BRINEURA 150mg solution for infusion medication leaflet

Brineura 150 mg solution for infusion

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.

*Produced in mammalian Chinese Hamster Ovary cells.

Each vial contains 17.4 mg of sodium in 5 ml of solution.

For the full list of excipients, see section 6.1.

Solution for infusion.

Clear to slightly opalescent and colourless to pale yellow solution, that may occasionally contain thintranslucent fibres or opaque particles.

Brineura is indicated for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2) disease, alsoknown as tripeptidyl peptidase 1 (TPP1) deficiency.

Brineura must only be administered by a trained healthcare professional knowledgeable inintracerebroventricular administration in a healthcare setting.

The recommended dose is 300 mg cerliponase alfa administered once every other week byintracerebroventricular 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 to60 minutes prior to the start of infusion.

Continuation of long-term treatment should be subject to regular clinical evaluation whether thebenefits are considered to outweigh the potential risks to individual patients.

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 approximatelyone-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 thetreating physician have a possible increase in intracranial pressure during the infusion as suggested bysymptoms such as headache, nausea, vomiting, or decreased mental state. These precautions are ofparticular importance in patients below 3 years of age.

Treatment of Brineura was initiated in children 1 to 9 years of age in clinical studies. There is noclinical data available in children below 1 year of age (see section 5.1). The posology proposed inchildren below 2 years has been estimated based on brain mass. Treatment should be based on thebenefits and risks to the individual patient as assessed by the physician. It is important to initiatetreatment in patients as early as possible.

The posology selected for patients is based on age at time of treatment and should be adjustedaccordingly (see Table 1).

Table 1: Dose and volume of Brineura

Age groups Total dose administered Volume of Brineura solutionevery other week (ml)(mg)

Birth to < 6 months 100 3.36 months to < 1 year 150 51 year to < 2 years 200 (first 4 doses) 6.7 (first 4 doses)300 (subsequent doses) 10 (subsequent doses)2 years and older 300 10

Intracerebroventricular use.

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 implantedreservoir and catheter (intracerebroventricular access device). The intracerebroventricular accessdevice must be implanted prior to the first infusion. The implanted intracerebroventricular accessdevice 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 theinfusion components including the intracerebroventricular access device in order to fully administerthe medicinal product and to maintain patency of the intracerebroventricular access device (seesection 6.6). Brineura and flushing solution vials should be thawed prior to administration. Theinfusion rate for the medicinal product and the flushing solution is 2.5 ml/hour. The complete infusiontime, including the medicinal product and the required flushing solution, is approximately 2 to4.5 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 connectthe syringe to the infusion set. The infusion set must be equipped with a 0.2 µm inlinefilter. See Figure 1.

3. Prime the infusion components with Brineura.4. Inspect the scalp for signs of intracerebroventricular access device leakage or failure andfor potential infections. Do not administer Brineura if there are signs and symptoms ofacute intracerebroventricular access device leakage, device failure, or device-relatedinfection (see sections 4.3 and 4.4).

5. Prepare the scalp for intracerebroventricular infusion using aseptic technique perinstitution 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 accessdevice.

* Do not return CSF to the intracerebroventricular access device. CSF samplesshould 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 todeliver 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 fordetails.

* 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 ordelivery failure.12. Verify that the “Brineura” syringe in the syringe pump is empty after the infusion iscomplete. Detach and remove the empty syringe from the pump and disconnect from thetubing. 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 infusioncomponents (see section 6.6).

2. Place the syringe containing the flushing solution into the syringe pump and program thepump 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 fordetails.

* 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 ordelivery failure.5. Verify that the “flushing solution” syringe in the syringe pump is empty after the infusionis complete. Detach and remove the empty syringe from the pump and disconnect fromthe infusion line.

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

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

For instructions on preparation of Brineura and flushing solution before administration, seesection 6.6.

Life-threatening anaphylactic reaction to the active substance or to any of the excipients listed insection 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 accessdevice leakage, device failure, or device-related infection (see sections 4.2 and 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

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 andmeningitis, have been observed in patients treated with Brineura (see section 4.8). Meningitis maypresent 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 detectsubclinical device infections. In clinical studies, antibiotics were administered, theintracerebroventricular access device was replaced, and Brineura treatment was continued.

Healthcare professionals should inspect the scalp for skin integrity to ensure theintracerebroventricular access device is not compromised prior to each infusion. Common signs ofdevice leakage and device failure include swelling, erythema of the scalp, extravasation of fluid, orbulging of the scalp around or above the intracerebroventricular access device. However, these signsmay also occur in the context of device-related infections.

Inspection of the infusion site and a patency check must be performed to detect intracerebroventricularaccess device leakage and/or failure prior to initiation of Brineura infusion (see sections 4.2 and 4.3).

The signs and symptoms of device-related infections may not be apparent, therefore, CSF samplesshould routinely be sent for testing to detect subclinical device infections. Consultation with aneurosurgeon may be needed to confirm the integrity of the device. Brineura treatment should beinterrupted in cases of device failure and may require replacement of the access device prior tosubsequent infusions.

Material degradation of the intracerebroventricular access device reservoir occurs after long periods ofuse according to preliminary results of benchtop testing and as observed in clinical trials withapproximately 4 years of use. In two clinical cases, the intracerebroventricular access devices did notshow signs of failure at the time of infusion; however, after removal, material degradation of thedevices were apparent and consistent with data from benchtop testing of intracerebroventricular accessdevices. The access devices were replaced and patients resumed treatment with Brineura. Accessdevice 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 inaccordance with the provisions of the respective medical device manufacturer.

In case of intracerebroventricular access device-related complications, refer to the manufacturer’slabelling for further instruction.

Caution should be taken in patients prone to complications from intracerebroventricular medicinalproduct administration, including patients with obstructive hydrocephalus.

Clinical and laboratory monitoring

Vital signs should be monitored before infusion starts, periodically during infusion, and post-infusionin a healthcare setting. Upon completion of the infusion, the patient status should be clinicallyassessed and observation may be necessary for longer periods if clinically indicated, particularly inpatients less than 3 years.

Electrocardiogram (ECG) monitoring during infusion should be performed in patients with a history ofbradycardia, conduction disorder, or with structural heart disease, as some patients with CLN2 diseasemay develop conduction disorders or heart disease. In cardiac normal patients, regular 12-lead ECGevaluations should be performed every 6 months.

CSF samples should routinely be sent for testing to detect subclinical device infections (seesection 4.2).

Anaphylactic reactions

Anaphylactic reactions have been reported with Brineura. As a precautionary measure, appropriatemedical support should be readily available when Brineura is administered. If anaphylactic reactionsoccur, the infusion should be immediately discontinued and appropriate medical treatment should beinitiated. Patients should be observed closely during and after the infusion. If anaphylaxis occurs,caution should be exercised upon re-administration.

Sodium and potassium content

This medicinal product contains 17.4 mg sodium per vial of Brineura and flushing solution, equivalentto 0.87% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains potassium, less than 1 mmol (39 mg) per vial, i.e. essentially‘potassium-free’.

There are limited data in patients with advanced disease progression at treatment initiation and noclinical data is available in children less than 1 year of age. Newborns may have decreased integrity ofthe blood-brain barrier. In children less than 3 years, increased medicinal product exposure in theperiphery was not associated with a clear change in the safety profile (see sections 4.8, pct. 5.2).

No interaction studies have been performed. Cerliponase alfa is a recombinant human protein andsystemic exposure is limited due to intracerebroventricular administration, therefore interactionsbetween cerliponase alfa and medicinal products metabolised by cytochrome P450 enzymes areunlikely to occur.

There are no data from the use of cerliponase alfa in pregnant women. Animal reproduction studieshave not been conducted using cerliponase alfa. It is not known whether cerliponase alfa can causefoetal harm when administered to a pregnant woman or can affect reproductive capacity. Brineurashould be given to a pregnant woman only if clearly needed.

There is insufficient information on the excretion of cerliponase alfa/metabolites in human milk. Arisk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued duringtreatment with Brineura.

No fertility studies with cerliponase alfa have been conducted in animals or humans.

No studies on the effect of cerliponase alfa on the ability to drive or use machines have beenperformed.

The adverse reactions described in this section were evaluated in 38 patients with CLN2 disease whoreceived at least one dose of Brineura in clinical studies of up to 309 weeks or in post-marketingexperience. The most frequent (>20%) adverse reactions observed during Brineura clinical trialsinclude pyrexia, convulsions, low CSF protein, ECG abnormalities, vomiting, needle issues, devicerelated infections, and hypersensitivity. No patients had to have their treatment discontinued due toadverse events.

Adverse reactions observed are listed below, by system organ class and frequency, following the

MedDRA frequency convention defined as: very common (≥1/10), common (≥1/100 to <1/10),uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known(cannot be estimated from the available data).

Table 2: Frequency of adverse reactions with Brineura

MedDRA MedDRA Frequency

System organ class Preferred term

Infections and infestations Device-related infectiona Very common

Meningitis Not known

Immune system disorders Hypersensitivity Very common

Anaphylactic reaction Common

Psychiatric disorders Irritability Very common

Nervous system disorders Convulsion eventsb Very common

Headache Very common

CSF Pleocytosis Very common

Cardiac disorders Bradycardia Common

Gastrointestinal disorders Vomiting Very common

Gastrointestinal disorder Common

Skin and subcutaneous tissue disorders Rash Common

Urticaria Common

General disorders and administration Pyrexiac Very commonsite conditions Feeling jittery Common

Medical device site irritation Common

Investigations CSF protein increased Very common

ECG abnormalities Very common

CSF protein decreased Very common

Product issues Device issue:

Device leakage Very common

Needle issued Very common

Device malfunction Very common

Device occlusione Common

Device breakage Common

Device dislocationf Not knowna Propionibacterium acnes, Staphylococcus epidermisb Atonic seizures, clonic convulsion, drop attacks, epilepsy, generalised tonic-clonic seizure,myoclonic epilepsy, partial seizures, petit mal epilepsy, seizure, seizure cluster, and status epilepticusc Pyrexia includes combined preferred terms “Pyrexia” and “Increased body temperature”d Dislodgement of infusion needlee Catheter flow obstructionf Device dislocation did not occur in clinical trials

Convulsions are a common manifestation of CLN2 disease and are expected to occur in thispopulation. In clinical studies, 31 of 38 (82%) patients who received cerliponase alfa experienced anevent that mapped to the Convulsions Standardised MedDRA Query. The most commonly reportedconvulsion events include seizure, epilepsy and generalised tonic-clonic seizure. Overall, 4% of allconvulsion events were considered related to cerliponase alfa and ranged from mild to severe, CTCAEgrade 1-4. Convulsions resolved with standard anti-convulsive therapies, and did not result indiscontinuation of Brineura treatment.

Hypersensitivity reactions were reported in 19 of 38 patients (50%) treated with Brineura. Severe(Common Terminology Criteria for Adverse Events (CTCAE) grade 3) hypersensitivity reactionsoccurred in 6 patients and no patients discontinued treatment. Hypersensitivity reactions were reportedin 5 of 8 (63%) patients < 3 years of age compared with14 of 30 (47%) patients ≥ 3 years of age. Themost common manifestations included pyrexia with vomiting, pleocytosis, or irritability, which areinconsistent with classic immune mediated hypersensitivity. These adverse reactions were observedduring or within 24 hours after completion of the Brineura infusion and did not interfere withtreatment. Symptoms resolved over time or with administration of antipyretics, antihistamines and/orglucocorticosteroids.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No information is available.

Pharmacotherapeutic group: other alimentary tract and metabolism products, enzymes, ATC code:

A16AB17.

Cerliponase alfa is a recombinant form of human tripeptidyl peptidase-1 (rhTPP1). Cerliponase alfa isa proteolytic inactive proenzyme (zymogen) that is activated in the lysosome. Cerliponase alfa is takenup 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 ofcerliponase alfa results in consistent cellular uptake and lysosomal targeting for activation.

The activated proteolytic enzyme (rhTPP1) cleaves tripeptides from the N-terminus of the targetprotein with no known substrate specificity. Inadequate levels of TPP1 cause CLN2 disease, resultingin neurodegeneration, loss of neurological function and death during childhood.

Anti-drug antibodies (ADA) in serum and CSF were very commonly detected. No evidence of ADAimpact on pharmacokinetics, efficacy or safety was observed. However data are limited.

The safety and efficacy of Brineura were assessed in three open-label clinical studies in a totalof 38 patients with CLN2 disease, ages 1 to 9 years at baseline, compared to untreated patients with

CLN2 disease from a natural history database (natural history control group). These studies used theaggregate of the motor and language domains of a disease-specific clinical rating scale (see Table 3) toassess disease progression (referred to as the ML score of the CLN2 clinical rating scale). Eachdomain encompasses scores of 3 (grossly normal) to 0 (profoundly impaired), for a total possible scoreof 6, with unit decrements representing milestone events in the loss of previously attained functions ofambulation and speech.

Table 3: Motor language score - CLN2 Clinical rating scale

Domain Score Rating

Motor3 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.

Language3 Apparently normal language. Intelligible and grossly age-appropriate. Nodecline noted yet.

Language has become recognisably abnormal: some intelligible words, may2 form short sentences to convey concepts, requests, or needs. This scoresignifies a decline from a previous level of ability (from the individualmaximum reached by the child).

1 Hardly understandable. Few intelligible words.

0 No intelligible words or vocalizations.

In pivotal study 190-201, a total of 24 patients, ages 3 to 9 years at baseline, were treated with

Brineura 300 mg every other week. Of these, 23 patients were treated for 48 weeks (1 patientwithdrew after week 1 due to the inability to continue with study procedures). The mean baseline MLscore was 3.5 (standard deviation (SD) 1.20) with a range from 1 to 6; no patients with advanceddisease progression were studied (inclusion criteria: mild to moderate progression of CLN2 disease).

A total of 20 out of 23 (87%) patients receiving Brineura for 48 weeks did not have an unreversed2 point decline compared to the 2 points per 48 weeks expected decline in the untreated patientpopulation (p=0.0002, binomial test assuming p0= 0.50). A total of 15 patients out of 23 (65%) had nooverall decline in ML score, irrespective of baseline score, and 2 of these 15 patients increased theirscore by one point during the treatment period. Five patients experienced a single point decrease, and3 patients experienced a 2 point decrease.

All 23 patients completed study 190-201 and continued to the extension study 190-202 where theywere treated with Brineura at 300 mg every other week for a total duration of 288 weeks. Efficacyresults from studies 190-201 and 190-202 were pooled and compared with a natural history controlgroup that included patients that satisfied the inclusion criteria for studies 190-201 and 190-202. Themedian time to an unreversed 2 point decline or ML score of 0 in patients treated with Brineura(N=23) was 272 weeks compared with 49 weeks among the natural history control group (N=42)(hazard ratio 0.14, 95% CI 0.06 to 0.33; p <0.0001). The median time until a ML score of 0, markingloss of all ability to ambulate and communicate, was not reached in Brineura treated patients comparedwith 109 weeks among the natural history control group (hazard ratio, 0.01; 95% CI, 0.00 to 0.08;p <0.0001).

An exploratory survival analysis showed the estimated median age of death for the natural historycontrol group was 10.4 years; 95% CI, 9.5 to 12.5 years. No deaths occurred in the Brineura treatedpatients during the study, median (min, max) age at last assessment was 10.3 (7.8, 13.1) years (N=23).

The mean rate of decline in patients treated with Brineura at 300 mg every other week was 0.38 pointsper 48 weeks. When compared to the estimated rate of decline in natural history of 2.13 points per48 weeks, the study results are statistically significant (p <0.0001) (see Table 4). The observedtreatment effect was considered clinically meaningful in light of the natural history of untreated CLN2disease.

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 190-201/202 Natural History(points/48 weeks)a participants Control Group p-valueb

Overall (n = 23) (n=42)

Mean (SD) 0.38 (0.499)c 2.13 (0.952)c <0.0001

Median 0.30 2.08

Min, Max 0.00, 2.18 0.45, 4.2795% CI Limits 0.16, 0.59 1.84, 2.43a Patient rate of decline per 48 weeks: (baseline CLN2 score - last CLN2 score)/(time elapsed in unitsof 48 weeks)b p-value based on 1-sample T-test comparing rate of decline to the value 2c Positive estimates indicate clinical decline; negative estimates indicate clinical improvement

The estimated mean change from baseline in patients treated with Brineura compared to the naturalhistory control group (N=42 patients) showed attenuation of disease progression and durability of thetreatment effect up to last assessment (Week 321) (see Figure 2).

Figure 2: Mean change from baseline in 0-6 point motor-language score(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

MRI volumetry measurements show attenuated rate of loss.

In Study 190-203 a total of 14 patients with CLN2 disease, ages 1 to 6 years at baseline (8 of 14 lessthan 3 years of age) were treated with Brineura for up to 142.6 weeks (1 patient withdrew to receivetreatment commercially) and a safety follow-up for 24 weeks. The mean (SD) baseline ML score was4.6 (1.69) with a range from 1 to 6.

Brineura treated patients were matched to natural history comparators on the basis of age, CLN2motor language score and pooled genotype. The mean (±SD) rate of decline on the ML scale was 0.15(0.243) points per 48 weeks for the matched Brineura treated patients (N=12) and 1.30 (0.857) pointsper 48 weeks for the matched natural history comparators (N=29). There was a mean difference of1.15 points (SE 0.174), 95% CI 0.80, 1.50 points in the rate of decline between the groups; p <0.0001).

The median time to an unreversed 2 point decline or score of 0 in patients treated with Brineura wasnot reached by last assessment (Week 169) compared with 103 weeks among the natural historycomparators (hazard ratio 0.091: 95% CI, 0.021, 0.393; p <0.0001). The median time to a ML scoreof 0 was not reached in Brineura treated patients compared with 163 weeks among the matched naturalhistory comparators (hazard ratio, 0.00; 95% CI, 0.00, 0.00; p=0.0032). A total of 10 of 12 (83%)treated patients had less than a 2 point decline on the ML scale from baseline to last assessment. Eightpatients (67%) showed no clinical progression on the ML scale, two (17%) lost a single point and2 (17%) lost 2 points. No treated patients reached an ML score of zero compared with 10 of 29 (34%)of the matched natural history comparators.

In patients below 3 years of age, the mean (SD) rate of decline on the ML scale was 0.04 (0.101)points per 48 weeks for matched treated patients (N=8) compared with 1.09 (0.562) points per48 weeks for matched natural history comparators (N=20) (difference 1.05 points; p <0.0001). Sevenof the treated patients below 3 years of age with an ML score of 6 at baseline remained at an ML scoreof 6 at the last measured timepoint, which represents grossly normal gait and language. Three of these7 patients remained with no other symptoms of CLN2 disease at week 145, as assessed by the CLN2rating scale, brain imaging and adverse events, whereas all matched comparators had becomesymptomatic. In this population Brinerua treated patients showed a delay in disease onset.

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who receivedintracerebroventricular 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 followinginfusions at week 5 and week 13, indicating no apparent accumulation or time dependentpharmacokinetics of cerliponase alfa in CSF or plasma when administered at of dose of 300 mg onceevery other week. The pharmacokinetic parameters in CSF were assessed in 17 patients and aresummarised in Table 5 below. Cerliponase alfa plasma pharmacokinetics were assessed in 13 patients,and a median Tmax of 12 hours (since start of infusion), a mean Cmax of 1.39 µg/ml, and mean AUC0-tof 24.1 µg-hour/ml were characterised. There was no apparent effect of serum or CSF ADA on theplasma 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)

T *max , 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], andoccurred at the first sampling timepoint post infusion

The estimated volume of distribution of cerliponase alfa following intracerebroventricular infusion of300 mg (Vz = 435 ml) exceeds the typical CSF volume (100 ml), suggesting distribution to tissuesoutside 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 localised within thecentral nervous system. Intracerebroventricular administration of cerliponase alfa is not expected toresult in therapeutic concentrations in the eye due to the limited access from the CSF to the affectedcells of the retina and the presence of the blood-retinal barrier.

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 cerliponasealfa.

Renal elimination of cerliponase alfa is considered a minor pathway for clearance.

Paediatric population from 0 to 3 years

Paediatric CLN2 patients ages 1 to < 2 years (n=2) and 2 to < 3 years (n=6) were administeredcerliponase alpha according to the recommended paediatric dosing regimen for up to 144 weeks. CSFexposure was within the range characterised to be safe and effective in the pivotal study. Plasmaexposure in younger patients trended higher than the range characterised in the pivotal study howeverthe greater plasma exposure was not associated with clear changes in the safety profile. There are nopharmacokinetic data in patients below 1 year of age.

Limited preclinical safety data of cerliponase alfa were generated from single dose toxicity studies inmonkeys and repeated-dose studies in a dachshund dog model of classic late infantile neuronal ceroidlipofuscinosis type 2. This disease model primarily served to investigate the pharmacodynamic andpharmacokinetic 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, becausethe regimen of cerliponase alfa infusions was different and highly variable even within the same studydue to difficulties with the indwelling catheter system and prominent hypersensitivity reactions. Inaddition, these investigations included very small animal numbers, mostly tested single dose groupsand lacked appropriate controls. Thus, the non-clinical development is inconclusive with respect to theclinical safety of cerliponase alfa. Genotoxicity, carcinogenicity and reproductive toxicityinvestigations have not been performed.

Brineura solution for infusion and flushing solution

Sodium phosphate dibasic heptahydrate

Sodium dihydrogen phosphate monohydrate

Sodium chloride

Potassium chloride

Magnesium chloride hexahydrate

Calcium chloride dihydrate

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

2 years

Thawed Brineura and flushing solution should be used immediately. The medicinal product shouldonly 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 in a refrigerator (2°C - 8°C) and usedwithin 24 hours.

Chemical and physical in-use stability has been demonstrated for up to 12 hours at roomtemperature (19°C - 25°C). From a microbiological point of view, open vials or medicinal productheld in syringes should be used immediately. If not used immediately, in-use storage times andconditions prior to use are the responsibility of the user.

Store upright in a freezer (-25°C to -15°C).

Store in the original package in order to protect from light.

Transportation of vials

Transport and distribute frozen (-85°C to -15°C).

Brineura solution for infusion and flushing solution

Vial (type I glass) with a stopper (butyl rubber), with fluropolymer coating, a flip-off cap(polypropylene) and crimp seal (aluminum). Brineura has a green flip-off cap and flushing solutionhas a yellow flip-off cap.

Each pack contains two vials, each containing 150 mg of cerliponase alfa in 5 ml of solution forinfusion, and one vial containing 5 ml of flushing solution.

Brineura should be administered with infusion components shown to be chemically and physicallycompatible with administration of Brineura and flushing solution. CE marked intracerebroventricularaccess devices, and disposable components listed below or equivalent should be used to deliver

Brineura.

Brineura is compatible with intracerebroventricular access devices made of a silicone dome with astainless steel or polypropylene base that is attached to a silicone catheter.

Brineura is compatible with disposable infusion components made of PVC, PVC (non-DEHP)polyethylene, polyethersulfone (PES), polypropylene (PP), and PTFE.

Preparation for administration of Brineura and flushing solution

The following components (not supplied) are required for proper administration of Brineura andflushing solution (see Figure 1 in section 4.2). All infusion components must be sterile. Brineura andflushing solution are supplied and stored frozen (see section 6.4).

* A programmable syringe pump with appropriate delivery range, delivery rate accuracy, andalarms for incorrect delivery or occlusion. The pump must be programmable to deliver themedicinal 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 mlis 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 cmto 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 inlinefilter 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. Referto 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. Donot thaw or warm vials any other way. Do not shake vials. Condensation will occur during thawingperiod. 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 slightlyopalescent and colourless to pale yellow. Brineura vials may occasionally contain thin translucentfibres or opaque particles. These naturally occurring particles are cerliponase alfa. These particles areremoved 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 flushingsolution should be clear and colourless.

Do not use if the solutions are discoloured or if there is other foreign particulate matter in thesolutions.

Withdraw Brineura

Label one unused sterile syringe “Brineura” and attach a syringe needle. Remove the green flip-offcaps from both Brineura vials. Using aseptic technique, withdraw the volume of Brineura solution perrequired dose (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 vialsper local requirements.

Withdraw flushing solution

Determine the volume of flushing solution needed to ensure complete delivery of Brineura to thecerebral ventricles. Calculate the flush volume by adding the priming volume of all infusioncomponents, including the intracerebroventricular access device.

Label one unused sterile syringe “flushing solution” and attach a syringe needle. Remove the yellowflip-off cap from the flushing solution vial. Using aseptic technique, withdraw the appropriate amountof flushing solution from the vial into the new sterile syringe labelled “flushing solution”. Discard theneedle and the vial with the remaining solution per local requirements.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

BioMarin International Limited

Shanbally, Ringaskiddy

County Cork

Ireland

EU/1/17/1192/001

Date of first authorisation: 30 May 2017

Date of latest renewal: 28 March 2022

Detailed information on this medicinal product is available on the website of the European Medicines

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