Sebelipase Alfa (Monograph)

Brand name: Kanuma
Drug class: Enzymes
Chemical name: Cholesterol (human gene LIPA) esterase,
Molecular formula: C₁₉₆₈H₂₉₄₅N₅₀₇O₅₅₁S₁₅
CAS number: 1276027-63-4

Introduction

Biosynthetic (recombinant DNA origin) form of human lysosomal acid lipase.

Uses for Sebelipase Alfa

Lysosomal Acid Lipase Deficiency

Treatment of lysosomal acid lipase deficiency (designated an orphan drug by FDA for this use).

Survival benefit demonstrated in patients with rapidly progressive infantile-onset disease (i.e., Wolman disease).

In pediatric patients and adults with late-onset disease (i.e., cholesterol ester storage disease), improvements in disease-related lipid and hepatic abnormalities demonstrated.

Effects on cardiovascular morbidity and mortality and progression of liver disease not established.

Sebelipase Alfa Dosage and Administration

Administration

IV Administration

For solution compatibility information, see Compatibility under Stability.

Administer by IV infusion.

Administer using an inline, low-protein-binding 0.2-µm filter.

Contains no preservatives; use immediately following preparation. (See Storage under Stability.) Discard any unused portions.

Dilution

Prior to administration, must dilute commercially available sebelipase alfa injection concentrate.

Determine number of vials to be diluted based on patient’s weight and recommended dose of 1 or 3 mg/kg.

Remove required number of vials from refrigerator and allow to reach room temperature; do not shake. Withdraw appropriate dose from vials and dilute with 0.9% sodium chloride injection to prepare a final concentration of 0.1–1.5 mg/mL.

See Table 1 for recommended total infusion volumes based on patient's weight and prescribed dose.

For patients presenting within the first 6 months of life who do not achieve optimal clinical response with a dose of 1 mg/kg.

Table 1: Total Infusion Volumes
Patient Weight (kg)	Total Infusion Volume (mL) for 1-mg/kg Dose	Total Infusion Volume (mL) for 3-mg/kg Dose
1–10.9	10	25
11–24.9	25	50
25–49.9	50	100
50–99.9	100	250
100–120.9	250	500

Mix diluted solution gently; do not shake. The solution should appear clear to slightly opalescent and colorless to slightly colored; thin translucent fibers or particles may be present. Do not administer if solution appears cloudy or if other particulate matter observed.

Rate of Administration

Infuse over at least 2 hours. Consider longer infusion times in patients receiving a dose of 3 mg/kg or in patients who experience hypersensitivity reactions. Consider shorter infusion time of 1 hour, if tolerated, in patients receiving a dose of 1 mg/kg.

Dosage

Pediatric Patients

Lysosomal Acid Lipase Deficiency

Infants with Rapidly Progressive Lysosomal Acid Lipase Deficiency Presenting Within the First 6 Months of Life

1 mg/kg once weekly. In patients not achieving optimal clinical response, may increase to 3 mg/kg once weekly.

Pediatric Patients with Lysosomal Acid Lipase Deficiency

1 mg/kg once every 2 weeks.

Adults

Lysosomal Acid Lipase Deficiency

IV

1 mg/kg once every 2 weeks.

Special Populations

No special population dosage recommendations at this time.

Cautions for Sebelipase Alfa

Contraindications

No known contraindications.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity

Hypersensitivity reactions, including anaphylaxis, reported. Generally during or within 4 hours of the infusion. Anaphylaxis reported as early as the sixth infusion to as late as 1 year after treatment initiation.

Ensure that appropriate medical support is readily available during administration. Closely observe patients during and after administration.

Manage hypersensitivity reactions based on severity. If anaphylaxis or other severe hypersensitivity reaction occurs, discontinue sebelipase alfa immediately and initiate appropriate medical treatment. For hypersensitivity reactions of lesser severity, may temporarily interrupt infusion, lower infusion rate, and/or administer antihistamines, antipyretics, and/or corticosteroids. If infusion is interrupted, resume at a slower rate; subsequently increase rate as tolerated.

To prevent subsequent reactions in patients experiencing hypersensitivity, may consider premedication with antipyretics and/or antihistamines. Consider risks and benefits of retreatment following a severe hypersensitivity reaction. If drug is readministered, monitor patient with appropriate resuscitation measures available.

Egg Allergy

Consider risks and benefits of treatment in patients with known systemic hypersensitivity reactions to eggs or egg products.

Antibody Formation

Development of antibodies, including neutralizing antibodies, to sebelipase alfa reported.

Hypersensitivity reactions and possible reduced efficacy (decreased growth) observed in antibody-positive infants. No clear association between development of antibodies and efficacy in adults and pediatric patients.

Specific Populations

Pregnancy

No available data in pregnant women; animal studies have not suggested any evidence of adverse embryofetal effects.

Lactation

Not known whether sebelipase alfa is distributed into milk. Consider known benefits of breast-feeding along with mother's need for sebelipase alfa and any potential adverse effects of the drug or disease on the infant.

Pediatric Use

Safety and efficacy established in pediatric patients ≥1 month of age.

Geriatric Use

Not studied in patients ≥65 years of age. Not known whether geriatric patients respond differently than younger patients.

Common Adverse Effects

Infants with rapidly progressive lysosomal acid lipase deficiency presenting within the first 6 months of life: Diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, urticaria.

Pediatric and adult patients with lysosomal acid lipase deficiency: Headache, fever, oropharyngeal pain, nasopharyngitis, abdominal pain, asthenia, constipation, nausea.

Drug Interactions

Formal drug interaction studies not performed to date.

Sebelipase Alfa Pharmacokinetics

Pharmacokinetic profile of sebelipase alfa is based on data from adults and pediatric patients; pharmacokinetics not characterized in infants.

Absorption

Bioavailability

Nonlinear pharmacokinetics; greater than dose-proportional increase in exposure observed at doses of 1–3 mg/kg.

No substantial accumulation following repeated dosing.

Peak plasma concentrations occur approximately 1.1–1.3 hours after a dose in pediatric patients and adults.

Onset

Increased LDL-cholesterol and triglyceride concentrations initially observed within the first 2–4 weeks; such parameters subsequently decreased to below pretreatment levels within 8 weeks of treatment. Decreased ALT concentrations typically observed within 2 weeks of treatment.

Special Populations

Pharmacokinetic profile similar between adolescents and adults.

Distribution

Extent

Not known whether sebelipase alfa distributes into milk.

Elimination

Half-life

Approximately 6 minutes.

Half-life similar across pediatric and adult patients of all age groups receiving 1 mg/kg once every other week.

Stability

Storage

Parenteral

Injection for IV Infusion

2–8°C. Protect from light. Do not freeze; do not shake.

Following dilution, 2–8°C for ≤24 hours if protected from light. Do not freeze.

Compatibility

Parenteral

Solution Compatibility1

Compatible
Sodium chloride 0.9%

Actions

Biosynthetic (recombinant DNA origin) form of human lysosomal acid lipase.
Binds to cell surface receptors and subsequently internalized into lysosomes; catalyzes lysosomal hydrolysis of cholesteryl esters and triglycerides to free cholesterol, glycerol, and free fatty acids.
Lysosomal acid lipase deficiency causes accumulation of cholesteryl esters and triglycerides in various cells and organs throughout the body leading to clinical manifestations including hepatomegaly, liver disease (e.g., jaundice, steatosis, fibrosis, cirrhosis), increased aminotransferase concentrations, malabsorption, growth failure, dyslipidemia (e.g., elevated LDL-cholesterol and triglyceride concentrations, decreased HDL-cholesterol concentrations), and atherosclerosis.
Treatment in patients with rapidly progressive infantile-onset lysosomal acid lipase deficiency (i.e., Wolman disease) increased survival rate beyond 12 months of age; treatment in pediatric and adult patients with later-onset disease (i.e., cholesterol ester storage disease) improved lipid parameters and decreased ALT concentrations.

Advice to Patients

Risk of severe hypersensitivity reactions, including anaphylaxis. Advise patients of the possible signs and symptoms of hypersensitivity reactions, and to seek immediate medical care if such manifestations occur.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (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.