Cerliponase alfa: Difference between revisions
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{{DrugProjectFormSinglePage | {{DrugProjectFormSinglePage | ||
|authorTag={{Y.A}} | |authorTag={{Y.A}}, {{Anmol}} | ||
|genericName=generic name | |genericName=generic name | ||
|aOrAn=a | |aOrAn=a | ||
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|fdaLIADPed======Indications:===== | |fdaLIADPed======Indications:===== | ||
* | *Cerliponase alfa is indicated to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency. | ||
=====Dosage:===== | =====Dosage:===== | ||
*The recommended dosage of | *The recommended dosage of cerliponase alfa in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion. Administer cerliponase alfa first followed by infusion of the intraventricular electrolytes each at an infusion rate of 2.5 mL/hr. The complete cerliponase alfa infusion, including the required infusion of Intraventricular Electrolytes, is approximately 4.5 hours. | ||
*Pre-treatment of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion. | *Pre-treatment of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion. | ||
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|offLabelPedNoGuideSupport=There is limited information regarding cerliponase alfa Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. | |offLabelPedNoGuideSupport=There is limited information regarding cerliponase alfa Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. | ||
|contraindications=* | |contraindications=*Cerliponase alfa is contraindicated in patients with: | ||
:* | :*Acute intraventricular access device-related complications (e.g., leakage, device failure, or device-related infection) | ||
:* | :*Ventriculoperitoneal shunts | ||
|warnings======Intraventricular Access Device‑Related Complications===== | |warnings======Intraventricular Access Device‑Related Complications===== | ||
* | *Cerliponase alfa must be administered using aseptic technique to reduce the risk of infection. Healthcare professionals should inspect the scalp for skin integrity to ensure the intraventricular access device is not compromised prior to each infusion. | ||
* | *Cerliponase alfa is contraindicated if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, discontinue the cerliponase alfa infusion and refer to the device manufacturer’s labeling for further instructions. | ||
*The signs and symptoms of device-related infections may not be apparent, therefore, CSF samples should routinely be sent for testing to detect subclinical device infections. | *The signs and symptoms of device-related infections may not be apparent, therefore, CSF samples should routinely be sent for testing to detect subclinical device infections. | ||
*In clinical studies with | *In clinical studies with cerliponase alfa, intraventricular access device-related infections were observed in two patients. In each case, antibiotics were administered, the intraventricular access device was replaced, and the patient continued on cerliponase alfa treatment. | ||
*Material degradation of the intraventricular access device reservoir may occur after approximately 105 perforations of the intraventricular access device. The intraventricular access device may require replacement as soon as, or prior to, 105 administrations of | *Material degradation of the intraventricular access device reservoir may occur after approximately 105 perforations of the intraventricular access device. The intraventricular access device may require replacement as soon as, or prior to, 105 administrations of cerliponase alfa, equating to approximately 4.3 years of regular administrations. | ||
=====Cardiovascular Adverse Reactions===== | =====Cardiovascular Adverse Reactions===== | ||
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*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. | *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 the clinical studies, hypotension was reported in 2 (8%) patients, which occurred during or up to eight hours after | *In the clinical studies, hypotension was reported in 2 (8%) patients, which occurred during or up to eight hours after cerliponase alfa infusion. Patients did not require alteration in treatment, and reactions resolved spontaneously or after intravenous fluid administration. | ||
=====Hypersensitivity Reactions===== | =====Hypersensitivity Reactions===== | ||
*Hypersensitivity reactions have been reported in | *Hypersensitivity reactions have been reported in cerliponase alfa-treated patients during the clinical studies. A total of 11 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. The signs and symptoms observed concomitantly with hypersensitivity reactions included pyrexia, vomiting, pleocytosis or irritability. Patients were routinely pre-medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of cerliponase alfa. | ||
*Due to the potential for anaphylaxis, appropriate medical support should be readily available when | *Due to the potential for anaphylaxis, appropriate medical support should be readily available when cerliponase alfa is administered. If anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. Inform patients/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 temporarily interrupting the infusion, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. | *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. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. | ||
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|clinicalTrials=*Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. | |clinicalTrials=*Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. | ||
*The safety of | *The safety of cerliponase alfa was evaluated in 24 patients with CLN2 disease who received at least one dose of cerliponase alfa in a clinical study with extension of up to 161 weeks. Table 1 summarizes the most common adverse reactions that occurred in cerliponase alfa-treated patients through 96 weeks. | ||
[[image:Cerliponase_Alfa_Adverse_Reactions_Table.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | [[image:Cerliponase_Alfa_Adverse_Reactions_Table.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | ||
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=====Description of Selected Adverse Reactions===== | =====Description of Selected Adverse Reactions===== | ||
Seizures | ''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 | *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 cerliponase alfa treatment. | ||
Device-Related Complications | ''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 of these patients (38%) experienced adverse reactions, which involved complications of the non-implanted delivery system components. Four 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 | *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 of these patients (38%) experienced adverse reactions, which involved complications of the non-implanted delivery system components. Four 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 cerliponase alfa treatment. | ||
Hematoma | ''Hematoma'' | ||
*Hematoma adverse reactions were reported in 5 (21%) patients treated with | *Hematoma adverse reactions were reported in 5 (21%) patients treated with cerliponase alfa and presented as hematoma, post procedural hematoma, traumatic hematoma and subdural hematoma. Hematomas did not require treatment and did not interfere with cerliponase alfa infusion. | ||
Hypersensitivity | ''Hypersensitivity'' | ||
*Hypersensitivity reactions were reported in 11 out of 24 patients (46%) treated with | *Hypersensitivity reactions were reported in 11 out of 24 patients (46%) treated with cerliponase alfa during or within 24 hours after completion of the cerliponase alfa infusion, despite pre-medication with antihistamines with or without antipyretics or corticosteroids [see Warnings and Precautions (5.1)]. 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 cerliponase alfa. | ||
*One patient experienced hypoxia (decreased oxygen saturation less than 88% by pulse oximeter), 8 hours after | *One patient experienced hypoxia (decreased oxygen saturation less than 88% by pulse oximeter), 8 hours after cerliponase alfa 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 cerliponase alfa 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 cerliponase alfa infusion without change to the infusion rate or dose. | ||
=====Immunogenicity===== | =====Immunogenicity===== | ||
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*As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cerliponase alfa in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. | *As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cerliponase alfa in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. | ||
*Anti-drug antibodies (ADAs) to cerliponase alfa were detected in both serum and CSF in 79% and 33%, respectively, of patients treated with | *Anti-drug antibodies (ADAs) to cerliponase alfa were detected in both serum and CSF in 79% and 33%, respectively, of patients treated with cerliponase alfa for up to 161 weeks. Patients who experienced hypersensitivity adverse reactions were tested for drug-specific IgE and found to be negative, including three patients for whom grade 3 (severe) hypersensitivity adverse reactions were reported. No association was found between serum or CSF ADA titers and incidence or severity of hypersensitivity. Drug-specific neutralizing antibodies (NAb) have not been evaluated. | ||
|postmarketing= | |postmarketing= | ||
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|useInPregnancyFDA======Risk Summary===== | |useInPregnancyFDA======Risk Summary===== | ||
*There are no available data on | *There are no available data on cerliponase alfa 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. | *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. | ||
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|useInNursing======Risk Summary===== | |useInNursing======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 | *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 cerliponase alfa to an infant during lactation; therefore, the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for cerliponase alfa and any potential adverse effects on the breastfed infant from cerliponase alfa or from the underlying maternal condition. | ||
|useInPed=*Safety and effectiveness of | |useInPed=*Safety and effectiveness of cerliponase alfa have been established in pediatric patients 3 years of age and older. Pediatric use of cerliponase alfa to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, is supported by a non-randomized single-arm dose escalation clinical study with extension in patients with CLN2 disease and compared to untreated patients with CLN2 disease from an independent natural history cohort [see Clinical Studies (14)]. Safety and effectiveness in patients less than 3 years of age have not been established. | ||
|useInGeri= | |useInGeri= | ||
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|useInImmunocomp= | |useInImmunocomp= | ||
|administration=* | |administration=*Cerliponase alfa and the Intraventricular Electrolytes must only be administered by the intraventricular route, using the provided Administration Kit for use with cerliponase alfa. Each vial of cerliponase alfa and Intraventricular Electrolytes is intended for a single dose only. | ||
*Each infusion consists of 10 mL of | *Each infusion consists of 10 mL of cerliponase alfa 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 cerliponase alfa and to maintain patency of the intraventricular access device. | ||
|monitoring=*Decreased loss of ambulation may indicate clinical efficacy. | |monitoring=*Decreased loss of ambulation may indicate clinical efficacy. | ||
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|PK=*The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received intraventricular infusions of 30 mg (0.1 times the approved recommended dosage), 100 mg (approximately 0.3 times the approved recommended dosage), and 300 mg over approximately 4.5 hours once every other week. | |PK=*The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received intraventricular infusions of 30 mg (0.1 times the approved recommended dosage), 100 mg (approximately 0.3 times the 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 | *Cerliponase alfa CSF exposure following the initial single dose administration of cerliponase alfa 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 cerliponase alfa 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 | *Cerliponase alfa pharmacokinetics have high inter-subject and intra-subject variability. Following intraventricular infusions of 300 mg of cerliponase alfa 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 2. | ||
[[image:Cerliponase_Alfa_Pharmacokinetics_Table.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | [[image:Cerliponase_Alfa_Pharmacokinetics_Table.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | ||
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*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. | *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. | ||
|clinicalStudies=*The efficacy of | |clinicalStudies=*The efficacy of cerliponase alfa was assessed over 96 weeks in a non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, confirmed by TPP1 deficiency. Cerliponase alfa-treated patients were compared to untreated patients from a natural history cohort. The Motor domain of a CLN2 Clinical Rating Scale was used to assess disease progression. Scores ranged from 3 (grossly normal) to 0 (profoundly impaired) with unit decrements representing milestone events in the loss of motor function (ability to walk or crawl). Due to the inability to establish comparability for the CLN2 Language domain ratings between the clinical study with extension and the natural history cohort, efficacy of cerliponase alfa for the Language domain cannot be established. | ||
*Twenty-four patients, aged 3 to 8 years were enrolled in the | *Twenty-four patients, aged 3 to 8 years were enrolled in the cerliponase alfa single-arm clinical study. Sixty-three percent of patients were female and 37% were male. Ninety-six percent of patients were Caucasian and 4% were Asian. One patient withdrew after week 1 due to inability to continue with study procedures; 23 patients were treated with cerliponase alfa 300 mg every other week for 48 weeks, and continued treatment during the extension period. | ||
*In the clinical study with extension, patients were assessed for decline in the Motor domain of the CLN2 Clinical Rating Scale at 48, 72 and 96 weeks. Decline was defined as having an unreversed (sustained) 2-category decline or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale. Patients’ responses to | *In the clinical study with extension, patients were assessed for decline in the Motor domain of the CLN2 Clinical Rating Scale at 48, 72 and 96 weeks. Decline was defined as having an unreversed (sustained) 2-category decline or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale. Patients’ responses to cerliponase alfa treatment were evaluated if at screening a combined Motor plus Language CLN2 score of less than 6 was recorded. Two patients with a combined Motor plus Language CLN2 score of 6 were excluded from the analyses; they maintained that score throughout the study period. The patient who terminated early was analyzed as having a decline at the time of termination. Data used in the analyses from the natural history cohort began at 36 months of age or greater and at the first time a Motor plus Language CLN2 score less than 6 was recorded. | ||
*Motor scores of the 22 | *Motor scores of the 22 cerliponase alfa-treated patients in the clinical study with extension were compared to scores of the independent natural history cohort that included 42 untreated patients who satisfied inclusion criteria for the clinical study. The results of logistic modeling with covariates (screening age, screening motor score, genotype: 0 key mutations (yes/no)), demonstrated the odds of cerliponase alfa-treated patients not having a decline by 96 weeks were 13 times the odds of natural history cohort patients not having a decline (Odds Ratio (95% CI): 13.1 (1.2, 146.9)). | ||
Descriptive non-randomized comparison | ''Descriptive non-randomized comparison'' | ||
*In an unadjusted non-randomized comparison, of the 22 patients treated with | *In an unadjusted non-randomized comparison, of the 22 patients treated with cerliponase alfa 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 | *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 cerliponase alfa-treated patients when compared to the natural history cohort (see Figure 7). | ||
[[image:Cerliponase_Alfa_Clinical_Studies_Table_1.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | [[image:Cerliponase_Alfa_Clinical_Studies_Table_1.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | ||
Motor Domain Scores: Matched Patients Only | ''Motor Domain Scores: Matched Patients Only'' | ||
*To further assess efficacy, the 22 patients from the | *To further assess efficacy, the 22 patients from the cerliponase alfa 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 | *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 cerliponase alfa-treated patients compared to untreated patients in the natural history cohort (see Table 3). | ||
[[image:Cerliponase_Alfa_Clinical_Studies_Table_2.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | [[image:Cerliponase_Alfa_Clinical_Studies_Table_2.png|none|thumb|400px|This image is provided by the National Library of Medicine.]] | ||
|howSupplied=* | |howSupplied=*Cerliponase alfa is supplied as a sterile, clear to slightly opalescent and colorless to pale yellow solution for intraventricular infusion and Intraventricular Electrolytes Injection is supplied as a clear to colorless solution for intraventricular infusion; both are included in package 1 of 2. The Administration Kit for use with cerliponase alfa is supplied separately as package 2 of 2. | ||
Package 1 of 2 | Package 1 of 2 | ||
*Each | *Each cerliponase alfa (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. | *Each Intraventricular Electrolytes Injection vial has a yellow flip‑off cap (plastic), and contains 5 mL of solution. | ||
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Package 2 of 2 | Package 2 of 2 | ||
*The Administration Kit for use with | *The Administration Kit for use with cerliponase alfa is supplied separately and contains the following single-use, sterile infusion components: | ||
:*Two 20-mL syringes. | :*Two 20-mL syringes. | ||
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:*One port needle (22 G, 16 mm). | :*One port needle (22 G, 16 mm). | ||
|storage=* | |storage=*Cerliponase alfa (cerliponase alfa) Injection and Intraventricular Electrolytes Injection: | ||
*Store upright in a freezer (‑25°C to ‑15°C) in original carton to protect from light. | *Store upright in a freezer (‑25°C to ‑15°C) in original carton to protect from light. | ||
*Administration Kit for use with | *Administration Kit for use with cerliponase alfa: | ||
*Store in original carton separately from | *Store in original carton separately from cerliponase alfa. Do not freeze. | ||
|packLabel=[[image:Cerliponase_Alfa_Package_Label_1.jpeg|none|thumb|400px|This image is provided by the National Library of Medicine.]] | |packLabel=[[image:Cerliponase_Alfa_Package_Label_1.jpeg|none|thumb|400px|This image is provided by the National Library of Medicine.]] | ||
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=====Cardiovascular Adverse Reactions===== | =====Cardiovascular Adverse Reactions===== | ||
*Advise patients and caregivers that hypotension and/or bradycardia may occur during and following the infusion of | *Advise patients and caregivers that hypotension and/or bradycardia may occur during and following the infusion of cerliponase alfa. Instruct patients immediately to contact their healthcare provider if these reactions occur. | ||
=====Hypersensitivity Reactions===== | =====Hypersensitivity Reactions===== | ||
*Advise patients and caregivers that hypersensitivity reactions related to | *Advise patients and caregivers that hypersensitivity reactions related to cerliponase alfa treatment, including fever, vomiting, and irritability may occur. Due to the potential for anaphylaxis, inform patients and caregivers of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. | ||
|nlmPatientInfo=(Link to patient information page) | |nlmPatientInfo=(Link to patient information page) | ||
Latest revision as of 22:22, 30 November 2018
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3]
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Overview
Cerliponase alfa is a hydrolytic lysosomal N-terminal tripeptidyl peptidase that is FDA approved for the slowing of the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency. Common adverse reactions include pyrexia, ECG abnormalities, decreased CSF protein, vomiting, seizures, hypersensitivity, increased CSF protein, hematoma, headache, irritability, pleocytosis, device-related infection, bradycardia, feeling jittery, and hypotension.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
There is limited information regarding Cerliponase alfa FDA-Labeled Indications and Dosage (Adult) in the drug label.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding cerliponase alfa Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
Non–Guideline-Supported Use
There is limited information regarding cerliponase alfa Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications:
- Cerliponase alfa is indicated to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Dosage:
- The recommended dosage of cerliponase alfa in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion. Administer cerliponase alfa first followed by infusion of the intraventricular electrolytes each at an infusion rate of 2.5 mL/hr. The complete cerliponase alfa infusion, including the required infusion of Intraventricular Electrolytes, is approximately 4.5 hours.
- Pre-treatment of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding cerliponase alfa Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
Non–Guideline-Supported Use
There is limited information regarding cerliponase alfa Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
Contraindications
- Cerliponase alfa is contraindicated in patients with:
- Acute intraventricular access device-related complications (e.g., leakage, device failure, or device-related infection)
- Ventriculoperitoneal shunts
Warnings
Intraventricular Access Device‑Related Complications
- Cerliponase alfa must be administered using aseptic technique to reduce the risk of infection. Healthcare professionals should inspect the scalp for skin integrity to ensure the intraventricular access device is not compromised prior to each infusion.
- Cerliponase alfa is contraindicated if there are signs of acute intraventricular access device-related complications (e.g., leakage, device failure or signs of device-related infection such as swelling, erythema of the scalp, extravasation of fluid, or bulging of the scalp around or above the intraventricular access device). In case of intraventricular access device complications, discontinue the cerliponase alfa infusion and refer to the device manufacturer’s labeling for further instructions.
- The signs and symptoms of device-related infections may not be apparent, therefore, CSF samples should routinely be sent for testing to detect subclinical device infections.
- In clinical studies with cerliponase alfa, intraventricular access device-related infections were observed in two patients. In each case, antibiotics were administered, the intraventricular access device was replaced, and the patient continued on cerliponase alfa treatment.
- Material degradation of the intraventricular access device reservoir may occur after approximately 105 perforations of the intraventricular access device. The intraventricular access device may require replacement as soon as, or prior to, 105 administrations of cerliponase alfa, equating to approximately 4.3 years of regular administrations.
Cardiovascular Adverse Reactions
- Monitor vital signs (blood pressure, heart rate) before infusion starts, periodically during infusion, and post-infusion in a healthcare setting. 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 the clinical studies, hypotension was reported in 2 (8%) patients, which occurred during or up to eight hours after cerliponase alfa infusion. Patients did not require alteration in treatment, and reactions resolved spontaneously or after intravenous fluid administration.
Hypersensitivity Reactions
- Hypersensitivity reactions have been reported in cerliponase alfa-treated patients during the clinical studies. A total of 11 (46%) patients experienced hypersensitivity reactions during the infusion or within 24 hours of completion of the infusion. The signs and symptoms observed concomitantly with hypersensitivity reactions included pyrexia, vomiting, pleocytosis or irritability. Patients were routinely pre-medicated with antihistamines with or without antipyretics or corticosteroids, prior to infusion of cerliponase alfa.
- Due to the potential for anaphylaxis, appropriate medical support should be readily available when cerliponase alfa is administered. If anaphylaxis occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. Inform patients/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 temporarily interrupting the infusion, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. If a severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment.
Adverse Reactions
Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- The safety of cerliponase alfa was evaluated in 24 patients with CLN2 disease who received at least one dose of cerliponase alfa in a clinical study with extension of up to 161 weeks. Table 1 summarizes the most common adverse reactions that occurred in cerliponase alfa-treated patients through 96 weeks.
Description of Selected Adverse Reactions
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 cerliponase alfa 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 of these patients (38%) experienced adverse reactions, which involved complications of the non-implanted delivery system components. Four 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 cerliponase alfa treatment.
Hematoma
- Hematoma adverse reactions were reported in 5 (21%) patients treated with cerliponase alfa and presented as hematoma, post procedural hematoma, traumatic hematoma and subdural hematoma. Hematomas did not require treatment and did not interfere with cerliponase alfa infusion.
Hypersensitivity
- Hypersensitivity reactions were reported in 11 out of 24 patients (46%) treated with cerliponase alfa during or within 24 hours after completion of the cerliponase alfa infusion, despite pre-medication with antihistamines with or without antipyretics or corticosteroids [see Warnings and Precautions (5.1)]. 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 cerliponase alfa.
- One patient experienced hypoxia (decreased oxygen saturation less than 88% by pulse oximeter), 8 hours after cerliponase alfa 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 cerliponase alfa 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 cerliponase alfa infusion without change to the infusion rate or dose.
Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to cerliponase alfa in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
- Anti-drug antibodies (ADAs) to cerliponase alfa were detected in both serum and CSF in 79% and 33%, respectively, of patients treated with cerliponase alfa for up to 161 weeks. Patients who experienced hypersensitivity adverse reactions were tested for drug-specific IgE and found to be negative, including three patients for whom grade 3 (severe) hypersensitivity adverse reactions were reported. No association was found between serum or CSF ADA titers and incidence or severity of hypersensitivity. Drug-specific neutralizing antibodies (NAb) have not been evaluated.
Postmarketing Experience
There is limited information regarding Cerliponase alfa Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Cerliponase alfa Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Risk Summary
- There are no available data on cerliponase alfa 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.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cerliponase alfa in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Cerliponase alfa during labor and delivery.
Nursing Mothers
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 cerliponase alfa to an infant during lactation; therefore, the development and health benefits of breastfeeding should be considered along with the mother’s clinical need for cerliponase alfa and any potential adverse effects on the breastfed infant from cerliponase alfa or from the underlying maternal condition.
Pediatric Use
- Safety and effectiveness of cerliponase alfa have been established in pediatric patients 3 years of age and older. Pediatric use of cerliponase alfa to slow the loss of ambulation in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, is supported by a non-randomized single-arm dose escalation clinical study with extension in patients with CLN2 disease and compared to untreated patients with CLN2 disease from an independent natural history cohort [see Clinical Studies (14)]. Safety and effectiveness in patients less than 3 years of age have not been established.
Geriatic Use
There is no FDA guidance on the use of Cerliponase alfa in geriatric settings.
Gender
There is no FDA guidance on the use of Cerliponase alfa with respect to specific gender populations.
Race
There is no FDA guidance on the use of Cerliponase alfa with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Cerliponase alfa in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Cerliponase alfa in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Cerliponase alfa in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Cerliponase alfa in patients who are immunocompromised.
Administration and Monitoring
Administration
- Cerliponase alfa and the Intraventricular Electrolytes must only be administered by the intraventricular route, using the provided Administration Kit for use with cerliponase alfa. Each vial of cerliponase alfa and Intraventricular Electrolytes is intended for a single dose only.
- Each infusion consists of 10 mL of cerliponase alfa 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 cerliponase alfa and to maintain patency of the intraventricular access device.
Monitoring
- Decreased loss of ambulation may indicate clinical efficacy.
- CSF testing: Routinely to identify device-related infection.
- Scalp skin integrity: Prior to infusion.
- Signs of acute intraventricular access device-related complications (eg, device leakage, failure, or infection): Prior to infusion.
- Blood pressure and heart rate: Prior to infusion, periodically during infusion, and after infusion; continue observation if clinically indicated.
- ECG: During infusion in patients with structural heart disease, conduction disorder, or history of bradycardia; every 6 months in patients with normal cardiac function.
- Signs and symptoms of anaphylaxis: During and after infusion.
IV Compatibility
There is limited information regarding the compatibility of Cerliponase alfa and IV administrations.
Overdosage
There is limited information regarding Cerliponase alfa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
Mechanism of Action
- 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.
Structure
There is limited information regarding Cerliponase alfa Structure in the drug label.
Pharmacodynamics
There is limited information regarding Cerliponase alfa Pharmacodynamics in the drug label.
Pharmacokinetics
- The pharmacokinetics of cerliponase alfa were evaluated in patients with CLN2 disease who received intraventricular infusions of 30 mg (0.1 times the approved recommended dosage), 100 mg (approximately 0.3 times the 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 cerliponase alfa 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 cerliponase alfa 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 cerliponase alfa 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 2.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- 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.
Clinical Studies
- The efficacy of cerliponase alfa was assessed over 96 weeks in a non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, confirmed by TPP1 deficiency. Cerliponase alfa-treated patients were compared to untreated patients from a natural history cohort. The Motor domain of a CLN2 Clinical Rating Scale was used to assess disease progression. Scores ranged from 3 (grossly normal) to 0 (profoundly impaired) with unit decrements representing milestone events in the loss of motor function (ability to walk or crawl). Due to the inability to establish comparability for the CLN2 Language domain ratings between the clinical study with extension and the natural history cohort, efficacy of cerliponase alfa for the Language domain cannot be established.
- Twenty-four patients, aged 3 to 8 years were enrolled in the cerliponase alfa single-arm clinical study. Sixty-three percent of patients were female and 37% were male. Ninety-six percent of patients were Caucasian and 4% were Asian. One patient withdrew after week 1 due to inability to continue with study procedures; 23 patients were treated with cerliponase alfa 300 mg every other week for 48 weeks, and continued treatment during the extension period.
- In the clinical study with extension, patients were assessed for decline in the Motor domain of the CLN2 Clinical Rating Scale at 48, 72 and 96 weeks. Decline was defined as having an unreversed (sustained) 2-category decline or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale. Patients’ responses to cerliponase alfa treatment were evaluated if at screening a combined Motor plus Language CLN2 score of less than 6 was recorded. Two patients with a combined Motor plus Language CLN2 score of 6 were excluded from the analyses; they maintained that score throughout the study period. The patient who terminated early was analyzed as having a decline at the time of termination. Data used in the analyses from the natural history cohort began at 36 months of age or greater and at the first time a Motor plus Language CLN2 score less than 6 was recorded.
- Motor scores of the 22 cerliponase alfa-treated patients in the clinical study with extension were compared to scores of the independent natural history cohort that included 42 untreated patients who satisfied inclusion criteria for the clinical study. The results of logistic modeling with covariates (screening age, screening motor score, genotype: 0 key mutations (yes/no)), demonstrated the odds of cerliponase alfa-treated patients not having a decline by 96 weeks were 13 times the odds of natural history cohort patients not having a decline (Odds Ratio (95% CI): 13.1 (1.2, 146.9)).
Descriptive non-randomized comparison
- In an unadjusted non-randomized comparison, of the 22 patients treated with cerliponase alfa 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 cerliponase alfa-treated patients when compared to the natural history cohort (see Figure 7).
Motor Domain Scores: Matched Patients Only
- To further assess efficacy, the 22 patients from the cerliponase alfa 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 cerliponase alfa-treated patients compared to untreated patients in the natural history cohort (see Table 3).
How Supplied
- Cerliponase alfa is supplied as a sterile, clear to slightly opalescent and colorless to pale yellow solution for intraventricular infusion and Intraventricular Electrolytes Injection is supplied as a clear to colorless solution for intraventricular infusion; both are included in package 1 of 2. The Administration Kit for use with cerliponase alfa is supplied separately as package 2 of 2.
Package 1 of 2
- Each cerliponase alfa (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.
Package 2 of 2
- The Administration Kit for use with cerliponase alfa is supplied separately and contains the following single-use, sterile infusion components:
- Two 20-mL syringes.
- Two syringe needles (21 G, 25.4 mm).
- One extension line.
- One infusion set with 0.2 micron inline filter.
- One port needle (22 G, 16 mm).
Storage
- Cerliponase alfa (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 cerliponase alfa:
- Store in original carton separately from cerliponase alfa. Do not freeze.
Images
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Patient Counseling Information
Intraventricular Access Device‑Related Complications
- Advise patients and caregivers of the risk of device-related infections. If any signs of infection are present, instruct patients to immediately contact their healthcare provider.
Cardiovascular Adverse Reactions
- Advise patients and caregivers that hypotension and/or bradycardia may occur during and following the infusion of cerliponase alfa. Instruct patients immediately to contact their healthcare provider if these reactions occur.
Hypersensitivity Reactions
- Advise patients and caregivers that hypersensitivity reactions related to cerliponase alfa treatment, including fever, vomiting, and irritability may occur. Due to the potential for anaphylaxis, inform patients and caregivers of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur.
Precautions with Alcohol
Alcohol-Cerliponase alfa interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
- Brineura
Look-Alike Drug Names
There is limited information regarding Cerliponase alfa Look-Alike Drug Names in the drug label.
Drug Shortage Status
Drug Shortage
Price
References
The contents of this FDA label are provided by the National Library of Medicine.