Gliadel 7.7 mg implant
Spain
Table of Contents
Package leaflet: Information for the user
Introduction
Package leaflet: information for the user
GLIADEL 7.7 mg implant
Carmustine
Read the entire leaflet carefully before you start using this medicine, because it contains important information for you.
- Keep this leaflet, as you may need to refer to it again.
- If you have any questions, consult your doctor.
- If you experience any adverse reactions, consult your doctor, even if they are adverse reactions not listed in this leaflet. See section 4.
Leaflet contents:
- What GLIADEL implant is and what it is used for
- What you need to know before using GLIADEL implant
- How to use GLIADEL implant
- Possible adverse effects
- How to store GLIADEL implant
- Contents of the pack and other information
1. What Gliadel implant is and what it is used for
GLIADEL implant is a system for delivering the active anticancer substance carmustine directly to the site where the brain tumor was located, after its surgical removal. Carmustine belongs to a group of anticancer agents that help combat the growth of tumor cells located in the brain.
GLIADEL implants may be used in combination with radiotherapy for the treatment of brain tumors.
It has been shown that GLIADEL implant prolongs the survival of patients with brain tumors.
2. What you need to know before using Gliadel implant
Do not use GLIADEL implant
- if you are allergic to the active substance or to any of the other components of this medicine (listed in section 6).
Warnings and precautions
After surgery to remove the brain tumor and insert the GLIADEL implant, your doctor or surgeon will closely monitor you for possible complications. In some cases, your surgeon may need to operate again (due to complications or tumor recurrence). Complications include:
- Seizures (fits)
- Brain infections (infections within the skull)
- Brain inflammation due to fluid accumulation
- Cerebrospinal fluid leakage
- Wound healing problems
Your doctor will closely monitor you if you are taking steroids due to inflammation or elevated fluid pressure in the brain.
Before implant placement, the surgeon may need to close off a channel in the brain to prevent the implants from passing through, which could lead to fluid accumulation within the skull.
After insertion of the GLIADEL implant, imaging techniques may detect brain inflammation due to fluid accumulation and inflammation caused by the GLIADEL implant or tumor progression.
Other medicines and GLIADEL implant
Tell your doctor if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.
Pregnancy and breastfeeding
If you are pregnant or breastfeeding, think you may be pregnant, or are planning to become pregnant, consult your doctor before using this medicine. GLIADEL implant has not been studied in pregnant women. The active substance, carmustine, has been shown to have harmful effects on fetal development. GLIADEL implant must not be used in pregnant or breastfeeding women. Women of childbearing potential should use effective contraception for 6 months after receiving GLIADEL implant. Men with partners of childbearing potential should use contraception for 90 days after receiving GLIADEL implant.
Driving and use of machines
Driving is not recommended after treatment. Consult your doctor before driving or operating tools or machinery.
3. How to use Gliadel implant
GLIADEL implant should only be used in adults.
The surgeon or pharmacist will ensure that the medication is available for your surgery. After removal of the brain tumor, the surgeon will insert up to eight implants into the space previously occupied by the tumor. Your surgeon will decide the number of implants to place in the cavity created after the brain tumor has been removed. The implants are positioned so as to cover as much of the cavity surface as possible. After surgery, the implants slowly dissolve over two to three weeks, thereby releasing carmustine directly into the surrounding cells.
If you have any further questions about the use of this product, ask your surgeon.
4. Possible adverse effects
Like all medicines, GLIADEL may produce adverse effects, although not everyone experiences them.
If you consider any of the adverse effects you experience to be severe, or if you notice any adverse effects not mentioned in this leaflet, inform your doctor.
The most frequently observed adverse effects during clinical trials in patients with newly diagnosed malignant glioma (brain tumor) (120 patients) or recurrent malignant glioma (110 patients) are listed below.
The following four categories of adverse effects may be associated with the use of GLIADEL wafer:
|
During clinical trials, the following adverse effects were observed in patients, which were similar to those observed in patients undergoing brain tumor surgery without GLIADEL wafer implantation.
Very common: may affect more than 1 in 10 patients
- Psychiatric disorders
Depression
- Nervous system disorders
Weakness, especially on one side of the body; seizures (spasms); confusion; headache; swelling of the skull; somnolence; speech disturbances
- Vascular disorders
Vascular inflammation
- Gastrointestinal disorders
Nausea; vomiting; constipation
- Skin and subcutaneous tissue disorders
Rash; hair loss
- Renal and urinary disorders
Urinary tract infection
- General disorders and administration site conditions
Worsening of general condition; infection; headache; feeling of weakness; fever or pain, abnormal (slow) healing of the surgical wound.
Common: may affect up to 1 in 10 patients
- Blood and lymphatic system disorders
Reduction in red blood cells (anemia), which may cause pale skin, fatigue, and breathlessness; reduction in blood platelets, which increases the risk of bleeding; increase in white blood cells
- Endocrine disorders (hormonal problems)
Diabetes mellitus
- Metabolism and nutrition disorders
Peripheral edema (excess fluid in arms or legs); low sodium concentration in blood, which may cause fatigue and confusion, muscle twitching, spasms, and coma; high blood sugar levels; low potassium concentration in blood, which may cause weakness and muscle twitching, and abnormal heart rhythm
- Psychiatric disorders
Personality changes, excessive anxiety, abnormal thinking, hallucinations, insomnia (poor sleep)
- Nervous system disorders
Amnesia (memory loss); increased intracranial pressure due to excess fluid; facial paralysis; lack of coordination; reduced sensitivity to stimulation; abnormal sensations of burning and itching; difficulty walking; dizziness; epileptic seizure (spasms); tremors; meningitis; abscess (localized collection of pus); loss of consciousness
- Eye disorders
Blurred or abnormal vision; inflammation around the eyes; eye pain
- Vascular disorders
Bleeding; high or low blood pressure
- Respiratory, thoracic and mediastinal disorders
Lung infection or pneumonia causing breathlessness, cough, and fever
- Gastrointestinal disorders
Microbial infection of the mouth; diarrhea; constipation; fecal incontinence (uncontrolled loss of stool); difficulty swallowing; gastric or intestinal bleeding
- Epidermal and subcutaneous disorders
Rash
- Musculoskeletal and connective tissue disorders
General infection
- Renal and urinary disorders
Urinary incontinence, urinary tract infections
- General disorders and administration site conditions
Abdominal pain radiating from back to chest; facial swelling; abscess (localized collection of pus); accidental injury; allergic reaction; neck pain; bloodstream infection
Uncommon adverse effects (between 1 and 10 patients in every 1,000)
Injury, poisoning and procedural complications
Pneumocephalus (accumulation of air in the implant area)
Reporting of adverse effects
If you experience any type of adverse effect, consult your doctor, even if it is a possible adverse effect not listed in this leaflet.
You may also report them directly via the Spanish Pharmacovigilance System for Human Medicines: www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.
5. Storage of Gliadel Implant
Keep this medicine out of the sight and reach of children.
Store in a freezer at a temperature of -20°C or lower.
Unopened outer pouches may be kept at a temperature below 22°C for a maximum of 6 hours. Pouches may be refrozen once if they have not been opened and have been kept for no longer than 6 hours at a temperature below 22°C. After refreezing, the medicine must be used within 30 days.
Do not use Gliadel implant after the expiry date stated on the packaging and/or on the pouch after EXP. The expiry date refers to the last day of the month indicated. Your surgeon or hospital pharmacist will check the expiry date before using the implants.
6. Contents of the pack and other information
Composition of GLIADEL implant
- The active substance is carmustine. Each implant contains 7.7 mg of carmustine.
- The other component is polifeprosan 20.
Appearance of the product and contents of the pack
GLIADEL implant is available in packs of eight circular, implantable wafers. These wafers are disk-shaped implants ranging in color from opaque white to yellow. Each implant is individually packaged in a pouch covered with an aluminum foil.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
CLINIGEN HEALTHCARE B.V.
Schiphol Boulevard 359
WTC Schiphol Airport, D Tower 11th floor
1118BJ Schiphol
The Netherlands
Manufacturer
ALMAC PHARMA SERVICES (IRELAND) LIMITED
Finnabair Industrial Estate
Dundalk
Co. Louth A91 P9KD
Ireland
Tel: +353 42 932 0718
Fax: +353 42 932 0718
Orion GMP Consulting Limited
Unit 4, W8 Centre
Church Lane
Manorhamilton
Leitrim, F91 H2YA
Ireland
Clinigen Clinical Supplies Management GmbH
Am Kronberger Hang 3
65824 Schwalbach am Taunus
Germany
Date of the most recent revision of this leaflet: 04/2021
Detailed and up-to-date information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/
INFORMATION LEAFLET FOR HEALTHCARE PROFESSIONALS
1. NAME OF THE MEDICINAL PRODUCT
GLIADEL 7.7 mg implant
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each implant contains 7.7 mg of carmustine.
For a complete list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Implant.
Disk-shaped implant ranging in color from opaque white to yellow.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
GLIADEL implant is indicated for the treatment of adult patients with newly diagnosed high-grade malignant glioma as adjuvant therapy to surgery and radiation.
GLIADEL implant is indicated as adjuvant therapy to surgery for the treatment of patients with recurrent, histologically confirmed recurrent glioblastoma multiforme, in whom surgical resection is indicated.
4.2 Posology and method of administration
Posology
For intralesional use only.
Each GLIADEL implant contains 7.7 mg of carmustine; therefore, placement of eight implants into the tumor resection cavity delivers a total dose of 61.6 mg.
Paediatric population
The safety and efficacy of GLIADEL implant in children under 18 years of age have not been established. No data are available.
Method of administration
Placement of up to eight implants is recommended, provided the size and shape of the resection cavity allow it. Implants may be halved, but any fragments smaller than half an implant must be discarded in appropriate biohazard waste containers (see section 6.6).
It is recommended that implants be transferred directly from their sterile inner packaging into the resection cavity. Oxycellulose pads may be placed over the implants to secure them in place on the cavity surface (see section 6.6).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Patients undergoing craniotomy and implantation of GLIADEL implant must be closely monitored for potential complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, cerebral edema, and pneumocephalus (see section 4.8). Cases of intracerebral mass effect unresponsive to corticosteroids, including one case resulting in cerebral herniation, have been reported in patients treated with GLIADEL implant. Patients treated with GLIADEL implant must be rigorously monitored for the development of cerebral edema/intracranial hypertension despite corticosteroid use (see section 4.8). Cerebrospinal fluid (CSF) leaks occurred more frequently in patients treated with GLIADEL implant. Careful attention to watertight dural closure and local wound management is recommended (see section 4.8).
Changes in the walls of cerebral blood vessels located near the Gliadel wafer, including cases of aneurysm leading to intracerebral hemorrhage several months after implantation, have been reported. Implantation of Gliadel wafers adjacent to large cerebral vessels should be avoided.
Development of cerebral edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may require reoperation and, in some cases, removal of the GLIADEL implant or its remnants.
Communication between the surgical resection cavity and the ventricular system should be avoided to prevent migration of implants into the ventricular system, which could lead to obstructive hydrocephalus. If a communication larger than the diameter of the implant exists, it should be closed prior to implantation of GLIADEL implant.
Computed tomography and magnetic resonance imaging may show increased density in the brain tissue surrounding the resection cavity after placement of GLIADEL implants. This increased intensity may reflect edema or inflammation caused by the implants, or tumor progression.
Women of childbearing potential must use effective contraception for at least 6 months after receiving GLIADEL implant.
Male patients with partners of childbearing potential should be advised to use effective contraception for at least 90 days after receiving GLIADEL implant.
4.5 Interaction with other medicinal products and other forms of interaction
Formal studies on interactions between GLIADEL implant and other drugs or chemotherapy have not been conducted.
4.6 Fertility, pregnancy and lactation
Pregnancy:
There are no studies of GLIADEL implant in pregnant women, nor studies evaluating the reproductive toxicity of GLIADEL implant.
When administered systemically, carmustine, the active substance in GLIADEL implant, may have genotoxic effects and adversely affect fetal development (see section 5.3). Therefore, GLIADEL implant is not recommended during pregnancy or in women of childbearing potential who are not using effective contraception. Women of childbearing potential must use effective contraception for at least 6 months after receiving GLIADEL implant.
Male patients with partners of childbearing potential should be advised to use effective contraception for at least 90 days after receiving GLIADEL implant. However, if use of GLIADEL implant during pregnancy is considered necessary, the patient must be informed of the potential risks to the fetus. In the event that a patient becomes pregnant after receiving GLIADEL implant, genetic counseling should be sought.
Lactation:
It is unknown whether components of GLIADEL implant are excreted in human milk. Since some drugs are excreted in breast milk and due to the potential risk of serious adverse reactions from carmustine in infants, breastfeeding is contraindicated.
Fertility:
Fertility studies with GLIADEL implant have not been conducted.
4.7 Effects on ability to drive and use machines
GLIADEL implant does not influence the ability to drive or operate machinery. However, craniotomy and GLIADEL implant may cause visual and nervous system disturbances. Therefore, patients should be aware of the potential impact of these reactions on their ability to drive or operate machinery.
4.8 Undesirable effects
The spectrum of adverse reactions observed in patients with newly diagnosed high-grade malignant glioma and recurrent malignant gliomas was consistent with that observed in patients undergoing craniotomy for malignant gliomas.
Below are listed the very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1000 to < 1/100) adverse reactions observed in patients treated with GLIADEL implant in clinical trials.
Adverse reactions are listed in order of decreasing severity within each frequency category.
Primary Surgery
The following data refer to the most common adverse reactions observed in ≥ 5% of the 120 patients with newly diagnosed malignant glioma treated with GLIADEL implant in the clinical trial.
Adverse reactions observed in ≥5% of patients treated with GLIADEL implant in initial surgery
System organ classification | Adverse reactions | |
Endocrine disorders | common* | Diabetes mellitus |
Psychiatric disorders | very common | Depression |
common | Personality disorder, anxiety, abnormal thinking, hallucinations, insomnia | |
Nervous system disorders | very common | Hemiplegia, seizures, confusion, cerebral edema, aphasia, somnolence, speech disorders |
common | Amnesia, increased intracranial pressure, personality disorders, anxiety, facial paralysis, neuropathy, ataxia, hypoesthesia, paresthesia, abnormal thinking, abnormal gait, dizziness, grand mal seizures, hallucinations, insomnia, tremor | |
Eye disorders | common | Conjunctival edema, abnormal vision, visual field defects |
Vascular disorders | very common | Thrombophlebitis |
common | Hemorrhage | |
Respiratory, thoracic and mediastinal disorders | common | Pulmonary embolism |
Infections and infestations | common | Pneumonia |
very common | Nausea, vomiting, constipation | |
Skin and subcutaneous tissue disorders | common | Diarrhea |
Skin and subcutaneous tissue disorders | very common | Rash, alopecia |
Renal and urinary disorders | common | Urinary tract infection, urinary incontinence |
General disorders and administration site conditions | very common | Worsening, headache, asthenia, infection, fever, pain, abnormal healing |
common | Abdominal pain, back pain, facial edema, chest pain, abscess, accidental injury, peripheral edema |
Intracranial hypertension was reported more frequently in patients treated with GLIADEL wafer than in those who received placebo (9.2% versus 1.7%), appearing as a late finding coinciding with tumor recurrence, and was considered unlikely to be associated with the use of GLIADEL wafer (see section 4.4).
Cerebrospinal fluid (CSF) leaks occurred more frequently in patients treated with GLIADEL wafer than in patients who received placebo. However, there was no increase in intracranial infections or other healing abnormalities (see section 4.4).
Surgery for recurrent disease
The following adverse reactions were observed after surgery in 4% or more of patients treated with GLIADEL wafer during repeat surgery. Only reactions that were more frequent in the GLIADEL wafer group than in the placebo group are listed, except for nervous system effects, which could potentially be caused by the placebo wafers. These adverse reactions were either absent prior to surgery or worsened after surgery during the follow-up period. The follow-up period was up to 71 months.
Adverse reactions observed frequently (≥ 4%) in patients treated with GLIADEL wafer during repeat surgery
System organ classification | Adverse reactions | |
Blood and lymphatic system disorders | common | Anemia |
Metabolism and nutrition disorders | common | Hypotremia |
Nervous system disorders | very common | Seizure, hemiplegia, headache, somnolence, confusion |
common | Aphasia, stupor, cerebral edema, increased intracranial pressure, meningitis or abscess | |
Vascular disorders | common | Thrombophlebitis |
Respiratory, thoracic and mediastinal disorders | common | Pulmonary embolism |
Gastrointestinal disorders | common | Nausea, vomiting |
Skin and subcutaneous tissue disorders | common | Skin rash |
Renal and urinary disorders | very common | Urinary tract infection |
General disorders and administration site conditions | very common | Abnormal healing |
common | Infection, pain |
The following adverse reactions, which are not included in the table below, were reported in patients treated with GLIADEL implant in all studies. The listed effects were either not present during the pre-surgical period or worsened in the post-surgical period. It was not possible to establish whether the GLIADEL implant was the cause of these effects.
Adverse reactions in patients receiving GLIADEL implant
System Organ Class | Adverse Reactions | |
Blood and lymphatic system disorders | common | Thrombocytopenia, leukocytosis |
Metabolism and nutrition disorders | common | Hypoglycemia, hyperglycemia, hypokalemia |
Nervous system disorders | common | Hydrocephalus, ataxia, dizziness, hemiplegia, coma, amnesia, diplopia, |
uncommon | Cerebral hemorrhage, cerebral infarction | |
Psychiatric disorders | common | Depression, abnormal thinking, insomnia, paranoid reaction |
Eye disorders | common | Visual disturbance, eye pain |
Cardiac and vascular disorders | common | Hypertension, hypotension |
Respiratory, thoracic and mediastinal disorders | common | Infection, aspiration pneumonia |
Gastrointestinal disorders | common | Diarrhea, constipation, dysphagia, gastrointestinal hemorrhage, fecal incontinence |
Skin and subcutaneous tissue disorders | common | Rash |
Musculoskeletal and connective tissue disorders | common | Infection |
Renal and urinary disorders | common | Urinary incontinence |
General disorders and administration site conditions | common | Peripheral edema, neck pain, accidental injury, back pain, allergic reaction, asthenia, chest pain, sepsis |
Injury, poisoning and procedural complications | uncommon | pneumocephalus |
Cases of air accumulation at the implant site have been reported with Gliadel, sometimes associated with neurological symptoms (hemiplegia, aphasia, seizures).
The following four categories of adverse reactions are possibly related to treatment with GLIADEL wafer.
Seizures:
In the initial surgery clinical trial, the incidence of seizures within the first five days after implantation was 2.5% in the GLIADEL wafer group.
In the recurrent disease surgery clinical trial, the incidence of seizures after surgery was 19% in patients treated with GLIADEL wafer. In this trial, 12/22 (54%) of patients treated with GLIADEL wafer experienced onset of seizures or worsening of pre-existing seizures during the first five days after surgery. The median time to onset of seizures or worsening of pre-existing seizures after surgery was 3.5 days in patients treated with GLIADEL wafer.
Cerebral edema:
Development of cerebral edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may necessitate reoperation and, in some cases, removal of the GLIADEL wafer or its remnants (see section 4.4).
Wound healing abnormalities:
The following wound healing abnormalities have been reported in clinical trials of GLIADEL wafer: wound dehiscence, delayed wound healing, subdural, subgaleal, or suture-line effusions, and cerebrospinal fluid (CSF) leaks.
In the trial conducted during initial surgery, CSF leaks occurred in 5% of individuals who received GLIADEL wafer. During surgery, a watertight closure of the dura mater must be ensured to minimize the risk of CSF leakage (see section 4.4).
Intracranial infection:
In the initial surgery clinical trial, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL wafer.
In surgery for recurrent disease, the incidence of brain abscess or meningitis was 4% in patients treated with GLIADEL wafer.
In a published clinical trial, cyst formation after treatment with GLIADEL wafer has been reported. This reaction occurred in 10% of patients observed in the trial. However, cyst formation is possible following resection of a malignant glioma.
Reporting suspected adverse reactions
It is important to report suspected adverse reactions to medicinal products following their authorization. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report suspected adverse reactions via the Spanish Pharmacovigilance System for Human Medicinal Products: https://www.notificaram.es.
4.9 Overdose
Not applicable.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, nitrosoureas, ATC code: L01AD01
Preclinical data
GLIADEL wafer releases carmustine directly into the surgical cavity created after tumor resection. When exposed to the aqueous environment of the cavity, the anhydride bonds of the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid. The carmustine released from GLIADEL wafer diffuses into the surrounding brain tissue and exerts an antineoplastic effect through alkylation of DNA and RNA.
Carmustine undergoes spontaneous degradation and metabolism, generating an alkylating group, presumably a chloroethyl carbonium ion, which leads to irreversible cross-linking of DNA.
The antitumor activity of GLIADEL wafer depends on the release of carmustine into the tumor cavity in sufficient quantities to achieve effective cytotoxicity.
More than 70% of the copolymer degrades within 3 weeks. The monomers have different metabolic and elimination pathways. Carboxyphenoxypropane is primarily eliminated via the kidneys, while sebacic acid, an endogenous fatty acid, is metabolized by the liver and exhaled as CO2 in animals.
Clinical efficacy and safety
Initial surgery
In a randomized, double-blind, placebo-controlled clinical trial involving 240 adults with newly diagnosed high-grade malignant glioma undergoing initial craniotomy for tumor resection, median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL wafer (p = 0.079, unstratified log-rank test) in the initial follow-up phase of the trial. The most common tumor type was glioblastoma multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). The hazard ratio for GLIADEL wafer was 0.77 (95% CI: 0.57 – 1.03). In the long-term follow-up phase, patients who were still alive at the end of the initial follow-up phase were followed for at least three years or until death. Median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL wafer (p < 0.05, log-rank test). The hazard ratio for GLIADEL wafer treatment was 0.73 (95% CI: 0.56 – 0.95).
Surgery in recurrent disease
In a randomized, double-blind, placebo-controlled clinical trial involving 145 adults with recurrent glioblastoma (GBM), GLIADEL wafer prolonged survival in these patients. 95% of patients treated with GLIADEL wafer received between 7 and 8 wafers.
The 6-month survival rate was 36% (26/73) with placebo versus 56% (40/72) with GLIADEL wafer treatment. Median survival in patients with GBM was 20 weeks with placebo versus 28 weeks with GLIADEL wafer treatment.
5.2 Pharmacokinetic properties
Absorption, distribution, metabolism, and elimination of the copolymer in humans are not known. Carmustine concentrations released by GLIADEL wafer into human brain tissue have not been determined. Plasma levels of carmustine cannot be determined after implantation of GLIADEL wafer. Carmustine is not detected in blood or cerebrospinal fluid in rabbits with 3.85% carmustine wafers.
After intravenous infusion of carmustine at doses between 30 and 170 mg/m², the mean terminal elimination half-life, clearance, and steady-state volume of distribution are 22 minutes, 56 ml/min/kg, and 3.25 l/kg, respectively. Approximately 60% of a 200 mg/m² intravenous dose of 14C-carmustine is excreted in urine within 96 hours, and 6% is exhaled as CO2.
GLIADEL wafers are biodegradable in the human brain when placed in the cavity following tumor resection. The rate of biodegradation varies between patients. Wafer remnants may be observed via brain imaging techniques or during subsequent surgery, even though extensive degradation of all components may have occurred.
5.3 Preclinical safety data
No carcinogenicity, mutagenicity, embryo-fetal toxicity, pre- and postnatal toxicity, or fertility impairment studies have been conducted with GLIADEL wafer.
Carmustine, the active substance in GLIADEL wafers, when administered systemically, has embryotoxic, teratogenic, genotoxic, and carcinogenic effects and may cause testicular degeneration in various animal models.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Polifeprosan 20
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
4 years.
6.4 Special precautions for storage
Store in a freezer. Do not store at temperatures above -20°C.
Unopened outer pouches may be kept at temperatures below 22°C for up to 6 hours.
The product may be refrozen once if the pouches have not been opened and have remained at temperatures below 22°C for no more than 6 hours. After refreezing, the product must be used within 30 days.
6.5 Nature and contents of container
GLIADEL wafer is available in a box containing 8 wafers. Each wafer is individually packaged in 2 laminated aluminum foil pouches.
6.6 Special precautions for disposal and other handling
The wafers must be handled by personnel wearing surgical gloves, as exposure to carmustine may cause severe skin burns and hyperpigmentation. Double gloving is recommended, and after use, the outer gloves should be discarded in a biohazard waste container. A dedicated surgical instrument should be used during wafer placement. If repeat neurosurgical intervention is indicated, any wafer or wafer remnants must be handled as potential cytotoxic agents. Disposal of unused medication and all materials that have come into contact with it must be carried out in accordance with local regulations for cytotoxic agents.
GLIADEL wafers must be handled with care. The pouches containing the wafers should be delivered to the operating room and must remain sealed until the time of placement into the resection cavity. Only the outer surface of the outer pouch is non-sterile. In any case, if a wafer is accidentally dropped, it must be properly discarded.
Instructions for opening the pouches containing the wafer:
Figure 1: To open the outer pouch,
locate the folded corner and gently pull outward.
Figure 2: Do not pull downward by rotating the knuckles
on the pouch. This could exert pressure on the wafer
and break it.
Figure 3: Remove the inner pouch using forceps
and pulling upward.
Figure 4: To open the inner pouch, gently hold it
and cut circularly around the wafer.
Figure 5: To remove the wafer, gently grasp it
with forceps and place it into the resection cavity.
In any case, if a wafer is dropped, it must be properly discarded.
After tumor resection, confirmation of tumor diagnosis by pathological anatomy, and achievement of hemostasis, up to 8 wafers may be placed to cover the resection cavity as completely as possible. Slight overlap between wafers is considered acceptable. Wafers may be cut in half, but if fragmented into more than two pieces, they must be discarded in biohazard waste containers.
Oxycellulose dressing strips may be placed over the wafers to secure them to the cavity surface. After wafer placement, the resection cavity should be irrigated and the dura mater must be closed in a watertight manner.
Disposal of unused medication and all materials that have come into contact with it must be carried out in accordance with local regulations for biohazardous waste.
7. MARKETING AUTHORIZATION HOLDER
CLINIGEN HEALTHCARE B.V.
Schiphol Boulevard 359
WTC Schiphol Airport, D Tower 11th floor
1118BJ Schiphol
The Netherlands
8. MARKETING AUTHORIZATION NUMBER(S)
AEMPS Reg. No. 62.745
9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION
Date of first authorization: 19/10/1999
Date of latest renewal: 10/12/2008
10. DATE OF TEXT REVISION
April 2021