Gliadel

PACKAGE LEAFLET

Package leaflet: information for the user

GLIADEL 7.7 mg Implant

Carmustine
Please read this leaflet carefully before receiving GLIADEL Implant, as it contains
important information for you

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet:

1. What GLIADEL is and what it is used for
2. What you need to know before using GLIADEL Implant
3. How GLIADEL Implants are used
4. Possible side effects
5. How to store GLIADEL
6. Contents of the pack and other information

1. What GLIADEL is and what it is used for

GLIADEL implants allow the delivery of carmustine directly to the site of the brain tumor. Carmustine belongs to a group of anticancer agents that help fight the proliferation of certain tumor cells located in the brain, as an adjunct to surgical intervention.
GLIADEL implants may be used in combination with radiation therapy in the treatment of brain tumors.
GLIADEL implants have been shown to prolong survival in patients with brain tumors.

2. What you should know before using GLIADEL Wafer

Do not use GLIADEL if you are allergic to carmustine or polifeprosan 20.
Warnings and precautions
After surgery for removal of the brain tumour and insertion of GLIADEL wafers, your doctor or surgeon will closely monitor you for possible known complications. In some cases, the surgeon may need to perform additional surgery (due to complications or tumour recurrence). Complications include:

• Seizures (convulsive seizures)
• Brain infections (infections within the cranial cavity)
• Cerebral oedema
• Cerebrospinal fluid leakage
• Problems with healing of the surgical wound

Your doctor will closely monitor you if you are taking steroid medications to prevent cerebral oedema or intracranial hypertension.
Before inserting the wafers, the surgeon may need to close an internal channel in the brain to prevent the wafers from migrating, which could cause fluid accumulation within the cranial cavity.
After insertion of GLIADEL wafers, clinical imaging may reveal cerebral oedema due to fluid accumulation and inflammation caused by the GLIADEL wafers or by progression of the tumour disease.
Other medicines and GLIADEL Wafers
Inform your doctor if you are taking, or have recently taken, any other medicines, including those without a prescription.
Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor before receiving this medicine. GLIADEL Wafers have not been studied in pregnant women. The active substance, carmustine, has been observed to have a negative effect on fetal development. GLIADEL Wafers must not be used in women during pregnancy and breastfeeding. Women of childbearing potential must use effective contraception for 6 months after insertion of GLIADEL wafers. Men with female partners of childbearing potential must use effective contraception for 90 days after insertion of GLIADEL wafers.
Driving and use of machinery
Driving vehicles and operating machinery are not recommended after treatment. Please consult your doctor to determine whether you are allowed to drive or operate tools or machinery.

3. How GLIADEL Implants Are Used

The use of GLIADEL implants is strictly reserved for adult patients.
The surgeon or pharmacist will ensure that the product is available at the time of surgery.
After removal of the brain tumor, the surgeon will insert up to eight implants into the space previously occupied by the tumor. The implants are placed so as to cover the tumor area as completely as possible. After surgery, the implants gradually dissolve over approximately two to three weeks, releasing carmustine into the surrounding tissue.
If you have any questions about the use of GLIADEL, consult your doctor.

4. Possible side effects

Like all medicines, GLIADEL can cause side effects, although not everyone gets them.
If you notice any side effects not listed in this leaflet, or if you consider any of the listed side effects to be severe, inform your doctor immediately.
The most commonly observed adverse events during clinical trials in both newly diagnosed malignant glioma (brain tumour) (120 patients) and recurrent malignant glioma (110 patients) are listed below.
The four categories below of adverse reactions may be related to the use of GLIADEL implants.

1. Seizures (epileptic attacks) were very common. Most of these were mild to moderate in intensity and occurred within 5 days after surgery.
2. Cerebral oedema was also very common. Cerebral oedema may necessitate further surgical intervention, either to remove the implants or their remnants.
3. Mild to severe problems with surgical wound healing were also very common.
4. Brain infections (infections within the skull), such as meningitis or abscesses (collections of pus), were common. During clinical trials, the following adverse effects were observed in patients. These side effects were similar to those seen in patients undergoing brain cancer surgery without GLIADEL implant insertion.

Very common: may affect more than 1 in 10 people

• Psychiatric disorders: Depression
• Nervous system disorders: Weakness, particularly on one side of the body; seizures (spasms); confusion; headache; cerebral oedema; drowsiness; speech difficulties
• Vascular disorders: Vasculitis (inflammation of blood vessels)
• 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 health; infection; headache; feeling of weakness; fever or pain; abnormal (delayed) surgical wound healing

Common: may affect up to 1 in 10 people

• Blood and lymphatic system disorders: Reduction in red blood cell count, which may cause pale skin, fatigue, and shortness of breath; reduction in platelet count, increasing the risk of bleeding; increase in white blood cell count
• Endocrine disorders (hormonal problems): Diabetes mellitus (abnormally high blood sugar levels)
• Metabolism and nutrition disorders: Peripheral oedema (excess fluid in arms or legs); low sodium levels in blood, causing fatigue, confusion, muscle twitching, spasms, and coma; high blood sugar levels; low potassium levels in blood, which may cause muscle weakness, twitching, or irregular heartbeat
• Psychiatric disorders: Personality changes; excessive anxiety; abnormal thinking; hallucinations; insomnia (poor quality sleep)
• Nervous system disorders: Amnesia (memory loss); increased intracranial pressure due to excess fluid; facial paralysis; lack of coordination; numbness; abnormal burning or tingling sensations; difficulty walking; dizziness; epileptic seizures (spasms); tremors; meningitis (inflammation of the membranes around the brain); abscess (collection of pus); loss of consciousness
• Eye disorders: Blurred or abnormal vision; swelling around the eyes; eye pain
• Vascular disorders: Bleeding; high or low blood pressure
• Respiratory, thoracic and mediastinal disorders: Lung infections or pneumonia, with shortness of breath, cough, and increased temperature
• Gastrointestinal disorders: Bacterial infection of the mouth; diarrhoea; constipation; faecal incontinence (involuntary bowel movements); difficulty swallowing; bleeding in the stomach or intestine
• Skin and subcutaneous tissue disorders: Rash
• Musculoskeletal and connective tissue disorders: General infection
• Renal and urinary disorders: Urinary tract infections; urinary incontinence
• General disorders and administration site conditions: Abdominal, back, or chest pain; facial swelling; abscess (collection of pus); accidental injury; allergic reaction; neck pain; blood system infection

Uncommon side effects (between 1 and 10 patients in 1,000)
Injury, poisoning and procedural complications:
Pneumocephalus (accumulation of air at the implant site)

Reporting of side effects:
If you experience any side effects, including those not listed in this leaflet, please contact your doctor. You may also report side effects directly via the national reporting system at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store GLIADEL Implants

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 not exceeding 22°C for a maximum period of six hours.
The product may be re-frozen only once, provided the pouches have not been opened and have been kept for a maximum of 6 hours at a temperature not exceeding 22°C. After re-freezing, the product must be used within 30 days.
Do not use GLIADEL after the expiry date stated on the outer packaging and/or on the pouch. The expiry date refers to the last day of the month indicated. The hospital surgeon or pharmacist will check the expiry date before using the implants.

6. Package contents and other information

What GLIADEL implants contain

• The active substance is carmustine. Each implant contains 7.7 mg of carmustine.
• The other ingredient is polifeprosan 20.

Description of the appearance of GLIADEL and contents of the pack
GLIADEL is available in packs containing eight flat, disc-shaped implants of off-white/pale yellow colour.
Each implant is individually packaged in a pouch covered by an aluminium foil sheet.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder Manufacturer 1 (Importer)
Clinigen Healthcare B.V. ALMAC PHARMA SERVICES (IRELAND)
Schiphol Boulevard 359 LIMITED
WTC Schiphol Airport, D Tower 11th floor Finnabair Industrial Estate,
1118BJ Schiphol Dundalk,
The Netherlands Co. Louth, A91 P9KD
Ireland Tel: +353 42 932 0718
Fax: +353 42 932 0718

Manufacturer 2 (Importer)
Orion GMP Consulting Limited
Unit 4, W8 Centre
Church Lane
Manorhamilton
Leitrim, F91 H2YA
Ireland

Manufacturer 3 (Importer)
Clinigen Clinical Supplies Management GmbH
Am Kronberger Hang 3
65824 Schwalbach am Taunus
Germany

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INFORMATION NOTE FOR MEDICAL PROFESSIONALS OR HEALTHCARE WORKERS

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 the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Implant.
Flat, disc-shaped implant, dirty white to pale yellow in color.

4. CLINICAL INFORMATION

4.1 Therapeutic indications
The use of GLIADEL Implant is indicated in the treatment of adult patients with newly diagnosed high-grade malignant glioma, as an adjunct to surgical resection and radiotherapy.
The use of GLIADEL Implant is indicated as an adjunct to surgery in the treatment of adult patients with recurrent glioblastoma multiforme confirmed histologically, for 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, providing a total dose of 61.6 mg when eight implants are placed into the tumor resection cavity.

Paediatric population
The safety and efficacy of GLIADEL Implant in patients under 18 years of age have not been established. No data are available.

Method of administration
If the size and morphology of the resection cavity allow, up to eight implants may be placed. Implants may be halved; however, implants divided into more than two parts must be discarded into appropriate biohazard waste containers (see section 6.6).
It is recommended that implants be placed directly into the resection cavity from their inner sterile packaging. To secure the implants to the cavity surface, oxidized regenerated cellulose may be placed over them (see section 6.6).

4.3 Contraindications
Hypersensitivity to the active substance carmustine or to any of the excipients of GLIADEL.

4.4 Special warnings and precautions for use
Patients undergoing craniotomy for glioblastoma and receiving GLIADEL Implant should be closely monitored due to the known complications of craniotomy, including seizures, intracranial infections, abnormal wound healing, cerebral edema, and pneumocephalus (see section 4.8 "Undesirable effects"). Intracranial mass effect not responsive to corticosteroids has been observed in patients treated with GLIADEL Implant, including one case resulting in cerebral herniation. Careful monitoring of patients treated with GLIADEL Implant is essential to detect possible cerebral edema/intracranial hypertension, with appropriate use of steroids (see section 4.8). Cerebrospinal fluid (CSF) leakage has been reported more frequently in patients treated with GLIADEL Implant. Careful watertight closure of the dura and local incisions is recommended (see section 4.8).
Vascular wall changes in cerebral blood vessels located near the Gliadel wafer have been observed, including cases of aneurysm leading to intracerebral hemorrhage several months after wafer implantation. Implantation of Gliadel wafers near major cerebral blood vessels should be avoided.
Development of cerebral edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may require further surgical intervention and, in some cases, removal of the GLIADEL Implant or its remnants.
To prevent migration of the implants into the ventricular system and the potential for obstructive hydrocephalus, communication between the surgical resection cavity and the ventricular system must be avoided. If a communication larger than the diameter of the implant exists, it should be closed prior to placement of the GLIADEL Implant.
Computed tomography and magnetic resonance imaging may show increased signal in brain tissue surrounding the resection cavity after placement of GLIADEL implants. This enhancement may reflect edema and inflammation caused by the implants or may indicate tumor progression.
Women of childbearing potential must use effective contraception for at least 6 months after implantation of GLIADEL Implant.
Male patients with female partners of childbearing potential should be advised to use effective contraception for at least 90 days after implantation of GLIADEL Implant.

4.5 Interaction with other medicinal products and other forms of interaction
Interactions of GLIADEL Implant with other medicinal products or with chemotherapy have not been formally evaluated.

4.6 Fertility, pregnancy and lactation
Pregnancy
There are no studies on GLIADEL Implant in pregnant women, nor studies assessing the reproductive toxicity of GLIADEL Implant.
Carmustine, the active ingredient in GLIADEL Implant, may have genotoxic effects and may adversely affect fetal development when administered systemically (see section 5.3). Therefore, GLIADEL Implant is not recommended during pregnancy and in women of childbearing potential who are not using contraceptive measures. Women of childbearing potential must use effective contraception for at least 6 months after implantation of GLIADEL Implant.
Male patients with female partners of childbearing potential should be advised to use effective contraception for at least 90 days after implantation of GLIADEL Implant.
If, despite these precautions, use of GLIADEL Implant is considered necessary during pregnancy, the patient must be informed of the potential risk to the fetus. Patients who become pregnant after implantation of GLIADEL Implant should be referred for genetic counselling.

Lactation
It is not known whether components of GLIADEL Implant are excreted in human milk. Since some drugs are excreted in human milk and due to the potential risk of serious adverse reactions to carmustine in breastfed infants, breastfeeding is contraindicated.

Fertility:
No studies have been conducted on the impact of GLIADEL Implant on fertility.

4.7 Effects on ability to drive and use machines
GLIADEL Implant does not directly affect the ability to drive or operate machinery. However, craniotomy and GLIADEL Implant may cause nervous system and visual disturbances. Therefore, patients should be warned about the potential impact of these events 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 in patients with recurrent malignant glioma has generally been consistent with that observed in patients undergoing craniotomy for malignant gliomas.
The very common (≥ 1/10), common (≥ 1/100 to < 1/10), and uncommon (≥ 1/1,000 to < 1/100) adverse reactions observed in patients treated with GLIADEL Implant in clinical trials are listed below.
Within each frequency category, adverse reactions are listed in order of decreasing severity.

Primary surgical intervention
The following data refer to adverse reactions occurring more frequently and observed in 5% or more of the 120 patients with newly diagnosed malignant glioma treated with GLIADEL Implant during the clinical study.

Common adverse reactions observed in ≥ 5% of patients treated with GLIADEL Implant during initial surgery

Intracranial hypertension occurred more frequently in patients treated with GLIADEL Implant than in those treated with placebo (9.2% vs. 1.7%). It was generally observed later, at the time of recurrence, and was unlikely to be associated with the use of GLIADEL Implant (see section 4.4).
Cerebrospinal fluid leakage was more common in patients treated with GLIADEL Implant than in those treated with placebo. However, intracranial infections and other healing abnormalities were not increased (see section 4.4).

Surgical intervention for recurrence
In a controlled clinical study, the following postoperative adverse reactions were observed in 4% or more of the 110 patients treated with GLIADEL Implant undergoing surgery for recurrence. Except for nervous system effects, which may have been caused by placebo implants, only those reactions more commonly observed in the GLIADEL Implant group are listed. These adverse reactions were either not present prior to surgery or worsened after surgery during the follow-up period, which lasted up to 71 months.

Common adverse reactions observed in ≥ 4% of patients treated with GLIADEL Implant
during surgical intervention for recurrence

In patients treated with GLIADEL (Implant), the following adverse events, not listed in the table above, have been reported across all studies. The listed events were either not present prior to surgical intervention or worsened in the period following surgery. It is not possible to determine whether GLIADEL (Implant) caused these events.

Adverse events in patients treated with GLIADEL (Implant)

With Gliadel, cases of air accumulation at the implant site have been observed, sometimes associated with neurological symptoms (hemiplegia, aphasia, convulsions).
The following four categories of adverse reactions are possibly related to treatment with GLIADEL Wafer.

Seizures
In the initial surgical procedure, the incidence of seizures within the first 5 days after wafer implantation was 2.5% in the GLIADEL Wafer-treated group.
In the surgical procedure for the clinical recurrence study, the incidence of postoperative seizures was 19% in patients treated with GLIADEL Wafer. 54% of patients (12 out of 22) treated with GLIADEL Wafer experienced the onset of new seizures or worsening of epileptic episodes within the first five days following surgery.
The median time to onset of first or worsened postoperative seizures was 3.5 days in patients treated with GLIADEL Wafer.

Cerebral edema
If cerebral edema with mass effect develops (due to tumor recurrence, intracranial infection, or necrosis), additional surgery may be required, and in some cases, removal of GLIADEL Wafer or its residues (see section 4.4).

Wound healing abnormalities
The following wound healing abnormalities have been reported in clinical studies with GLIADEL Wafer: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leakage.
In the clinical study concerning the initial surgical procedure, cerebrospinal fluid leakage occurred in 5% of patients treated with GLIADEL Wafer. During surgery, to minimize the risk of cerebrospinal fluid leakage, a watertight closure of the dura mater must be achieved (see section 4.4).

Intracranial infection
In the clinical study concerning the initial surgical procedure, the incidence of brain abscess or meningitis was 5% in patients treated with GLIADEL Wafer.
In procedures for recurrence, the incidence of brain abscess or meningitis was 4% in patients treated with GLIADEL Wafer.
In a published clinical study, cyst formation has been reported after treatment with GLIADEL Wafer. This reaction occurred in 10% of patients observed in the study; however, cyst formation is also possible after resection of a malignant glioma.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions occurring after marketing authorization is important, as it allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system available at: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse

4.9 Overdose
Not applicable

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties
Pharmacotherapeutic category: antineoplastic agents, ATC code: L01AD01
Preclinical data
GLIADEL Wafer releases carmustine directly into the surgical cavity created after tumor resection. Upon exposure to the aqueous environment of the cavity, the anhydride bonds in 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 by alkylating DNA and RNA.
Carmustine undergoes spontaneous degradation and metabolism. The alkylating moiety thus produced, presumably chloroethyl carbonium ion, causes irreversible cross-linking in DNA. The tumoricidal activity of GLIADEL Wafer depends on the release of carmustine into the tumor cavity at concentrations sufficient for effective cytotoxicity.
More than 70% of the copolymer degrades within three weeks. The metabolic transformation and excretion of the monomers differ. Carboxyphenoxypropane is primarily eliminated by the kidneys, while sebacic acid, an endogenous fatty acid, is metabolized in the liver and exhaled as CO₂ in animals.
Clinical data
Initial surgery
In a randomized, double-blind, placebo-controlled clinical study involving 240 adults with newly diagnosed high-grade malignant glioma scheduled for initial craniotomy for tumor resection, median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL Wafer (p-value = 0.079, unstratified log-rank test) in the original study phase. The most common tumor type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). The relative risk for GLIADEL Wafer was 0.77 (95% CI: 0.57–1.03). In the long-term follow-up phase, patients still alive at the end of the original 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-value <0.05, log-rank test). The relative risk for treatment with GLIADEL Wafer was 0.73 (95% CI: 0.56–0.95).
Surgery for recurrence
In a randomized, double-blind, placebo-controlled clinical study involving 145 adults with recurrent glioblastoma (GBM), GLIADEL Wafer prolonged survival in these patients. Ninety-five percent of patients treated with GLIADEL Wafer received between 7 and 8 wafers. The six-month survival rate was 36% (26 out of 73 patients) with placebo versus 56% (40 out of 72 patients) with GLIADEL Wafer treatment. Median survival in patients with GBM was 20 weeks with placebo and 28 weeks with GLIADEL Wafer treatment.

5.2 Pharmacokinetic Properties
Absorption, distribution, metabolism, and excretion of the copolymer in humans are unknown. Carmustine concentrations delivered by GLIADEL Wafer into human brain tissue have not been determined. Plasma levels of carmustine after placement of GLIADEL Wafer could not be established. Carmustine was not detected in blood or cerebrospinal fluid of rabbits implanted with wafers containing 3.85% carmustine.
Following intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m², the mean 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 a 200 mg/m² intravenous dose of ¹⁴C-carmustine is excreted in urine within 96 hours, and 6% is exhaled as ¹⁴CO₂.
GLIADEL Wafer is biodegradable in the human brain when placed in the cavity following tumor resection. The rate of biodegradation varies between patients. During the biodegradation process, residual implant material may be observed on imaging scans or during subsequent surgical procedures, even after extensive degradation of all components.

5.3 Preclinical Safety Data
No studies on carcinogenicity, mutagenicity, embryo-fetal toxicity, prenatal and postnatal toxicity, or impairment of fertility have been conducted with GLIADEL Wafer.
Carmustine, the active substance in GLIADEL Wafer, when administered systemically, has embryotoxic, teratogenic, genotoxic, and carcinogenic effects and may cause testicular degeneration in various animal models.

6. PHARMACEUTICAL INFORMATION

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 at a temperature of –20 °C or lower.
Unopened outer pouches may be kept at a temperature not exceeding 22 °C for a maximum period of six hours.
The product may be refrozen only once if the pouches have not been opened and have been kept for a maximum of 6 hours at a temperature not exceeding 22 °C. After refreezing, the product must be used within 30 days.
6.5 Nature and contents of container
GLIADEL Implant is available in packs containing eight implants. Each implant is individually packaged in two aluminum laminated pouches.
6.6 Special precautions for disposal and other handling
Implants must be handled by personnel wearing surgical gloves, as exposure to carmustine may cause severe skin burning and hyperpigmentation. It is recommended to wear two pairs of gloves and to discard the outer gloves after use into an appropriate container for biological hazard waste. A suitable surgical instrument must be used for implant placement. If further neurosurgical intervention is indicated, any implant or implant residue must be handled as a potential cytotoxic agent. Unused product or waste materials must be disposed of in accordance with local regulations for cytotoxic agents.
GLIADEL Implant must be handled with care. The pouches containing GLIADEL Implant must be delivered to the operating room and kept sealed until ready for implant placement into the resection cavity. Only the outer surface of the outer pouch is non-sterile. However, if an implant is dropped, it must be properly discarded.

Instructions for opening the pouches containing the implant:

Figure 1: To open the outer pouch, locate the folded corner and gently pull outward.

Figure 2: Do not pull downward, avoiding rolling knuckles over the pouch, as such pressure on the implant may cause breakage.

Figure 3: Remove the inner pouch using surgical forceps by pulling upward.

Figure 4: To open the inner pouch, gently grasp it and cut it in a semicircular fashion around the implant.

Figure 5: To remove the implant, gently grasp it using surgical forceps and place it directly into the resection cavity. However, if the implant is dropped, it must be properly discarded.
After tumor resection, confirmation of tumor pathology, and achievement of hemostasis, up to eight implants may be placed to cover as much of the resection cavity as possible. Slight overlapping of implants is acceptable. Implants may be cut in half; however, implants divided into more than two pieces must be discarded into appropriate containers for biological hazard waste.
Regenerated oxidized cellulose may be placed over the implants to secure them to the cavity surface. After implant placement, the resection cavity must be irrigated and the dura must be closed watertight.
Any unused or discarded product must be disposed of in accordance with local requirements for biological hazard waste.

7. MARKETING AUTHORISATION HOLDER

Clinigen Healthcare B.V.
Schiphol Boulevard 359
WTC Schiphol Airport, D Tower 11th floor
1118BJ Schiphol
Netherlands

8. MARKETING AUTHORISATION NUMBERS

AIC No. 034709016

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 28/05/1999
Date of latest renewal: 10/06/2008

10. DATE OF TEXT REVISION

04/2026