.

• Geriatric Use: Clinical trials did not involve enough patients aged 65 and over to determine if they responded differently from younger patients.