Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2015 Publisher: MGI PHARMA LIMITED, Holborn Gate, 1st Floor, 330 High Holborn, London,WC1V 7QT, United Kingdom
Hypersensitivity to the active substance carmustine or to any of the excipients of GLIADEL Implant.
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.
Interactions of GLIADEL Implant with other drugs or chemotherapy have not been formally evaluated.
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.
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.
No effects on ability to drive and use machines have been observed. However, driving is not advisable following treatment.
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.
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:
Common: Diabetes mellitus
Very common: Healing abnormal
Common: Peripheral oedema
Very common: Hemiplegia, convulsion, confusion, brain oedema, aphasia, depression, somnolence, speech disorder
Common: Amnesia, intracranial hypertension, personality disorder, anxiety, facial paralysis, neuropathy, ataxia, hypoesthesia, paresthesia, thinking abnormal, abnormal gait, dizziness, grand mal convulsion, hallucinations, insomnia, tremor
Common: Conjonctival oedema, abnormal vision, visual field defect
Very common: Deep thrombophlebitis
Common: Pulmonary embolism, haemorrhage
Common: Pneumonia
Very common: Nausea, vomiting, constipation
Common: Diarrhoea
Very common: Rash, alopecia
Common: Urinary tract infection, urinary incontinence
Very common: Aggravation reaction, headache, asthenia, infection, fever, pain
Common: 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).
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.
Common Adverse Events in ≥4% of Patients Receiving GLIADEL Implant at Recurrent Surgery:
Common: Anaemia
Very common: Healing abnormal
Common: Hyponatraemia
Very common: Convulsion, hemiplegia, headache, somnolence, confusion
Common: Aphasia, stupor, brain oedema, intracranial hypertension, meningitis or abscess
Common: Deep thrombophlebitis, Pulmonary embolism
Common: Pneumonia
Common: Nausea, nausea and vomiting, oral moniliasis
Common: Rash
Very common: Urinary tract infection
Very common: Fever
Common: 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:
Common: Thrombocytopenia, leukocytosis
Common: Hyponatraemia, hyperglycaemia, hypokalaemia
Common: Hydrocephalus, depression, abnormal thinking, ataxia, dizziness, insomnia, hemiplegia, coma, amnesia, diplopia, paranoid reaction
Uncommon: Cerebral haemorrhage, cerebral infarct
Common: Visual defect, eye pain
Common: Hypertension, hypotension
Common: Infection, aspiration pneumonia
Common: Diarrhoea, constipation, dysphagia, gastrointestinal haemorrhage, faecal incontinence
Common: Rash
Common: Infection
Common: Urinary incontinence
Common: Peripheral oedema, neck pain, accidental injury, back pain, allergic reaction, asthenia, chest pain, sepsis
The following four categories of adverse events are possibly related to treatment with GLIADEL Implant.
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.
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).
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).
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.
Not applicable.
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