GLIADEL 7.7 MG IMPLANT - summary of medicine characteristics

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 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 for the treatment of adult patients with newly-diagnosed highgrade malignant glioma as an adjunct to surgery and radiation.

GLIADEL Implant is indicated as an adjunct to surgery for the treatment of adult patients with recurrent histologically proved glioblastoma multiforme and 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, resulting in a dose of 61.6 mg when eight implants are placed in the tumour resection cavity.

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

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, brain oedema and pneumocephalus (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).

Changes of wall of cerebral blood vessels located close to Gliadel wafer, including cases of aneurysms leading to cerebral bleeding several months after Gliadel wafer implantation, have been described. Gliadel wafers implantation adjacent to large cerebral vessels should be avoided.

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 Fertility, 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.

Breastfeeding:

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.

Fertility:

No impairment of fertility studies have been conducted with GLIADEL Implants.

4.7 Effects on ability to drive and use machines

GLIADEL Implant has no influence on the ability to drive and use machines. However, craniotomy and GLIADEL Implant may cause nervous system and vision abnormalities. Therefore patient should be warned of the potential effect of these events on the ability to drive or to use machines.

4.8 Undesirable effects

The following post-operative adverse reactions 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 reactions more common in the GLIADEL Implant group are listed. These adverse reactions were either not present pre-operatively or worsened post-operatively during the follow-up period. The follow-up period was up to 71 months.

Common Adverse Reactions in >4% of Patients Receiving GLIADEL Implant at Recurrent Surgery

The following adverse reactions, not listed in the table above, were reported in patients treated with GLIADEL Implant in all studies. The reactions listed were either not present pre-operatively or worsened post-operatively. Whether GLIADEL Implant caused these events cannot be determined.

Adverse Reactions in Patients Receiving GLIADEL Implant

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

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 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Not applicable

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Antineoplastic agents, ATC Code: LO1ADO1 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 randomized, 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 ration 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 can not 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 170 mg/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 14C-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 postnatal 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 the 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 other 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. Any unused product or waste material should be disposed of in accordance with local requirements for cytotoxic agents.

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:

To open the outer sachet, locate the folded corner and slowly pull in an outward motion. Do not pull in a downward motion rolling knuckles over the sachet. This may exert pressure on the implant and cause it to break

Remove the inner sachet by grabbing with the aid of forceps and pulling upward

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

To remove the implant, gently grasp the implant with the aid of forceps and place it directly into the resection cavity

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

PL 18753/0001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 28/05/1999

Date of last renewal:         10/12/2008