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.

{ "type": "p", "children": [], "text": "\nBRINEURA 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.\n" }

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).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 1: BRINEURA Dose, Volume, and Infusion Rate by Age</span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule"><span class="XmChange">Age groups</span></th><th align="center" class="Rrule">BRINEURA dose administered every other week</th><th align="center" class="Rrule">Volume of BRINEURA solution</th><th align="center" class="Rrule">Infusion rate</th> </tr> </thead> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule"><span class="XmChange">Birth to &lt; 6 months</span></td><td align="center" class="Rrule">100 mg</td><td align="center" class="Rrule">3.3 mL</td><td align="center" class="Rrule">1.25 mL/hr</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="XmChange">6 months to &lt; 1 year</span></td><td align="center" class="Rrule">150 mg</td><td align="center" class="Rrule">5 mL</td><td align="center" class="Rrule">2.5 mL/hr</td> </tr> <tr> <td align="center" class="Lrule Rrule"><span class="XmChange">1 year to &lt; 2 years</span></td><td align="center" class="Rrule">200 mg (first 4 doses)</td><td align="center" class="Rrule">6.7 mL (first 4 doses)</td><td align="center" class="Rrule">2.5 mL/hr</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"><span class="XmChange"> </span></td><td align="center" class="Rrule">300 mg (subsequent doses)</td><td align="center" class="Rrule">10 mL (subsequent doses)</td><td align="center" class="Rrule"></td> </tr> <tr class="Botrule Last"> <td align="center" class="Lrule Rrule"><span class="XmChange">2 years and older</span></td><td align="center" class="Rrule">300 mg</td><td align="center" class="Rrule">10 mL</td><td align="center" class="Rrule">2.5 mL/hr</td> </tr> </tbody> </table></div>

Missed Dose

If one or more doses are missed, restart BRINEURA treatment as soon as possible, maintaining the 2-week interval between infusions thereafter.

In the event of a severe hypersensitivity reaction (e.g., anaphylaxis), immediately discontinue BRINEURA administration and initiate appropriate medical treatment. If the decision is made to readminister BRINEURA after the occurrence of anaphylaxis, initiate the subsequent infusion at approximately one-half the infusion rate at which the anaphylactic reaction occurred with appropriate premedication. For additional recommendations in the event of a hypersensitivity reaction, see Warnings and Precautions (5.1).

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.

BRINEURA is administered into the cerebrospinal fluid (CSF) by infusion via a surgically implanted reservoir and catheter (the "intraventricular access device system"). 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 reservoir and catheter 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 (Product Code: 8713030U). If an alternative pump must be used, the essential performance requirements for this syringe pump used to deliver BRINEURA are as follows:

Administer BRINEURA and the Intraventricular Electrolytes using the provided Administration Kit for use with BRINEURA components [see How Supplied/Storage and Handling (16)].

Each infusion consists of 3.3 to 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.

Supplies for Infusion Preparation

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 20°C to 25°C (68°F to 77°F) 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.

Storage of Thawed Product

Use thawed BRINEURA and Intraventricular Electrolytes immediately. If thawed BRINEURA and Intraventricular Electrolytes is not used immediately, store in the refrigerator at 2°C to 8°C (36°F to 46°F) for no more than 24 hours. Discard the thawed product after 24 hours if refrigerated.

Storage of Product in Syringe

Use product held in labeled syringes immediately. If product held in labeled syringe is not used immediately, store in the refrigerator at 2°C to 8°C (36°F to 46°F) for no more than 4 hours prior to infusion. Discard the product held in labeled syringe after 4 hours if refrigerated.

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.

<div class="scrollingtable"><table class="Noautorules" width="100%"> <col align="center" valign="middle" width="100%"/> <tbody class="Headless"> <tr> <td align="center"><a name="fig1"></a><img alt="Figure 1" src="/dailymed/image.cfm?name=brineura-01.jpg&amp;setid=485ab3c5-0359-4878-872f-2fe1e7df4047"/></td> </tr> <tr> <td align="center"><span class="Bold">Figure 1</span></td> </tr> </tbody> </table></div>

Intraventricular Infusion of Intraventricular Electrolytes

Administer the Intraventricular Electrolytes provided after BRINEURA infusion is complete.

Dispose of the infusion components, needles, unused solutions and other waste materials in accordance with local requirements.

Injection: BRINEURA 150 mg/5 mL (30 mg/mL) solution, two single-dose vials per carton co-packaged with Intraventricular Electrolytes Injection 5 mL in a single-dose vial. BRINEURA is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution [see How Supplied/Storage and Handling (16)].

{ "type": "p", "children": [], "text": "Injection: BRINEURA 150 mg/5 mL (30 mg/mL) solution, two single-dose vials per carton co-packaged with Intraventricular Electrolytes Injection 5 mL in a single-dose vial. BRINEURA is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution [see How Supplied/Storage and Handling (16)]." }

BRINEURA is contraindicated in patients with:

{ "type": "p", "children": [], "text": "BRINEURA is contraindicated in patients with:" }

{ "type": "ul", "children": [ "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)].\n", "ventriculoperitoneal shunts." ], "text": "" }

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.

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 entire intraventricular access device, and in which patients resumed treatment with BRINEURA after the device was replaced [see Adverse Reactions (6.1)]. 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 supervision of, a physician experienced in intraventricular 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 (4)].

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.

During the clinical trials 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 (6.1)]. 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 (4)].

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.

Monitor vital signs (blood pressure, heart rate) before infusion starts, periodically during infusion, and post-infusion in a healthcare setting [see Dosage and Administration (2.6)]. 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 clinical Trial 1 and Trial 2 to 96 weeks, hypotension was reported in 2 of 24 (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)].

Infusion-associated reactions (IARs) such as vomiting, seizure, rash, pyrexia, hypersensitivity, and anaphylactic reaction have been observed in patients treated with BRINEURA [see Adverse Reactions (6.1)].

Premedication of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion. If an IAR occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administering antihistamines and/or antipyretics may ameliorate the symptoms. Closely monitor patients who have experienced IARs when re-administering BRINEURA.

In Trial 3, infusion-associated reactions were reported in 8 of 8 patients less than 3 years of age at baseline as compared to 4 of 6 patients ≥ 3 years of age at baseline.

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.

<div class="scrollingtable"><table width="75%"> <caption> <span>Table 2: Adverse Reactions Reported in ≥ 8% of Symptomatic Pediatric Patients with CLN2 Disease in BRINEURA Trial 1 and Trial 2 at Week 96</span> </caption> <col align="center" valign="top" width="55%"/> <col align="center" valign="top" width="45%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">Patients Treated with BRINEURA<br/>n=24 (%)</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="2"> <dl class="Footnote"> <dt> <a href="#footnote-reference-1" name="footnote-1">*</a> </dt> <dd>Increased body temperature includes: increased body temperature and pyrexia</dd> <dt> <a href="#footnote-reference-2" name="footnote-2">†</a> </dt> <dd>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</dd> <dt> <a href="#footnote-reference-3" name="footnote-3">‡</a> </dt> <dd>Seizures include: atonic, generalized tonic-clonic, focal, and absence</dd> <dt> <a href="#footnote-reference-4" name="footnote-4">§</a> </dt> <dd>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.</dd> <dt> <a href="#footnote-reference-5" name="footnote-5">¶</a> </dt> <dd>Hypersensitivity includes only hypersensitivity <span class="Italics">[see <a href="#S5.4">Warnings and Precautions (5.4)</a>]</span> </dd> <dt> <a href="#footnote-reference-6" name="footnote-6">#</a> </dt> <dd>Device-related infections include: <span class="Italics">Propionibacterium acnes</span> and <span class="Italics">Staphylococcus epidermidis</span> </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">Increased body temperature<a class="Sup" href="#footnote-1" name="footnote-reference-1">*</a></td><td align="center" class="Rrule">17 (71)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">ECG abnormalities<a class="Sup" href="#footnote-2" name="footnote-reference-2">†</a></td><td align="center" class="Rrule">17 (71)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Decreased CSF protein</td><td align="center" class="Rrule">17 (71)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">15 (63)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Seizures<a class="Sup" href="#footnote-3" name="footnote-reference-3">‡</a></td><td align="center" class="Rrule">12 (50)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Device-related complications<a class="Sup" href="#footnote-4" name="footnote-reference-4">§</a></td><td align="center" class="Rrule">12 (50)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Hypersensitivity<a class="Sup" href="#footnote-5" name="footnote-reference-5">¶</a></td><td align="center" class="Rrule">9 (38)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Increased CSF protein</td><td align="center" class="Rrule">5 (21)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Hematoma</td><td align="center" class="Rrule">5 (21)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">4 (17)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Irritability</td><td align="center" class="Rrule">4 (17)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Pleocytosis</td><td align="center" class="Rrule">4 (17)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Device-related infections<a class="Sup" href="#footnote-6" name="footnote-reference-6">#</a></td><td align="center" class="Rrule">2 (8)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Bradycardia</td><td align="center" class="Rrule">2 (8)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Feeling jittery</td><td align="center" class="Rrule">2 (8)</td> </tr> <tr class="Last"> <td align="center" class="Lrule Rrule">Hypotension</td><td align="center" class="Rrule">2 (8)</td> </tr> </tbody> </table></div>

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 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.

Hematoma

Hematoma adverse reactions were reported in 5 of 24 (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. 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.

Trial 3

Trial 3 enrolled 14 patients aged 1 to 6 years at baseline who received BRINEURA at the recommended dose based on the age of the patient, every other week for a median of 142 weeks. Adverse reactions that occurred in at least 5% of patients are described in Table 3.

The most frequent adverse reactions reported in patients < 3 years treated with BRINEURA were similar to those observed in patients ≥ 3 years of age except for hypersensitivity reactions, which were reported in 5 of 8 (63%) in patients < 3 years at baseline compared with 0 of 6 in patients ≥ 3 years of age at baseline. The most common manifestations of hypersensitivity were pyrexia and vomiting and the timing and resolution were similar to Trials 1 and 2. Symptoms of severe hypersensitivity reactions (e.g., anaphylaxis) included tachycardia, bronchospasm, rash, diarrhea, hypotension, increased body temperature and vomiting.

Drug-related IARs

In Trial 3, 12 patients (86%) who received BRINEURA had 83 IARs. Of those, 8 patients were < 3 years of age and 4 were ≥ 3 years of age. The symptoms occurring in more than one patient consisted of vomiting, seizure, rash, pyrexia, hypersensitivity, and abnormal electrocardiogram. Eight (57%) patients had serious IARs: pyrexia, hypersensitivity, anaphylactic reaction, seizure, and pleocytosis.

Device-related IARs

In Trial 3, 3 patients (21%) who received BRINEURA had 3 IARs related to the intraventricular device. Of those, 2 were < 3 years of age and 1 was ≥ 3 years of age. The events were: device leakage, device breakage, and CSF red blood cell count positive. One (7%) patient had a serious IAR of device leakage.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 3: Adverse Reactions Reported in ≥ 5% of Pediatric Patients (1 to 6 years of age) with CLN2 Disease treated with BRINEURA in Trial 3</span> </caption> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <col align="center" valign="top" width="25%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Adverse Reaction</th><th align="center" class="Rrule">Age 1 to 3 years <br/>n=8 (%)</th><th align="center" class="Rrule">Age 3 to 6 years<br/>n=6 (%)</th><th align="center" class="Rrule">Total<br/>n=14 (%)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="4">Note: Incidence numbers are based on baseline age group</td> </tr> <tr> <td align="left" colspan="4"> <dl class="Footnote"> <dt> <a href="#footnote-reference-7" name="footnote-7">*</a> </dt> <dd>ECG abnormalities include: non-specific repolarization abnormality, supraventricular extrasystoles, possible left ventricular hypertrophy, intermittent 2<span class="Sup">nd</span> degree AV Block (type 2 Mobitz), incomplete right bundle branch block, and prominent Q wave.</dd> <dt> <a href="#footnote-reference-8" name="footnote-8">†</a> </dt> <dd>Increased body temperature includes: increased body temperature and pyrexia.</dd> <dt> <a href="#footnote-reference-9" name="footnote-9">‡</a> </dt> <dd>Seizures include: atonic, febrile convulsion, generalized tonic-clonic, partial, partial with secondary generalization, petit mal epilepsy, myoclonic and status epilepticus.</dd> <dt> <a href="#footnote-reference-10" name="footnote-10">§</a> </dt> <dd>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.)</dd> <dt> <a href="#footnote-reference-11" name="footnote-11">¶</a> </dt> <dd>Hypersensitivity includes only the term of hypersensitivity</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="center" class="Lrule Rrule">ECG abnormalities<a class="Sup" href="#footnote-7" name="footnote-reference-7">*</a></td><td align="center" class="Rrule">8 (100)</td><td align="center" class="Rrule">6 (100)</td><td align="center" class="Rrule">14 (100)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Decreased CSF protein</td><td align="center" class="Rrule">8 (100)</td><td align="center" class="Rrule">4 (67)</td><td align="center" class="Rrule">12 (86)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Increased body temperature<a class="Sup" href="#footnote-8" name="footnote-reference-8">†</a></td><td align="center" class="Rrule">6 (75)</td><td align="center" class="Rrule">6 (100)</td><td align="center" class="Rrule">12 (86)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Seizures<a class="Sup" href="#footnote-9" name="footnote-reference-9">‡</a></td><td align="center" class="Rrule">4 (50)</td><td align="center" class="Rrule">4 (67)</td><td align="center" class="Rrule">8 (57)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Device-related complications<a class="Sup" href="#footnote-10" name="footnote-reference-10">§</a></td><td align="center" class="Rrule">3 (36)</td><td align="center" class="Rrule">2 (33)</td><td align="center" class="Rrule">5 (36)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Vomiting</td><td align="center" class="Rrule">2 (25)</td><td align="center" class="Rrule">3 (50)</td><td align="center" class="Rrule">5 (36)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Hypersensitivity<a class="Sup" href="#footnote-11" name="footnote-reference-11">¶</a></td><td align="center" class="Rrule">4 (50)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">4 (29)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Hematoma</td><td align="center" class="Rrule">2 (25)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">2 (14)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Increased CSF protein</td><td align="center" class="Rrule">1 (13)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (7)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Pleocytosis</td><td align="center" class="Rrule">1 (13)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (7)</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule">Irritability</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (17)</td><td align="center" class="Rrule">1 (7)</td> </tr> <tr class="Botrule Last"> <td align="center" class="Lrule Rrule">Headache</td><td align="center" class="Rrule">1 (13)</td><td align="center" class="Rrule">0</td><td align="center" class="Rrule">1 (7)</td> </tr> </tbody> </table></div>

The following adverse reactions have been identified during post-approval use of BRINEURA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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.

Risk Summary

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.

The safety and effectiveness of BRINEURA have been established to slow the loss of ambulation in pediatric patients with CLN2 disease and the information on this use is discussed throughout the labeling.

BRINEURA is not recommended for use 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 due to physiologic immaturity which may increase risk of serious and clinically significant adverse reactions observed with BRINEURA [see Warnings and Precautions (5)].

Patients less than 3 years of age may be at increased risk for developing hypersensitivity reactions with BRINEURA use compared to patients 3 years of age and older [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Cerliponase alfa is a purified human enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. The active substance is a recombinant human tripeptidyl peptidase-1 (rhTPP1), a lysosomal exopeptidase. The primary activity of the mature enzyme is the cleavage of N-terminal tripeptides from a broad range of protein substrates.

{ "type": "p", "children": [], "text": "Cerliponase alfa is a purified human enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. The active substance is a recombinant human tripeptidyl peptidase-1 (rhTPP1), a lysosomal exopeptidase. The primary activity of the mature enzyme is the cleavage of N-terminal tripeptides from a broad range of protein substrates." }

Cerliponase alfa contains 544 amino acids with an average molecular mass of 59 kDa. The mature enzyme is 368 amino acids in length. There are 5 consensus N-glycosylation sites on rhTPP1 that contain high mannose, phosphorylated high mannose and complex glycosylation structures.

{ "type": "p", "children": [], "text": "Cerliponase alfa contains 544 amino acids with an average molecular mass of 59 kDa. The mature enzyme is 368 amino acids in length. There are 5 consensus N-glycosylation sites on rhTPP1 that contain high mannose, phosphorylated high mannose and complex glycosylation structures." }

BRINEURA (cerliponase alfa) Injection and Intraventricular Electrolytes Injection are administered by intraventricular infusion. The solutions are sterile, nonpyrogenic, and free of foreign particulates. BRINEURA is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution.

{ "type": "p", "children": [], "text": "BRINEURA (cerliponase alfa) Injection and Intraventricular Electrolytes Injection are administered by intraventricular infusion. The solutions are sterile, nonpyrogenic, and free of foreign particulates. BRINEURA is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution." }

BRINEURA and Intraventricular Electrolytes Injection are packaged in 10 mL clear Type 1 single-dose glass vials [see How Supplied/Storage and Handling (16)]. Each vial of BRINEURA provides 5 mL of solution containing 150 mg cerliponase alfa. Each vial of Intraventricular Electrolytes Injection provides 5 mL of solution. Both BRINEURA and Intraventricular Electrolytes Injection are formulated with the following excipients: calcium chloride dihydrate (1.05 mg); magnesium chloride hexahydrate (0.8 mg); potassium chloride (1.1 mg); sodium chloride (43.85 mg); sodium phosphate, dibasic, heptahydrate (0.55 mg); sodium phosphate, monobasic, monohydrate (0.4 mg); and Water for Injection, USP. The pH of the solution is between 6.2 to 6.8 for BRINEURA, and between 6.0 to 7.0 for Intraventricular Electrolytes Injection.

{ "type": "p", "children": [], "text": "BRINEURA and Intraventricular Electrolytes Injection are packaged in 10 mL clear Type 1 single-dose glass vials [see How Supplied/Storage and Handling (16)]. Each vial of BRINEURA provides 5 mL of solution containing 150 mg cerliponase alfa. Each vial of Intraventricular Electrolytes Injection provides 5 mL of solution. Both BRINEURA and Intraventricular Electrolytes Injection are formulated with the following excipients: calcium chloride dihydrate (1.05 mg); magnesium chloride hexahydrate (0.8 mg); potassium chloride (1.1 mg); sodium chloride (43.85 mg); sodium phosphate, dibasic, heptahydrate (0.55 mg); sodium phosphate, monobasic, monohydrate (0.4 mg); and Water for Injection, USP. The pH of the solution is between 6.2 to 6.8 for BRINEURA, and between 6.0 to 7.0 for Intraventricular Electrolytes Injection." }

Each vial contains: sodium: 0.76 mEq, and potassium: 0.015 mEq.

{ "type": "p", "children": [], "text": "Each vial contains: sodium: 0.76 mEq, and potassium: 0.015 mEq." }

CLN2 disease is a neurodegenerative disease caused by deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1), which catabolizes polypeptides in the CNS. TPP1 has no known substrate specificity. Deficiency in TPP1 activity results in the accumulation of lysosomal storage materials normally metabolized by this enzyme in the central nervous system (CNS), leading to progressive decline in motor function.

Cerliponase alfa (rhTTP1), a proenzyme, is taken up by target cells in the CNS and is translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate Receptor (CI-MPR, also known as M6P/IGF2 receptor). Cerliponase alfa is activated in the lysosome and the activated proteolytic form of rhTPP1 cleaves tripeptides from the N-terminus of proteins.

No formal pharmacodynamic studies have been conducted with cerliponase alfa.

Patients 3 years of age and older

The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received intraventricular infusions of 30 mg (0.1 times the maximum approved recommended dosage), 100 mg (approximately 0.3 times the maximum approved recommended dosage), and 300 mg over approximately 4.5 hours once every other week.

Cerliponase alfa CSF exposure following the initial single dose administration of BRINEURA increased less than proportionally across doses of 30 mg, 100 mg, and 300 mg. There was no apparent accumulation of cerliponase alfa in CSF or plasma when BRINEURA was administered at a dose of 300 mg once every other week.

Cerliponase alfa pharmacokinetics have high inter-subject and intra-subject variability. Following intraventricular infusions of 300 mg of BRINEURA at Day 1, Week 5, and Week 13, the pharmacokinetic parameters in CSF and plasma were assessed in 14 patients and are summarized in Table 4.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 4: Pharmacokinetic Parameters of Cerliponase Alfa Following Intraventricular Infusion (approximately 4.5 hours in duration) of BRINEURA 300 mg Every Two Weeks in Patients ≥ 3 years</span> </caption> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="20%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First"> <th align="center" class="Lrule Rrule" rowspan="2"></th><th align="center" class="Rrule" rowspan="2">Parameter</th><th align="center" class="Botrule Rrule" colspan="3">Median [Min, Max]</th> </tr> <tr class="Last"> <th align="center" class="Lrule Rrule">Day 1</th><th align="center" class="Rrule">Week 5</th><th align="center" class="Rrule">Week 13</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-12" name="footnote-12">*</a> </dt> <dd>T<span class="Sub">max</span> expressed as time since start of ~4.5 hour infusion.</dd> <dt> <a href="#footnote-reference-13" name="footnote-13">†</a> </dt> <dd>V<span class="Sub">ss</span>, CL, and t<span class="Sub">1/2</span> were not estimated due to insufficient plasma pharmacokinetic data</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">13</td><td align="center" class="Botrule Rrule">14</td><td align="center" class="Botrule Rrule">13</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">T<span class="Sub">max</span><a class="Sup" href="#footnote-12" name="footnote-reference-12">*</a>, hr</td><td align="center" class="Botrule Rrule">4.5 [4.3, 5.8]</td><td align="center" class="Botrule Rrule">4.3 [3.8, 4.5]</td><td align="center" class="Botrule Rrule">4.3 [4.0, 4.5]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">1260 [359, 4380]</td><td align="center" class="Botrule Rrule">1630 [376, 4670]</td><td align="center" class="Botrule Rrule">1390 [1110, 2340]</td> </tr> <tr> <td align="center" class="Lrule Rrule"><span class="Bold">CSF</span></td><td align="center" class="Botrule Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Botrule Rrule">9290 [3660, 19000]</td><td align="center" class="Botrule Rrule">12400 [4620, 26200]</td><td align="center" class="Botrule Rrule">10500 [7000, 18200]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">V<span class="Sub">ss</span>, mL</td><td align="center" class="Botrule Rrule">245 [78.4, 909]</td><td align="center" class="Botrule Rrule">196 [85.4, 665]</td><td align="center" class="Botrule Rrule">186 [131, 257]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">CL, mL/hr</td><td align="center" class="Botrule Rrule">32.3 [15.8, 81.9]</td><td align="center" class="Botrule Rrule">24.2 [11.4, 64.9]</td><td align="center" class="Botrule Rrule">28.7 [16.5, 42.9]</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule">t<span class="Sub">1/2</span>, hr</td><td align="center" class="Rrule">6.2 [5.5, 16.3]</td><td align="center" class="Rrule">7.4 [3.3, 9.5]</td><td align="center" class="Rrule">7.7 [5.1, 9.4]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">9</td> </tr> <tr> <td align="center" class="Lrule Rrule"><span class="Bold">Plasma</span><a class="Sup" href="#footnote-13" name="footnote-reference-13">†</a></td><td align="center" class="Botrule Rrule">T<span class="Sub">max</span><a class="Sup" href="#footnote-12">*</a>, hr</td><td align="center" class="Botrule Rrule">12.0 [4.3, 24.5]</td><td align="center" class="Botrule Rrule">12.0 [7.5, 24.2]</td><td align="center" class="Botrule Rrule">12.3 [4.3, 75.9]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">1.3 [0.2, 3.9]</td><td align="center" class="Botrule Rrule">1.9 [0.2, 4.3]</td><td align="center" class="Botrule Rrule">1.0 [0.03, 2.6]</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Rrule">16.2 [1.1, 69.9]</td><td align="center" class="Rrule">40.1 [11.1, 78.9]</td><td align="center" class="Rrule">9.5 [0.2, 51.6]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">11</td><td align="center" class="Botrule Rrule">12</td><td align="center" class="Botrule Rrule">9</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule" rowspan="2"><span class="Bold">CSF/Plasma Ratio</span></td><td align="center" class="Rrule">C<span class="Sub">max</span></td><td align="center" class="Rrule">1200 [305, 4530]</td><td align="center" class="Rrule">809 [202, 9370]</td><td align="center" class="Rrule">1320 [541, 51200]</td> </tr> <tr class="Last"> <td align="center" class="Rrule">AUC<span class="Sub">0-t</span></td><td align="center" class="Rrule">393 [115, 1910]</td><td align="center" class="Rrule">340 [126, 1780]</td><td align="center" class="Rrule">1330 [167, 38900]</td> </tr> </tbody> </table></div>

The estimated CSF volume of distribution of cerliponase alfa following intraventricular infusion of 300 mg of BRINEURA (median Vss = 245 mL) exceeds the typical CSF volume (100 mL).

Pediatric patients less than 3 years

Pediatric CLN2 patients ages 1 to < 2 years (n=2) and 2 to < 3 years (n=6) were administered cerliponase alfa according to the recommended dosing regimen based on age for up to 144 weeks. CSF exposure with 300 mg cerliponase alfa was within the range characterized to be safe and effective in pivotal Trial 1.

Plasma exposure in younger patients trended higher than the range characterized in the pivotal study. The pharmacokinetic parameters summarized by age at time of visit and dose are shown in Table 5.

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 5: Pharmacokinetic Parameters of Cerliponase Alfa by Age at Visit and Dose Following Intraventricular Infusion of BRINEURA Every Two Weeks in Pediatric Patients &lt; 3 years</span> </caption> <col align="center" valign="top" width="12%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="14%"/> <col align="center" valign="top" width="30%"/> <col align="center" valign="top" width="30%"/> <thead> <tr class="First Last"> <th align="center" class="Lrule Rrule">Age at Visit</th><th align="center" class="Rrule">Dose<br/>(mg)</th><th align="center" class="Rrule"></th><th align="center" class="Rrule">Parameter</th><th align="center" class="Rrule">Median [Min, Max]</th> </tr> </thead> <tfoot> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-14" name="footnote-14">*</a> </dt> <dd>N=1 due to less than 3 evaluable datapoints for determination of AUC<span class="Sub">0-t</span> </dd> <dt> <a href="#footnote-reference-15" name="footnote-15">†</a> </dt> <dd>N=5 due to less than 3 evaluable datapoints for determination of AUC<span class="Sub">0-t</span> </dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="First"> <td align="center" class="Lrule Rrule" rowspan="2"><span class="Bold">1 to &lt; 2 years</span></td><td align="center" class="Rrule"><span class="Bold">200</span></td><td align="center" class="Rrule"><span class="Bold">CSF</span></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">3</td> </tr> <tr> <td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">511 [163, 987]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Botrule Rrule">2720 [1100, 5050]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"><span class="Bold">Plasma</span></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">10.4 [9.46, 11.3]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Botrule Rrule">91.8 [72.7, 111]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"><span class="Bold"><span class="Bold">300</span></span></td><td align="center" class="Rrule"><span class="Bold"><span class="Bold">CSF</span></span></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">566 [496, 636]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Botrule Rrule">8030 [8030, 8030]<a class="Sup" href="#footnote-14" name="footnote-reference-14">*</a></td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"><span class="Bold">Plasma</span></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">2</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">14.1 [11.2, 17.0]</td> </tr> <tr class="Botrule"> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Rrule">145 [82.7, 206]</td> </tr> <tr> <td align="center" class="Lrule Rrule" rowspan="2"><span class="Bold">2 to &lt; 3 years</span></td><td align="center" class="Rrule"><span class="Bold">300</span></td><td align="center" class="Rrule"><span class="Bold">CSF</span></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">896 [508, 1790]</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule"></td><td align="center" class="Botrule Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Botrule Rrule">4100 [2380, 6720]<a class="Sup" href="#footnote-15" name="footnote-reference-15">†</a></td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"><span class="Bold">Plasma</span></td><td align="center" class="Botrule Rrule">N</td><td align="center" class="Botrule Rrule">6</td> </tr> <tr> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Botrule Rrule">C<span class="Sub">max</span>, mcg/mL</td><td align="center" class="Botrule Rrule">14.9 [9.08, 35.3]</td> </tr> <tr class="Botrule Last"> <td align="center" class="Lrule Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule"></td><td align="center" class="Rrule">AUC<span class="Sub">0-t</span>, mcg-hr/mL</td><td align="center" class="Rrule">163 [91.5, 320]</td> </tr> </tbody> </table></div>

Cerliponase alfa is a protein and is expected to be degraded through peptide hydrolysis.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies including cerliponase alfa.

In Trials 1 and 2 [see Clinical Studies (14)], 19 of 24 (79%) and 10 of 24 (42%) patients treated with BRINEURA developed anti-drug antibodies (ADAs) in serum and CSF, respectively. Drug-specific neutralizing antibodies (NAb) capable of inhibiting receptor-mediated cellular uptake of cerliponase alfa were detected in the CSF of 3 of 24 (13%) patients at a single visit and were undetectable in all other CSF samples tested in ADA positive patients. In Trial 3 [see Clinical Studies (14)], 14 of 14 (100%) and 3 of 14 (21%, all of the 3 patients were < 3 years of age) patients treated with BRINEURA developed ADAs in serum and CSF, respectively. NAb responses were not detected in the CSF of any ADA positive patients. Overall, patients younger than 3 years of age had higher ADA titers compared to patients 3 years of age and older.

In Trials 1 and 2, patients who experienced moderate to severe hypersensitivity adverse reactions were tested for drug-specific IgE and found to be negative. No association was found between serum ADA titers and incidence or severity of hypersensitivity. In Trial 3, hypersensitivity occurred in higher percentage in BRINEURA-treated patients < 3 years of age at baseline (amongst these patients, one patient experienced anaphylaxis), and higher ADA titers were also observed in this age group compared to patients ≥ 3 years of age at baseline. There was no identified clinically significant effect of ADA on pharmacokinetics or efficacy of BRINEURA. There is insufficient information to characterize the effects of ADA on safety.

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.

Descriptive non-randomized comparison

In an unadjusted non-randomized comparison, of the 22 patients treated with BRINEURA and evaluated for efficacy at week 96, 21 (95%) did not decline, and only the patient who terminated early was deemed to have a decline in the Motor domain of the CLN2 Clinical Rating Scale. Results from the natural history cohort demonstrated progressive decline in motor function; of the 42 patients in the natural history cohort, 21 (50%) experienced an unreversed (sustained) 2-category decline or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale over 96 weeks.

Given the non-randomized study design, a Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype was used to evaluate time to unreversed 2-category decline or unreversed score of 0 in the Motor domain. This model showed a lesser decrease in motor function in the BRINEURA-treated patients when compared to the natural history cohort (see Figure 7).

<div class="scrollingtable"><table class="Noautorules" width="100%"> <caption> <span>Figure 7. Estimated Time to Unreversed (Sustained) 2-Category Decline or Unreversed Score of Zero in Motor Domain for Symptomatic Pediatric Patients in the BRINEURA Trials 1 and 2 at 96 Weeks and for Patients in a Natural History Cohort (Based on the Cox Proportional Hazards Model Adjusting for Covariates)</span> </caption> <col align="center" valign="top" width="100%"/> <tfoot> <tr> <td align="left">Shading represents 95% confidence intervals.<br/>Follow-up for the natural history cohort begins at 36 months of age or greater and at the first time a Motor plus Language CLN2 score less than 6 was recorded.<br/>The BRINEURA-treated population is the full population (N=24) minus two patients with baseline Motor plus Language CLN2 score = 6.<br/>Covariates: screening age, screening Motor score, genotype: 0 key mutations (yes/no). "Screening age" was defined in the natural history cohort as the age at the first time a Motor plus Language CLN2 score less than 6 was recorded, and no earlier than 36 months of age. The "screening Motor score" of the natural history cohort was defined as the Motor score at the screening age. <br/>Decline is defined as an unreversed (sustained) 2-category decline or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.</td> </tr> </tfoot> <tbody class="Headless"> <tr> <td align="left"> <p class="First"> <img alt="Figure 7" src="/dailymed/image.cfm?name=brineura-07.jpg&amp;setid=485ab3c5-0359-4878-872f-2fe1e7df4047"/></p> </td> </tr> </tbody> </table></div>

Motor Domain Scores: Matched Patients Only

To further assess efficacy, the 22 patients from the BRINEURA clinical study with a baseline combined Motor plus Language CLN2 score less than 6 were matched to 42 patients in the natural history cohort. Patients were matched based on the following covariates: baseline age at time of screening within 3 months, genotype (0, 1, or 2 key mutations), and baseline Motor domain CLN2 score at time of screening.

Using the Motor domain of the CLN2 Clinical Rating Scale, decline was defined as having an unreversed 2-category decline or an unreversed score of 0. At 96 weeks, the matched analysis based on 17 pairs demonstrated fewer declines in the Motor domain for BRINEURA-treated patients compared to untreated patients in the natural history cohort (see Table 6).

<div class="scrollingtable"><table width="85%"> <caption> <span>Table 6: Proportion of Matched Symptomatic Pediatric Patients with CLN2 Disease without Decline<a class="Sup" href="#footnote-16" name="footnote-reference-16">*</a> in the BRINEURA Trials 1 and 2 and in the Natural History Cohort assessed at Weeks 48, 72, and 96</span> </caption> <col align="left" valign="top" width="22%"/> <col align="center" valign="top" width="22%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="17%"/> <col align="center" valign="top" width="22%"/> <thead> <tr class="First"> <th align="left" class="Lrule Rrule" rowspan="2">Time Point/Period</th><th align="center" class="Botrule Rrule">Natural History Cohort<br/>(N=17)</th><th align="center" class="Botrule Rrule">BRINEURA-Treated (N=17)</th><th align="center" class="Botrule Rrule">Difference</th><th align="center" class="Botrule Rrule">Odds Ratio<a class="Sup" href="#footnote-17" name="footnote-reference-17">†</a></th> </tr> <tr class="Last"> <th align="center" class="Rrule">n (%)</th><th align="center" class="Rrule">n (%)</th><th align="center" class="Rrule">% (95% CI<a class="Sup" href="#footnote-18" name="footnote-reference-18">‡</a>)</th><th align="center" class="Rrule">OR (95% CI)</th> </tr> </thead> <tfoot> <tr class="First Last"> <td align="left" colspan="5" valign="top">Matched on baseline age at time of screening within 3 months, genotype (0, 1, or 2 key mutations), and baseline Motor domain CLN2 score at time of screening. <br/>The BRINEURA-treated population is based on the full population minus two patients with baseline Motor plus Language CLN2 score = 6.</td> </tr> <tr> <td align="left" colspan="5"> <dl class="Footnote"> <dt> <a href="#footnote-reference-16" name="footnote-16">*</a> </dt> <dd>Decline is defined as an unreversed (sustained) 2-category decline or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale.</dd> <dt> <a href="#footnote-reference-17" name="footnote-17">†</a> </dt> <dd>Based on McNemar's Exact test</dd> <dt> <a href="#footnote-reference-18" name="footnote-18">‡</a> </dt> <dd>Exact confidence interval for risk difference (Santner and Snell)</dd> </dl> </td> </tr> </tfoot> <tbody> <tr class="Botrule First"> <td align="left" class="Lrule Rrule">Follow-up through Week 48</td><td align="center" class="Rrule">13 (76)</td><td align="center" class="Rrule">16 (94)</td><td align="center" class="Rrule">18% (-19, 51)</td><td align="center" class="Rrule">4 (0.4, 200)</td> </tr> <tr class="Botrule"> <td align="left" class="Lrule Rrule">Follow-up through Week 72</td><td align="center" class="Rrule">11 (65)</td><td align="center" class="Rrule">16 (94)</td><td align="center" class="Rrule">29% (-7, 61)</td><td align="center" class="Rrule">5.9 (0.7, 250)</td> </tr> <tr class="Last"> <td align="left" class="Lrule Rrule">Follow-up through Week 96</td><td align="center" class="Rrule">6 (35)</td><td align="center" class="Rrule">16 (94)</td><td align="center" class="Rrule">59% (24, 83)</td><td align="center" class="Rrule">11 (1.6, 500)</td> </tr> </tbody> </table></div>

Trial 3 (NCT02678689) was a Phase 2, open label clinical study designed to enroll symptomatic and presymptomatic CLN2 patients less than 18 years of age. The trial enrolled 14 patients ranging in age from 1 to 6 years at baseline, including 8 patients less than 3 years of age, the median age was 2.7 years. Patients received BRINEURA at the recommended dose every 2 weeks by intraventricular infusion for 144 weeks (1 patient withdrew to receive treatment commercially). Fifty-seven percent of patients were female and 43% were male. All patients were White; for ethnicity, 14% identified as Hispanic/Latino, 86% as non-Hispanic/Latino. The mean baseline CLN2 Motor score was 2.3 (standard deviation (SD) 0.83) with a range from 1 to 3.

Thirteen of the 14 BRINEURA treated patients were matched with up to 3 natural history comparators on the basis of age within 3 months, equal CLN2 Motor score, and genotype (0, 1, or 2 key mutations). None of the BRINEURA treated patients (N=14) had a 2-point decline or score of zero in the Motor scale by Week 169. Among the matched natural history comparators (N=31), 20 subjects (65%) had an unreversed 2-point decline or score of zero by last assessment.

The median time to an unreversed 2-point decline in Motor score or score of 0 was 133 weeks among the natural history comparators and was not reached by last assessment (Week 169) in patients treated with BRINEURA.

In patients below 3 years of age, none (0%) of the BRINEURA treated patients (N=8) had a 2-point decline or score of zero in the Motor score by Week 169. Among the 8 treated patients, 7 were matched to 18 untreated patients from the natural history cohort. Among the matched natural history comparators (N=18), 11 subjects (61%) had an unreversed 2-point decline or score of zero in the Motor score by last assessment. All seven of the treated patients below 3 years of age with a motor score of 3 at baseline remained at a motor score of 3 at the last measured timepoint, which represents grossly normal gait. In this population BRINEURA treated patients showed a delay in disease onset.

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.

<div class="scrollingtable"><table width="85%"> <col align="left" valign="top" width="80%"/> <col align="left" valign="top" width="20%"/> <thead> <tr class="First Last"> <th align="left" class="Lrule Rrule">Contents of Package 1</th><th align="left" class="Rrule">NDC Number</th> </tr> </thead> <tbody> <tr class="First Last"> <td align="left" class="Lrule Rrule">BRINEURA (cerliponase alfa) Injection (2 vials of 150 mg/5 mL)<br/>Intraventricular Electrolytes Injection (1 vial, 5 mL)</td><td align="left" class="Rrule">68135-811-02</td> </tr> </tbody> </table></div>

Package 2 of 2

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

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.

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Manufactured by:BioMarin Pharmaceutical Inc.Novato, CA 94949US License Number 16491-866-906-6100 (phone)

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Codman® and the B Braun Perfusor® are the registered trademarks of their respective owners and are not trademarks of BioMarin® Pharmaceutical Inc.

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NDC 68135-811-02

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Brineura® (cerliponase alfa)Injection

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150 mg/5 mL (30 mg/mL)

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For Intraventricular Infusion Only

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Each vial of Brineura® contains 150 mg cerliponase alfain 5 mL of solution (30 mg/mL)

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No preservativesSingle-Dose Vial. Discard unused portion.

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Brineura® and Intraventricular Electrolytes must beadministered with the Administration Kit provided.

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Each carton contains:2 vials, each containing Brineura® (cerliponase alfa) Injection, 150 mg/5 mL1 vial of Intraventricular ElectrolytesInjection, 5 mL

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Package 1 of 2

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Administration Kit is suppliedand stored separately aspackage 2 of 2.

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Rx Only

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BIOMARIN®

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Brineura® (cerliponase alfa)Injection

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150 mg/5 mL(30 mg/mL)

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For Intraventricular Infusion OnlyUse before IntraventricularElectrolytes

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IntraventricularElectrolytes

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Injection

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Use after Brineura® (cerliponase alfa)

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5 mL

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For IntraventricularInfusion Only

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Administration Kit for use with Brineura® (cerliponase alfa)Intraventricular infusion only

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Recommended Dosage: See Prescribing Information

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Contents of Administration Kit:

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Package 2 of 2

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Brineura® and Intraventricular Electrolytes Injection are separately supplied andstored frozen as package 1 of 2Not for resaleOnly for use with Brineura®

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Caution:

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NOTE:

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Manufactured forBioMarin Pharmaceutical Inc.Novato, CA 94949www.bmrn.com

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Rx Only

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BIOMARIN®

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