41/15 PRODUCT DETAILS 

Drug Name-                KANUMA

Active Ingredient-      Sebelipase alfa

 Approved date         12/08/2015                                                                                       

FDA approved use-  To treat patients with a rare disease known as lysosomal acid                                          lipase (LAL)- deficiency                                     

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.

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.

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

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.

• 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. 

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.

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

 Administration Instructions-

 • 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.

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

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

CLINICAL PHARMACOLOGY

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).

Reference ID: 3857111 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.

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.

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 Tmax and T1/2 were similar across all age groups. 

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) Cmax (ng/mL) 490 (205) 784 (480) 957 (303) Tmax (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) Vc (L) 3.6 (3.0) 5.4 (2.4) 5.3 (1.6) T1/2 (min) 5.4 (4.3) 6.6 (3.7) 6.6

 Parameter values were estimated using a population pharmacokinetic model. Reference ID: 3857111 AUC = Area under the plasma concentration time curve. C max = Maximum concentration. Tmax = Time to maximum concentration. CL = Clearance. Vc = Central volume of distribution. T1/2 = Half-life. 13

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-                                                                                             There are no available data on KANUMA in pregnant women to inform any drug-associated risk.

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.

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.

3.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) 

4. 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