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Mechanism of Action
US Drug Names
NOTE: The FDA has designated cerliponase alfa as an orphan drug for this indication.
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.
Safety and efficacy have not been established.
300 mg/dose via intraventricular infusion once every other week.
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.
Specific guidelines for dosage adjustments in hepatic impairment are not available; cerliponase alfa has not been studied in patients with hepatic impairment.
Specific guidelines for dosage adjustments in renal impairment are not available; cerliponase alfa has not been studied in patients with renal impairment.
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. Cerliponase alfa is the first FDA-approved treatment indicated to slow loss of ambulation in symptomatic pediatric patients 3 years of age and older.
For storage information, see the specific product information within the How Supplied section.
Intraventricular Infusion of Cerliponase alfa
Intraventricular Infusion of Intraventricular Electrolytes
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cerliponase alfa is associated with a risk of serious hypersensitivity reactions or anaphylaxis. Premedication with antihistamines with or without antipyretics or corticosteroids is recommended 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. 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.
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.
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.
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.
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.
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:
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]
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