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GLIADEL 7.7 MG IMPLANT

Active substance(s): CARMUSTINE

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- Renal (kidney) and urinary disorders
Infection of the urinary tract
- General disorders and administration site
conditions
A worsening of your condition; infection; headache; feeling of weakness; fever or pain
Common side effects
(between 1 and 10 patients in every 100)
- Blood and lymphatic (immune) system
disorders
Reduction in red blood cells which can make the
skin pale and cause weakness and breathlessness; reduction in blood platelets which
increases the risk of bleeding; increase in white
blood cells
- Endocrine disorders (hormonal disorders)
Diabetes mellitus (abnormally high sugar level in
blood)
- Metabolism and nutrition disorders
Peripheral oedema (excess fluid in the arms and
legs); low blood levels of sodium which can
cause tiredness and confusion; muscle twitching,
fits or coma; low blood levels of potassium which
can cause muscle weakness, twitching or
abnormal heart rhythm
- Nervous system disorders
Amnesia (loss of memory);an increase in the
blood pressure in the skull due to abnormal build
up of fluid; changes in your personality; excessive anxiety; paralysis of the face; lack of coordination; diminished sensitivity to stimulation; abnormal burning or prickling sensation; abnormal
thinking; problems with walking; dizziness; epileptic seizures (fits); hallucinations; insomnia (little
or poor sleep); tremor (small shaking movements); meningitis (inflammation of the brain);
abscess (localised collection of pus), loss of
consciousness
- Eye disorders
Blurred or abnormal vision; swelling of the eye
lining; eye pain

- Respiratory disorders (lung related
disorders)
Lung infection or pneumonia which causes
breathlessness, cough and raised temperature
- Gastrointestinal disorders (stomach and
intestinal related disorders)
Yeast infection of the mouth; diarrhoea; constipation; faecal incontinence (uncontrolled bowel
movements); difficulty in swallowing; bleeding in
the stomach or in bowels
- Muscle, skeletal and soft tissue related
disorders
General infection
- Renal (kidney) and urinary disorders
Urinary incontinence
- General disorders and administration site
conditions
Abdominal, back and chest pain; swelling of the
face; abscess (localised collection of pus); accidental injury; allergic reaction; neck pain and
infection in the blood stream

5.

HOW TO STORE GLIADEL IMPLANT

Keep out of the reach and sight of children.
Store in a freezer at or below -20°C.
Unopened outer sachets may be kept at a temperature of not more than 22°C for a maximum of
six hours.
The product may be refrozen only once if the
sachets have been unopened and kept for a
maximum of 6 hours at a temperature of not
more than 22°C. After the refreezing, the product
should be used within 30 days.
Do not use GLIADEL Implants after the expiry date
which is stated on the outer carton and / or the
sachet. The expiry date refers to the last day of the
month. Your surgeon or hospital pharmacist will
check the expiry date before implants are used.

6.

FURTHER INFORMATION

This leaflet was last approved
12/2011

What Gliadel Implants contain
Each implant contains 7.7mg of the active ingredient carmustine.
The implants also contain the inactive ingredient
polifeprosan 20.
What GLIADEL Implants look like and
contents of the pack
GLIADEL Implants are available in boxes containing eight implantable wafers. These wafers are
off-white to pale yellow flat discoid implants.
Each wafer is individually packaged in an aluminium foil laminate sachet.

Marketing Authorisation Holder Manufacturer
and Importer
Marketing Authorization Holder
MGI PHARMA LIMITED
European Knowledge Centre
Mosquito Way, Hatfield
Hertfordshire AL10 9SN
United Kingdom
Tel: +44 (0) 208 600 1400
Fax: +44 (0) 208 600 1401
Email: eumedinfo@eisai.net
Manufacturer 1 (Importer)
IDIS Limited
Unit 3, Canada Road, Byfleet
West Byfleet
Surrey, KT14 7JX
United Kingdom
Tel: +44 (0) 1932 824026
Fax: +44 (0) 1932 824226
Manufacturer 2 (Importer)
ALMAC PHARMA SERVICES LIMITED
20 Seagoe Industrial Estate
Craigavon BT63 5QD
United Kingdom
Tel: +44 (0) 28 3836 3363
Fax: +44 (0) 28 3836 3300

MP-5500A
202747

IN-5500D
202746

GLIADEL 7.7mg Implant

carmustine

WARNING:
The external sachets are not sterile

The internal sachet and
the implant are sterile

FRAGILE
The internal sachet content is sterile
unless the external sachet is
deteriorated or open
Read carefully the inside leaflet
for more detailed information

GLIADEL 7.7mg Implant
carmustine

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 full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Implant
Off - white to pale yellow flat discoid implant.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
GLIADEL Implant is indicated in newly-diagnosed high-grade malignant glioma
patients as an adjunct to surgery and radiation.
GLIADEL Implant is indicated for use as an adjunct to surgery in patients with
recurrent histologically proved glioblastoma multiforme for whom surgical resection is indicated.

4.2 Posology and method of administration
For intralesional use in adults only.
Each GLIADEL Implant contains 7.7 mg of carmustine, resulting in a dose of
61.6 mg when eight implants are placed in the tumour resection cavity.
It is recommended that a maximum of eight implants be placed if the size and
shape of the resection cavity allows it. Implants broken in half may be used, but
implants broken in more than two pieces should be discarded in the dedicated
biohazard waste containers (see section 6.6).
It is recommended that the placement of the implants should be directly from the
product’s inner sterile packaging into the resection cavity. Oxidised regenerated
cellulose may be placed over the implants to secure them to the cavity surface
(see section 6.6).
4.3 Contraindications
Hypersensitivity to the active substance carmustine or to any of the excipients of
GLIADEL Implant.
4.4 Special warnings and precautions for use
Patients undergoing craniotomy for glioblastoma and implantation of GLIADEL
Implant should be monitored closely in view of known complications of craniotomy which includes convulsions, intracranial infections, abnormal wound
healing, and brain oedema (see section 4.8). Cases of intracerebral mass effect
unresponsive to corticosteroids have been described in patients treated with
GLIADEL Implant, including one case leading to brain herniation. Careful monitoring of GLIADEL Implant-treated patients for cerebral oedema/intracranial
hypertension with consequent steroid use is warranted (see section 4.8). CSF
leak was more common in GLIADEL Implant-treated patients. Attention to a
water-tight dural closure and local wound care is indicated (see section 4.8).
Development of brain oedema with mass effect (due to tumour recurrence,
intracranial infection, or necrosis) may necessitate re-operation and, in some
cases, removal of GLIADEL Implant or its remnants.
Communication between the surgical resection cavity and the ventricular system
should be avoided to prevent the implants from migrating into the ventricular
system and possibly causing obstructive hydrocephalus. If a communication
larger than the diameter of the implant exists, it should be closed prior to GLIADEL
Implant implantation.
Computed tomography and magnetic resonance imaging may demonstrate
enhancement in the brain tissue surrounding the resection cavity after placement
of GLIADEL Implants. This enhancement may represent oedema and inflammation caused by GLIADEL Implants or tumour progression.
4.5 Interaction with other medicinal products and other forms
of interaction
Interactions of GLIADEL Implant with other drugs or chemotherapy have not
been formally evaluated.
4.6 Pregnancy and lactation
Pregnancy:
There are no studies of GLIADEL Implant in pregnant women and no studies
assessing the reproductive toxicity of GLIADEL Implant.
Carmustine, the active component of GLIADEL Implant, when administered
systemically, can have genotoxic effects and can adversely affect foetal development. GLIADEL Implant, therefore, should not be used during pregnancy. If
the use of GLIADEL Implant during pregnancy is still considered, the patient
should be informed of the potential risk to the foetus. Women of childbearing
potential should be advised to avoid pregnancy while receiving GLIADEL
Implant. In case of patients getting pregnant during treatment with GLIADEL
Implant, the opportunity for genetic advice should be seized.
Lactation:
It is not known if GLIADEL Implant components are excreted in human milk.
Since some drugs are excreted in human milk and because of the potential risk
of serious adverse reactions of carmustine in nursing infants, breast-feeding is
contra-indicated.
4.7
Effects on ability to drive and use machines
No effects on ability to drive and use machines have been observed. However,
driving is not advisable following treatment.
4.8
Undesirable effects
The spectrum of undesirable effects observed in patients with newly-diagnosed
high-grade malignant glioma and recurrent malignant gliomas was generally consistent with that encountered in patients undergoing craniotomy for malignant
gliomas. Very common (≥ 1/10), common (≥ 1/100 to <1/10) and uncommon

(≥ 1/1000 to < 1/100) adverse reactions reported in patients receiving GLIADEL
Implant during the clinical trials are listed below.
Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
Primary Surgery
The following data are the most frequently occurring adverse events observed in
5% or more of the 120 newly-diagnosed malignant glioma patients receiving
GLIADEL Implant during the trial.
Common Adverse Events Observed in ≥ 5% of Patients Receiving
GLIADEL Implant at Initial Surgery
Class organ
Endocrine disorders
Metabolism and nutrition
disorders

common
very common
common
very common

common
Nervous system disorders

common
Eye disorders
Cardiac disorders

very common
common

Respiratory, thoracic and
mediastinal disorders

common

Gastrointestinal disorders
common
very common
common
very common
General disorders and
administration site conditions

Class organ
Blood and lymphatic system
disorders
Metabolism and nutrition
disorders

Nervous system disorders

common
very common
common
very common
common

Cardiac disorders

common

Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders

common

Skin and subcutaneous
tissue disorders
Renal and urinary disorders
General disorders and
administration site conditions

common

common

Nausea, vomiting, constipation
Diarrhoea
Rash, alopecia
Urinary tract infection, urinary incontinence
Aggravation reaction,
headache, asthenia, infection, fever, pain
Abdominal pain, back
pain, face oedema, chest
pain, abscess, accidental
injury

Intracranial hypertension was present in more GLIADEL Implant-treated patients
than in placebo patients (9.2% vs. 1.7%). It was typically observed late, at the
time of tumour recurrence, and was unlikely to be associated with GLIADEL
Implant use (see section 4.4).
CSF leak was more common in GLIADEL Implant-treated patients than in
placebo patients. However intracranial infections and other healing abnormalities were not increased (see section 4.4).
Surgery for Recurrent Disease
The following post-operative adverse events were observed in 4% or more of the
110 patients receiving GLIADEL Implant at recurrent surgery in a controlled clinical trial. Except for nervous system effects, where there is a possibility that the
placebo implants could have been responsible, only events more common in the
GLIADEL Implant group are listed. These adverse events were either not present
pre-operatively or worsened post-operatively during the follow-up period. The
follow-up period was up to 71 months.

Adverse events
Anaemia
Healing abnormal
Hyponatraemia
Convulsion, hemiplegia,
headache, somnolence,
confusion
Aphasia, stupor, brain
oedema, intracranial
hypertension, meningitis
or abscess
Deep thrombophlebitis,
Pulmonary embolism
Pneumonia

common

Nausea, nausea and
vomiting, oral moniliasis
Rash

very common
very common
common

Urinary tract infection
Fever
Infection, pain

The following adverse events, not listed in the table above, were reported in less
than 4% but at least 1% of patients treated with GLIADEL Implant in all studies.
The events listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL Implant caused these events cannot be determined.
Common Adverse Events in 1% to 4% of Patients Receiving GLIADEL
Implant
Class organ
Blood and lymphatic system
disorders
Metabolism and nutrition
disorders

common

Adverse events
Thrombocytopenia,
leukocytosis
Hyponatraemia, hyperglycaemia, hypokalaemia
Hydrocephalus, depression, abnormal thinking,
ataxia, dizziness, insomnia, hemiplegia, coma,
amnesia, diplopia, paranoid reaction
Cerebral haemorrhage,
cerebral infarct
Visual defect, eye pain
Hypertension, hypotension
Infection, aspiration
pneumonia
Diarrhoea, constipation,
dysphagia, gastrointestinal haemorrhage, faecal
incontinence
Rash

common

Infection

common
1 - <10%

Urinary incontinence
Peripheral oedema, neck
pain, accidental injury,
back pain, allergic reaction, asthenia, chest pain,
sepsis

common
common
common

very common

Skin and subcutaneous
tissue disorders
Renal and urinary disorders

Adverse events
Diabetes mellitus
Healing abnormal
Peripheral oedema
Hemiplegia, convulsion,
confusion, brain oedema,
aphasia, depression, somnolence, speech disorder
Amnesia, intracranial
hypertension, personality
disorder, anxiety, facial
paralysis, neuropathy,
ataxia, hypoesthesia,
paresthesia, thinking
abnormal, abnormal gait,
dizziness, grand mal convulsion, hallucinations,
insomnia, tremor
Conjonctival oedema,
abnormal vision, visual
field defect
Deep thrombophlebitis
Pulmonary embolism,
haemorrhage
Pneumonia

Common Adverse Events in ≥4% of Patients Receiving GLIADEL
Implant at Recurrent Surgery

Nervous system disorders
uncommon
Eye Disorders
Cardiac and vascular Disorders

common
common

Respiratory, thoracic and
mediastinal disorders
Gastrointestinal disorders

common

Skin and subcutaneous tissue
disorders
Musculoskeletal and connective
tissue disorders
Renal and urinary disorders
General disorders and
administration site conditions

common

The following four categories of adverse events are possibly related to treatment
with GLIADEL Implant.
Seizures:
In the initial surgery trial, the incidence of seizures within the first 5 days after
implantation was 2.5% in the GLIADEL Implant group.
In the surgery for recurrent disease trial, the incidence of post-operative
seizures was 19% in patients receiving GLIADEL Implant. 12/22 (54%) of
patients treated with GLIADEL Implant experienced the first new or worsened
seizure within the first five post-operative days. The median time to onset of
the first new or worsened post-operative seizure was 3.5 days in patients treated with GLIADEL Implant.
Brain Oedema:
Development of brain oedema with mass effect (due to tumour recurrence,
intracranial infection, or necrosis) may necessitate re-operation and, in some
cases, removal of GLIADEL Implant or its remnants (see section 4.4).
Healing Abnormalities:
The following healing abnormalities have been reported in clinical trials of
GLIADEL Implant: wound dehiscence, delayed wound healing, subdural, subgaleal or wound effusions, and cerebrospinal fluid leak.
In the initial surgery trial, cerebrospinal fluid leaks occurred in 5% of GLIADEL
Implant recipients. During surgery, a water-tight dural closure should be
obtained to minimise the risk of cerebrospinal fluid leak (see section 4.4)
Intracranial Infection:
In the initial surgery trial, the incidence of brain abscess or meningitis was 5%
in patients treated with GLIADEL Implant.
In the recurrent setting, the incidence of brain abscess or meningitis was 4% in
patients treated with GLIADEL Implant.
In a published clinical study, cyst formation after GLIADEL Implant treatment has
been reported. This reaction occurred in 10% of the patients observed in the study,
however, the formation of cysts is possible after resection of a malignant glioma.
4.9
Overdose
Not applicable.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, ATC Code: L01AD0I
Preclinical Data
GLIADEL Implant delivers carmustine directly into the surgical cavity created
after tumoural resection. On exposure to the aqueous environment of the cavity
the anhydride bonds in the copolymer are hydrolysed, releasing carmustine, carboxyphenoxypropane and sebacic acid. The carmustine released from GLIADEL
Implant diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA.
Carmustine is spontaneously both degraded and metabolised. The alkylating
moiety thus produced and presumed to be chloroethyl carbonium ion, leads to
the formation of irreversible DNA cross-links.
The tumourcidal activity of GLIADEL Implant is dependent on release of carmustine into the tumour cavity in concentrations sufficient for effective cytotoxicity.
More than 70% of the copolymer degrades by three weeks. The metabolic disposition and excretion of the monomers differ. Carboxyphenoxypropane is predominantly eliminated by the kidney and sebacic acid, an endogenous fatty acid,
is metabolised by the liver and expired as CO2 in animals.
Clinical Data
Primary surgery
In a randomised, double-blind, placebo-controlled clinical trial in 240 adults with
newly-diagnosed high grade malignant glioma undergoing initial craniotomy for
tumour resection median survival increased from 11.6 months with placebo to
13.9 months with GLIADEL Implant (p-value 0.079, unstratified log-rank test) in
the original study phase. The most common tumour type was Glioblastoma
Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11),
anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). The hazard ratio for GLIADEL Implant was 0.77 (95% CI: 0.57 to 1.03). In the long term
follow-up phase, patients still alive at the completion of the original phase were followed for up to at least three years or until death. Median survival increased from
11.6 months with placebo to 13.9 months with GLIADEL Implant (p-value <0.05,
log-rank test). The hazard ratio for GLIADEL Implant treatment was 0.73 (95% CI:
0.56 to 0.95).

Surgery for Recurrent Disease
In a randomised, double-blind, placebo-controlled clinical trial in 145 adults with
recurrent glioblastoma (GBM), GLIADEL Implant prolonged survival in these
patients. Ninety-five percent of the patients treated with GLIADEL Implant
received 7 to 8 implants.
The six-month survival rate was 36% (26/73) with placebo compared to 56%
(40/72) with GLIADEL Implant treatment. Median survival of GBM patients is
20 weeks with placebo versus 28 weeks with GLIADEL Implant treatment.
5.2
Pharmacokinetic properties
The absorption, distribution, metabolism, and excretion of the copolymer in
humans is unknown. Carmustine concentrations delivered by GLIADEL Implant
in human brain tissue have not been determined. Plasma levels of carmustine
after GLIADEL Implant implantation cannot be assayed. In rabbits that had
implants containing 3.85% carmustine placed, carmustine is not detected in the
blood or cerebrospinal fluid.
Following an intravenous infusion of carmustine at doses ranging from 30 to
170mg/m2, the average terminal half-life, clearance, and steady-state volume of
distribution are 22 minutes, 56mL/min/kg, and 3.25L/kg, respectively.
Approximately 60% of the intravenous 200mg/m2 dose of 14 C-carmustine is
excreted in the urine over 96 hours and 6% is expired as CO2.
GLIADEL Implants are biodegradable in human brain when placed into the cavity after tumour resection. The rate of biodegradation is variable from patient to
patient. During the biodegradation process an implant remnant may be observed
on brain imaging scans or at re-operation even though extensive degradation of
all components has occurred.
5.3
Preclinical safety data
No carcinogenicity, mutagenicity, embryo-foetal toxicity, pre- and post-natal toxicity and impairment of fertility studies have been conducted with GLIADEL
Implants.
Carmustine, the active component of GLIADEL Implant, when administered systemically, has embryotoxic, genotoxic and carcinogenic effects and can cause
testicular degeneration in several 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 at or below -20°C.
Unopened outer sachets may be kept at a temperature of not more than 22°C for
a maximum of six hours.
The product may be refrozen only once if the sachets have been unopened and
kept for a maximum of 6 hours at a temperature of not more than 22°C. After
refreezing, the product should be used within 30 days.
6.5
Nature and contents of container
GLIADEL Implant is available in a box containing eight implants. Each implant is
individually packaged in two aluminium foil laminate sachets.
6.6
Special precautions for disposal and handling
Implants should be handled by personnel wearing surgical gloves because exposure to carmustine can cause severe burning and hyperpigmentation of the skin.
Use of double gloves is recommended and the outer gloves should be discarded into a dedicated biohazard waste container after use. A surgical instrument
dedicated to the handling of the implants should be used for implant placement.
If repeat neurosurgical intervention is indicated, any implant or implant remnant
should be handled as a potentially cytotoxic agent.
GLIADEL Implants should be handled with care. The sachets containing GLIADEL
Implants should be delivered to the operating room and remain unopened until
ready to place the implants in the resection cavity. Only the outside surface of the
outer sachet is not sterile. In any case, if an implant is dropped, it should be discarded accordingly.

Instructions for opening sachets containing the implant:

Illustration 1: To open the outer sachet, locate the
folded corner and slowly pull in an outward motion.

Illustration 4: To open the inner sachet, gently
hold it and cut in an arc-like fashion around the implant.

Illustration 5: To remove the implant, gently grasp
the implant with the aid of forceps and place it directly
into the resection cavity. The forceps must be kept
for the manipulation of the implants only.
Illustration 2: Do not pull in a downward motion
rolling knuckles over the sachet. This may exert
pressure on the implant and cause it to break.

Illustration 3: The implant and the inner sachet
should be handled with surgical gloves. Remove
the inner sachet by grabbing with the aid of forceps
and pulling upward.

In any case, if an implant is dropped, it should be discarded accordingly.
Once the tumour is resected, tumour pathology is confirmed and haemostasis is
obtained, up to eight implants may be placed to cover as much of the resection
cavity as possible. Slight overlapping of the implants is acceptable. Implants broken in half may be used, but implants broken in more than two pieces should be
discarded in the dedicated biohazard waste containers.
Oxidised regenerated cellulose may be placed over the implants to secure them
to the cavity surface. After placement of the implants, the resection cavity should
be irrigated and the dura closed in a water, tight fashion.
Any unused product or waste material should be disposed of in accordance with
local requirements for biohazardous waste.
7. MARKETING AUTHORISATION HOLDER
MGI PHARMA LIMITED
European Knowledge Centre
Mosquito Way, Hatfield
Hertfordshire AL10 9SN
United Kingdom
8. MARKETING AUTHORISATION NUMBER
United Kingdom
PL 18753/0001
Republic of Ireland PA 1018/1/1
9. DATE OF FIRST AUTHORISATION/RENEWAL OF
AUTHORISATION
UK Date of first authorisation: 28/05/1999
UK Date of last renewal: 10/12/2008
IR Date of first authorisation: 07/07/1999
IR Date of last renewal: 10/12/2008
10.
DATE OF REVISION OF THE TEXT
December 2011

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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