Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: BioMarin International Limited, Shanbally, Ringaskiddy, County Cork, Ireland
Life-threatening anaphylactic reaction to the active substance or to any of the excipients listed in section 6.1, if re-challenge is unsuccessful (see section 4.4).
CLN2 patients with ventriculo-peritoneal shunts.
Brineura must not be administered as long as there are signs of acute intracerebroventricular access device leakage, device failure, or device-related infection (see section 4.2 and 4.4).
Brineura must be administered using aseptic technique to reduce the risk of infection. Intracerebroventricular access device-related infections, including sub-clinical infections and meningitis, have been observed in patients treated with Brineura. Meningitis may present with the following symptoms: fever, headache, neck stiffness, light sensitivity, nausea, vomiting, and change in mental status. CSF samples should routinely be sent for testing to detect subclinical device infections. In clinical studies, antibiotics were administered, the intracerebroventricular access device was replaced, and Brineura treatment was continued.
Healthcare professionals should inspect the scalp for skin integrity to ensure the intracerebroventricular access device is not compromised prior to each infusion. Common signs of device leakage and device failure include swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intracerebroventricular access device. However, these signs may also occur in the context of device-related infections.
Inspection of the infusion site and a patency check must be performed to detect intracerebroventricular access device leakage and/or failure prior to initiation of Brineura infusion (see section 4.2 and 4.3). The signs and symptoms of device-related infections may not be apparent, therefore, CSF samples should routinely be sent for testing to detect subclinical device infections. Consultation with a neurosurgeon may be needed to confirm the integrity of the device. Brineura treatment should be interrupted in cases of device failure and may require replacement of the access device prior to subsequent infusions.
Material degradation of the intracerebroventricular access device reservoir occurs after long periods of use according to preliminary results of benchtop testing and as observed in clinical trials with approximately 4 years of use. In two clinical cases, the ICV access devices did not show signs of failure at the time of infusion; however, after removal, material degradation of the devices were apparent and consistent with data from benchtop testing of ICV access devices. The access devices were replaced and patients resumed treatment with Brineura.
Access device replacement should be considered prior to 4 years of regular administration of Brineura, however it must always be ensured, that the intracerebroventricular access device is used in accordance with the provisions of the respective medical device manufacturer.
In case of intracerebroventricular access device-related complications, refer to the manufacturer’s labelling for further instruction.
Caution should be taken in patients prone to complications from intracerebroventricular medicinal product administration, including patients with obstructive hydrocephalus.
Vital signs should be monitored before infusion starts, periodically during infusion, and post-infusion in a healthcare setting. Upon completion of the infusion, the patient status should be clinically assessed and observation may be necessary for longer periods if clinically indicated, particularly in patients less than 3 years.
Electrocardiogram (ECG) monitoring during infusion should be performed in patients with a history of bradycardia, conduction disorder, or with structural heart disease, as some patients with CLN2 disease may develop conduction disorders or heart disease. In cardiac normal patients, regular 12-lead ECG evaluations should be performed every 6 months.
CSF samples should routinely be sent for testing to detect subclinical device infections (see section 4.2).
There were no patients with advanced disease progression at treatment initiation who were included in clinical trials and no clinical data is available in children <2 years. Patients with advanced CLN2 disease and newborns may have decreased integrity of the blood-brain barrier. Effects of the potentially increased medicinal product exposure on the periphery are unknown.
Anaphylactic reactions have been reported with Brineura. As a precautionary measure, appropriate medical support should be readily available when Brineura is administered. If anaphylactic reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. If anaphylaxis occurs, caution should be exercised upon re-administration.
This medicinal product contains 17.4 mg sodium per vial of Brineura and flushing solution, equivalent to 0.87% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Each vial contains less than 1 mmol (39 mg) of potassium, i.e. essentially ‘potassium-free’.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
No interaction studies have been performed. Cerliponase alfa is a recombinant human protein and systemic exposure is limited due to intracerebroventricular administration, therefore interactions between cerliponase alfa and medicinal products metabolised by cytochrome P450 enzymes are unlikely to occur.
There are no data on the use of Brineura in pregnant women. Animal reproduction studies have not been conducted using Brineura. It is not known whether Brineura can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Brineura should be given to a pregnant woman only if clearly needed.
There are no data on the presence of cerliponase alfa in human milk, the effects of cerliponase alfa on the breastfed child, or the effects of cerliponase alfa on milk production. Breastfeeding should be discontinued during treatment with Brineura.
No fertility studies with cerliponase alfa have been conducted in animals or humans.
No studies on the effect of Brineura on the ability to drive or use machines have been performed.
The adverse reactions described in this section were evaluated in 24 patients with CLN2 disease who received at least one dose of Brineura in clinical studies of up to 141 weeks or in post-marketing experience. The most frequent (>20%) adverse reactions observed during Brineura clinical trials include pyrexia, low CSF protein, ECG abnormalities, vomiting, upper respiratory tract infections, and hypersensitivity. No patients had to have their treatment discontinued due to adverse events.
Adverse reactions observed are listed below, by system organ class and frequency, following the MedDRA frequency convention defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Adverse reactions are presented in order of decreasing seriousness.
Table 2. Frequency of adverse reactions with Brineura:
Very common: Upper respiratory tract infection
Common: Conjunctivitis, Device-related infectiona
Not known: Meningitis
Very common: Hypersensitivity
Common: Anaphylactic reaction
Very common: Irritability
Common: Bradycardia
Very common: Convulsion eventsb, Headache, CSF Pleocytosis
Common: Dropped head syndrome
Very common: Vomiting
Common: Abdominal pain, Oral mucosal blistering, Tongue blistering, Gastrointestinal disorder
Common: Rash, Urticaria
Very common: Pyrexiac
Common: Feeling jittery, Pain
Very common: CSF protein increased, ECG abnormalities, CSF protein decreased
Device issue:
Common: Device leakage, Device occlusiond
Not known: Device dislocatione
Very common: Needle issuef
a Propionibacterium acnes, staphylococcus epidermis
b Atonic seizures, clonic convulsion, drop attacks, epilepsy, generalised tonic-clonic seizure, myoclonic epilepsy, partial seizures, petit mal epilepsy, seizure, seizure cluster, and status epilepticus
c Pyrexia includes combined preferred terms “Pyrexia” and "Increased body temperature"
d Catheter flow obstruction
e Device dislocation did not occur in clinical trials
f Dislodgement of infusion needle
Convulsions are a common manifestation of CLN2 disease and are expected to occur in this population. Overall, 23 (96%) subjects who received cerliponase alfa experienced an event that mapped to the Convulsions Standardized MedDRA Query. The most commonly reported convulsion events include seizure, epilepsy and generalized tonic-clonic seizure. Total convulsion events with a temporal relationship to cerliponase alfa administration was 17% and were mild to moderate, grade 1 to 2 in severity. Overall, 6% of all convulsion events were considered related to cerliponase alfa and ranged from mild to severe, CTCAE grade 1-4. Convulsions resolved with standard anti-convulsive therapies, and did not result in discontinuation of Brineura treatment.
Hypersensitivity reactions were reported in 14 out of 24 patients (58%) treated with Brineura. Severe (Common Terminology Criteria for Adverse Events (CTCAE) grade 3) hypersensitivity reactions occurred in three patients and no patients discontinued treatment. The most common manifestations included pyrexia with vomiting, pleocytosis, or irritability, which are inconsistent with classic immune mediated hypersensitivity. These adverse reactions were observed during or within 24 hours after completion of the Brineura infusion and did not interfere with treatment. Symptoms resolved over time or with administration of antipyretics, antihistamines and/or glucocorticosteroids.
Anti-drug antibodies (ADAs) were detected in both serum and CSF in 79% and 21%, respectively, of patients treated with cerliponase alfa for up to 107 weeks. Drug-specific neutralizing antibodies (NAb) capable of inhibiting receptor-mediated cellular uptake of cerliponase alfa were not detected in the CSF. No association was found between serum or CSF ADA titres and incidence or severity of hypersensitivity. Patients who experienced moderate hypersensitivity adverse events were tested for drug-specific IgE and found to be negative. No correlations were found between higher ADA titres and reductions in efficacy measurements. There was no apparent effect of serum or CSF ADA on the plasma or CSF pharmacokinetics, respectively.
An ongoing study provides experience with two patients aged 2 years of age treated with Brineura at 300 mg every other week (see section 5.1). Both patients have received 8 infusions and the overall safety profile of Brineura in these younger patients appears consistent with the safety profile observed in older children. Currently no clinical experience of Brineura in children below 2 years of age is available.
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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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