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    Cerliponase alfa

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    Jul.18.2024

    Cerliponase alfa

    Indications/Dosage

    Labeled

    • late-infantile neuronal ceroid lipofuscinosis type 2

    Off-Label

      † Off-label indication

      For the treatment of patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a form of Batten disease

      NOTE: The FDA has designated cerliponase alfa as an orphan drug for this indication.

      Intraventricular dosage

      Children and Adolescents 3 to 17 years

      300 mg intraventricularly every other week. Administer cerliponase alfa first at an infusion rate of 2.5 mL/hour, then follow with the required infusion of Intraventricular Electrolytes at the same infusion rate of 2.5 mL/hour (complete infusion time is approximately 4.5 hours). Pre-treatment with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of the infusion.[61904]

      Therapeutic Drug Monitoring

      Maximum Dosage Limits

      • Adults

        Safety and efficacy have not been established.

      • Geriatric

        Safety and efficacy have not been established.

      • Adolescents

        300 mg/dose via intraventricular infusion once every other week.

      • Children

        3 to 12 years: 300 mg/dose via intraventricular infusion once every other week.

        younger than 3 years: Safety and efficacy have not been established.

      • Infants

        Safety and efficacy have not been established.

      • Neonates

        Safety and efficacy have not been established.

      Patients with Hepatic Impairment Dosing

      Specific guidelines for dosage adjustments in hepatic impairment are not available; cerliponase alfa has not been studied in patients with hepatic impairment.[61904]

      Patients with Renal Impairment Dosing

      Specific guidelines for dosage adjustments in renal impairment are not available; cerliponase alfa has not been studied in patients with renal impairment.[61904]

      † Off-label indication
      Revision Date: 07/18/2024, 09:38:24 AM

      References

      61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

      How Supplied

      Calcium Chloride, Magnesium Chloride, Potassium Chloride, Sodium Chloride, Sodium Phosphate, Dibasic, Heptahydrate, Sodium Phosphate, Monobasic, Sterile Water For Injection Solution for infusion, Cerliponase alfa Solution for infusion

      Brineura 150mg/5mL Solution for Injection (68135-0811) (BioMarin Pharmaceutical Inc) null

      Description/Classification

      Description

      Cerliponase alfa is an enzyme replacement therapy for the management of patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), a form of Batten disease. CLN2 is a rare, genetic, fatal neurodegenerative disease caused by a deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Cerliponase alfa is a recombinant form of TPP1 that is administered into the cerebrospinal fluid (CSF) by intraventricular infusion using a specific surgically implanted intraventricular access device. Patients must be monitored closely during administration for cardiac adverse events and/or hypersensitivity reactions. Premedication with antihistamines, antipyretics, and/or corticosteroids is recommended and resuscitative equipment should be readily available during administration.[61904] Cerliponase alfa is the first FDA-approved treatment indicated to slow loss of ambulation in symptomatic pediatric patients 3 years of age and older.

      Classifications

      • Alimentary Tract and Metabolism
        • Metabolic Disorder Agents
          • Lysosomal Storage Disorder Agents
            • Acid Sphingomyelinase Deficiency (ASMD) Agents
            • Alpha-mannosidosis Agents
            • Batten Disease Agents
            • Cystinosis Agents
            • Fabry Disease Agents
            • Gauchers Disease Agents
            • Mucopolysaccharidosis (MPS) Agents
            • Pompe Disease Agents
      Revision Date: 07/18/2024, 09:38:24 AM

      References

      61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

      Administration Information

      General Administration Information

      For storage information, see the specific product information within the How Supplied section.

      Route-Specific Administration

      Injectable Administration

      • Administer by intraventricular route using the provided Administration Kit.
      • Administration should be supervised by a health care provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate therapy in a health care setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment.
      • Visually inspect parenteral products for particulate matter and discoloration prior to administration. Cerliponase alfa is a clear to slightly opalescent and colorless to pale yellow solution. Intraventricular Electrolytes is a clear to colorless solution.
        • Cerliponase alfa may occasionally contain thin translucent fibers or opaque particles. These naturally occurring particles are cerliponase alfa and are removed via the 0.2 micron inline filter.
        • Intraventricular Electrolytes may contain particles, which appear during the thaw period; however, these will dissolve when the solution reaches room temperature.
      • Visually inspect the Administration Kit infusion components to ensure the components are in the individual packages and have not been compromised.[61904]

      Other Injectable Administration

      • Thaw cerliponase alfa and Intraventricular Electrolytes injection vials at room temperature for approximately 60 minutes; condensation will occur during thawing period. Do NOT thaw or warm vials any other way. Do NOT shake vials. Do NOT re-freeze vials or freeze syringes containing cerliponase alfa or Intraventricular Electrolytes.
      • Administer the complete infusion (cerliponase alfa and Intraventricular Electrolytes) using an infusion set with a 0.2 micron inline filter.[61904]

      Intraventricular Infusion of Cerliponase alfa

      • Administer pre-medication 30 to 60 minutes prior to the start of infusion.
      • Using aseptic technique, label 1 sterile syringe "Brineura" and attach the syringe needle.
      • After removing the green flip-off caps from the 2 cerliponase alfa vials, withdraw a total of 10 mL of cerliponase alfa into the "Brineura" labeled syringe. Do not dilute or mix with any other drug.
      • Label the infusion line "intraventricular infusion only," attach the syringe containing cerliponase alfa to the extension line, and then connect the extension line to the infusion set with a 0.2 micron inline filter. Prime the infusion components with cerliponase alfa.
      • Inspect scalp for signs of intraventricular access device leakage or failure and for potential infections. Then, prepare the scalp for intraventricular infusion per institution standard of care.
      • Insert port needle into intraventricular access device and connect a separate empty sterile single-use luer lock syringe (no larger than 3 mL) to the port needle. Withdraw 0.5 to 1 mL of cerebrospinal fluid (CSF) to check patency of intraventricular access device and send specimen for culture. Do NOT return CSF to intraventricular access device. Routinely send CSF samples for infection monitoring.
      • Attach the infusion set with 0.2 micron inline filter to the port needle and secure the components per institution standard of care.
      • Place the "Brineura" syringe into the syringe pump, program pump to deliver at an infusion rate of 2.5 mL/hour, and set the occlusion alarm setting to alert at pressure <= 281 mmHg. Do NOT deliver as a bolus or manually.
      • Monitor vital signs (blood pressure, heart rate) prior to the start of infusion, periodically during infusion, and post-infusion.
      • During infusion, periodically inspect the infusion system for signs of leakage or delivery failure.
      • When the infusion is complete, detach and remove the empty syringe from the pump and disconnect from the tubing.
      • Storage of thawed product: Use thawed cerliponase alfa immediately. If not used immediately, store unopened vials in the refrigerator at 2 to 8 degrees C and use within 24 hours.
      • Storage of product in syringes: Use product held in labeled syringes immediately. If not used immediately, store product held in labeled syringes in the refrigerator at 2 to 8 degrees C up to 4 hours prior to infusion.[61904]

      Intraventricular Infusion of Intraventricular Electrolytes

      • Intraventricular Electrolytes flush the infusion line, port needle, and intraventricular access device ensuring the full cerliponase alfa dose is administered and also maintain patency of the intraventricular access device.
      • Administer AFTER cerliponase alfa is complete.
      • Using aseptic technique, label 1 sterile syringe "Intraventricular Electrolytes" and attach the syringe needle.
      • After removing the yellow flip-off cap from the Intraventricular Electrolytes Injection vial, withdraw 2 mL of Intraventricular Electrolytes into the "Intraventricular Electrolytes" labeled syringe. Discard the remaining unused portion.
      • Attach syringe to the extension line.
      • Place the "Intraventricular Electrolytes" syringe into the syringe pump, program pump to deliver at an infusion rate of 2.5 mL/hour, and set the occlusion alarm setting to alert at pressure <= 281 mmHg. Do NOT deliver as a bolus or manually.
      • During infusion, periodically inspect the infusion system for signs of leakage or delivery failure.
      • When the infusion is complete, detach and remove the empty syringe from the pump and disconnect from the infusion line.
      • Remove the port needle and gently apply pressure. Bandage the infusion site per institution standard of care.
      • Dispose of the infusion components, needles, unused solutions, and other waste materials in accordance with local requirements.
      • Storage of thawed product: Use thawed Intraventricular Electrolytes immediately. If not used immediately, store unopened vials in the refrigerator at 2 to 8 degrees C and use within 24 hours.
      • Storage of product in syringes: Use product held in labeled syringes immediately. If not used immediately, store product held in labeled syringes in the refrigerator at 2 to 8 degrees C up to 4 hours prior to infusion.[61904]

      Clinical Pharmaceutics Information

      From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
        Revision Date: 07/18/2024, 09:38:24 AM

        References

        61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

        Adverse Reactions

        Moderate

        • antibody formation
        • hematoma
        • hypotension
        • hypoxia
        • sinus tachycardia
        • ST-T wave changes

        Mild

        • fever
        • headache
        • infection
        • irritability
        • vomiting

        Severe

        • anaphylactoid reactions
        • bradycardia
        • seizures

        ECG abnormalities, including non-specific repolarization abnormality, notched QRS segment elevation, ST-T wave changes (ST segment elevation and biphasic T wave abnormality), supraventricular extrasystoles, bradycardia (8%), sinus tachycardia, and intraventricular conduction delay, were reported in 17 of 24 (71%) patients treated with cerliponase alfa in a single-arm clinical study. Hypotension, which occurred during or up to 8 weeks after cerliponase alfa infusion, was reported in 8% of patients. Patients did not require alteration in treatment and reactions resolved spontaneously or after IV fluid administration. Monitor vital signs (blood pressure, heart rate) prior to cerliponase alfa infusion, periodically during infusion, and post-infusion in a health-care setting; continued monitoring may be necessary if clinically indicated. Additionally, monitor ECG during cerliponase alfa infusion in patients with a history of bradycardia, conduction disorder, or structural heart disease. In patients without cardiac abnormalities, monitor 12-lead ECG every 6 months.[61904]

        CNS adverse reactions, including seizures (50%), headache (17%), irritability (17%), and feeling jittery (8%), were reported in patients treated with cerliponase alfa in a single-arm clinical study (n = 24). Seizure types included atonic, generalized, tonic-clonic, focal, and absence. Seizures were managed with anticonvulsant therapy and did not require discontinuation of cerliponase alfa therapy.[61904]

        Hypersensitivity reactions occurred in 46% of patients treated with cerliponase alfa in a single-arm clinical study (n = 24), and anaphylactoid reactions have been reported during postmarketing surveillance. Patients experienced hypersensitivity reactions during the infusion or within 24 hours of infusion completion. Anaphylactic reactions were characterized by acute pyrexia, respiratory distress (bronchospasm, hypoxemia, perioral cyanosis), tachycardia, hypotension, diarrhea, and rash. Epinephrine was administered in 1 case. Patients received subsequent cerliponase alfa infusion without recurrence of anaphylaxis. In clinical trials, hypersensitivity reactions occurred despite pre-treatment with antihistamines, with or without antipyretics or corticosteroids. The most common reactions associated with hypersensitivity included fever with vomiting, pleocytosis, or irritability, which are not consistent with classic immune-mediated hypersensitivity. Symptoms resolved over time with administration of antipyretics, antihistamines, and/or corticosteroids; no patient discontinued cerliponase alfa treatment due to these reactions. Vomiting (63%) and pyrexia (71%) were also reported independently of hypersensitivity reactions. One patient developed hypoxia 8 hours after cerliponase alfa infusion and another patient developed decreased oxygen saturation during the infusion; symptoms resolved after oxygen administration in both patients.[61904]

        Device-related complications, including infection (8%), delivery system-related complications, and pleocytosis (4%), were reported in 50% of patients treated with cerliponase alfa in a single-arm clinical study (n = 24). Decreased CSF protein (71%) and increased CSF protein (21%) were also reported. Four patients had device-related adverse reactions that required medical intervention, including 2 patients with intraventricular access device-related CNS infections, and 1 patient each with leakage of the intraventricular access device and pleocytosis. Device-related infections were diagnosed by CSF pleocytosis and microbiology culture, without 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 cerliponase alfa treatment. Bacterial meningitis has been reported during postmarketing surveillance. Because signs and symptoms of device-related infections may not be apparent, CSF samples should be routinely sent for testing to detect subclinical device infections.[61904]

        Hematoma was reported in 21% of patients treated with cerliponase alfa in a single-arm clinical study (n = 24). The hematomas, which did not require treatment and did not interfere with the infusion, presented as hematoma, post procedural hematoma, traumatic hematoma, and subdural hematoma.[61904]

        As with all therapeutic proteins, there is a potential for immunogenicity with cerliponase alfa treatment. Anti-drug antibody formation was detected in serum and CSF in 79% and 33%, respectively, of patients treated with cerliponase alfa for up to 161 weeks. Patients who had hypersensitivity reactions to cerliponase alfa were tested for drug-specific IgE and found to be negative, including 3 patients who experienced severe (grade 3) hypersensitivity reactions. No association was found between serum or CSF anti-drug antibodies and incidence or severity of hypersensitivity. Drug-specific neutralizing antibodies have not been studied.[61904]

        Revision Date: 07/18/2024, 09:38:24 AM

        References

        61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

        Contraindications/Precautions

        Absolute contraindications are italicized.

        • infection
        • ventriculoperitoneal (VP) shunt
        • bradycardia
        • breast-feeding
        • cardiac disease
        • pregnancy
        • requires a specialized care setting
        • requires an experienced clinician
        • serious hypersensitivity reactions or anaphylaxis

        Cerliponase alfa is contraindicated in patients with a ventriculoperitoneal (VP) shunt and acute intraventricular access device-related complications (e.g., leakage, device failure, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). Material degradation of the intraventricular access device reservoir may occur after approximately 105 perforations; replacement of the device will likely be required after about 4 years of regular administration. Discontinue cerliponase alfa and refer to the device manufacturer's labeling for further instructions if there are intraventricular access device complications.[61904]

        Cerliponase alfa 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). Cerliponase alfa must be administered using aseptic technique to reduce the risk of infection. Inspect the scalp for skin integrity to ensure the intraventricular access device is not compromised prior to each infusion. Do not administer if there are localized signs of infection on or around the device insertion site, such as erythema, tenderness, discharge, or suspected or confirmed CNS infection. Since the signs and symptoms of device-related infections may not be apparent, CSF samples should routinely be sent for testing to detect subclinical device infections. Bacterial meningitis requiring antibiotic treatment and removal of the device was reported during postmarketing use of cerliponase alfa. During clinical trials and postmarketing use, other reports of device-related clinical infections were confirmed by positive CSF cultures and treated with antibiotics and removal of the device. In all cases, patients resumed treatment once the device was replaced.[61904]

        Administration of cerliponase alfa requires an experienced clinician skilled in aseptic technique and intraventricular administration. Since the signs and symptoms of infections may not be readily apparent in patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, cerliponase alfa should only be administered by, or under the direction of, a physician experienced in intraventricular administration to reduce the risk of infectious complications.[61904]

        Perform electrocardiogram (ECG) monitoring during infusion of cerliponase alfa in patients with a history of bradycardia, conduction disorder, or with structural heart disease, as some patients with neuronal ceroid lipofuscinosis type 2 (CLN2) disease may develop conductions disorders or cardiac disease. In patients without cardiac abnormalities, perform regular 12-lead ECG evaluations every 6 months. Routinely monitor vital signs (blood pressure, heart rate) in all patients before infusion starts, periodically during infusion, and post-infusion in a healthcare setting; hypotension has been reported during and after infusion. Clinically assess patient status after completion of infusion; continued observation may be necessary if clinically indicated.[61904]

        Cerliponase alfa is associated with a risk of serious hypersensitivity reactions or anaphylaxis. Anaphylaxis has occurred during the early course of therapy and after extended duration of therapy. The initiation of therapy requires a specialized care setting where appropriate medical monitoring and support measures, including cardiopulmonary resuscitation equipment, are available. Administration should be supervised by a health care provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Premedication with antihistamines, with or without antipyretics or corticosteroids, is recommended 30 to 60 minutes prior to cerliponase alfa infusion. Signs and symptoms observed concomitantly with hypersensitivity reactions include pyrexia, vomiting, pleocytosis, or irritability. If a severe hypersensitivity reaction or anaphylaxis occurs, immediately discontinue cerliponase alfa infusion and initiate appropriate medical treatment, including use of epinephrine. Observe patients closely during and after the infusion. Inform patients and/or 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 temporary interruption of the infusion, treatment with antihistamines, antipyretics, and/or corticosteroids, or discontinuation of the infusion. Resume subsequent infusions at approximately one-half the initial infusion rate at which the anaphylactic reaction occurred.[61904]

        There are no available data on cerliponase alfa use during pregnancy to inform a drug-associated risk of pregnancy-related outcomes. Animal studies have not been conducted using cerliponase alfa.[61904]

        There are no data on the presence of cerliponase alfa in human milk, the effects on a breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.[61904]

        Revision Date: 07/18/2024, 09:38:24 AM

        References

        61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

        Mechanism of Action

        Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a neurodegenerative disease caused by a 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 the enzyme in the central nervous system (CNS), leading to a progressive decline in motor function. Cerliponase alfa, a proenzyme, is a recombinant form of human TPP1. It 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.[61904]

        Revision Date: 07/18/2024, 09:38:24 AM

        References

        61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

        Pharmacokinetics

        Cerliponase alfa is administered as an intraventricular infusion. After the initial single dose administration, cerliponase alfa cerebrospinal fluid (CSF) exposure increased less than proportionally across the 3 doses studied (30 mg, 100 mg, and 300 mg). There was no apparent accumulation of cerliponase alfa in CSF or plasma when it was administered at a dose of 300 mg once every other week. The estimated CSF volume of distribution of cerliponase alfa 300 mg given intraventricularly is 245 mL, which exceeds the typical CSF volume of 100 mL. Cerliponase alfa is a protein and is expected to be degraded through peptide hydrolysis.[61904]

        Special Populations

        Pediatrics

        Cerliponase alfa pharmacokinetics have high inter- and intra-subject variability. Maximum plasma concentrations of cerliponase alfa after single and multiple doses are approximately 1 to 2 mcg/mL indicating minimal systemic absorption. The pharmacokinetic CSF parameters after intraventricular infusions of cerliponase alfa 300 mg once every other week are below:[61904]

         

        Day 1 (n = 13)

        Tmax (hours) = 4.5 [4.3, 5.8]

        Cmax (mcg/mL) = 1,260 [359, 4,380]

        AUC (hour x mcg/mL) = 9,290 [3,660, 19,000]

        Vd (mL) = 245 [78.4, 909]

        CL (mL/hour) = 32.3 [15.8, 81.9]

        t1/2 (hours) = 6.2 [5.5, 16.3]

         

        Week 5 (n = 14)

        Tmax (hours) = 4.3 [3.8, 4.5]

        Cmax (mcg/mL) = 1,630 [376, 4,670]

        AUC (hour x mcg/mL) = 12,400 [4,620, 26,200]

        Vd (mL) = 196 [85.4, 665]

        CL (mL/hour) = 24.2 [11.4, 64.9]

        t1/2 (hours) = 7.4 [3.3, 9.5]

         

        Week 13 (n = 13)

        Tmax (hours) = 4.3 [4, 4.5]

        Cmax (mcg/mL) = 1,390 [1,110, 2,340]

        AUC (hour x mcg/mL) = 10,500 [7,000, 18,200]

        Vd (mL) = 186 [131, 257]

        CL (mL/hour) = 28.7 [16.5, 42.9]

        t1/2 (hours) = 7.7 [5.1, 9.4]

        Revision Date: 07/18/2024, 09:38:24 AM

        References

        61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

        Pregnancy/Breast-feeding

        pregnancy

        There are no available data on cerliponase alfa use during pregnancy to inform a drug-associated risk of pregnancy-related outcomes. Animal studies have not been conducted using cerliponase alfa.[61904]

        breast-feeding

        There are no data on the presence of cerliponase alfa in human milk, the effects on a breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.[61904]

        Revision Date: 07/18/2024, 09:38:24 AM

        References

        61904 - Brineura (cerliponase alfa) package insert. Novato, CA: BioMarin Pharmaceutical Inc.; 2024 July.

        Interactions

        There are no drug interactions associated with Cerliponase alfa products.
        Revision Date: 07/18/2024, 09:38:24 AM

        References

        Monitoring Parameters

        • cerebrospinal fluid (CSF) assessment
        • ECG

        US Drug Names

        • Brineura
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