Brineura

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 

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This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See 
section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Brineura 150 mg solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial of Brineura contains 150 mg of cerliponase alfa* in 5 ml of solution.  
 
Each ml of solution for infusion contains 30 mg of cerliponase alfa. 
 
*Cerliponase alfa is produced in mammalian Chinese Hamster Ovary cells. 
 
Excipients with known effect: 
 
Each vial contains 17.4 mg of sodium in 5 ml of solution. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for infusion.  
 
Clear to slightly opalescent and colourless to pale yellow solution, that may occasionally contain thin 
translucent fibres or opaque particles.   
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Brineura is indicated for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, also known 
as tripeptidyl peptidase 1 (TPP1) deficiency. 
 
4.2 Posology and method of administration 
 
Brineura must only be administered by a trained healthcare professional knowledgeable in 
intracerebroventricular administration in a healthcare setting. 
 
Posology 
 
The recommended dose is 300 mg cerliponase alfa administered once every other week by 
intracerebroventricular infusion.  
 
In patients less than 2 years of age, lower doses are recommended, see paediatric population section. 
 
Pre-treatment of patients with antihistamines with or without antipyretics is recommended 30 to 60 minutes 
prior to the start of infusion. 
 
Continuation of long-term treatment should be subject to regular clinical evaluation whether the benefits are 
considered to outweigh the potential risks to individual patients. 

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Dose adjustments 
 
Consideration of dose adjustments may be necessary for patients who may not tolerate the infusion. The dose 
may be reduced by 50% and/or the infusion rate decreased to a slower rate. 
 
If the infusion is interrupted due to a hypersensitivity reaction, it should be restarted at approximately one-
half the initial infusion rate at which the hypersensitivity reaction occurred. 
 
The infusion should be interrupted and/or the rate slowed in patients who in the judgement of the treating 
physician have a possible increase in intracranial pressure during the infusion as suggested by symptoms 
such as headache, nausea, vomiting, or decreased mental state. These precautions are of particular 
importance in patients below 3 years of age. 
 
Paediatric population 
 
The safety and efficacy of Brineura in children less than 3 years of age has not yet been established. Limited 
data are available for children aged 2 years and no clinical data is available in children below 2 years of age 
(see section 5.1). The posology proposed in children below 2 years has been estimated based on brain mass. 
 
Treatment of Brineura was initiated in children 2 to 8 years of age in clinical studies. There is limited data in 
patients older than 8 years of age. Treatment should be based on the benefits and risks to the individual 
patient as assessed by the physician. 
 
The posology selected for patients is based on age at time of treatment and should be adjusted accordingly 
(see Table 1). In patients less than 3 years of age the recommended dose is in accordance with the posology 
used in the ongoing clinical study 190-203, see section 5.1.  
 

Table 1: Dose and volume of Brineura 
 

Age groups Total dose administered every 
other week 

(mg) 

Volume of Brineura solution 
(ml) 

Birth to < 6 months 100 3.3 
6 months to < 1 year 150 5 
1 year to < 2 years 200 (first 4 doses) 

300 (subsequent doses) 
6.7 (first 4 doses) 

10 (subsequent doses) 
2 years and older 

 
300 10 

 
Method of administration 
 
Intracerebroventricular use.  
 
Precautions to be taken before handling or administering the medicinal product 
 
Aseptic technique must be strictly observed during preparation and administration. 
 
Brineura and the flushing solution must only be administered by the intracerebroventricular route. Each vial 
of Brineura and flushing solution are intended for single use only.  
 
Brineura is administered to the cerebrospinal fluid (CSF) by infusion via a surgically implanted reservoir and 
catheter (intracerebroventricular access device). The intracerebroventricular access device must be implanted 
prior to the first infusion. The implanted intracerebroventricular access device should be appropriate for 
accessing the cerebral ventricles for therapeutic administration. 

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Following Brineura infusion, a calculated amount of flushing solution must be used to flush the infusion 
components including the intracerebroventricular access device in order to fully administer Brineura and to 
maintain patency of the intracerebroventricular access device (see section 6.6). Brineura and flushing 
solution vials should be thawed prior to administration. The infusion rate for Brineura and the flushing 
solution is 2.5 ml/hour. The complete infusion time, including Brineura and the required flushing solution, is 
approximately 2 to 4.5 hours, depending on the dose and volume administered. 
 
Intracerebroventricular Infusion of Brineura  
 
Administer Brineura before the flushing solution. 

1. Label the infusion line for “Intracerebroventricular infusion only”. 
2. Attach the syringe containing Brineura to the extension line, if used, otherwise connect the syringe to 

the infusion set. The infusion set must be equipped with a 0.2 µm inline filter. See Figure 1. 
3. Prime the infusion components with Brineura.  
4. Inspect the scalp for signs of intracerebroventricular access device leakage or failure and for 

potential infections. Do not administer Brineura if there are signs and symptoms of acute 
intracerebroventricular access device leakage, device failure, or device-related infection (see section 
4.3 and 4.4). 

5. Prepare the scalp for intracerebroventricular infusion using aseptic technique per institution standard 
of care. 

6. Insert the port needle into the intracerebroventricular access device. 
7. Connect a separate empty sterile syringe (no larger than 3 ml) to the port needle. 

Withdraw 0.5 ml to 1 ml of CSF to check patency of the intracerebroventricular access device. 
 Do not return CSF to the intracerebroventricular access device. CSF samples should 

routinely be sent for infection monitoring (see section 4.4). 
8. Attach the infusion set to the port needle (see Figure 1).  

 Secure the components per institution standard of care. 
9. Place the syringe containing Brineura into the syringe pump and program the pump to deliver at an 

infusion rate of 2.5 ml per hour.  
 Program the pump alarms to sound at the most sensitive settings for pressure, rate, and volume 

limits. See the syringe pump manufacturer’s operating manual for details.  
 Do not deliver as a bolus or manually.  

10. Initiate infusion of Brineura at a rate of 2.5 ml per hour. 
11. Periodically inspect the infusion system during the infusion for signs of leakage or delivery failure. 
12. Verify that the “Brineura” syringe in the syringe pump is empty after the infusion is complete. 

Detach and remove the empty syringe from the pump and disconnect from the tubing.  Discard the 
empty syringe in accordance with local requirements. 

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Figure 1: Infusion System Set Up 
 
Intracerebroventricular infusion of the flushing solution  
 
Administer the flushing solution provided after the Brineura infusion is complete.  

1. Attach the syringe containing the calculated volume of flushing solution to the infusion components 
(see section 6.6). 

2. Place the syringe containing the flushing solution into the syringe pump and program the pump to 
deliver an infusion rate of 2.5 ml per hour.  
 Program the pump alarms to sound at the most sensitive settings for pressure, rate, and volume 

limits. See the syringe pump manufacturer’s operating manual for details. 
 Do not deliver as a bolus or manually. 

3. Initiate infusion of the flushing solution at a rate of 2.5 ml per hour.  
4. Periodically inspect the infusion components during the infusion for signs of leakage or delivery 

failure.  
5. Verify that the “flushing solution” syringe in the syringe pump is empty after the infusion is 

complete. Detach and remove the empty syringe from the pump and disconnect from the infusion 
line.  

6. Remove the port needle. Apply gentle pressure and bandage the infusion site per institution standard 
of care. 

7. Dispose of the infusion components, needles, unused solutions and other waste materials in 
accordance with local requirements. 

 
For instructions on preparation of Brineura and flushing solution before administration, see section 6.6.  
 
4.3 Contraindications 
 
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). 
 

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4.4 Special warnings and precautions for use 
 
Device-related complications 
 
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. 
 
Clinical and laboratory monitoring 
 
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). 
 
Paediatric population 
 

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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 
  
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. 
 
Sodium content 
 
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’. 
 
Traceability 
In order to improve the traceability of biological medicinal products, the name and the batch number of the 
administered product should be clearly recorded. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
 
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.  
 
Breast-feeding 
 
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. 
 
Fertility 
 
No fertility studies with cerliponase alfa have been conducted in animals or humans. 
 
4.7 Effects on ability to drive and use machines 
 
No studies on the effect of Brineura on the ability to drive or use machines have been performed. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 

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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.  
 
Tabulated list of adverse reactions 
 
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 
 

MedDRA 
System organ class 

MedDRA 
Preferred term 

Frequency 

Infections and infestations Upper respiratory tract infection 
Conjunctivitis 
Device-related infectiona 
Meningitis 

Very common 
Common 
Common 
Not known 

Immune system disorders Hypersensitivity 
Anaphylactic reaction 

Very common 
Common 

Psychiatric disorders Irritability Very common 
Cardiac disorders Bradycardia Common 
Nervous system disorders Convulsion eventsb 

Headache 
CSF Pleocytosis 
Dropped head syndrome 

Very common 
Very common 
Very common 
Common 

Gastrointestinal disorders Vomiting 
Abdominal pain 
Oral mucosal blistering 
Tongue blistering 
Gastrointestinal disorder 

Very common 
Common 
Common 
Common 
Common 

Skin and subcutaneous tissue disorders Rash 
Urticaria 

Common 
Common 

General disorders and administration site 
conditions 

Pyrexiac  
Feeling jittery 
Pain 

Very common 
Common 
Common 

Investigations CSF protein increased 
ECG abnormalities 
CSF protein decreased 

Very common 
Very common 
Very common 

Product issues Device issue:   
Device leakage 
Device occlusiond 
Device dislocatione 
Needle issuef  

 
Common 
Common 
Not known 
Very common 

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 
 

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Description of selected adverse reactions 
 
Convulsions 
 
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 
 
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. 
 
Immunogenicity 
 
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.  
 
Paediatric population 
 
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 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 
 
No information is available. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 

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http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


Pharmacotherapeutic group: other alimentary tract and metabolism products, enzymes, ATC code: 
A16AB17. 
 
Mechanism of action 
 
Cerliponase alfa is a recombinant form of human tripeptidyl peptidase-1 (rhTPP1). Cerliponase alfa is a 
proteolytic inactive proenzyme (zymogen) that is activated in the lysosome. Cerliponase alfa is taken up by 
target cells and translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate 
Receptor (CI-MPR, also known as M6P/IGF2 receptor). The glycosylation profile of cerliponase alfa results 
in consistent cellular uptake and lysosomal targeting for activation.  
 
The activated proteolytic enzyme (rhTPP1) cleaves tripeptides from the N-terminus of the target protein with 
no known substrate specificity. Inadequate levels of TPP1 cause CLN2 disease, resulting in 
neurodegeneration, loss of neurological function and death during childhood. 
 
Clinical efficacy and safety 
 
The safety and efficacy of Brineura were assessed in an open label, dose escalation clinical study (190-201) 
and an ongoing long term extension study (190-202) in patients with CLN2 disease compared to untreated 
patients with CLN2 disease from a natural history database (natural history control group). These studies 
used the aggregate of the motor and language domains of a disease-specific clinical rating scale (see Table 3) 
to assess disease progression. Each domain encompasses scores of 3 (grossly normal) to 0 (profoundly 
impaired), for a total possible score of 6, with unit decrements representing milestone events in the loss of 
previously attained functions of ambulation and speech. 
 

Table 3: CLN2 Clinical Rating Scale 
 

Domain Score Rating 

3 Grossly normal gait. No prominent ataxia, no pathologic falls. 

2 Independent gait, as defined by ability to walk without support for 10 steps. Will have obvious instability, and may have intermittent falls. 

1 Requires external assistance to walk, or can crawl only. 

Motor 

0 Can no longer walk or crawl. 

3 Apparently normal language. Intelligible and grossly age-appropriate. No decline noted yet. 

2 

Language has become recognizably abnormal: some intelligible words, may 
form short sentences to convey concepts, requests, or needs. This score 
signifies a decline from a previous level of ability (from the individual 
maximum reached by the child). 

1 Hardly understandable. Few intelligible words. 

Language 

0 No intelligible words or vocalizations. 

 

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A total of 24 patients, aged 3 to 8 years, were treated with Brineura 300 mg every other week. In study 190-
201, 23 patients were treated for 48 weeks (1 patient withdrew after week 1 due to the inability to continue 
with study procedures). The mean baseline CLN2 score was 3.5 (standard deviation (SD) 1.20) with a range 
from 1 to 6; no patients with advanced disease progression were studied (inclusion criteria: mild to moderate 
progression of CLN2 disease). All 23 patients completed study 190-201 and continued to the ongoing 
extension study 190-202 treated with Brineura at 300 mg every other week to a maximum of 124 weeks.  
 
Findings from studies 190-201 and 190-202 were compared with a natural history control group that 
included patients that satisfied the inclusion criteria for studies 190-201 and 190-202. Results from the 
natural history control group demonstrate CLN2 disease is a rapidly progressive neurodegenerative disease 
with predictable decline in motor and language function with an estimated mean rate of decline in the CLN2 
score of 2 points per 48 weeks. 
 
Treatment effect in patients receiving Brineura was assessed using the CLN2 clinical rating scale, and results 
were compared to the 2 points per 48 weeks predicted decline in the natural history control group. In study 
190-201, 20 out of 23 (87%) patients receiving Brineura for 48 weeks did not have an unreversed 2 point 
decline as observed in the untreated patient population (p=0.0002, binomial test assuming p0= 0.50). A total 
of 15 patients out of 23 (65%) had no overall decline in CLN2 score, irrespective of baseline score, and 2 of 
these 15 patients increased their score by one point during the treatment period. Five patients experienced a 
single point decrease, and 3 patients experienced a 2 point decrease. 
 
In study 190-201, the mean rate of decline in patients treated with Brineura at 300 mg every other week was 
0.40 points per 48 weeks. When compared to the expected rate of decline based on natural history, the study 
results are statistically significant (p < 0.0001) (see Table 4). The observed treatment effect was considered 
clinically meaningful in light of the natural history of untreated CLN2 disease. 
 

Table 4:  0 to 6 Point Motor-Language CLN2 Clinical Rating Scale: Rate of Decline over 48 weeks 
(Intent to Treat (ITT) population) 

 
Rate of Decline (points/48 weeks)a Overall (n = 23) p-valueb 
Mean (SD) 0.40 (0.809)c 
Median 0.00 
Min, Max -0.88, 2.02 
95% CI Limits 0.05, 0.75 

<0.0001 
 

a Patient rate of decline per 48 weeks: (baseline CLN2 score - last CLN2 score) / (time elapsed in units of 48 weeks) 
b p-value based on 1-sample T-test comparing rate of decline to the value 2 
c Positive estimates indicate clinical decline; negative estimates indicate clinical improvement 
 
In the ongoing study 190-202 (as of 03 June 2016), the rate of decline in patients treated with Brineura 
compared to the natural history control group (N=42 patients) continues to show durability of the treatment 
effect (see Figure 2).  
 

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Figure 2:  CLN2 Score Mean Change from Baseline  
(Natural History Control Group vs Brineura treated patients, 300 mg every other week) 

 

 
   Vertical bars represent standard error of the mean 

Solid line: 190-201 and 190-202 clinical studies 
Dash line: 190-901 Natural history control group 

 
Vision and seizure scores when combined with CLN2 score (motor and language domains) remain stable. 
MRI volumetry measurements show attenuated rate of loss.  
 
Paediatric population 
 
It is important to initiate treatment in children as young as possible, although patients less than 3 years of age 
were not included in the pivotal study. 
 
Study 190-203 is an ongoing open label clinical study evaluating the safety and efficacy in patients from 
birth to 18 years of age. Posology was based upon analysis of differences in brain mass values for children 
less than 3 years of age. So far safety results in 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 (see section 4.8). 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with Brineura in 
one or more subsets of the paediatric population in CLN2 (see section 4.2 for information on paediatric use). 
 
This medicinal product has been authorised under ‘exceptional circumstances’. This means that due to the 
rarity of the disease it has not been possible to obtain complete information on this medicinal product. 
 
The European Medicines Agency will review any new information which may become available every year 
and this SmPC will be updated as necessary. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received 
intracerebroventricular infusions of 300 mg over approximately 4.5 hours once every other week.    
 
All pharmacokinetic parameters were similar following the initial infusion on Day 1 and following infusions 
at Week 5 and Week 13, indicating no apparent accumulation or time dependent PK of cerliponase alfa in 

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CSF or plasma when administered at of dose of 300 mg once every other week. The pharmacokinetic 
parameters in CSF were assessed in 17 patients and are summarized in Table 5 below. Cerliponase alfa 
plasma pharmacokinetics were assessed in 13 patients, and a median Tmax of 12.0 hours (since start of 
infusion), a mean Cmax of 1.39 µg/ml, and mean AUC0-t of 24.1 µg-hour/ml were characterized. There was no 
apparent effect of serum or CSF ADA on the plasma or CSF pharmacokinetics, respectively.  
 
Table 5: Pharmacokinetic properties following first Intracerebroventricular infusion (approximately 4 

hours in duration) of 300 mg cerliponase alfa in CSF 
 

Parameter CSF (N=17) 
Mean (SD) 

Tmax*, hr 4.50 [4.25, 5.75]  
Cmax, µg/ml 1490 (942) 
AUC0-t, µg-hr/ml 9510 (4130) 
Vz, ml 435 (412) 
CL, ml/hr 38.7 (19.8) 
t1/2, hr 7.35 (2.90) 
*Tmax expressed as time since start of ~4 hour infusion and presented as median [min, max], and occurred at the first sampling 

timepoint post infusion 
 
Distribution 
 
The estimated volume of distribution of cerliponase alfa following intracerebroventricular infusion of 
300 mg (Vz = 435 ml) exceeds the typical CSF volume (100 ml), suggesting distribution to tissues outside 
the CSF.  The large CSF to plasma ratios in Cmax and AUC0-t (approximately 1000 and 400, respectively) 
suggest that the majority of administered cerliponase alfa remains localized within the CNS. 
Intracerebroventricular administration of cerliponase alfa is not expected to result in therapeutic 
concentrations in the eye due to the limited access from the CSF to the affected cells of the retina and the 
presence of the blood-retinal barrier. 
 
Elimination 
 
Cerliponase alfa is a protein and is expected to be metabolically degraded through peptide hydrolysis. 
Consequently, impaired liver function is not expected to affect the pharmacokinetics of cerliponase alfa. 
 
 
Renal elimination of cerliponase alfa is considered a minor pathway for clearance. 
 
5.3 Preclinical safety data 
 
Limited preclinical safety data of cerliponase alfa were generated from single dose toxicity studies in 
monkeys and repeated-dose studies in a dachshund dog model of classic late infantile neuronal ceroid 
lipofuscinosis type 2. This disease model primarily served to investigate the pharmacodynamic and 
pharmacokinetic properties of cerliponase alfa, but also aimed to evaluate the toxicity of the substance. 
However, the results of these studies in dachshund dogs cannot reliably predict human safety, because the 
regimen of cerliponase alfa infusions was different and highly variable even within the same study due to 
difficulties with the indwelling catheter system and prominent hypersensitivity reactions. In addition, these 
investigations included very small animal numbers, mostly tested single dose groups and lacked appropriate 
controls. Thus, the non-clinical development is inconclusive with respect to the clinical safety of cerliponase 
alfa. Genotoxicity, carcinogenicity and reproductive toxicity investigations have not been performed. 
 

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6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Brineura and flushing solution 
Sodium phosphate dibasic heptahydrate 
Sodium dihydrogen phosphate monohydrate  
Sodium chloride 
Potassium chloride 
Magnesium chloride hexahydrate 
Calcium chloride dihydrate 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
2 years 
 
Thawed Brineura and flushing solution should be used immediately. Product should only be withdrawn from 
the unopened vials immediately prior to use. If immediate use is not possible, unopened vials of Brineura or 
flushing solution should be stored at 2-8°C and used within 24 hours. 
 
Chemical and physical in-use stability has been demonstrated for up to 12 hours at room 
temperature (19-25°C). From a microbiological point of view, open vials or medicinal product held in 
syringes should be used immediately. If not used immediately, in-use storage times and conditions prior to 
use are the responsibility of the user. 
 
6.4 Special precautions for storage 
 
Store upright in a freezer (-25°C to -15°C). 
Transport and distribute frozen (-85°C to -15°C). 
Store in the original package in order to protect from light. 
 
6.5 Nature and contents of container 
 
Vial (type I glass) with a stopper (butyl rubber), a flip-off cap (polypropylene) and crimp seal (aluminium). 
Brineura has a green flip-off cap and flushing solution has a yellow flip-off cap. 
 
Pack size of three vials: two 10 ml vials, each containing 150 mg of cerliponase alfa in 5 ml of solution; and 
one 10 ml vial, containing 5 ml flushing solution. 
 
6.6 Special precautions for disposal and other handling  
 
Brineura should be administered with infusion components shown to be chemically and physically 
compatible with administration of Brineura and flushing solution. CE marked intracerebroventricular access 
devices, and disposable components listed below or equivalent should be used to deliver Brineura. 
 
Intracerebroventricular access devices shown to be compatible with Brineura and flushing solution and used 
in Brineura clinical studies include CodmanHOLTER RICKHAM and HOLTER SALMON-RICKHAM 
Reservoirs, Codman Ventricular Catheter, and Medtronic CSF-Ventricular Reservoir (with catheter). 
 

14 



Brineura is compatible with disposable infusion components made of PVC, PVC (non-DEHP) polyethylene, 
polyethersulfone (PES), polypropylene (PP), and PTFE. The following CE marked disposable infusion 
components were used in Brineura clinical trials: 
 Syringe: Braun and BD Luer-Lok 
 Extension Set: Fresenius Injectomat® line, Alaris CC Extension set, Vygon Lectro-Cath Extension 

tube 
 Extension Set with 0.2 micron filter: Impromediform GmbH 
 Port needle: Deltec GRIPPER Needles 
 
Preparation for administration of Brineura and flushing solution  
 
The following components (not supplied) are required for proper administration of Brineura and flushing 
solution (see Figure 1 in section 4.2). All infusion components must be sterile. Brineura and flushing solution 
are supplied and stored frozen (see section 6.4). 
 
 A programmable syringe pump with appropriate delivery range, delivery rate accuracy, and alarms for 

incorrect delivery or occlusion. The pump must be programmable to deliver the medicinal product at a 
constant rate of 2.5 ml/hr. 

 Two single-use syringes compatible with the pump equipment. A syringe volume of 10 to 20 ml is 
recommended.  

 Two single-use hypodermic syringe needles, (21 G, 25.4 mm). 
 One single-use infusion set. An extension line may be added if needed. A length of 150 to 206 cm (not 

to exceed 400 cm) and an inner diameter of 0.1 cm is recommended. 
 A 0.2 µm inline filter is required. The inline filter may be integral to the infusion set. The inline filter 

should be placed as close as practically possible to the port needle. 
 A non-coring port needle with a gauge of 22 or smaller and a suggested length of 16 mm. Refer to the 

intracerebroventricular access device manufacturer’s recommendation for the port needle. 
 One empty sterile single-use syringe (for collection of CSF to check patency). 
 
Thaw Brineura and flushing solution 
  
Thaw Brineura vials and flushing solution vial at room temperature for approximately 60 minutes. Do not 
thaw or warm vials any other way. Do not shake vials. Condensation will occur during thawing period. 
Thawing the vials outside the carton is recommended.   

 
Brineura and flushing solution must be completely thawed and used immediately (see section 6.3). 

 
Do not re-freeze vials or freeze syringes containing Brineura or flushing solution.  
 
Inspect thawed Brineura and flushing solution vials 
 
Inspect the vials to ensure they are fully thawed. Brineura solution should be clear to slightly opalescent and 
colourless to pale yellow. Brineura vials may occasionally contain thin translucent fibres or opaque particles. 
These naturally occurring particles are cerliponase alfa. These particles are removed via the 0.2 μm inline 
filter without having a detectable effect on the purity or strength of Brineura. 
 
The flushing solution may contain particles that dissolve when the vial is fully thawed. The flushing solution 
should be clear and colourless. 
 
 
Do not use if the solutions are discoloured or if there is other foreign particulate matter in the solutions. 
 
Withdraw Brineura 
 
Label one unused sterile syringe “Brineura” and attach a syringe needle. Remove the green flip-off caps from 
both Brineura vials. Using aseptic technique, withdraw the volume of Brineura solution per required dose 

15 



(see Table 1 in section 4.2) into the sterile syringe labelled “Brineura”. Do not dilute Brineura. Do not mix 
Brineura with any other medicinal product. Discard the needle and empty vials per local requirements. 
 
Withdraw flushing solution 
 
Determine the volume of flushing solution needed to ensure complete delivery of Brineura to the cerebral 
ventricles. Calculate the flush volume by adding the priming volume of all infusion components, including 
the intracerebroventricular access device. 
 
Label one unused sterile syringe “flushing solution” and attach a syringe needle. Remove the yellow flip-off 
cap from the flushing solution vial. Using aseptic technique, withdraw the appropriate amount of flushing 
solution from the vial into the new sterile syringe labelled “flushing solution”. Discard the needle and the 
vial with the remaining solution per local requirements. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1192/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 May 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

16 

http://www.ema.europa.eu/


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION 

MEASURES FOR THE MARKETING AUTHORISATION UNDER 
EXCEPTIONAL CIRCUMSTANCES 

 
 
 

17 



A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturers of the biological active substance  

BIOMARIN PHARMACEUTICAL INC 
GALLI DRIVE FACILITY,  
46 GALLI DRIVE, NOVATO,  
94949,  
United States 
 
BioMarin International Limited 
Shanbally 
Ringaskiddy 
Cork 
Co. Cork 
IRELAND  
 
Name and address of the manufacturer(s) responsible for batch release 

BioMarin International Limited 
Shanbally 
Ringaskiddy 
Cork 
Co. Cork 
IRELAND  
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  

 
 Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent 
updates published on the European medicines web-portal. 

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months 
following authorisation. 

 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 
OF THE MEDICINAL PRODUCT 

 
 Risk Management Plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and 
interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any 
agreed subsequent updates of the RMP. 

18 



An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.  

 

 Additional risk minimisation measures  
 

Prior to the launch of BRINEURA in each Member State (MS), the Marketing Authorisation Holder (MAH) 
must agree about the content and format of the educational materials, including communication media, 
distribution modalities, and any other aspects of the programme, with the National Competent Authority 
(NCA).  
The MAH shall ensure that in each MS where BRINEURA is marketed, all HCPs who are expected to 
handle / administer the product are provided with an educational programme (i.e. a dosing and administration 
guide), aiming at preventing and/or minimising the important identified risk of Device issues 
(infection/blockage/dislocation), containing information about: 
- How to store BRINEURA; 
- The device-related complications (i.e. infections, device’s leakage and/or failure; the integrity of the device 
should be confirmed by a neurosurgeon); 
- How to prepare BRINEURA and the flushing solution; 
- A detailed step-by step description of BRINEURA intra-cerebro-ventricular infusion and the administration 
of the flushing solution (provided after BRINEURA infusion is complete) 
- How to monitor the patients receiving BRINEURA. 
 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR 
THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES  

 

This being a marketing authorisation under exceptional circumstances and pursuant to Article 14(8) of 
Regulation (EC) No 726/2004, the MAH shall complete, within the stated timeframe, the following 
measures: 

 

Description Due date 
Non-interventional post-authorisation safety study (PASS): Study 190-504. In order to 
evaluate the long-term safety of cerliponase alfa, including the occurrence of serious 
hypersensitivity reactions and anaphylactic reactions, the MAH should submit the 
results of a study based on adequate source of data deriving from a registry of patients 
with neuronal ceroid lipfuscinosis Type 2 (CLN2). 
 
 

Annual 
reports to be 
submitted as 
part of the 
annual re-
assessment 
 
 

Post-authorisation efficacy study (PAES): Study 190-203. In order to further evaluate 
the treatment effectiveness as a delay in progression of CLN2 motor-language clinical 
sale and to further evaluate the safety and tolerability of cerliponase alfa, the MAH 
will submit the results of study 190-203 including at least 5 patients below the age of 2 
years. 

July 2020 

 

19 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

20 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 

21 



 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Brineura 150 mg solution for infusion  
cerliponase alfa 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial of Brineura contains 150 mg cerliponase alfa in 5 ml of solution (30 mg/ml) 
 
 
3. LIST OF EXCIPIENTS 
 
Brineura and flushing solution excipients: 
Sodium phosphate dibasic heptahydrate; 
Sodium dihydrogen phosphate monohydrate; 
Sodium chloride; 
Potassium chloride; 
Magnesium chloride hexahydrate; 
Calcium chloride dihydrate; 
Water for injections; 
 
See leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for infusion 
Two vials of Brineura  
One vial of flushing solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
For single use only 
Thaw at room temperature and use immediately. 
Read the package leaflet before use. 
Intracerebroventricular use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 

22 



8. EXPIRY DATE 
 
EXP: 
 
Open vials or product in syringes should be used immediately. In-use storage times and conditions prior to 
use are the responsibility of the user.  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store upright in a freezer (-20°C ± 5°C). 
Store in the original package in order to protect from light. 
Transport and distribute frozen (-85°C to -15°C). 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1192/001 
 
 
13. BATCH NUMBER 
 
LOT: 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted. 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 

23 



18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 

24 



 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Brineura 150 mg solution for infusion 
cerliponase alfa 
Intracerebroventricular use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
150 mg/5 ml 
 
 
6. OTHER 
 
Thaw before use. 
Administer Brineura before flushing solution. 

25 



 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Flushing solution for Brineura 
Intracerebroventricular use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP: 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
5 ml 
 
 
6. OTHER 
 
Thaw before use. 

Administer flushing solution after Brineura.

26 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 

27 



   Package leaflet: Information for the user 
 

Brineura 150 mg solution for infusion  
cerliponase alfa 

 
This medicine is subject to additional monitoring. This will allow quick identification of new safety 

information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you are given this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you or your child gets any side effects, talk to your doctor.  
- This includes any possible side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Brineura is and what it is used for 
2. What you need to know before you or your child is given Brineura 
3. How Brineura is given 
4. Possible side effects 
5. How to store Brineura 
6. Contents of the pack and other information 
 
1. What Brineura is and what it is used for 
 
Brineura contains the active substance cerliponase alfa, which belongs to a group of medicines known as 
enzyme replacement therapies. It is used to treat patients with neuronal ceroid lipofuscinosis type 2 (CLN2) 
disease, also known as tripeptidyl peptidase-1 (TPP1) deficiency. 
 
People with CLN2 disease do not have any enzyme called TPP1 or they have too little of it and this causes a 
build-up of substances called lysosomal storage materials. In people with CLN2 disease, these materials 
build-up in certain parts of the body, mainly the brain. 
 
How Brineura works 
This medicine replaces the missing enzyme, TPP1, which minimises the build-up of the lysosomal storage 
materials. This medicine works to slow the progression of the disease.  
 
 
2. What you need to know before you or your child is given Brineura 
 
You must not receive Brineura 
- If you or your child has had life-threatening allergic reactions to cerliponase alfa or any of the other 

ingredients of this medicine (listed in section 6), and the reactions continue to happen when cerliponse 
alfa is given again. 

- If you or your child has a device implanted to drain extra fluid from the brain. 
- If you or your child currently has signs of a device infection or problems with the device. Your doctor 

may decide to continue treatment once the device infection or problems are resolved.  
 
Warnings and precautions 
Talk to your doctor before you or your child is given Brineura. 
- You or your child may get problems with the implanted device used during treatment with Brineura 

(see section 4 “Possible side effects”), including infection or a fault in the device. Signs that you or 
your child may have an infection include fever, headache, neck stiffness, light sensitivity, nausea, 
vomiting, and change in mental status.  Signs of problems with the device include swelling, redness 
of the scalp, fluid leaking from device and bulging of the scalp. Treatment may be interrupted if the 

28 



- Life-threatening allergic reactions are possible with Brineura. Your doctor will monitor you or your 
child for symptoms of life threatening allergic reactions, such as hives, itching or flushing, swollen 
lips, tongue, and/or throat, chills, accelerated heart rhythm, shortness of breath, hoarseness, turning 
blue around finger tips or lips, low muscle tone, fainting, diarrhoea or incontinence. Seek immediate 
medical care should these symptoms occur. 

- Your doctor will check your or your child’s heart rate, blood pressure, respiratory rate, and 
temperature before, during, and after treatment.  The doctor may decide on additional monitoring if it 
is needed. 

- Your doctor will check for abnormal heart electrical activities (ECG) every 6 months. If you or your 
child has a history of heart problems, your doctor or nurse will monitor your heart activity during 
each infusion. 

- Your doctor may send samples of brain fluid to check for signs of infection. 
- Brineura has not been given to patients with advanced disease at the start of treatment or in children 

younger than 2 years of age.  Your doctor will discuss whether Brineura treatment is right for you or 
your child. 

 
Other medicines and Brineura 
Tell your doctor if you or your child is taking, has recently taken, or might take any other medicines. 
 
Pregnancy, breast-feeding and fertility 
If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your 
doctor for advice before treatment with this medicine. 
You should not receive Brineura treatment during pregnancy unless clearly necessary. It is not known 
whether Brineura is excreted in human breast milk. Breastfeeding should be discontinued during treatment 
with Brineura. It is not known if Brineura impacts human fertility. 
 
Driving and using machines 
It is not known if Brineura will impact the ability to drive or use machines. Please consult your doctor. 
 
Brineura contains sodium and potassium 
 
This medicine contains 17.4 mg sodium (main component of cooking/table salt) in each vial. This is 
equivalent to 0.87% of the recommended maximum daily dietary intake of sodium for an adult. 
 
This medicine contains potassium, less than 1 mmol (39 mg) per vial, i.e. essentially ‘potassium-free’. 
 
3. How Brineura is given 
 
You or your child will need to have surgery to implant the device for giving Brineura. The device helps the 
medicine to reach a specific part of the brain. 
 
Brineura will be given by a doctor with knowledge of giving medicines by intracerebroventricular use 
(infusion into the fluid of the brain) in a hospital or clinic. 
 
Brineura has not been given to patients younger than 2 years of age or older than 8 years of age (at the start 
of the clinical trial). There is limited experience in a few patients aged 2 years old. 
 
The recommended dose of Brineura is based upon your or your child’s age, and is given once every other 
week as follows: 
 
- birth to < 6 months: 100 mg 
- 6 months to < 1 year: 150 mg 
- 1 year to < 2 years: 200 mg (first 4 doses), 300 mg (all other doses) 
- ≥ 2 years: 300 mg 

29 



 
Your doctor may adjust you or your child’s dose or the amount of time the medicine is given if the infusion 
is not tolerated, there is an allergic reaction or there is a possible increase of pressure in the brain. 
   
The medicine is slowly pumped through the implanted device. After the medicine has been given, a shorter 
infusion of a solution is given to flush Brineura out of the infusion equipment so that the full dose reaches 
the brain. The medicine and solution will be given over about 2 to 4 hours and 30 minutes according to your 
or your child’s dose. Your doctor may lower the dose or the speed of the infusion based on your response 
during the treatment. 
 
Your doctor may give you or your child medicines, such as antipyretics to reduce fever or antihistamines to 
treat allergic reactions before each treatment with Brineura to reduce side effects that can occur during or 
shortly after treatment. 
 
If you have any further questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Talk to your doctor or nurse immediately if you experience any of the following: 
 
Very common side effects (may affect more than 1 in 10 people): 
- fever 
- vomiting 
- feeling irritable  
- convulsions (seizures) 
- reactions during or shortly after being given the medicine, such as hives, itching or flushing, swollen 

lips, tongue and/or throat, shortness of breath, hoarseness, turning blue around finger tips or lips, low 
muscle tone, fainting or incontinence 
 

Common side effects (may affect up to 1 in 10 people): 
- device-related bacterial infections  
- slower heart beat  
- device does not function correctly due to a blockage detected during preparation for infusion 
- severe allergic reaction 

 
Not known (frequency cannot be estimated based on available data) 
- device is displaced and does not function correctly when preparing for infusion 
- inflammation of the brain due to device-related infection 
 
This medicine may cause other side effects: 
 
Very common side effects: 
- headache 
- increased or decreased protein in the brain fluid 
- abnormal results of heart electrical activity (ECG) 
- increased cells in the spinal fluid detected by laboratory monitoring 
- infection of your nose or throat (cold) 
- needle issue (infusion needle falls out of implanted device) 
 
Common side effects: 
- pain 
- rash 
- hives 
- head dropping (so that the chin drops towards the chest) 

30 



- stomach pain  
- leakage of the device 
- mouth or tongue blisters 
- swelling or redness of the eyelid and the white part of the eye 
- feeling nervous 
- disorder of the stomach or intestines 
 
Reporting of side effects 
If you or your child gets any side effects, talk to your doctor. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 
 
 
5. How to store Brineura 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the vials and carton after EXP. The expiry 
date refers to the last day of that month.  
 
Store upright in a freezer (-25°C to -15°C). Transport and distribute frozen (-85°C to -15°C). Store in the 
original package, in order to protect from light. 
 
Thawed Brineura and flushing solution should be used immediately. Product should only be withdrawn from 
the unopened vials immediately prior to use. If immediate use is not possible, unopened vials of Brineura or 
flushing solution should be stored at 2-8°C and used within 24 hours. 
 
Chemical and physical in-use stability has been demonstrated for up to 12 hours at room temperature (19-
25°C). From a microbiological point of view, open vials or medicinal product held in syringes should be 
used immediately. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user. 
 
Your doctor or pharmacist is responsible for storing Brineura. They are also responsible for disposing of any 
unused Brineura properly. 
 
 
6. Contents of the pack and other information 
 
What Brineura contains 
- The active substance is cerliponase alfa. Each vial of Brineura contains 150 mg of cerliponase alfa in 

5 ml of solution. Each ml of solution for infusion contains 30 mg of cerliponase alfa.  
- The other ingredients of Brineura and the flushing solution are: sodium phosphate dibasic 

heptahydrate, sodium dihydrogen phosphate monohydrate, sodium chloride, potassium chloride, 
magnesium chloride hexahydrate, calcium chloride dihydrate, and water for injections 
(see section 2 “Brineura contains sodium”) 

 
What Brineura looks like and contents of the pack 
Brineura and the flushing solution are solutions for infusion. The Brineura solution is clear to slightly 
opalescent, colourless to pale yellow and the flushing solution is clear and colourless; the Brineura solution 
may occasionally contain thin translucent fibres or opaque particles.  
 
Pack size: 3 vials (two vials of Brineura and one vial of flushing solution), each containing 5 ml of solution 
 

31 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


32 

Marketing Authorisation Holder and Manufacturer 
BioMarin International Limited 
Shanbally, Ringaskiddy 
County Cork 
Ireland 
 
This leaflet was last revised in MM/YYYY 
 
This medicine has been authorised under ‘exceptional circumstances’. This means that because of the rarity 
of this disease it has been impossible to get complete information on this medicine. 
 
The European Medicines Agency will review any new information on this medicine every year and this 
leaflet will be updated as necessary. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES 
	A. LABELLING
	B. PACKAGE LEAFLET