Posology : מינונים

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 have 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           Volume of Brineura solution other week                               (ml)
(mg)
Birth to < 6 months                            100                                     3.3 6 months to < 1 year                           150                                       5 1 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


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 the medicinal product 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 the medicinal product and the flushing solution is 2.5 ml/hour. The complete infusion time, including the medicinal product and the required flushing solution, is approximately 2 to 4.5 hours, depending on the dose and volume administered.

Intracerebroventricular infusion of Brineura

Administer Brineura before the flushing solution.
1. Label the infusion line for “Intracerebroventricular infusion only”.
2. Attach the syringe containing Brineura to the extension line, if used, otherwise connect the syringe to the infusion set. The infusion set must be equipped with a 0.2 µm inline filter. See Figure 1.
3. Prime the infusion components with Brineura.
4. Inspect the scalp for signs of intracerebroventricular access device leakage or failure and for potential infections. Do not administer Brineura if there are signs and symptoms of acute intracerebroventricular access device leakage, device failure, or device-related infection (see sections 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.