GLIADEL

Posology For intralesional use only. 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. 6). It is recommended that the placement of the implants should be directly from the product’s inner sterile packaging into the resection cavity.

6).

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 (≥ 1/1,000 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 reactions observed in 5% or more of the 120 newly-diagnosed malignant glioma patients receiving GLIADEL Implant during the trial. 2% vs. 7%). 4). CSF leak was more common in GLIADEL Implant-treated patients than in placebo patients.

4). Surgery for Recurrent Disease 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 System Organ Class Adverse reactions Blood and lymphatic system disorders common Anaemia Metabolism and nutrition disorders common Hyponatraemia very common Convulsion, hemiplegia, headache, somnolence, confusion Nervous system disorders common Aphasia, stupor, brain oedema, intracranial pressure increased, meningitis or abscess Vascular disorders common Thrombophlebitis, Respiratory, thoracic and mediastinal disorders common Pulmonary embolism Infections and infestations common Pneumonia, oral candidias Gastrointestinal disorders common Nausea, vomiting, Skin and subcutaneous tissue disorders common Rash Renal and urinary disorders very common Urinary tract infection very common Fever, healing abnormalGeneral disorders and administration site conditions common Infection, pain 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 System Organ Class Adverse reactions Blood and lymphatic system disorders common Thrombocytopenia, leukocytosis Metabolism and nutrition disorders common Hyponatraemia, hyperglycaemia, hypokalaemia common Hydrocephalus, ataxia, dizziness, hemiplegia, coma, amnesia, diplopia, Nervous system disorders uncommon Cerebral haemorrhage, cerebral infarct Psychiatric disorders common Depression, abnormal thinking, insomnia, paranoid reaction Eye Disorders common Visual defect, eye pain Cardiac and vascular disorders common Hypertension, hypotension System Organ Class Adverse reactions Respiratory, thoracic and mediastinal disorders common Infection, aspiration pneumonia Gastrointestinal disorders common Diarrhoea, constipation, dysphagia, gastrointestinal haemorrhage, faecal incontinence Skin and subcutaneous tissue disorders common Rash Musculoskeletal and connective tissue disorders common Infection Renal and urinary disorders common Urinary incontinence General disorders and administration site conditions common Peripheral oedema, neck pain, accidental injury, back pain, allergic reaction, asthenia, chest pain, sepsis Injury, poisoning and procedural complications uncommon pneumocephalus Cases of air accumulation at the implant site, 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 […]

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. 8). CSF leak was more common in GLIADEL Implant-treated patients.

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. Women of child-bearing potential should use effective contraception for at least 6 months after receiving GLIADEL Implant. Male patients with female partners of child-bearing potential should be advised to use effective contraception for at least 90 days after receiving GLIADEL Implant.

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