Brineura

1 INDICATIONS AND USAGE BRINEURA is indicated to slow the loss of ambulation in pediatric patients with neuronal ceroid lipofuscinosis type 2 (CLN2 disease), also known as tripeptidyl peptidase 1 (TPP1) deficiency. BRINEURA is a hydrolytic lysosomal N-terminal tripeptidyl peptidase indicated to slow the loss of ambulation in pediatric patients with neuronal ceroid lipofuscinosis type 2 (CLN2 disease), also known as tripeptidyl peptidase 1 (TPP1) deficiency. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. ( 2.1 ) BRINEURA should be administered by or under the supervision of a physician experienced in intraventricular administration. ( 2.1 ) Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended. ( 2.1 ) Prior to each infusion, inspect the scalp for signs of intraventricular access device reservoir leakage, failure, or potential infection. ( 2.1 ) Recommended BRINEURA dosage is 300 mg administered once every other week as an intraventricular infusion. In patients less than 2 years of age, lower doses are recommended. ( 2.2 ) Dosing is not recommended in patients less than 37 weeks post-menstrual age or those weighing less than 2.5 kg. ( 2.2 ) See the full prescribing information for dosage modifications due to hypersensitivity reactions. ( 2.3 ) See the full prescribing information for preparation and administration instructions. ( 2.4 , 2.6 ) 2.1 Recommendations Prior to BRINEURA Treatment Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate BRINEURA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1) ] . BRINEURA should be administered by or under the supervision of a physician experienced in intraventricular administration via a surgically implanted intraventricular access device system which consists of the reservoir and catheter components [see Dosage and Administration (2.6) ] . Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion [see Warnings and Precautions (5.1 , 5.5) ] . Aseptic technique must be strictly observed during preparation and administration [see Dosage and Administration (2.6) ] . Prior to each infusion of BRINEURA, inspect the scalp for signs of intraventricular access device reservoir leakage, failure or potential infection [see Warnings and Precautions (5.2 , 5.3) ] . Prior to each infusion of BRINEURA and when clinically indicated, obtain a sample of CSF for cell count and culture [see Warnings and Precautions (5.2) ] . Replace the intraventricular access device reservoir prior to 4 years of single-puncture administrations [see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage and Administration The recommended dosage of BRINEURA in pediatric patients is provided in Table 1. The dose is administered once every other week by intraventricular infusion. BRINEURA is not recommended in patients less than 37 weeks post-menstrual age (gestational age at birth plus post-natal age) or those weighing less than 2.5 kg [see Use in Specific Populations (8.4) ]. Administer BRINEURA first followed by infusion of the Intraventricular Electrolytes. The complete BRINEURA infusion, including the required infusion of Intraventricular Electrolytes, is approximately 2 to 4.5 hours, depending on the dose and volume administered. See Table 1 for the appropriate volume and infusion rate. For volumes that are not whole numbers, see Dosage and Administration (2.6) . Table 1: BRINEURA Dose, Volume, and Infusion Rate by Age Age groups BRINEURA dose administered every other week Volume of BRINEURA solution Infusion rate Birth to < 6 months 100 mg 3.3 mL 1.25 mL/hr 6 months to < 1 year 150 mg 5 mL 2.5 mL/hr 1 year to < 2 years 200 mg (first 4 doses) 6.7 mL (first 4 doses) 2.5 mL/hr 300 mg (subsequent doses) 10 mL (subsequent doses) 2 years and older 300 mg 10 mL 2.5 mL/hr Missed Dose If one or more doses are missed, restart BRINEURA treatment as soon as possible, maintaining the 2-week interval between infusions thereafter. 2.3 Administration Modificati…

5 WARNINGS AND PRECAUTIONS Meningitis and Other Intraventricular Access Device-Related Infections : Monitor the device insertion site for signs of infection. ( 4 , 5.2 ) Intraventricular Access Device-Related Complications : Consult a neurosurgeon for any complications with the implanted device. In case of device-related complication, discontinue the infusion and refer to the device labeling for further instructions. ( 4 , 5.3 ) Cardiovascular Adverse Reactions : Monitor vital signs before, during, and post-infusion. Monitor Electrocardiogram (ECG) in patients with a history of bradycardia, conduction disorder, or with structural heart disease, during the infusion. In patients without cardiac abnormalities, perform regular 12-lead ECG evaluations every 6 months. ( 2.5 , 5.4 ) Infusion-Associated Reactions (IARs) : If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics may ameliorate the symptoms. ( 5.5 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions including anaphylaxis have been reported in patients treated with enzyme replacement therapies, including BRINEURA . BRINEURA-treated patients have had these reactions occur in clinical studies and postmarketing use [see Adverse Reactions (6) ] . In clinical Trial 1 and Trial 2 to 96 weeks, a total of 11 of 24 (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 these patients, and they received subsequent BRINEURA infusions without recurrence of anaphylaxis. In Trial 3, hypersensitivity reactions were reported in 5 of 8 (63 %) patients less than 3 years of age at baseline as compared to 0 of 6 patients ≥ 3 years of age at baseline [see Adverse Reactions (6.1) ] . Of the reported hypersensitivity reactions, a single anaphylactic reaction occurred in a subject < 3 years of age. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of BRINEURA should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate BRINERUA in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion. Observe patients closely during and after the infusion. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue BRINEURA and immediately initiate appropriate medical treatment including use of epinephrine. Inform patients and caregivers of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should 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. 5.2 Meningitis and Other Intraven…

4 CONTRAINDICATIONS BRINEURA is contraindicated in patients with: any sign or symptom of acute, unresolved localized infection on or around the device insertion site (e.g., cellulitis or abscess); or suspected or confirmed CNS infection (e.g., cloudy CSF or positive CSF gram stain, or meningitis) [see Warnings and Precautions (5.2) ] . any acute intraventricular access device-related complication (e.g., leakage, extravasation of fluid, or device failure) [see Warnings and Precautions (5.3) ]. ventriculoperitoneal shunts. Any sign or symptom of acute or unresolved localized infection on or around the device insertion site (e.g. cellulitis or abscess); or suspected or confirmed CNS infection (e.g., cloudy CSF or positive CSF gram stain, or meningitis). ( 4 ) Any acute intraventricular access device-related complication (e.g., leakage, extravasation of fluid, or device failure). ( 4 ) Patients with ventriculoperitoneal shunts. ( 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.

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions (5.1) ] Meningitis and Other Intraventricular Access Device-Related Infections [see Warnings and Precautions (5.2) ] Intraventricular Access Device-Related Complications [see Warnings and Precautions (5.3) ] Cardiovascular Adverse Reactions [see Warnings and Precautions (5.4) ] Infusion-Associated Reactions [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥8%) are: pyrexia, ECG abnormalities, decreased CSF protein, vomiting, seizures, device-related complications, hypersensitivity, increased CSF protein, hematoma, headache, irritability, pleocytosis, device-related infections, bradycardia, feeling jittery, and hypotension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact BioMarin at 1-866-906-6100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Trial 1 and Trial 2 The safety of BRINEURA was evaluated in 24 patients with CLN2 disease who received at least one 300 mg dose of BRINEURA given by intraventricular infusion in a clinical trial with extension (Trials 1 and 2) of up to 161 weeks [see Clinical Studies (14) ] . Table 2 summarizes the most common adverse reactions that occurred in BRINEURA-treated patients through 96 weeks. Table 2: Adverse Reactions Reported in ≥ 8% of Symptomatic Pediatric Patients with CLN2 Disease in BRINEURA Trial 1 and Trial 2 at Week 96 Adverse Reaction Patients Treated with BRINEURA n=24 (%) Increased body temperature Increased body temperature includes: increased body temperature and pyrexia 17 (71) ECG abnormalities 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 17 (71) Decreased CSF protein 17 (71) Vomiting 15 (63) Seizures Seizures include: atonic, generalized tonic-clonic, focal, and absence 12 (50) Device-related complications Device-related complications include device-related infection, delivery system-related complications (needle issues, device leakage, device malfunction, device difficult to use, medical device site irritation, device breakage, etc.) and pleocytosis. 12 (50) Hypersensitivity Hypersensitivity includes only hypersensitivity [see Warnings and Precautions (5.4) ] 9 (38) Increased CSF protein 5 (21) Hematoma 5 (21) Headache 4 (17) Irritability 4 (17) Pleocytosis 4 (17) Device-related infections Device-related infections include: Propionibacterium acnes and Staphylococcus epidermidis 2 (8) Bradycardia 2 (8) Feeling jittery 2 (8) Hypotension 2 (8) Description of Selected Adverse Reactions from Trial 1 and Trial 2 at 96 weeks 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 ac…