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 knowledgeable in intraventricular administration.

• 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. 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

• 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)].

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 (5.2)].

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 (5.1)].

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       Intraventricular Access Device‑Related Complications

Brineura must be administered using aseptic technique to reduce the risk of infection. Healthcare professionals should inspect the scalp for skin integrity to ensure the intraventricular access device is not compromised prior to each infusion [see Dosage and Administration (2.5)].

Brineura is contraindicated if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device) [see Contraindications (4)]. In case of intraventricular access device complications, discontinue the Brineura infusion and refer to the device manufacturer’s labeling for further instructions.

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 [see Dosage and Administration (2.5)].

In clinical studies with Brineura, intraventricular access device-related infections were observed in two patients. In each case, antibiotics were administered, the intraventricular access device was replaced, and the patient continued on Brineura treatment.

Material degradation of the intraventricular access device reservoir may occur after approximately 105 perforations of the intraventricular access device. The intraventricular access device may require replacement as soon as, or prior to, 105 administrations of Brineura, equating to approximately 4.3 years of regular administrations.

5.2       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 eva luations 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)].

5.3       Hypersensitivity Reactions

Hypersensitivity reactions have been reported in Brineura-treated patients during the clinical studies. A total of 11 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. The signs and symptoms observed concomitantly with hypersensitivity reactions included pyrexia, vomiting, pleocytosis or irritability. Patients were routinely pre-medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of Brineura.

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