KANUMA

Main information

  • Trade name:
  • KANUMA- sebelipase alfa injection, solution, concentrate
  • Composition:
  • Sebelipase alfa 2 mg in 1 mL
  • Administration route:
  • INTRAVENOUS
  • Prescription type:
  • PRESCRIPTION DRUG
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • KANUMA- sebelipase alfa injection, solution, concentrate
    United States
  • Language:
  • English

Therapeutic information

  • Therapeutic indications:
  • KANUMA® is indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency. None. Risk Summary There are no available data on KANUMA in pregnant women to inform any drug-associated risk. Animal reproductive studies conducted with sebelipase alfa showed no evidence of embryolethality, fetotoxicity, teratogenicity, or abnormal early embryonic development at dosages up to 164 and 526 times the human dosage of 1 mg/kg every other week (based on AUC) in rats and rabbits, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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. Animal Data Sebelipase alfa administered during the period of organogenesis to rats (on gestation days 6, 9, 12, 15 and 17) and rabbits (on gestation days 7, 10, 13, 16 and 19) at intravenous doses up to 60 and 50 mg/kg, respe
  • Product summary:
  • 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.

Status

  • Source:
  • DailyMed - NLM - National Library of Medicine
  • Authorization status:
  • Biologic Licensing Application
  • Authorization number:
  • 25682-007-01
  • Last update:
  • 28-05-2019

Summary of Product characteristics: dosage, interactions, side effects

KANUMA- sebelipase alfa injection, solution, concentrate

Alexion Pharmaceuticals, Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use KANUMA safely and effectively. See full

prescribing information for KANUMA.

KANUMA (sebelipase alfa) injection, for intravenous use

Initial U.S. Approval: 2015

INDICATIONS AND USAGE

KANUMA® is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme indicated for the treatment of

patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency. (1)

DOSAGE AND ADMINISTRATION

Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life: The recommended starting

dosage is 1 mg/kg as an intravenous infusion once weekly. For patients who do not achieve an optimal clinical response,

increase to 3 mg/kg once weekly. (2.1)

Pediatric and Adult Patients with LAL Deficiency: The recommended dosage is 1 mg/kg as an intravenous infusion once

every other week. (2.1)

Administration Instructions (2.3):

Infuse over at least 2 hours.

Consider further prolonging the infusion time for the 3 mg/kg dose or if a hypersensitivity reaction occurs.

Consider a 1-hour infusion for the 1 mg/kg dose in patients who tolerate the infusion.

DOSAGE FORMS AND STRENGTHS

Injection: 20 mg/10 mL (2 mg/mL) solution in single-use vials. (3)

CONTRAINDICATIONS

None. (4)

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions including Anaphylaxis: Observe patients during and after the infusion. Consider interrupting

the infusion or lowering the infusion rate, based on the severity of the reaction. If a severe hypersensitivity reaction

occurs, immediately stop the infusion and initiate appropriate treatment. Pre-treatment with antipyretics and/or

antihistamines may prevent subsequent reactions in those cases where symptomatic treatment is required. (5.1)

Hypersensitivity to Eggs or Egg Products: Consider the risks and benefits of treatment in patients with known systemic

hypersensitivity reactions to eggs or egg products. (5.2)

ADVERSE REACTIONS

The most common adverse reactions are:

Patients with Rapidly Progressive Disease Presenting within the First 6 Months of Life (≥30%): diarrhea, vomiting,

fever, rhinitis, anemia, cough, nasopharyngitis, and urticaria. (6.1)

Pediatric and Adult Patients (≥8%): headache, fever, oropharyngeal pain, nasopharyngitis, asthenia, constipation, and

nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Alexion at 1-844-259-6783 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

2.2 Preparation Instructions

2.3 Administration Instructions

2.4 Storage of Diluted Solution

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions Including Anaphylaxis

5.2 Hypersensitivity to Eggs or Egg Products

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Immunogenicity

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of

Life

14.2 Pediatric and Adult Patients with LAL Deficiency

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

KANUMA® is indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL)

deficiency.

2 DOSAGE AND ADMINISTRATION

2.1 Dosage

Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life:

The recommended starting dosage is 1 mg/kg administered once weekly as an intravenous infusion. For

patients who do not achieve an optimal clinical response, increase to 3 mg/kg once weekly.

Pediatric and Adult Patients with LAL Deficiency:

The recommended dosage is 1 mg/kg administered once every other week as an intravenous infusion.

2.2 Preparation Instructions

Sections or subsections omitted from the full prescribing information are not listed.

KANUMA is for intravenous infusion only. Prepare KANUMA using the following steps.

1. Determine the number of vials needed based on the patient's weight and the recommended dose of 1

mg/kg or 3 mg/kg, using the following calculations (a-b):

a. Total dose (mg) = Patient's weight (kg) × Recommended dose (mg/kg)

b. Total number of vials = Total dose (mg) divided by 20 mg/vial

2. Round to the next whole vial and remove the required number of vials from the refrigerator to allow

them to reach room temperature.

a. Volume (mL) of calculated total dose = Total dose (mg) divided by the 2 mg/mL concentration

b. Volume (mL) of 0.9% Sodium Chloride for dilution = Total infusion volume (mL) for patient's

weight (see Table 1) – Volume (mL) of calculated total dose

Table 1: Total Infusion Volumes

Weight Range (kg)

1 mg/kg dose

3 mg/kg dose

Total Infusion

Volume (mL)

Total Infusion

Volume (mL)

1 to 10.9

11 to 24.9

25 to 49.9

50 to 99.9

100 to 120.9

3. Mix gently by inversion. Do not shake the vials or the prepared infusion.

4. The solution should be 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.

5. Vials are for single-use only. Discard any unused product. Do not freeze.

2.3 Administration Instructions

Administer the diluted solution as an intravenous infusion using a low-protein binding infusion set with

an in-line, low-protein binding 0.2 micron filter.

Infuse over at least 2 hours. Consider further prolonging the infusion time for patients receiving the 3

mg/kg dose or those who have experienced hypersensitivity reactions [see Warnings and Precautions

(5.1)]. A 1-hour infusion may be considered for those patients receiving the 1 mg/kg dose who tolerate

the infusion.

2.4 Storage of Diluted Solution

KANUMA contains no preservatives; therefore, product should be used immediately after dilution. If

immediate use is not possible, the diluted product may be stored up to 24 hours in the refrigerator at

2°C to 8°C (36°F to 46°F). Do not freeze or shake. Protect from light.

3 DOSAGE FORMS AND STRENGTHS

Injection: 20 mg/10 mL (2 mg/mL) solution in single-use vials.

*

The infusion volume should be based on the prescribed dose and should be

prepared to a final KANUMA concentration of 0.1 mg/mL to 1.5 mg/mL.

For patients with LAL deficiency presenting within the first 6 months of life who

do not achieve an optimal clinical response with a dose of 1 mg/kg.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis, have been reported in KANUMA-treated patients. In

clinical trials, 3 of 106 (3%) patients treated with KANUMA experienced signs and symptoms

consistent with anaphylaxis. These patients experienced reactions during infusion with signs and

symptoms including chest discomfort, conjunctival injection, dyspnea, generalized and itchy rash,

hyperemia, swelling of eyelids, rhinorrhea, severe respiratory distress, tachycardia, tachypnea, and

urticaria. Anaphylaxis has occurred as early as the sixth infusion and as late as 1 year after treatment

initiation.

In clinical trials, 21 of 106 (20%) KANUMA-treated patients, including 9 of 14 (64%) infants and 12 of

92 (13%) pediatric patients, 4 years and older, and adults, experienced signs and symptoms either

consistent with or that may be related to a hypersensitivity reaction. Signs and symptoms of

hypersensitivity reactions, occurring in two or more patients, included abdominal pain, agitation, fever,

chills, diarrhea, eczema, edema, hypertension, irritability, laryngeal edema, nausea, pallor, pruritus,

rash, and vomiting. The majority of reactions occurred during or within 4 hours of the completion of

the infusion. Patients were not routinely pre-medicated prior to infusion of KANUMA in these clinical

trials.

Due to the potential for anaphylaxis, appropriate medical support should be readily available when

KANUMA is administered. If anaphylaxis occurs, immediately discontinue the infusion and initiate

appropriate medical treatment. Observe patients closely during and after the infusion. Inform patients 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, lowering 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 in those cases where symptomatic treatment was required. If a severe

hypersensitivity reaction occurs, immediately discontinue the infusion and initiate appropriate medical

treatment.

Consider the risks and benefits of re-administering KANUMA following a severe reaction. Monitor

patients, with appropriate resuscitation measures available, if the decision is made to re-administer the

product.

5.2 Hypersensitivity to Eggs or Egg Products

KANUMA is produced in the egg whites of genetically engineered chickens. Patients with a known

history of egg allergies were excluded from the clinical trials. Consider the risks and benefits of

treatment with KANUMA in patients with known systemic hypersensitivity reactions to eggs or egg

products.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in clinical practice.

In clinical trials, a total of 106 patients received treatment with KANUMA. The data described below

reflect exposure to KANUMA in 75 patients who received KANUMA at dosages up to 3 mg/kg once

weekly in clinical trials:

Nine patients (5 males, 4 females) who had growth failure or other evidence of rapidly progressive

LAL deficiency presenting within the first 6 months of life received KANUMA for up to 165

weeks (median 60 weeks) at escalating doses ranging between 0.35 mg/kg and 5 mg/kg once weekly

[see Clinical Studies (14.1)]. The recommended initial dosage for these patients is 1 mg/kg escalating

to 3 mg/kg once weekly [see Dosage and Administration (2.1)].

66 pediatric and adult patients with LAL deficiency aged 4 to 58 years (33 males, 33 females)

received KANUMA 1 mg/kg every other week up to 36 weeks.

Table 2 summarizes the most common adverse reactions occurring in >30% of patients with rapidly

progressive LAL deficiency presenting within the first 6 months of life receiving KANUMA.

Table 2: Most Common Adverse Reactions

in

Patients with Rapidly Progressive LAL

Deficiency Presenting within the First 6 Months

of Life

Adverse Reactions

KANUMA

N=9

n (%)

Diarrhea

6 (67)

Vomiting

6 (67)

Fever

5 (56)

Rhinitis

5 (56)

Anemia

4 (44)

Cough

3 (33)

Nasopharyngitis

3 (33)

Urticaria

3 (33)

Other less common adverse reactions reported in patients with rapidly progressive disease presenting

within the first 6 months of life who received KANUMA included hypotonia, decreased oxygen

saturation, retching, sneezing, and tachycardia.

Table 3 summarizes the most common adverse reactions that occurred in ≥8% of pediatric and adult

patients with LAL deficiency receiving KANUMA at a dosage of 1 mg/kg once every other week

during the 20-week double-blind treatment period [see Clinical Studies (14.2)].

Table 3: Most Common Adverse Reactions

in Pediatric and Adult

Patients with LAL Deficiency

Adverse Reactions

KANUMA

N = 36

Placebo

N = 30

n (%)

n (%)

Headache

10 (28)

6 (20)

Fever

9 (25)

7 (23)

Oropharyngeal pain

6 (17)

1 (3)

Nasopharyngitis

4 (11)

3 (10)

*

Reported in more than 30% of patients receiving

KANUMA

*

Asthenia

3 (8)

1 (3)

Constipation

3 (8)

1 (3)

Nausea

3 (8)

2 (7)

Other less common adverse reactions reported in pediatric and adult patients who received KANUMA

included anxiety and chest discomfort.

Hyperlipidemia

Increases in circulating LDL-cholesterol (LDL-c) and triglycerides above pre-treatment values were

observed in 29 of 36 (81%) and 21 of 36 (58%) patients, respectively, at 2 and 4 weeks following

initiation of KANUMA [see Clinical Pharmacology (12.2)]. The maximum mean percentage increase was

18% for LDL-c at Week 2 and 5% for triglycerides at Week 4.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. Patients have developed anti-

drug antibodies (ADA) to KANUMA. Immunogenicity assay results are highly dependent on the

sensitivity and specificity of the assay and may be influenced by several factors such as: assay

methodology, sample handling, timing of sample collection, concomitant medications, and underlying

disease. For these reasons, comparison of the incidence of antibodies to KANUMA with the incidence

of antibodies to other products may be misleading.

Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life

Seven of the 9 infants with rapidly progressive disease had at least one post-treatment ADA assessment,

and 4 of these 7 (57%) patients developed ADA during treatment with KANUMA. Two of the 4 ADA-

positive patients were determined to be positive for neutralizing antibodies that inhibit in vitro enzyme

activity and cellular uptake of the enzyme. At the time of initial ADA positivity, 3 patients were

receiving a dosage of 1 mg/kg once weekly and 1 patient was receiving a dosage of 3 mg/kg once

weekly. Three of the 4 ADA-positive patients had ADA titers monitored from the initiation of treatment,

and developed measureable ADA titers within the first 2 months of exposure. One of the 4 ADA-

positive patients had persistent ADA titers. ADA titers decreased to undetectable levels in the

remaining 3 patients while receiving continued treatment at a dosage of 3 mg/kg once weekly.

Hypersensitivity reactions occurred in all 4 of the ADA-positive patients, whereas they occurred in

only 1 of the 3 ADA-negative patients. None of the patients discontinued treatment. In 1 patient,

decreased growth velocity in a setting of neutralizing antibodies to KANUMA was observed.

Pediatric and Adult Patients with LAL Deficiency

Five of 35 (14%) KANUMA-treated pediatric and adult patients who completed the 20-week double-

blind period of study treatment developed ADA. All patients were receiving 1 mg/kg once every other

week. All 5 ADA-positive patients first developed measurable ADA titers within the first 3 months of

exposure. Two of the 5 ADA-positive patients had a measurable ADA titer at only one time point. In the

3 patients with measurable ADA titers at multiple time points, ADA titers decreased to undetectable

levels during continued treatment. Two patients developed in vitro neutralizing antibodies during the

open-label extension phase after 20 weeks and 52 weeks of treatment with KANUMA, respectively.

There is no clear association between the development of ADA and decreased efficacy in pediatric and

adult patients treated with KANUMA.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Reported in at least 8% of pediatric and adult patients receiving KANUMA and at a

higher incidence than in patients receiving placebo

Risk Summary

There are no available data on KANUMA in pregnant women to inform any drug-associated risk. Animal

reproductive studies conducted with sebelipase alfa showed no evidence of embryolethality,

fetotoxicity, teratogenicity, or abnormal early embryonic development at dosages up to 164 and 526

times the human dosage of 1 mg/kg every other week (based on AUC) in rats and rabbits, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.

Animal Data

Sebelipase alfa administered during the period of organogenesis to rats (on gestation days 6, 9, 12, 15

and 17) and rabbits (on gestation days 7, 10, 13, 16 and 19) at intravenous doses up to 60 and 50 mg/kg,

respectively, (approximately164 and 526 times the human AUC of 1387 ng.h/mL at 1 mg/kg dose

administered once every other week, respectively) did not cause any adverse effects on embryofetal

development. A pre- and postnatal development study in rats showed no evidence of adverse effects on

pre- and postnatal development at intravenous doses (administered on gestation days 6, 9, 12, 15, 18, and

20 and days 4, 7, 10, 14, and 17 postpartum) of sebelipase alfa up to 60 mg/kg/day (approximately 164

times the human AUC of 1387 ng.h/mL at 1 mg/kg dose administered once every other week).

8.2 Lactation

Risk Summary

There are no data on the presence of sebelipase alfa in human milk, the effects on the breastfed infant,

or the effects on milk production. It is not known if sebelipase alfa is present in animal milk. The

developmental and health benefits of breastfeeding should be considered along with the mother's

clinical need for KANUMA and any potential adverse effects on the breastfed infant from sebelipase

alfa or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of KANUMA have been established in pediatric patients aged 1 month and

older. Clinical trials with KANUMA were conducted in 56 pediatric patients (range 1 month to <18

years old) [see Clinical Studies (14)].

8.5 Geriatric Use

Clinical trials of KANUMA did not include any patients aged 65 years old and older. It is not known

whether they respond differently than younger patients.

11 DESCRIPTION

KANUMA (sebelipase alfa) is a recombinant human lysosomal acid lipase (rhLAL). Lysosomal acid

lipase (EC 3.1.1.13) is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of cholesteryl

esters to free cholesterol and fatty acids and the hydrolysis of triglycerides to glycerol and free fatty

acids.

KANUMA is produced by recombinant DNA technology in the egg white of eggs laid by genetically

engineered chickens. Purified sebelipase alfa is a monomeric glycoprotein containing 6 N-linked

glycosylation sites and has a molecular mass of approximately 55,000 daltons. The amino acid sequence

for sebelipase alfa is the same as the amino acid sequence for human LAL. The specific activity of

sebelipase alfa is 195 to 345 units/mg. One unit is the amount of enzyme activity that catalyzes the

hydrolysis of 1 micromole of the synthetic substrate 4-methylumbelliferyl oleate per minute at 37°C

under specified assay conditions.

KANUMA is supplied as a sterile, preservative-free, non-pyrogenic aqueous solution in single-use

vials for intravenous infusion. Each vial contains sebelipase alfa 20 mg/10 mL. Each mL of solution

contains sebelipase alfa (2 mg), citric acid monohydrate (1.57 mg), Human Serum Albumin (10 mg), and

trisodium citrate dihydrate (13.7 mg) at pH 5.9.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 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.

12.3 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 T

were similar across all age groups.

Table 4: Mean (SD) Pharmacokinetics Parameters at Week 22 in

Pediatric and Adult Patients Receiving 1 mg/kg Once Every Other Week

Parameter

4-11 years old

12-17 years old

≥18 years old

N=24

N=23

N=18

AUC (ng·hr/mL)

942 (388)

1454 (699)

1861 (599)

(ng/mL)

490 (205)

784 (480)

957 (303)

(hr)

1.3 (0.6)

1.1 (0.3)

1.3 (0.6)

CL (L/hr)

31.1 (7.1)

37.4 (12.4)

38.2 (12.5)

Parameter values were estimated using a population pharmacokinetic model.

AUC = Area under the plasma concentration time curve. C

= Maximum

concentration.

= Time to maximum concentration. CL = Clearance. V = Central

volume of distribution. T

= Half-life.

V (L)

3.6 (3.0)

5.4 (2.4)

5.3 (1.6)

(min)

5.4 (4.3)

6.6 (3.7)

6.6 (3.7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential or studies to evaluate mutagenic

potential have not been performed with sebelipase alfa. Sebelipase alfa at intravenous doses up to 60

mg/kg administered twice weekly (approximately 164 times the human AUC of 1387 ng.h/mL at 1 mg/kg

dose administered once every other week) was found to have no adverse effect on fertility and

reproductive performance of male and female rats.

13.2 Animal Toxicology and/or Pharmacology

In a rat disease model of LAL deficiency that exhibits several abnormalities analogous to the human

disease, sebelipase alfa administered intravenously at dosages up to 3 mg/kg once weekly showed

improvements in survival, body weight gain, organ weight reduction, reduction in serum transaminases

(ALT and aspartate aminotransferase [AST]), reduction in serum and hepatic lipids, and improvement in

liver histopathology.

14 CLINICAL STUDIES

14.1 Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of

Life

A multicenter, open-label, single-arm clinical study of KANUMA was conducted in 9 infants with LAL

deficiency who had growth failure or other evidence of rapidly progressive disease prior to 6 months

of age. The age range at entry was 1 to 6 months. Patients received KANUMA at 0.35 mg/kg once

weekly for the first 2 weeks and then 1 mg/kg once weekly. Due to suboptimal clinical response, doses

in all 6 surviving patients were escalated to 3 mg/kg once weekly, between 4 and 88 weeks (median 11

weeks) after starting treatment at 1 mg/kg. In one patient, the dose was escalated to 5 mg/kg once weekly

at Week 88 due to decreased growth velocity in a setting of positive neutralizing anti-drug antibodies to

KANUMA. The recommended dosage for these patients is 1 mg/kg to 3 mg/kg once weekly [see Dosage

and Administration (2.1)].

Efficacy of KANUMA was assessed by comparing the survival of 9 KANUMA-treated patients at 12

months of age with an untreated historical cohort of 21 patients with a similar age at disease

presentation and clinical characteristics. Of the 9 KANUMA-treated infants, 6 patients survived beyond

12 months of age, compared to 0 of 21 patients in the historical cohort, all of whom died by 8 months of

age. The median age of the 6 surviving KANUMA-treated patients was 18.1 months (range 12 to 42.2

months).

Following initiation of treatment with KANUMA 1 mg/kg once weekly, weight-for-age z-scores

improved in 3 of 5 surviving patients with growth failure, and all 6 surviving patients demonstrated

improvements in weight-for-age z-scores following dose escalation to 3 mg/kg once weekly.

14.2 Pediatric and Adult Patients with LAL Deficiency

The safety and efficacy of KANUMA were assessed in 66 pediatric and adult patients with LAL

deficiency, aged 4 to 58 years (71% were less than 18 years old), in a multicenter, double-blind,

placebo-controlled trial. Patients were randomized to receive KANUMA at a dosage of 1 mg/kg (n=36)

or placebo (n=30) once every other week for 20 weeks in the double-blind period. Sixty-two of the 66

(94%) patients had LDL-c of 130 mg/dL or greater at study entry. The majority of patients (58%) had

LDL-c above 190 mg/dL at study entry, and 24% of patients with LDL-c above 190 mg/dL remained on

lipid lowering medications.

At the completion of the 20-week double-blind period of the trial, a statistically significant

improvement in percent change from baseline in LDL-c was observed in the KANUMA-treated group

as compared to the placebo group (mean difference and 95% C.I.: -22%, [-33%, -15%]; p<0.0001).

LDL-c of less than 130 mg/dL was achieved in 13 of 32 (41%; 95% C.I.: [24%, 58%]) KANUMA-

treated patients and in only 2 of 30 (7%; 95% C.I.: [0%, 16%]) placebo-treated patients with baseline

LDL-c of 130 mg/dL or greater. A statistically significant improvement in percent change from baseline

at 20 weeks was also observed in the KANUMA-treated group compared to the placebo group for

other parameters related to LAL deficiency, including decreases in non-HDL-c (mean difference and

95% C.I.: -21%, [-30%, -15%]; p<0.0001) and triglycerides (mean difference and 95% C.I.: -14%, [-

28%, -1%]; p=0.0375), and increases in HDL-c (mean difference and 95% C.I.: 20%, [12%, 26%];

p<0.0001). The effect of KANUMA on cardiovascular morbidity and mortality has not been

established.

Patients treated with KANUMA had larger reductions from baseline in ALT values and liver fat content

(measured by MRI), compared to patients treated with placebo. The significance of these findings as

they relate to progression of liver disease in LAL deficiency has not been established.

Open-label Extension

Pediatric and adult patients who participated in the randomized, placebo-controlled trial were eligible to

continue treatment in an open-label extension. Sixty-five of 66 patients (98%) entered the open-label

period in which all patients received KANUMA at a dosage of 1 mg/kg once every other week. During

the open-label extension, patients treated with KANUMA for up to 36 weeks demonstrated

improvements in lipid parameters, including LDL-c and HDL-c levels, and ALT.

16 HOW SUPPLIED/STORAGE AND HANDLING

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.

17 PATIENT COUNSELING INFORMATION

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.

100 College Street, New Haven, CT 06510

US License Number: 1743

1-888-765-4747 (phone)

KANUMA is a trademark of Alexion Pharmaceuticals Inc.

PRINCIPAL DISPLAY PANEL - 20 mg/10 mL Vial Carton

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

®

®

KANUMA

sebelipase alfa injection, solution, concentrate

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:256 8 2-0 0 7

Route of Administration

INTRAVENOUS

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Sebelipa se a lfa (UNII: K4YTU42T8 G) (Sebelipase alfa - UNII:K4YTU42T8 G)

Sebelipase alfa

2 mg in 1 mL

Alexion Pharmaceuticals, Inc.

Inactive Ingredients

Ingredient Name

Stre ng th

Triso dium citra te dihydra te (UNII: B22547B9 5K)

Citric a cid mo no hydra te (UNII: 29 6 8 PHW8 QP)

Albumin Huma n (UNII: ZIF514RVZR)

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:256 8 2-0 0 7-

1 in 1 CARTON

12/0 8 /20 15

1

10 mL in 1 VIAL, GLASS; Type 0 : No t a Co mbinatio n

Pro duc t

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

BLA12556 1

12/0 8 /20 15

Labeler -

Alexion Pharmaceuticals, Inc. (789359510)

Revised: 12/2018