2.1 Important Preparation and Administration Information

• Aseptic technique must be strictly observed during preparation and administration.

• Brineura should be administered by, or under the direction of, a physician experienced in intraventricular administration.

• Prior to each infusion of Brineura, inspect the scalp for signs of intraventricular access device leakage, failure or potential infection [see Warnings and Precautions (5.1, 5.2)].

• Prior to each infusion of Brineura and when clinically indicated, obtain a sample of CSF for cell count and culture [see Warnings and Precautions (5.1)].

• Brineura is administered into the cerebrospinal fluid (CSF) by infusion via a surgically implanted reservoir and catheter (intraventricular access device). Brineura is intended to be administered via the Codman® HOLTER RICKHAM Reservoirs (Part Numbers: 82-1625, 82-1621, 82-1616) with the Codman® Ventricular Catheter (Part Number: 82-1650). The intraventricular access device must be implanted prior to the first infusion. It is recommended that the first dose be administered at least 5 to 7 days after device implantation.

• Brineura is intended to be administered with the B Braun Perfusor® Space Infusion Pump System (Product Code: 8713030U). If an alternative pump must be used, the essential performance requirements for this syringe pump used to deliver Brineura are as follows:

  • Delivery rate of 2.5 mL/hr with delivery accuracy of +/- 1 mL/hr

  • Compatible with 20 mL syringes provided in the Administration Kit for use with Brineura

  • Occlusion alarm setting to ≤ 281 mm Hg

  • Cleared for intraventricular route of administration

• Administer Brineura and the Intraventricular Electrolytes using the provided Administration Kit for use with Brineura components [see How Supplied/Storage and Handling (16)].

2.2 Dosage

The recommended dosage of Brineura in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion. Administer Brineura first followed by infusion of the Intraventricular Electrolytes each at an infusion rate of 2.5 mL/hr. The complete Brineura infusion, including the required infusion of Intraventricular Electrolytes, is approximately 4.5 hours.

Pre-treatment of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion.

2.3 Method of Administration

Brineura and the Intraventricular Electrolytes must only be administered by the intraventricular route, using the provided Administration Kit for use with Brineura. Each vial of Brineura and Intraventricular Electrolytes is intended for a single dose only.

Each infusion consists of 10 mL of Brineura followed by 2 mL of Intraventricular Electrolytes. The complete infusion must be administered using an infusion set with a 0.2 micron inline filter. The Intraventricular Electrolytes are used to flush the infusion line, port needle, and intraventricular access device in order to fully administer Brineura and to maintain patency of the intraventricular access device.

2.4 Preparation for Infusion

Gather supplies:

• Brineura and Intraventricular Electrolytes Injection vials (package 1 of 2) [see How Supplied/Storage and Handling (16)]

• Administration Kit for use with Brineura (package 2 of 2) [see How Supplied/Storage and Handling (16)]

• Syringe pump (not supplied)

Inspect the Administration Kit infusion components to ensure the components are in the individual packages and have not been compromised.

Thaw Brineura and Intraventricular Electrolytes Injection vials 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. Do not re‑freeze vials or freeze syringes containing Brineura or Intraventricular Electrolytes.

Inspect fully thawed Brineura and Intraventricular Electrolytes Injection vials. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Brineura is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution. Do not use if the solutions are discolored or if there is other foreign particulate matter in the solutions. Brineura vials may occasionally contain thin translucent fibers or opaque particles. These naturally occurring particles are cerliponase alfa. These particles are removed via the 0.2 micron inline filter without having a detectable effect on the purity or strength of Brineura. Intraventricular Electrolytes may contain particles, which appear during the thaw period; however, these dissolve when the solution reaches room temperature.

2.5 Intraventricular Infusion Procedure

Intraventricular Infusion of Brineura

Figure 1 represents the intraventricular infusion system set up. Use aseptic technique during the infusion. Follow the steps below to proceed with the intraventricular infusion.

Figure 1

1. Use aseptic technique when preparing the Brineura syringe for infusion. Label one sterile syringe “Brineura” and attach the syringe needle. Remove the green flip-off caps from the two Brineura vials. Use the “Brineura” labeled syringe to withdraw a total of 10 mL from the Brineura vials. Do not dilute Brineura. Do not mix Brineura with any other drug.

2. Label the infusion line “intraventricular infusion only” (see Figure 1).

3. Attach the syringe containing Brineura to the extension line (see Figure 2). Then connect the extension line to the infusion set with a 0.2 micron inline filter (see Figure 1).

Figure 2

4. Prime the infusion components with Brineura.

5. Inspect scalp for signs of intraventricular access device leakage or failure and for potential infections [see Warnings and Precautions (5.1, 5.2)].

6. Prepare the scalp for intraventricular infusion per institution standard of care.

7. Insert port needle into intraventricular access device (see Figure 3).

Figure 3

8. Connect a separate empty sterile single-use luer lock syringe, no larger than 3 mL (not provided) to the port needle. Withdraw 0.5 mL to 1 mL of CSF to check patency of intraventricular access device (see Figure 4) and send specimen for culture.

• Do not return CSF to intraventricular access device.
• Routinely send CSF samples for infection monitoring [see Warnings and Precautions (5.1)].

Figure 4

9. Attach the infusion set with 0.2 micron inline filter to the port needle (see Figure 1).

• Secure the components per institution standard of care.

10. Place the syringe containing Brineura into the syringe pump and program pump to deliver at an infusion rate of 2.5 mL per hour. Set the occlusion alarm setting to alert at pressure ≤ 281 mm Hg. See syringe pump operating manual for details. Do not deliver as a bolus or manually.

11. Administer pre-medication 30 to 60 minutes prior to the start of infusion [see Dosage and Administration (2.2)].

12. Monitor vital signs (blood pressure, heart rate) prior to the start of infusion, periodically during infusion, and post-infusion [see Warnings and Precautions (5.3)].

13. Initiate infusion of Brineura at a rate of 2.5 mL per hour.

14. Periodically inspect the infusion system during the infusion for signs of leakage or delivery failure [see Warnings and Precautions (5.2)].

15. When the Brineura infusion is complete, detach and remove the empty syringe from the pump and disconnect from the tubing (see Figure 5). Proceed to Step 16 for Intraventricular Electrolytes infusion.

Figure 5

Intraventricular Infusion of Intraventricular Electrolytes

Administer the Intraventricular Electrolytes provided after Brineura infusion is complete.

16. Use aseptic technique when preparing the Intraventricular Electrolytes syringe for infusion. Label one sterile syringe “Intraventricular Electrolytes” and attach the syringe needle. Remove the yellow flip-off cap from the Intraventricular Electrolytes Injection vial. Withdraw 2 mL of Intraventricular Electrolytes. Discard the remaining unused portion.

17. Attach the syringe to the extension line (see Figure 6).

Figure 6

18. Place the syringe containing Intraventricular Electrolytes into the syringe pump and program pump to deliver at an infusion rate of 2.5 mL per hour. Set the occlusion alarm setting to alert at pressure ≤ 281 mm Hg. See syringe pump operating manual for details. Do not deliver as a bolus or manually.

19. Initiate infusion of Intraventricular Electrolytes at a rate of 2.5 mL per hour.

20. Periodically inspect the infusion system during the infusion for signs of leakage or delivery failure.

21. When the Intraventricular Electrolytes infusion is complete, detach and remove the empty syringe from the pump and disconnect from the infusion line.

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

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

Storage of Thawed Product

Use thawed Brineura and Intraventricular Electrolytes immediately. If not used immediately, store unopened vials in the refrigerator at 2°C to 8°C and use within 24 hours.

Storage of Product in Syringes

Use product held in labeled syringes immediately. If not used immediately, store product held in labeled syringes in the refrigerator at 2°C to 8°C up to 4 hours prior to infusion.

5.1 Meningitis and Other Intraventricular Access Device-Related Infections

Bacterial meningitis requiring antibiotic treatment and removal of the device was reported during postmarketing use of Brineura. Additionally, in clinical trials and during postmarketing use there were reports of other device-related clinical infections which were confirmed by positive CSF cultures, treated with antibiotics and removal of the device, and in which patients resumed treatment with Brineura after the device was replaced [see Adverse Reactions (6.1)]. In all cases, antibiotics were administered, the intraventricular access devices were removed and replaced, and patients resumed treatment with Brineura.

The signs and symptoms of infections may not be readily apparent in patients with CLN2 disease. To reduce the risk of infectious complications, Brineura should be administered by, or under the direction of, a physician experienced in intraventricular administration [see Dosage and Administration (2.3)]. Prior to each infusion of Brineura, and when clinically indicated, obtain a sample of CSF for cell count and culture. Do not administer Brineura if there are localized signs of infection on or around the device insertion site, such as erythema, tenderness, or discharge or suspected or confirmed CNS infection (e.g. cloudy CSF or positive CSF gram stain, or meningitis) [see Contraindications (4)].

Healthcare providers should be vigilant for the development of signs and symptoms of infection, including meningitis, during treatment with Brineura and monitor the device insertion site for signs of infection.

5.2 Intraventricular Access Device-Related Complications

During the clinical trial and in postmarketing reports, intraventricular access device-related complications were reported (e.g., device leakage, device failure extravasation of CSF fluid, or bulging of the scalp around or above the intraventricular access device) [see Adverse Reactions (6.2)]. For any complications with the implanted intraventricular access device, consult with a neurosurgeon to confirm the integrity or performance of the device. In case of intraventricular access device-related complications, discontinue the Brineura infusion and refer to the device manufacturer’s labeling for further instructions [see Contraindications (4)].

Material degradation of the intraventricular access device reservoir was reported after approximately 4 years of administration, which may impact the effective and safe use of the device. During benchtop testing such material degradation was recognized after approximately 105 perforations of the intraventricular access device. The intraventricular access device should be replaced prior to 4 years of single-puncture administrations, which equates to approximately 105 administrations of Brineura.

5.3 Cardiovascular Adverse Reactions

Monitor vital signs (blood pressure, heart rate) before infusion starts, periodically during infusion, and post-infusion in a healthcare setting [see Dosage and Administration (2.5)]. Upon completion of the infusion, clinically assess the patient status. Continued observation may be necessary if clinically indicated.

Perform electrocardiogram (ECG) monitoring during infusion 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 patients without cardiac abnormalities, regular 12-lead ECG evaluations should be performed every 6 months.

In the clinical studies, hypotension was reported in 2 (8%) patients, which occurred during or up to eight hours after Brineura infusion. Patients did not require alteration in treatment, and reactions resolved spontaneously or after intravenous fluid administration [see Adverse Reactions (6.1)].

5.4 Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis have been reported in Brineura-treated patients during clinical studies and postmarketing use [see Adverse Reactions (6.1, 6.3)]. In clinical trials, a total of 11 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. Patients in clinical trials were routinely pre-medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of Brineura. During postmarketing use, anaphylactic reactions occurred during or within several hours of Brineura infusion. Epinephrine was administered in one case. Patients received subsequent Brineura infusions without recurrence of anaphylaxis.

Due to the potential for anaphylaxis, appropriate medical support should be readily available when Brineura is administered. Observe patients closely during and after the infusion. If a severe hypersensitivity reaction or anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Inform patients/caregivers of the signs and symptoms of hypersensitivity reactions and anaphylaxis and instruct them to seek immediate medical care should signs and symptoms occur.

The management of hypersensitivity reactions should be based on the severity of the reaction and may include temporarily interrupting the infusion, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. Consider the risks and benefits of readministration of Brineura following an anaphylactic reaction. If the decision is made to readminister Brineura after the occurrence of anaphylaxis, ensure appropriately trained personnel and equipment for emergency resuscitation (including epinephrine and other emergency medicines) are readily available during infusion. Initiate subsequent infusion at approximately one-half the initial infusion rate at which the anaphylactic reaction occurred.

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of Brineura was evaluated in 24 patients with CLN2 disease who received at least one dose of Brineura in a clinical study with extension of up to 161 weeks [see Clinical Studies (14)]. Table 1 summarizes the most common adverse reactions that occurred in Brineura-treated patients through 96 weeks.

Table 1: Adverse Reactions Reported in ≥ 8% of Symptomatic Pediatric Patients with CLN2 Disease in the Brineura Single-Arm Clinical Study with Extension at Week 96

1Pyrexia includes: pyrexia and increased body temperature

2ECG abnormalities include: non-specific repolarization abnormality, notched QRS, ST segment elevation, biphasic T wave abnormality, supraventricular extrasystoles, bradycardia, sinus tachycardia, and intraventricular conduction delay

3Seizures include: atonic, generalized tonic-clonic, focal, and absence

4Device-related complications include device-related infection, delivery system-related complications (needle issues, device leakage, device malfunction, device difficult to use, etc.) and pleocytosis.

5Hypersensitivity includes: immune reactions and signs and symptoms observed concomitantly with hypersensitivity reactions including pyrexia, vomiting, pleocytosis or irritability [see Warnings and Precautions (5.4)]

6Device-related infections include:Propionibacterium acnes and Staphylococcus epidermidis

Description of Selected Adverse Reactions

Seizures

Seizures were reported in 12 of 24 (50%) patients. The seizure types reported include atonic, generalized tonic-clonic, focal, and absence. Seizures were managed with standard anti-convulsive therapies and did not result in discontinuation of Brineura treatment.

Device-Related Complications

Adverse reactions related to the device were observed in 12 of 24 (50%) of patients. Device-related adverse reactions include infection, delivery system-related complications, and pleocytosis. Nine out of 24 patients (38%) experienced adverse reactions, which involved complications of the non-implanted delivery system components. Four out of 24 patients (16%) had device-related adverse reactions, which required medical intervention, including two patients (8%) with intraventricular access device-related CNS infections, and one patient (4%) each with leakage of the intraventricular access device and pleocytosis. Device-related infections were diagnosed by increased CSF pleocytosis and microbiology culture and organism identification, without accompanying signs and symptoms of meningitis. Intraventricular access devices were replaced and infections were treated with antibiotics. Device-related complications did not result in discontinuation of Brineura treatment [see Warnings and Precautions (5.1, 5.2)].

Hematoma

Hematoma adverse reactions were reported in 5 (21%) patients treated with Brineura and presented as hematoma, post procedural hematoma, traumatic hematoma and subdural hematoma. Hematomas did not require treatment and did not interfere with Brineura infusion.

Hypersensitivity

Hypersensitivity reactions were reported in 11 out of 24 patients (46%) treated with Brineura during or within 24 hours after completion of the Brineura infusion, despite pre-medication with antihistamines with or without antipyretics or corticosteroids [see Warnings and Precautions (5.1)]. The most common manifestations observed concomitantly with hypersensitivity included pyrexia with vomiting, pleocytosis, or irritability, which are not consistent with classic immune mediated hypersensitivity. Symptoms resolved over time or with administration of antipyretics, antihistamines and/or corticosteroids and no patient discontinued treatment with Brineura.

One patient experienced hypoxia (decreased oxygen saturation less than 88% by pulse oximeter), 8 hours after Brineura infusion, followed by a low mean arterial pressure at 15 hours post infusion. Symptoms resolved after oxygen administration, airway repositioning and normal saline infusion. One patient reported decreased oxygen saturation (90% by pulse oximeter), 45 minutes after starting Brineura with associated low diastolic blood pressures. Hypoxia resolved after oxygen administration. No treatment was administered for the low diastolic blood pressure, which returned to normal while the patient continued to receive Brineura infusion without change to the infusion rate or dose.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cerliponase alfa in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Anti-drug antibodies (ADAs) to cerliponase alfa were detected in both serum and CSF in 79% and 33%, respectively, of patients treated with Brineura for up to 161 weeks. Patients who experienced hypersensitivity adverse reactions were tested for drug-specific IgE and found to be negative, including three patients for whom grade 3 (severe) hypersensitivity adverse reactions were reported. No association was found between serum or CSF ADA titers and incidence or severity of hypersensitivity. Drug-specific neutralizing antibodies (NAb) have not been evaluated.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Brineura. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: Bacterial meningitis [see Warnings and Precautions (5.1)].

Immune system disorders: Anaphylactic reaction characterized by acute pyrexia, respiratory distress (bronchospasm, hypoxemia, perioral cyanosis), tachycardia, hypotension, diarrhea, and rash [see Warnings and Precautions (5.4)].

8.1 Pregnancy

Risk Summary

There are no available data on Brineura use in pregnant women to inform a drug-associated risk of pregnancy-related outcomes. Animal reproduction studies have not been conducted using cerliponase alfa.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

8.2 Lactation

Risk Summary

There are no data on the presence of cerliponase alfa in human milk, the effects on the breastfed child, or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of Brineura to an infant during lactation; therefore, the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Brineura and any potential adverse effects on the breastfed infant from Brineura or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of Brineura have been established in pediatric patients 3 years of age and older. Pediatric use of Brineura to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, is supported by a non-randomized single-arm dose escalation clinical study with extension in patients with CLN2 disease and compared to untreated patients with CLN2 disease from an independent natural history cohort [see Clinical Studies (14)]. Safety and effectiveness in patients less than 3 years of age have not been established.

12.1 Mechanism of Action

CLN2 disease is a neurodegenerative disease caused by deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1), which catabolizes polypeptides in the CNS. TPP1 has no known substrate specificity. Deficiency in TPP1 activity results in the accumulation of lysosomal storage materials normally metabolized by this enzyme in the central nervous system (CNS), leading to progressive decline in motor function.

Cerliponase alfa (rhTTP1), a proenzyme, is taken up by target cells in the CNS and is translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate Receptor (CI-MPR, also known as M6P/IGF2 receptor). Cerliponase alfa is activated in the lysosome and the activated proteolytic form of rhTPP1 cleaves tripeptides from the N-terminus of proteins.

12.3 Pharmacokinetics

The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received intraventricular infusions of 30 mg (0.1 times the approved recommended dosage), 100 mg (approximately 0.3 times the approved recommended dosage), and 300 mg over approximately 4.5 hours once every other week.

Cerliponase alfa CSF exposure following the initial single dose administration of Brineura increased less than proportionally across doses of 30 mg, 100 mg, and 300 mg. There was no apparent accumulation of cerliponase alfa in CSF or plasma when Brineura was administered at a dose of 300 mg once every other week.

Cerliponase alfa pharmacokinetics have high inter-subject and intra-subject variability. Following intraventricular infusions of 300 mg of Brineura at Day 1, Week 5, and Week 13, the pharmacokinetic parameters in CSF and plasma were assessed in 14 patients and are summarized in Table 2.

Table 2: Pharmacokinetic Parameters of Cerliponase Alfa Following Intraventricular Infusion (approximately 4.5 hours in duration) of Brineura 300 mg Every Two Weeks

1Tmax expressed as time since start of ~4.5 hour infusion.

2Vss, CL, and t1/2 were not estimated due to insufficient plasma pharmacokinetic data

The estimated CSF volume of distribution of cerliponase alfa following intraventricular infusion of 300 mg of Brineura (median Vss = 245 mL) exceeds the typical CSF volume (100 mL).

Cerliponase alfa is a protein and is expected to be degraded through peptide hydrolysis.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, genotoxicity, and fertility studies have not been performed with cerliponase alfa. Based on the mechanism of action, cerliponase alfa is not expected to be tumorigenic.