Label: information for the user

GLIADEL 7.7 mg implant

Carmustine

Read this label carefully before starting to use the medicine, as it contains important information for you.

• Keep this label, as you may need to read it again.
• If you have any questions, consult your doctor.
• If you experience any side effects, consult your doctor, even if they are not listed in this label. See section 4.

Gliadel implant is a delivery system of the anticancer active principle carmustin directly into the location where the brain tumor was, after its removal by surgery. Carmustin belongs to a group of anticancer substances that allow for the fight against the growth of localized brain tumor cells.

Gliadel implant may be used in combination with radiation therapy for the treatment of brain tumors.

It has been demonstrated that Gliadel implant prolongs the survival of patients with brain tumors.

Do not use GLIADEL implant

• if you are allergic to the active ingredient or to any of the other components of this medication (listed in section 6).

Warnings and precautions

After surgery to remove the brain tumor and insert GLIADEL implant, your doctor or surgeon will closely monitor you for any complications. In some cases, the surgeon may need to operate again (due to complications or recurrence of the tumor). Complications include:

• Seizures (convulsions)
• Brain infections (infections within the skull)
• Cerebral inflammation due to fluid accumulation
• Cerebral fluid loss
• 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 inserting the implants, the surgeon may need to close a channel in the brain to prevent the implants from passing through it, which could cause fluid accumulation within the skull.

After GLIADEL implant insertion, imaging techniques can detect brain inflammation due to fluid accumulation and inflammation caused by GLIADEL implant or tumor progression.

Other medications and GLIADEL implant

Inform your doctor if you are using or have recently used other medications, including those obtained without a prescription.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor before using this medication. GLIADEL implant has not been studied in pregnant women. The active ingredient, carmustine, has been shown to negatively affect fetal development. GLIADEL implant should not be used in pregnant women or breastfeeding women. Women of childbearing age are advised to use effective contraceptive methods for 6 months after receiving GLIADEL implant. Men who have a partner of childbearing age should use contraceptive methods for 90 days after receiving GLIADEL implant.

Driving and operating machinery

Driving is not recommended after treatment. Consult your doctor before driving or using tools or machinery.

Gliadel implant should only be used in adults.

The surgeon or pharmacist will ensure that the medication is available for your operation. After the removal of the brain tumor, the surgeon will insert up to eight implants into the space where the tumor was located. Your surgeon will decide the number of implants to be inserted into the cavity created after the removal of the brain tumor. The implants are placed so that they cover as much surface area as possible of this cavity. After the operation, the implants will slowly dissolve over two to three weeks, releasing carmustine directly to the surrounding cells.

If you have any other questions about the use of this product, ask your surgeon.

Like all medicines, GLIADEL can cause side effects, although not everyone will experience them.

If you consider that any of the side effects you are experiencing are severe or if you notice any side effect not mentioned in this leaflet, inform your doctor.

The following four categories of side effects may be associated with the use of GLIADEL implants:

During clinical trials, the following side effects were observed in patients, which were similar to those observed in patients undergoing brain tumor surgery without GLIADEL implant placement.

Very frequent: may affect more than 1 in 10 patients

• Mental disorders

Depression

• Nervous system disorders

Weakness, especially on one side of the body; convulsions (spasms); confusion; headache, brain inflammation; drowsiness; speech alterations

• Vascular disorders

Vascular inflammation

• Gastrointestinal disorders

Nausea; vomiting; constipation

• Skin and subcutaneous tissue disorders

Skin 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 wound healing (slow) of the surgical wound.

Frequent: may affect up to 1 in 10 patients

• Blood and lymphatic system disorders

Red blood cell decrease (anemia), which may cause pale skin, fatigue, and shortness of breath; platelet decrease in the blood, which increases the risk of bleeding; white blood cell increase

• Endocrine disorders (hormonal problems)

Diabetes mellitus

• Metabolism and nutrition disorders

Peripheral edema (excess fluid in the arms or legs); low sodium concentration in the blood, which may cause fatigue and confusion, muscle twitches, spasms, and coma; high blood sugar levels, low potassium concentration in the blood, which may cause weakness and muscle twitches, and abnormal heart rhythm

• Mental disorders

Personality changes, excessive anxiety, abnormal thinking, hallucinations, insomnia (little 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 seizures (spasms); tremors; meningitis; abscess (localized pus concentration); loss of consciousness

• Eye disorders

Blurred or abnormal vision; eye contour inflammation; eye pain

• Vascular disorders

Bleeding, high or low blood pressure

• Respiratory, thoracic, and mediastinal disorders

Pulmonary infection or pneumonia causing shortness of breath, cough, and fever

• Gastrointestinal disorders

Oral microbial infection; diarrhea; constipation; fecal incontinence (uncontrolled bowel movements); difficulty swallowing; gastrointestinal bleeding or intestinal hemorrhage

• Epithelial and subcutaneous tissue disorders

Skin 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, from the back to the chest; facial inflammation; abscess (localized pus concentration); accidental injury; allergic reaction; neck pain; septicemia

Rare side effects (between 1 and 10 patients per 1000)

Accidents, poisonings, and complications of therapeutic procedures

Neumocephalia (air accumulation in the implant area)

Reporting side effects

If you experience any type of side effect, consult your doctor, even if it is a possible side effect not mentioned in this leaflet.

You can also report them directly through the Spanish System for Pharmacovigilance of Medicines for Human Use:www.notificaram.es. By reporting side effects, you can contribute to providing more information on the safety of this medication.

Keep this medication out of the sight and reach of children.

Store in a freezer at a temperature of -20°C or below.

Unopened outer packets may be stored at a temperature below 22°C for a maximum of 6 hours. They may be re-frozen once if they have not been opened and have remained for a maximum of 6 hours at a temperature below 22°C. After re-freezing, the medication must be used within 30 days.

Do not use the GLIADEL implant after the expiration date that appears on the packaging and/or on the packet after CAD. The expiration date is the last day of the month indicated. Your surgeon or the hospital pharmacist will verify the expiration date before use of the implants.

Composition of GLIADEL implant

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

Appearance of the product and contents of the package

GLIADEL implant is available in boxes of eight circular implantable sheets. These sheets are white opaque to yellow-colored disk-shaped implants. Each implant is individually packaged in an aluminum-coated pouch.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

MGI PHARMA GmbH

Edmund-Rumpler- Straße 3

60549 Frankfurt am Main

Germany

Phone: +49 (69) 66 58 50

Fax: +49 (69) 66 58 525

Email: [email protected]

Responsible for manufacturing

ALMAC PHARMA SERVICES (IRELAND) LIMITED

Finnabair Industrial Estate

Dundalk

Co. Louth A91 P9KD

Ireland

Phone: +353 42 932 0718

Fax: +353 42 932 0718

ALMAC PHARMA SERVICES LIMITED

20 Seagoe Industrial Estate

Craigavon, BT63 5QD,

UK

Phone: +44 (0)28 3836 3363

Fax: +44 (0)28 3836 3300

Local Representative:

Eisai Farmacéutica, S.A.Parque Empresarial Cristalia

Vía de los Poblados 3, Edf. 7/8, 4ª planta

28033 Madrid

Spain

Phone: +34 91 455 94 55

Last review date of this leaflet: 04/2021

The detailed and updated information on this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

INFORMATION LEAFLET FOR HEALTHCARE PROFESSIONALS

1.NAME OF THE MEDICINE

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.

White opaque to yellow-colored disk-shaped implant.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

GLIADEL implant is indicated for the treatment of adult patients with high-grade malignant glioma as adjuvant therapy to surgery and radiation.

GLIADEL implant is indicated as adjuvant therapy to surgery for the treatment of adult patients with recurrent, resectable glioblastoma multiforme, in whom surgical resection is indicated.

4.2Dosage and administration method

Dosage

Only intralesional administration.

Each GLIADEL implant contains 7.7 mg of carmustine, so that after the placement of eight implants in the tumor resection cavity, a dose of 61.6 mg is released.

Pediatric population

No safety and efficacy of GLIADEL implant have been established in children under 18 years. No data are available.

Administration method

It is recommended to place a maximum of eight implants if the size and shape of the resection cavity allow it. Sectioned implants by half may be used, but implants fragmented into more than two parts must be disposed of in appropriate containers for biohazardous waste (see section 6.6).

It is recommended to proceed to place the implants directly from the sterile inner packaging of the product to the resection cavity. Oxycelulosa dressings may be placed over the implants to fix them to the surface of the cavity (see section 6.6).

4.3Contraindications

Hypersensitivity to the active ingredient, or to any of the excipients listed in section 6.1.

4.4Warnings and precautions for use

Patients undergoing craniotomy and GLIADEL implant placement must be strictly monitored to detect possible complications of craniotomy, including seizures, intracranial infections, abnormal healing, cerebral edema, and pneumocephalus (see section 4.8). In patients treated with GLIADEL implant, cases of mass effect intracerebral that did not respond to corticosteroids, including one case that resulted in cerebral hernia, have been described. In patients treated with GLIADEL implant, cerebral edema/ intracranial hypertension must be strictly monitored after the use of corticosteroids (see section 4.8). Cerebrospinal fluid (CSF) leaks were more frequent in patients treated with GLIADEL implant. Special care should be taken for the impermeable closure of the dura mater and in the treatment of local wounds (see section 4.8).

Changes in the wall of cerebral blood vessels located near the Gliadel disk, including cases of aneurysm that cause cerebral hemorrhage several months after Gliadel implant placement, have been described. Gliadel implants should be avoided near large cerebral blood vessels.

The development of cerebral edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may require reintervention and, in some cases, removal of GLIADEL implant or its remnants.

The communication between the resection cavity and the ventricular system should be avoided to prevent the implants from being displaced into the ventricular system and causing obstructive hydrocephalus. If a communication greater than the diameter of the implant exists, it should be closed before GLIADEL implant placement.

Computed tomography and magnetic resonance imaging may show an increase in the density of the cerebral tissue surrounding the resection cavity after the placement of GLIADEL implants. This increase in density may reflect edema or inflammation caused by the GLIADEL implants or tumor progression.

Women of childbearing age should use effective contraceptive methods for at least 6 months after receiving GLIADEL implant.

Men with partners of childbearing age should use effective contraceptive methods for at least 90 days after receiving GLIADEL implant.

4.5Interaction with other medicines and other forms of interaction

The interactions of GLIADEL implant with other drugs or chemotherapy have not been formally studied.

4.6Fertility, pregnancy, and lactation

Pregnancy:

No studies of GLIADEL implant have been conducted in pregnant women, nor have studies evaluated the toxicity of GLIADEL implant on reproduction.

When administered systemically, carmustine, the active ingredient of GLIADEL implant, may have genotoxic effects and negatively affect fetal development (see section 5.3). Therefore, GLIADEL implant should not be used during pregnancy, or in women of childbearing age who are not using effective contraceptive methods. Women of childbearing age should use effective contraceptive methods for at least 6 months after receiving GLIADEL implant.

Men with partners of childbearing age should use effective contraceptive methods for at least 90 days after receiving GLIADEL implant. However, if GLIADEL implant is considered necessary during pregnancy, the patient should be informed of the potential risks to the fetus. In the event that the patient becomes pregnant after receiving GLIADEL implant, genetic counseling should be sought.

Lactation:

The components of GLIADEL implant are unknown to be excreted in breast milk. Given that some drugs are eliminated through breast milk and due to the potential risk of severe reactions to carmustine in infants, breastfeeding is contraindicated.

Fertility:

No fertility studies have been conducted with GLIADEL implant.

4.7Effects on the ability to drive and use machines

GLIADEL implant does not affect the ability to drive vehicles and use machinery. However, craniotomy and GLIADEL implant may cause visual and nervous system alterations. Therefore, the patient should be aware of the potential effect of these reactions on the ability to drive or use machines.

4.8Adverse reactions

The spectrum of adverse reactions observed in patients with high-grade malignant glioma and recurrent malignant gliomas was consistent with that observed in patients undergoing craniotomy for malignant gliomas.

The following adverse reactions were very common (≥ 1/10), common (≥ 1/100 to <1/10), and uncommon (≥ 1/1000 to <1/100) in the clinical trials.

Surgery Primary

The following data correspond to the most frequent adverse reactions observed in the 5% or more of the 120 patients with high-grade malignant glioma treated with GLIADEL implant in the clinical trial.

Common adverse reactions observed in ≥ 5% of patients treated with GLIADEL implant in primary surgery

Intracranial hypertension was more frequently reported in patients treated with GLIADEL implant than in those receiving placebo (9.2% vs 1.7%), and was considered unlikely to be associated with GLIADEL implant use (see section 4.4).

CSF leaks were more frequent in patients treated with GLIADEL implant than in those receiving placebo. However, they did not increase intracranial infections or other wound healing abnormalities (see section 4.4).

Surgery in recurrent disease

The following adverse reactions were observed in the 4% or more of the patients treated with GLIADEL implant in repeated surgery. Only reactions that were more frequent in the GLIADEL implant group than in the placebo group, except for effects on the nervous system, which may be caused by the placebo implants, are listed. These reactions, or were not present before surgery, or worsened during the follow-up period. The follow-up period was up to 71 months.

Common adverse reactions observed in ≥ 4% of patients treated with GLIADEL implant in repeated surgery

The following adverse reactions, which are not included in the table below, were reported in patients treated with GLIADEL implant in all studies. The reactions listed either were not present during the pre-surgery period or worsened during the post-surgery period. It was not possible to establish whether the GLIADEL implant was the cause of these reactions.

Adverse reactions in patients receiving GLIADEL implant

Cases of air accumulation in the area of the implant with Gliadel have been reported, sometimes associated with neurological symptoms (hemiplegia, aphasia, seizures).

The following four categories of adverse reactions are possibly related to treatment with GLIADEL implant.

Seizures:

In the initial surgery trial, the incidence of seizures in the first five days after implantation was 2.5% in the GLIADEL implant group.

In the recurrent disease surgery trial, the incidence of seizures after surgery was 19% in patients treated with GLIADEL implant. In this trial, 12/22 (54%) of patients treated with GLIADEL implant experienced the onset of seizures or worsening of existing seizures during the first five days after surgery. The median time to the onset of seizures or worsening of existing seizures after surgery was 3.5 days in patients treated with GLIADEL implant.

Cerebral edema:

The development of cerebral edema with mass effect (due to tumor recurrence, intracranial infection, or necrosis) may require reintervention and, in some cases, removal of GLIADEL implant or its remnants (see section 4.4).

Anomalies in wound healing:

The following anomalies in wound healing have been reported in GLIADEL implant trials: wound dehiscence, delayed wound healing, subdural, subgaleal, or through the suture effusions, and CSF leaks.

In the initial surgery trial, CSF leaks occurred in 5% of patients treated with GLIADEL implant. During surgery, the dura mater should be closed impermeably to minimize the risk of CSF leaks (see section 4.4).

Intracranial infection:

In the initial surgery trial, the incidence of cerebral abscess or meningitis was 5% in patients treated with GLIADEL implant.

In recurrent disease surgery, the incidence of cerebral abscess or meningitis was 4% in patients treated with GLIADEL implant.

A case of cyst formation after treatment with GLIADEL implant has been reported in a published study. This reaction occurred in 10% of patients observed in the study. However, cyst formation is possible after resection of a malignant glioma.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions to the medicine after its authorization. This allows for continuous monitoring of the benefit-risk ratio of the medicine. Healthcare professionals are invited to report suspected adverse reactions through the Spanish System for Pharmacovigilance of Medicines for Human Use:https://www.notificaram.es.

4.9Overdose

Not applicable.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, alkylating agents, nitrosoureas, ATC code: L01AD01

Preclinical data

GLIADEL implant releases carmustine directly into the surgical cavity created after tumor resection. When exposed to the aqueous medium of the cavity, the anhydride linkages of the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxipropano, and sebacic acid. The released carmustine diffuses into the surrounding cerebral tissue and exerts an antineoplastic effect by alkylation of DNA and RNA.

Carmustine degrades and metabolizes spontaneously, forming the alkylating group, presumably a chloroethyl ion, which leads to the formation of irreversible cross-links (cross-linking) in DNA.

The antitumor activity of GLIADEL implant depends on the release of carmustine in the tumor cavity in sufficient quantities for effective cytotoxicity.

In 3 weeks, more than 70% of the copolymer degrades. The monomers have different metabolism and elimination. Carboxyphenoxipropano is mainly eliminated by the kidneys, and sebacic acid, an endogenous fatty acid, is metabolized by the liver and exhaled as CO2in animals.

Clinical efficacy and safety

Initial surgery

In a randomized, double-blind, placebo-controlled trial in 240 adults with high-grade malignant glioma undergoing initial craniotomy for tumor resection, the median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL implant (p = 0.079, log-rank testnot stratified) in the initial 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 (hazard ratio) for GLIADEL implant 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 up for at least 3 years or until death. The median survival increased from 11.6 months with placebo to 13.9 months with GLIADEL implant (p <0.05, log-rank test). The hazard ratio (hazard ratio) of treatment with GLIADEL implant was 0.73 (95% CI: 0.56 – 0.95).

Recurrent disease surgery

In a randomized, double-blind, placebo-controlled trial in 145 adults with glioblastoma (GBM) recurrence, GLIADEL implant prolonged the survival of these patients. The 95% of patients treated with GLIADEL implant received 7 to 8 implants.

The survival rate with placebo at 6 months was 36% (26/73), compared to 56% (40/72) with GLIADEL implant treatment. The median survival of patients with GBM was 20 weeks with placebo, compared to 28 weeks with GLIADEL implant treatment.

5.2Pharmacokinetic properties

No information is available on the absorption, distribution, metabolism, or elimination of the copolymer in humans. The concentrations of carmustine released by GLIADEL implant in human cerebral tissue have not been determined. It is not possible to determine the plasma levels of carmustine after GLIADEL implant placement. Carmustine is not detectable in blood or cerebrospinal fluid in rabbits with carmustine implants at 3.85%.

After intravenous infusion of carmustine with doses between 30 and 170 mg/m2, the mean terminal elimination half-life, clearance, and volume of distribution in the steady state are approximately 22 minutes, 56 ml/min/kg, and 3.25 l/kg, respectively. Approximately 60% of an intravenous dose of 200 mg/m2of14C-carmustine is excreted in urine in 96 hours, and 6% is exhaled as CO2.

GLIADEL implants are biodegradable in the human brain when placed in the tumor cavity after resection. The rate of biodegradation varies between patients. During the biodegradation process, remnants of the implants may be observed using cerebral imaging techniques or in the next surgery, even if a wide degradation of all components has occurred.

5.3Preclinical data on safety

No carcinogenicity, mutagenicity, embryotoxicity, teratogenicity, pre- and postnatal toxicity, or fertility studies have been conducted with GLIADEL implant.

Carmustine, the active ingredient of GLIADEL implant, when administered systemically, has genotoxic effects, teratogenic effects, and carcinogenic effects, and may cause testicular degeneration in various animal models.

6.PHARMACEUTICAL PARTICULARS

6.1Excipients

Polifeprosan 20

6.2Incompatibilities

Not applicable.

6.3Shelf life

4 years.

6.4Special precautions for storage

Store in a freezer.Do not store at a temperature above-20º C.