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Cerliponase Alfa

Class: Enzymes
Chemical Name: I tripeptidyl aminopeptidase
Molecular Formula: C2657H4042N734O793S11
CAS Number: 151662-36-1
Brands: Brineura

Medically reviewed on Dec 18, 2017

Introduction

Biosynthetic (recombinant DNA origin) form of human tripeptidyl peptidase-1 (TPP1), a lysosomal enzyme that catabolizes polypeptides in the CNS.1 5

Uses for Cerliponase Alfa

Late Infantile Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease

Used to slow the loss of ambulation in symptomatic pediatric patients with late infantile CLN2 disease, also known as TPP1 deficiency.1

Beneficial effects on motor symptoms demonstrated; effects on verbal manifestations of the disease not established.1 3

Designated an orphan drug by FDA for use in this disease.2

Cerliponase Alfa Dosage and Administration

General

  • Administer by or under the direction of a clinician knowledgeable in intraventricular administration.1

  • Take special precautions (e.g., strict aseptic technique, labeling of syringes and infusion lines) to minimize potential for device-related complications and administration errors.1 For specific procedures and techniques of administration, consult manufacturer's full prescribing information.1

  • Monitor vital signs (e.g., BP, heart rate) prior to, periodically during, and after infusion.1

  • Monitor for hypersensitivity reactions.1 Pretreatment with antihistamines with or without antipyretics or corticosteroids recommended 30–60 minutes prior to start of infusion.1

Administration

Intraventricular Administration

Administer directly into CSF by intraventricular infusion via a surgically implanted intraventricular access device (reservoir [Codman Holter Rickham reservoir] and catheter [Codman ventricular catheter]); intraventricular access device must be implanted prior to (manufacturer recommends 5–7 days) the first infusion.1

Administer infusions using a controlled infusion device (B Braun Perfusor Space infusion pump system).1 Administer with an infusion set with 0.2-µm inline filter.1

Follow each infusion of cerliponase alfa with an infusion of intraventricular electrolytes (supplied by manufacturer) to facilitate drug delivery and maintain patency of the intraventricular access device.1 3

Prior to intraventricular infusion, thaw vials of cerliponase alfa and intraventricular electrolytes at room temperature for approximately 60 minutes; do not thaw or warm in any other way and do not shake.1 Condensation will occur during the thawing period.1

Once vials are completely thawed, inspect visually for particulate matter or discoloration.1 Cerliponase alfa is a clear to slightly opalescent and colorless to pale yellow solution; intraventricular electrolytes is a clear to colorless solution.1 Do not use if solutions are discolored or contain foreign particulate matter other than a few naturally occurring particles of the drug (e.g., thin translucent fibers or opaque matter that is removed by the 0.2-µm filter); particulate matter also may appear in the electrolyte solution during the thawing process but should dissolve once solution reaches room temperature.1

Immediately use once thawed; if not used immediately, refrigerate unopened vials at 2–8°C and use within 24 hours.1 Do not refreeze thawed solutions.1

To prepare drug for administration, withdraw a total of 10 mL from two 5-mL vials containing cerliponase alfa into a syringe; label syringe as containing cerliponase alfa.1 To prepare electrolyte solution, withdraw a total of 2 mL from vial containing intraventricular electrolytes injection into a syringe; label syringe as containing intraventricular electrolytes.1

Vials are for single use only; discard any unused contents.1

Use syringes immediately after preparation.1 If not used immediately, may refrigerate at 2–8°C for up to 4 hours; do not freeze.1

Prior to administration, inspect patient's scalp for signs of leakage or failure of the intraventricular access device and for potential infections; prepare scalp for intraventricular infusion per institution standard of care.1

Withdraw a total of 0.5–1 mL of CSF to check patency of intraventricular access device and send specimen for culture.1 (See Intraventricular Access Device-related Complications under Cautions.)

Dispose of infusion components, needles, unused solutions, and other waste materials in accordance with local requirements.1

Do not dilute or mix with any other drug.1

Rate of Administration

Administer cerliponase alfa and intraventricular electrolytes at a rate of 2.5 mL/hour over approximately 4.5 hours.1

Dosage

Pediatric Patients

Late Infantile CLN2 Disease
Intraventricular

Pediatric patients ≥3 years of age: 300 mg once every other week by intraventricular infusion.1

Manufacturer recommends that first dose be administered at least 5–7 days after intraventricular access device is implanted.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1

Renal Impairment

Manufacturer makes no specific dosage recommendations.1

Cautions for Cerliponase Alfa

Contraindications

  • Acute intraventricular access device-related complications (e.g., leakage, device failure, device-related infection).1

  • Ventriculoperitoneal shunts.1

Warnings/Precautions

Intraventricular Access Device-related Complications

Intraventricular access device-related complications (e.g., infections, leakage, pleocytosis) reported.1 (See Contraindications under Cautions.)

Medical intervention (e.g., antibiotic therapy, replacement of intraventricular access device) required in some patients, but complications did not result in discontinuance of therapy.1

Because signs and symptoms of device-related infections may not be evident, manufacturer recommends routine testing of CSF samples to detect subclinical device-related infections.1 (See Intraventricular Administration under Dosage and Administration.)

Discontinue infusion and consult device manufacturer's labeling for additional instructions if complications related to the intraventricular access device develop.1

Because of material degradation, replacement of the intraventricular access device may be necessary as soon as (or prior to) 105 administrations of cerliponase alfa (equivalent to approximately 4.3 years of regular administrations).1

Adverse Cardiovascular Effects

Hypotension reported during or up to 8 hours following infusion; resolved spontaneously or following administration of IV fluid.1

Some patients with CLN2 disease may develop conduction disorders or heart disease.1 Perform ECG monitoring during infusion in patients with a history of bradycardia, conduction disorder, or structural heart disease.1 Perform regular 12-lead ECG evaluations every 6 months in patients without cardiac abnormalities.1

Monitor vital signs (BP, heart rate) prior to, periodically during, and following completion of infusion; in addition, perform clinical assessment following completion of infusion.1 Continued observation may be warranted if clinically indicated.1

Sensitivity Reactions

Hypersensitivity reactions reported during or within 24 hours after completion of infusion.1 Symptoms resolved spontaneously over time or with antipyretics, antihistamines, and/or corticosteroids and did not result in discontinuance of therapy.1

Manifestations that occurred concomitantly with hypersensitivity included pyrexia with vomiting, pleocytosis, and irritability.1

Ensure appropriate medical support is readily available during administration.1

Closely observe patients during and after infusion for hypersensitivity.1

Management of hypersensitivity reactions may include temporary interruption of the infusion and/or treatment with antihistamines, antipyretics, and/or corticosteroids depending on severity of the reaction.1 Immediately discontinue cerliponase alfa and initiate appropriate medical treatment if a severe hypersensitivity reaction (e.g., anaphylaxis) occurs.1

Immunogenicity

Potential for immunogenicity.1 Antibodies to cerliponase alfa detected in serum and CSF in patients who received the drug for up to 161 weeks.1 Presence of antibodies does not appear to be associated with hypersensitivity reactions.1

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.1 Animal reproduction studies not performed to date.1

Lactation

Not known whether cerliponase alfa is distributed into human milk, affects milk production, or affects the breast-fed infant.1 Consider known benefits of breast-feeding along with the mother's clinical need for cerliponase alfa and any potential adverse effects of the drug or disease on the infant.1

Pediatric Use

Safety and efficacy not established in pediatric patients <3 years of age.1

Hepatic Impairment

No information regarding exposure of drug in patients with hepatic impairment.1

Renal Impairment

No information regarding exposure of drug in patients with renal impairment.1

Common Adverse Effects

Pyrexia,1 ECG abnormalities,1 decreased CSF protein,1 vomiting,1 seizures,1 hypersensitivity,1 increased CSF protein,1 hematoma,1 headache,1 irritability,1 pleocytosis,1 device-related infection,1 bradycardia,1 feeling jittery,1 hypotension.1

Interactions for Cerliponase Alfa

No formal drug interaction studies performed to date.1

Cerliponase Alfa Pharmacokinetics

Absorption

Bioavailability

Extensive intrapatient and interpatient variability in pharmacokinetics observed.1

CSF exposure following single-dose intraventricular administration increased in a less than proportional manner across doses of 30, 100, and 300 mg.1

No apparent accumulation in CSF or plasma when administered at a dosage of 300 mg once every other week.1

CSF concentrations peaked at 15 minutes postinfusion and declined in a biphasic manner following administration of single and multiple intraventricular doses.1 3

Plasma concentrations peaked at approximately 12 hours following end of infusion and declined in a biexponential manner.1 3

Distribution

Extent

Does not cross blood-brain barrier.3

Following intraventricular administration in animals, widely distributed in CNS tissue.3

Estimated CSF volume of distribution following intraventricular infusion of cerliponase alfa 300 mg exceeds the usual CSF volume of 100 mL.1

Not known whether distributed into human milk.1

Elimination

Metabolism

Expected to be degraded through peptide hydrolysis.1

Half-life

Approximately 7 hours in CSF.1 3

Stability

Storage

Parenteral

Injection for Intraventricular Infusion

Cerliponase alfa injection and intraventricular electrolytes injection: Store upright in freezer (−25° to −15°C) in original container.1 Protect from light.1

Administration kit: Store in original container separately from cerliponase alfa injection.1 Do not freeze.1

Actions

  • Biosynthetic (recombinant DNA origin) form of TPP1, a lysosomal enzyme that catabolizes polypeptides in the CNS.1 5 Replaces the deficient TPP1 enzyme in CLN2 disease.1 3

  • CLN2 disease is an extremely rare, rapidly progressive neurodegenerative disease caused by a deficiency of TPP1; deficiency of this enzyme results in accumulation of lysosomal storage material in the CNS leading to progressive motor and cognitive impairment.1 3 4 5

  • Following intraventricular administration, the drug is taken up by target cells in the CNS and translocated to lysosomes where it is activated.1 5

  • Principal activity of proteolytic (active) form of enzyme is cleavage of tripeptides from the N-terminus of proteins.1 5

Advice to Patients

  • Importance of informing patients and caregivers of the risk of device-related infections.1 Instruct patients and caregivers to immediately contact their clinician if any signs of infection emerge.1

  • Importance of informing patients and caregivers that hypotension and/or bradycardia may occur during and following infusion of cerliponase alfa.1 Advise patients and caregivers to immediately contact their clinician if hypotension or bradycardia occurs.1

  • Importance of informing patients and caregivers that hypersensitivity reactions, including fever, vomiting, and irritability, may occur.1 Because of the potential risk of anaphylaxis, inform patients and caregivers of the signs and symptoms of anaphylaxis, and instruct them to immediately seek medical attention should such manifestations occur.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of informing patients and caregivers of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Cerliponase Alfa

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for intraventricular use only

30 mg/mL

Brineura (available with single-use 5 mL vial of intraventricular electrolytes injection, syringes, needles, extension line, infusion set, and port needle)

BioMarin

AHFS DI Essentials. © Copyright 2018, Selected Revisions December 18, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. BioMarin Pharmaceutical Inc. Brineura (cerliponase alfa) intraventricular prescribing information. Novato, CA; 2017 Apr.

2. FDA orphan drug designation https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=391913

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 761052Orig1s000: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761052Orig1s000SumR.pdf

4. Williams RE, Adams HR, Blohm M et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017; 69:102-112. http://www.ncbi.nlm.nih.gov/pubmed/28335910?dopt=AbstractPlus

5. Markham A. Cerliponase Alfa: First Global Approval. Drugs. 2017; 77:1247-1249. http://www.ncbi.nlm.nih.gov/pubmed/28589525?dopt=AbstractPlus

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