CLASSES
Lysosomal Storage Disorder Agents
DESCRIPTION
Recombinant human lysosomal acid lipase (rhLAL) protein
Used for lysosomal acid lipase (LAL) deficiency
Dosed once weekly in infants with rapidly progressive LAL deficiency; dosed once every other week in pediatric and adult patients with LAL deficiency
COMMON BRAND NAMES
Kanuma
HOW SUPPLIED
Kanuma Intravenous Inj Sol: 1mL, 2mg
DOSAGE & INDICATIONS
For the treatment of patients with lysosomal acid lipase (LAL) deficiency (Wolman disease).
For rapidly progressive LAL deficiency presenting within the first 6 months of life.
Intravenous dosage
Infants and Children
1 mg/kg/dose IV infusion administered once weekly. For patients not achieving an optimal clinical response, increase dose to 3 mg/kg/dose IV once weekly then to 5 mg/kg/dose IV once weekly if clinical response continues to be suboptimal. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers, or persistent or worsening organomegaly.
For patients with LAL deficiency (non-rapidly progressive form).
Intravenous dosage
Adults
1 mg/kg/dose IV infusion administered once every other week. For patients not achieving an optimal clinical response, increase dose to 3 mg/kg/dose IV once every other week. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and/or parameters of lipid metabolism (e.g., low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)).
Infants, Children, and Adolescents
1 mg/kg/dose IV infusion administered once every other week. For patients not achieving an optimal clinical response, increase dose to 3 mg/kg/dose IV once every other week. A suboptimal clinical response is defined as any of the following: poor growth, deteriorating biochemical markers (e.g., alanine aminotransferase (ALT), aspartate aminotransferase (AST)), and/or parameters of lipid metabolism (e.g., low-density lipoprotein cholesterol (LDL-c), triglycerides (TG)).
MAXIMUM DOSAGE
Adults
3 mg/kg/dose IV once every other week.
Geriatric
3 mg/kg/dose IV once every other week.
Adolescents
3 mg/kg/dose IV once every other week.
Children
5 mg/kg/dose IV weekly for patients with rapidly progressive LAL deficiency; 3 mg/kg/dose IV once every other week for all other patients.
Infants
5 mg/kg/dose IV weekly for patients with rapidly progressive LAL deficiency; 3 mg/kg/dose IV once every other week for all other patients.
Neonates
Although neonates were not included in clinical trials, if the drug is used in this population, do not exceed the maximum recommended dose for infants: 5 mg/kg/dose IV weekly for patients with rapidly progressive LAL deficiency; 3 mg/kg/dose IV once every other week for all other patients.
DOSING CONSIDERATIONS
Hepatic Impairment
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Renal Impairment
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
ADMINISTRATION
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
The solution should be a clear to slightly opalescent, colorless to slightly colored solution. Thin, translucent particles or fibers may be present in the vials or diluted solution. Do not use if the solution is cloudy or if other particulate matter is observed.
Intravenous Administration
Dilution
Determine the number of vials needed based on the calculated dose.
Remove vials from the refrigerator and allow them to reach room temperature before withdrawing the dose.
Dilute sebelipase alfa with an appropriate amount of 0.9% NaCl injection to achieve the recommended final volume for infusion (final concentration should be between 0.1 mg/mL and 1.5 mg/mL). The total infusion volume is based on the prescribed dose and patient weight:
For a 1 mg/kg dose the total infusion volumes (mL) are as follows:
Patient weight 1 to 2.9 kg: 4 mL final infusion volume
Patient weight 3 to 5.9 kg: 6 mL final infusion volume
Patient weight 6 to 10.9 kg: 10 mL final infusion volume
Patient weight 11 to 24.9 kg: 25 mL final infusion volume
Patient weight 25 to 49.9 kg: 50 mL final infusion volume
Patient weight 50 to 99.9 kg: 100 mL final infusion volume
Patient weight 100 to 120.9 kg: 250 mL final infusion volume
For a 3 mg/kg dose the total infusion volumes (mL) are as follows:
Patient weight 1 to 2.9 kg: 8 mL final infusion volume
Patient weight 3 to 5.9 kg: 12 mL final infusion volume
Patient weight 6 to 10.9 kg: 25 mL final infusion volume
Patient weight 11 to 24.9 kg: 50 mL final infusion volume
Patient weight 25 to 49.9 kg: 100 mL final infusion volume
Patient weight 50 to 99.9 kg: 250 mL final infusion volume
Patient weight 100 to 120.9 kg: 500 mL final infusion volume
For a 5 mg/kg dose the total infusion volumes (mL) are as follows:
Patient weight 1 to 2.9 kg: 12 mL final infusion volume
Patient weight 3 to 5.9 kg: 20 mL final infusion volume
Patient weight 6 to 10.9 kg: 50 mL final infusion volume
Patient weight 11 to 24.9 kg: 150 mL final infusion volume
Patient weight 25 to 49.9 kg: 250 mL final infusion volume
Patient weight 50 to 99.9 kg: 500 mL final infusion volume
Patient weight 100 to 120.9 kg: 600 mL final infusion volume
Mix gently by inversion. Do NOT shake the vials or the prepared infusion.
Vials are for single-use only. Discard any unused product. Do not freeze.
Storage: Use immediately after dilution; vial does not contain preservatives. If immediate use is not possible, diluted product may be stored for up to 24 hours in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). Do not freeze or shake. Protect from light.
Intermittent IV Infusion
Administer the diluted solution using a low-protein binding infusion set equipped with a low-protein binding 0.2 micron in-line filter.
Infuse over at least 2 hours. Consider further prolonging the infusion time for patients receiving doses greater than 1 mg/kg or those who have experienced hypersensitivity reactions.
A 1-hour infusion may be considered for those patients receiving the 1 mg/kg dose who tolerate the infusion.
STORAGE
Kanuma:
- Discard product if it contains particulate matter, is cloudy, or discolored
- Do not freeze
- Store at refrigerated temperature (2 to 8 degrees C) (36 to 46 degrees F) until required for use
- Store in the original carton to protect from light
CONTRAINDICATIONS / PRECAUTIONS
General Information
At the time of FDA approval, the product labeling reported no contraindications for the use of sebelipase alfa in patients with Lysosomal Acid Lipase (LAL) deficiency.
Requires a specialized care setting
Due to the risk of serious hypersensitivity reactions or anaphylaxis, the administration of sebelipase alfa requires a specialized care setting and readily available medical support. Anaphylaxis has occurred as early as the sixth infusion and as late as 1 year after treatment initiation. If anaphylaxis or other severe hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical treatment. Consider the risks and benefits of administering future doses of sebelipase after a severe reaction. If a less severe reaction occurs, management depends on the severity and may include temporarily interrupting the infusion, slowing the infusion rate, and/or treatment with antihistamines, antipyretics, and/or corticosteroids. If interrupted, the infusion may be resumed at a slower rate with increases as tolerated. Pre-treatment with antipyretics and/or antihistamines may prevent subsequent reactions.
Egg hypersensitivity
Sebelipase alfa is produced in the egg whites of genetically engineered chickens. Patients with a known egg hypersensitivity were excluded from clinical trials. Consider the risks and benefits of treatment with sebelipase alfa in patients with known systemic hypersensitivity reactions to eggs or egg products.
Pregnancy
Available data regarding sebelipase alfa use during human pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal data (rats and rabbits) did not reveal evidence of impaired fertility or harm to the fetus when sebelipase alfa was administered during the period of organogenesis at doses resulting in exposures up to 164 and 526 times the exposure at the recommended human dosage of 1 mg/kg every other week.
Breast-feeding
There are no data on the presence of sebelipase alfa in animal or human milk, the effects on breast-feeding infants, or the effects on milk production.
ADVERSE REACTIONS
Severe
anaphylactic shock / Rapid / Incidence not known
Moderate
antibody formation / Delayed / 8.0-57.0
anemia / Delayed / 0-44.0
constipation / Delayed / 8.0-8.0
hypertension / Early / 1.8
edema / Delayed / 1.8
hypotonia / Delayed / Incidence not known
dyspnea / Early / Incidence not known
tachypnea / Early / Incidence not known
chest pain (unspecified) / Early / Incidence not known
hyperemia / Delayed / Incidence not known
hyperlipidemia / Delayed / Incidence not known
Mild
vomiting / Early / 0-67.0
diarrhea / Early / 0-67.0
rhinitis / Early / 0-56.0
fever / Early / 25.0-56.0
pharyngitis / Delayed / 11.0-33.0
cough / Delayed / 0-33.0
urticaria / Rapid / 0-33.0
headache / Early / 28.0-28.0
nausea / Early / 8.0-8.0
asthenia / Delayed / 8.0-8.0
pallor / Early / 1.8
agitation / Early / 1.8
rash / Early / 1.8
chills / Rapid / 1.8
irritability / Delayed / 1.8
abdominal pain / Early / 1.8
dizziness / Early / 8.0
sneezing / Early / Incidence not known
anxiety / Delayed / Incidence not known
rhinorrhea / Early / Incidence not known
pruritus / Rapid / Incidence not known
DRUG INTERACTIONS
There are no drug interactions associated with Sebelipase alfa products.
PREGNANCY AND LACTATION
Pregnancy
Available data regarding sebelipase alfa use during human pregnancy are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal data (rats and rabbits) did not reveal evidence of impaired fertility or harm to the fetus when sebelipase alfa was administered during the period of organogenesis at doses resulting in exposures up to 164 and 526 times the exposure at the recommended human dosage of 1 mg/kg every other week.
There are no data on the presence of sebelipase alfa in animal or human milk, the effects on breast-feeding infants, or the effects on milk production.
MECHANISM OF ACTION
Lysosomal acid lipase (LAL) deficiency is an autosomal recessive genetic lysosomal storage disorder that results in a marked decrease or loss in activity of the LAL enzyme, which normally breaks down lipid particles including LDL-c. Deficient LAL enzyme activity results in an accumulation of fats within the cells and progressive complications in multiple organs, including the liver, spleen, intestine, and the walls of blood vessels. Lipid accumulation in the liver can lead to increased liver fat content and progression of liver disease, including fibrosis and cirrhosis, accumulation in the intestinal wall leads to malabsorption and growth failure, and accumulation in blood vessels can lead to premature cardiovascular disease. Sebelipase alfa is a recombinant human lysosomal acid lipase (rhLAL) that functions in place of the missing or inactive LAL protein. The drug binds to cell surface receptors via glycans expressed on the protein and is internalized into lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and triglycerides to fee cholesterol, glycerol and free fatty acids.
PHARMACOKINETICS
Sebelipase alfa is administered as an intravenous infusion. Its pharmacokinetics were nonlinear with a greater than dose-proportional increase in exposure between 1 and 3 mg/kg based on non-compartmental analysis of data from 26 adults. No accumulation was observed after once weekly or once every other week dosing.
Using a population pharmacokinetic model, pharmacokinetic parameters were estimated for 65 patients, including 18 adults, who received sebelipase alfa 1 mg/kg/dose IV once every other week. At week 22, the pharmacokinetic profiles were similar between adolescents and adults. The Tmax (1.1 to 1.3 hours) and t1/2 (5.4 to 6.6 minutes) were similar across all age groups. The following mean PK parameters were calculated for adults: Cmax = 957 +/- 303 ng/mL, AUC = 1,861 +/- 599 h x ng/mL, clearance = 38.2 +/- 12.5 L/h, central volume of distribution = 6.6 +/- 3.7 L.
In clinical trials, LDL-c and triglycerides increased within the first 2 to 4 weeks after initiation of treatment with sebelipase alfa. In general, after increases in LDL-c and triglycerides, these parameters decreased to below pre-treatment values within 8 weeks of treatment. Reductions in ALT values were observed, generally within 2 weeks after initiation of treatment. Treatment interruption resulted in increases in LDL-c and ALT values and decrease in HDL-c.