Included as part of the "PRECAUTIONS" Section
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]. 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]. 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].
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.
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]. 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].
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.
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]. 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].
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.
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.
Use In Specific Populations
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.
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.
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]. Safety and effectiveness in patients less than 3 years of age have not been established.