Kanuma

1. Kanuma

Dosage Forms & Strengths

solution for injection

• 20mg/10mL per vial (2mg/mL)

Lysosomal Acid Lipase Deficiency

Indicated for enzyme replacement in patients with lysosomal acid lipase (LAL) deficiency

1 mg/kg IV infusion administered every other week (see Administration)

Dosage Forms & Strengths

solution for injection

• 20mg/10mL per vial (2mg/mL)

Lysosomal Acid Lipase Deficiency

Indicated for enzyme replacement in patients with lysosomal acid lipase (LAL) deficiency

1 mg/kg IV infusion administered every other week (see Administration)

Rapidly progressive LAL deficiency presenting within the first 6 months of life

• Starting dose: 1 mg/kg IV infusion administered once weekly
• May increase to 3 mg/kg once weekly for patients who do not achieve an optimal clinical response with the starting dose

IV Preparation

Determine number of vials needed for dose based on patient’s weight; round to the next whole vial and remove the required number of vials from the refrigerator to allow them to reach room temperature

Determine the volume of the calculated dose and the necessary volume of 9% NaCl for dilution; the infusion volume should be based on the prescribed dose and should be prepared to a final concentration of 0.1-1.5 mg/mL (see total volume sections listed below)

Mix gently by inversion; do not shake the vials or the prepared infusion

Inspected visually for particulate matter and discoloration prior to administration; 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

Vials are for single use only; discard any unused product

Contains no preservatives; therefore, product should be used immediately after dilution; if this is not possible, may store refrigerated (see Storage)

1 mg/kg dose total infusion volume

• Drug volume plus 0.9% NaCl for dilution
• 1-10.9 kg: 10 mL
• 11-24.9 kg: 25 mL
• 25-49.9 kg: 50 mL
• 50-99.9 kg: 100 mL
• 100-120.9 kg: 250 mL

3 mg/kg dose total infusion volume

• Drug volume plus 0.9% NaCl for dilution
• 1-10.9 kg: 25 mL
• 11-24.9 kg: 50 mL
• 25-49.9 kg: 100 mL
• 50-99.9 kg: 250 mL
• 100-120.9 kg: 500 mL

IV Administration

Administer IV infusion using a low-protein binding infusion set with an in-line, low-protein binding 0.2 micron filter

Infuse over at least 2 hr

Consider further prolonging the infusion time for patients receiving the 3 mg/kg dose or those who have experienced hypersensitivity reactions (see Cautions)

A 1-hr infusion may be considered for those patients receiving the 1 mg/kg dose who tolerate the infusion

Storage

Unopened vials

• Refrigerate between 2-8°C (36-46°F) in original carton to protect from light
• Do not shake or freeze the vials

Diluted solution

• If immediate use is not possible, the diluted product may be stored up to 24 hr in the refrigerator at 2-8°C (36-46°F)
• Do not freeze or shake
• Protect from light

Kanuma is a prescription medication used to treat children and adults with lysosomal acid lipase (LAL) deficiency. LAL deficiency is also known as Wolman disease and cholesteryl ester storage disease (CESD). People with these conditions have little or no LAL enzyme activity, which can cause a build-up of fats within cells of different tissues that can lead to liver and heart disease, as well as other health problems.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Kanuma crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Kanuma.

Make sure to keep all appointments with your doctor and the laboratory.

Lysosomal Acid Lipase Deficiency

Treatment of lysosomal acid lipase deficiency1 7 (designated an orphan drug by FDA for this use).2

Survival benefit demonstrated in patients with rapidly progressive infantile-onset disease (i.e., Wolman disease).1 8 9

In pediatric patients and adults with late-onset disease (i.e., cholesterol ester storage disease), improvements in disease-related lipid and hepatic abnormalities demonstrated.1 7

Effects on cardiovascular morbidity and mortality and progression of liver disease not established.1 7

Pharmacokinetic profile of sebelipase alfa is based on data from adults and pediatric patients; pharmacokinetics not characterized in infants.10

Absorption

Bioavailability

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

No substantial accumulation following repeated dosing.1

Peak plasma concentrations occur approximately 1.1–1.3 hours after a dose in pediatric patients and adults.1

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.1 7 Decreased ALT concentrations typically observed within 2 weeks of treatment.1 7

Special Populations

Pharmacokinetic profile similar between adolescents and adults.1

Distribution

Extent

Not known whether sebelipase alfa distributes into milk.1

Elimination

Half-life

Approximately 6 minutes.1 9

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

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loose stools (diarrhea).
• Upset stomach or throwing up.
• Cough.
• Nose and throat irritation.
• Headache.
• Hard stools (constipation).

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Mechanism of Action

LAL deficiency is an autosomal recessive lysosomal storage disorder characterized by a genetic defect resulting in a marked decrease or loss in activity of the lysosomal acid lipase (LAL) enzyme. The primary site of action of the LAL enzyme is the lysosome, where the enzyme normally causes the breakdown of lipid particles including LDL-c. Deficient LAL enzyme activity results in progressive complications due to the lysosomal accumulation of cholesteryl esters and triglycerides in multiple organs, including the liver, spleen, intestine, and the walls of blood vessels. The resulting lipid accumulation in the liver may lead to increased liver fat content and progression of liver disease, including fibrosis and cirrhosis. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. In parallel, dyslipidemia due to impaired degradation of lysosomal lipid is common with elevated LDL-c and triglycerides and low HDL-cholesterol (HDL-c).

Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalized into lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and triglycerides to free cholesterol, glycerol and free fatty acids.

Pharmacodynamics

In clinical trials, after initiation of dosing with Kanuma, breakdown of accumulated lysosomal lipid led to initial increases in LDL-c and triglycerides within the first 2 to 4 weeks of treatment. In general, following increases in LDL-c and triglycerides, these parameters decreased to below pre-treatment values within 8 weeks of treatment with Kanuma.

In all patients with elevated alanine aminotransferase (ALT) values at baseline (82 of 84 patients in clinical trials), reductions in ALT values were observed, generally within 2 weeks after initiation of treatment with Kanuma. Treatment interruption resulted in increases in LDL-c and ALT values and decreases in HDL-c.

Pharmacokinetics

The pharmacokinetic profile of sebelipase alfa was 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 following once weekly or once every other week dosing.

Using a population pharmacokinetic model, sebelipase alfa pharmacokinetic parameters were estimated for 65 pediatric and adult patients who received intravenous infusions of Kanuma at 1 mg/kg at Week 22 (Table 4); 24 patients were 4 to 11 years old, 23 were 12 to 17 years old, and 18 were adults. The pharmacokinetic profiles of sebelipase alfa were similar between adolescents and adults. The Tmax and T1/2 were similar across all age groups.

Kanuma 20 mg/10 mL vials are supplied as a sterile, preservative-free, nonpyrogenic solution in single-use, glass vials.

NDC 25682-007-01: 20 mg/10 mL vial

Store Kanuma under refrigeration between 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not shake or freeze the vials.

Hypersensitivity Reactions, including Anaphylaxis

Advise patients and caregivers that reactions related to administration and infusion may occur during and after Kanuma treatment, including life-threatening anaphylaxis and severe hypersensitivity reactions. Inform patients of the signs and symptoms of anaphylaxis and hypersensitivity reactions, and have them seek immediate medical care should signs and symptoms occur [see Warnings and Precautions (5.1)].

Manufactured by:
Alexion Pharmaceuticals Inc.
Cheshire, CT 06410
US License Number: 1743
1-888-765-4747 (phone)

Kanuma is a trademark of Alexion Pharmaceuticals Inc.

NDC 25682-007-01
Rx only

Kanuma™
(sebelipase alfa)
Injection

20 mg/10 mL
(2 mg/mL)

For Intravenous Infusion Only
Dilute Before Use
Single-Use Only
Discard Unused Portion

1 vial
ALEXION®