Brineura

The following adverse reactions are described below and elsewhere in the labeling:

• Intraventricular Access Device-Related Complications [see WARNINGS AND PRECAUTIONS]
• Cardiovascular Adverse Reactions [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

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]. 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

Description Of Selected Adverse Reactions

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.

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 of these patients (38%) experienced adverse reactions, which involved complications of the non-implanted delivery system components. Four 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].

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 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]. 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.

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.

• Intraventricular Access Device-Related Complications
  Advise patients and caregivers of the risk of device-related infections. If any signs of infection are present, instruct patients to immediately contact their healthcare provider [see WARNINGS AND PRECAUTIONS].
• Cardiovascular Adverse Reactions
  Advise patients and caregivers that hypotension and/or bradycardia may occur during and following the infusion of Brineura. Instruct patients immediately to contact their healthcare provider if these reactions occur [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions
  Advise patients and caregivers that hypersensitivity reactions related to Brineura treatment, including fever, vomiting, and irritability may occur. Due to the potential for anaphylaxis, inform patients and caregivers of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur [see WARNINGS AND PRECAUTIONS].

Your child should not be treated with cerliponase alfa if he or she is allergic to it, or if the child has:

• complications with the surgically implanted catheter used to deliver this medicine; or

• a shunt in the brain (to help drain fluid build-up around the brain).

To make sure cerliponase alfa is safe for your child, tell your doctor if the child has ever had:

• slow heartbeats;

• a heart defect; or

• heart rhythm problems.

Cerliponase alfa is not approved for use by anyone younger than 3 years old.

Your child's caregivers will manage and monitor all medications given to the child during treatment with this medicine. A drug interaction between cerliponase alfa and other medications is not expected to occur.

Do not give any medications to your child that have not been prescribed by your doctor. This includes vitamins, minerals, or herbal products.

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly. Blood tests may be needed to check for unwanted effects.

This medicine may cause serious types of allergic reactions, including infusion reaction and anaphylaxis. These can be life-threatening and require immediate medical attention. Tell your doctor right away if you or your child start to have cough, trouble breathing, hives, itching, or skin rash, lightheadedness, dizziness, or fainting, tightness in the chest, or swelling of the face or lips.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

The following adverse reactions are described below and elsewhere in the labeling:

• Intraventricular Access Device-Related Complications [see Warnings and Precautions (5.1)]

• Cardiovascular Adverse Reactions [see Warnings and Precautions (5.2)]

• Hypersensitivity Reactions [see Warnings and Precautions (5.3)]

    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

*Pyrexia includes: pyrexia and increased body temperature

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

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

§Hypersensitivity includes: immune reactions and signs and symptoms observed concomitantly with hypersensitivity reactions including pyrexia, vomiting, pleocytosis or irritability

¶Device-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 of these patients (38%) experienced adverse reactions, which involved complications of the non-implanted delivery system components. Four 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)].

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.

    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.

Brineura is supplied as a sterile, clear to slightly opalescent and colorless to pale yellow solution for intraventricular infusion and Intraventricular Electrolytes Injection is supplied as a clear to colorless solution for intraventricular infusion; both are included in package 1 of 2. The Administration Kit for use with Brineura is supplied separately as package 2 of 2 [see Dosage and Administration (2.2)].

Package 1 of 2

Each Brineura (cerliponase alfa) Injection vial has a green flip‑off cap (plastic), and contains 150 mg cerliponase alfa per 5 mL (30 mg/mL).

Each Intraventricular Electrolytes Injection vial has a yellow flip‑off cap (plastic), and contains 5 mL of solution.

Package 2 of 2

The Administration Kit for use with Brineura is supplied separately and contains the following single-use, sterile infusion components:

• Two 20-mL syringes
• Two syringe needles (21 G, 25.4 mm)
• One extension line
• One infusion set with 0.2 micron inline filter
• One port needle (22 G, 16 mm)

Storage

Brineura (cerliponase alfa) Injection and Intraventricular Electrolytes Injection:

Store upright in a freezer (‑25°C to ‑15°C) in original carton to protect from light.

Administration Kit for use with Brineura:

Store in original carton separately from Brineura. Do not freeze.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Your child's caregivers will manage and monitor all medications given to the child during treatment with this medicine. A drug interaction between cerliponase alfa and other medications is not expected to occur.

Do not give any medications to your child that have not been prescribed by your doctor. This includes vitamins, minerals, or herbal products.

Applies to cerliponase alfa: injectable kit

General

The most frequently reported side effects were pyrexia, ECG abnormalities, decreased cerebrospinal fluid (CSF) protein, vomiting, seizures, hypersensitivity, increased CSF protein, hematoma, headache, irritability, pleocytosis, device-related infection, bradycardia, feeling jittery, and hypotension.[Ref]

Cardiovascular

Very common (10% or more): ECG abnormalities (71%), hematoma (21%)
Common (1% to 10%): Bradycardia, hypotension[Ref]

ECG abnormalities occurred in 71% of symptomatic pediatric patients during clinical studies and included non-specific repolarization abnormality, notched QRS, ST segment elevation, biphasic T wave abnormality, supraventricular asystole, bradycardia, sinus tachycardia, and intraventricular conduction delay.

Hematoma occurred in 21% of symptomatic pediatric patients during clinical trials and included hematoma, post-procedural hematoma, traumatic hematoma, and subdural hematoma, none of which required treatment and did not interfere with infusion.[Ref]

Nervous system

Very common (10% or more): Seizure (50%), headache (17%), pleocytosis (17%)[Ref]

Seizures occurred in 50% of symptomatic pediatric patients during clinical studies and included atonic, generalized tonic-clonic, focal, and absence seizure.[Ref]

Local

Very common (10% or more): Device-related complication (50%)
Common (1% to 10%): Device-related infection[Ref]

Device-related adverse reactions occurred in 50% of symptomatic pediatric patients during clinical studies and included infection (e.g., Propionibacterium acnes, Staphylococcus epidermidis), deliver system-related complications, and pleocytosis. Complications of the non-implanted delivery system components occurred in 9 of these patients (38%). Four patients (16%) had device-related adverse reactions that required medical intervention including 2 patients (8%) with intraventricular access device-related central nervous system infections and 1 patient (4%) each with leakage of the intraventricular access device and pleocytosis.[Ref]

Gastrointestinal

Very common (10% or more): Vomiting (63%)[Ref]

Other

Very common (10% or more): Pyrexia (71%), CSF protein decreased (71%), CSF protein increased (21%)
Common (1% to 10%): Feeling jittery[Ref]

Immunologic

Antidrug antibodies (ADAs) were detected in both serum and CSF in 79% and 33%, respectively, of patients treated with this drug for up to 161 weeks. Patients who experienced hypersensitivity reactions were tested for drug-specific IgE and were found to be negative, including 3 patients who reported grade 3 (severe) hypersensitivity reactions. No association has been found between serum CSF ADA titers and incidence/severity of hypersensitivity.[Ref]

Very common (10% or more): Antidrug antibodies developed (up to 79%), hypersensitivity (46%)[Ref]

Psychiatric

Very common (10% or more): Irritability (17%)[Ref]

Respiratory

Frequency not reported: Hypoxia[Ref]

Some side effects of Brineura may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.