Brineura - summary of medicine characteristics

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 PARTICULARS4.1 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.

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.

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 ^m 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.

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).

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

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

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 infection3 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

aPropionibacterium 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

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

4.9 Overdose

No information is available.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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
Motor	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.
	0	Can no longer walk or crawl.
Language	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.
	0	No intelligible words or vocalizations.

A total of 24 patients, aged 3 to 8 years, were treated with Brineura 300 mg every other week. In study 190201, 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	<0.0001
Median	0.00
Min, Max	–0.88, 2.02
95% CI Limits	0.05, 0.75

aPatient 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

cPositive 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).

Figure 2: CLN2 Score Mean Change from Baseline

(Natural History Control Group vs Brineura treated patients, 300 mg every other week)

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

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 gg/ml, and mean AUCo-t of 24.1 gg-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, gg/ml	1490 (942)
AUCo-t, gg-hr/ml	9510 (4130)
Vz, ml	435 (412)
CL, ml/hr	38.7 (19.8)
ti/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.

6. PHARMACEUTICAL PARTICULARS6.1 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).

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 gm 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).

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