NDC 0069-0106 Elelyso

Taliglucerase Alfa

NDC Product Code 0069-0106

NDC CODE: 0069-0106

Proprietary Name: Elelyso What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Taliglucerase Alfa What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Taliglucerase is used to treat a certain rare genetic problem (Gaucher disease). Taliglucerase replaces a certain natural substance (an enzyme called glucocerebrosidase) that is missing in people with Gaucher disease. This medication improves blood, bone, liver, and spleen problems caused by Gaucher disease. Taliglucerase does not correct the genetic problem, and treatment must be continued for life.

NDC Code Structure

  • 0069 - Pfizer Laboratories Div Pfizer Inc

NDC 0069-0106-01

Package Description: 1 VIAL, GLASS in 1 BOX > 5 mL in 1 VIAL, GLASS

NDC Product Information

Elelyso with NDC 0069-0106 is a a human prescription drug product labeled by Pfizer Laboratories Div Pfizer Inc. The generic name of Elelyso is taliglucerase alfa. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Pfizer Laboratories Div Pfizer Inc

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Elelyso Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TALIGLUCERASE ALFA 200 U/5mL

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Hydrolytic Lysosomal Glucocerebroside-specific Enzyme - [EPC] (Established Pharmacologic Class)
  • Glucosylceramidase - [CS]

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Pfizer Laboratories Div Pfizer Inc
Labeler Code: 0069
FDA Application Number: BLA022458 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: BLA - A product marketed under an approved Biologic License Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-01-2012 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Elelyso Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications And Usage

ELELYSO is indicated for the treatment of patients with a confirmed diagnosis of Type 1 Gaucher disease.

Other

Treatment-naïve patients: The recommended dosage of ELELYSO for long-term treatment is 60 units/kg of body weight administered every other week as a 60 to 120 minute intravenous infusion.

Patients switching from imiglucerase: Patients currently being treated with imiglucerase for Type 1 Gaucher disease can be switched to ELELYSO. Patients previously treated on a stable dosage of imiglucerase are recommended to begin treatment with ELELYSO at that same units/kg dosage when they switch from imiglucerase to ELELYSO. Administer ELELYSO for long-term treatment every other week as a 60 to 120 minute intravenous infusion. Dosage adjustments can be made based on achievement and maintenance of each patient's therapeutic goals [see Clinical Studies (14.2)].

  • Clinical Trials of ELELYSO as Initial TherapyClinical Trial in Patients 19 Years and OlderThe safety of ELELYSO at dosages of either 30 units/kg (n=16) or 60 units/kg (n=16) every other week was assessed in 32 adult treatment-naïve patients (aged 19 to 74 years) with Type 1 Gaucher disease in a 9-month double-blind, randomized clinical trial.Table 1:Adverse Reactions in ≥5% of Treatment-Naïve Adult Patients Treated with ELELYSOPreferred TermTreatment-Naïve Adults (N=32)n (%)Headache6 (19)Arthralgia4 (13)Fatigue3 (9)Nausea3 (9)Dizziness3 (9)Abdominal pain2 (6)Pruritus2 (6)Flushing2 (6)Vomiting2 (6)Urticaria2 (6)Clinical Trial in Patients 16 Years and Younger The safety of ELELYSO at dosages of either 30 units/kg (n=4) or 60 units/kg (n=5) every other week was assessed in 9 pediatric treatment-naïve patients (aged 2 to 13 years) with Type 1 Gaucher disease in a 12-month randomized clinical trial.The most common adverse reaction (≥10%) was vomiting, which occurred in 4 of 9 patients. Two patients developed hypersensitivity reactions; one patient experienced severe vomiting and gastrointestinal inflammation, and 1 experienced mild throat irritation and chest discomfort. Both patients responded to treatment with antihistamines and continued ELELYSO treatment.

Clinical Trial in Patients Switching from Imiglucerase Treatment to ELELYSOThe safety of ELELYSO was assessed in 31 patients (26 adult and 5 pediatric patients), ages 6 to 66 years old, with Type 1 Gaucher disease who had previously been receiving treatment with imiglucerase for a minimum of 2 years. ELELYSO was administered for 9 months at the same number of units as each patient's previous imiglucerase dose.Table 2: Adverse Reactions in ≥10% of Patients Switched from Imiglucerase to ELELYSO (after 9 months on treatment)Preferred TermPatients Switched from Imiglucerase(N=31; 26 adults and 5 children)n (%)Arthralgia4 (13)Headache4 (13)Pain in extremity3 (10)

Risk SummaryThe limited available data on ELELYSO use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations]. In animal reproduction studies when pregnant rats and rabbits were administered taliglucerase alfa at intravenous doses up to 5 times the recommended human dose (RHD),there was no evidence of embryo-fetal toxicity [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are 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.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal RiskWomen with Type 1 Gaucher disease have an increased risk of spontaneous abortion if disease symptoms are not treated and controlled pre-conception and during a pregnancy. Pregnancy may exacerbate existing Type 1 Gaucher disease symptoms or result in new disease manifestations. Type 1 Gaucher disease manifestations may lead to adverse pregnancy outcomes, including hepatosplenomegaly which can interfere with the normal growth of a fetus and thrombocytopenia which can lead to increased bleeding and possible postpartum hemorrhage requiring transfusion.

Data

Animal DataReproduction studies have been performed with taliglucerase alfa administered during the period of organogenesis in rats and rabbits. In rats, intravenous doses up to 55 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not cause any adverse effects on embryo-fetal development. In rabbits, intravenous doses up to 27.8 mg/kg/day (about 5 times the RHD of 60 units/kg based on the body surface area) did not show any embryo-fetal toxicity.

Risk SummaryThere are no data on the presence of taliglucerase in human milk, the effects on the breast fed infant or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ELELYSO and any potential adverse effects on the breastfed child from ELELYSO or from the underlying maternal condition.

Clinical Trial in Patients 19 Years and OlderThe safety and efficacy of ELELYSO were assessed in 31 adult patients with Type 1 Gaucher disease. The trial was a 9-month, multi-center, double-blind, randomized trial in patients with Gaucher disease-related enlarged spleens (>8 times normal) and thrombocytopenia (<120,000 /mm3). Sixteen patients had enlarged livers and ten patients had anemia at baseline. All patients were naïve to ERT. Patients with severe neurological symptoms were excluded from the trial. Patients were 19 to 74 years of age (mean age 36 years), and 48% were male. Patients were randomized to receive ELELYSO at a dosage of either 30 units/kg (n=15) or 60 units/kg (n=16) every other week. The recommended dosage in treatment-naïve adult patients is 60 units/kg every other week. ELELYSO 30 units/kg every other week is not a recommended dosage [see Dosage and Administration (2.1)].Table 4 shows the baseline values and mean (SD) changes in clinical parameters (spleen volume, liver volume, platelet count, and hemoglobin) after 9 months of treatment with ELELYSO. For all clinical trials, liver and spleen volumes were measured by MRI and are reported as percentage of body weight (%BW) and multiples of normal (MN). The observed change from baseline in the primary endpoint, reduction in spleen volume, was considered to be clinically meaningful in light of the natural history of untreated Gaucher disease.Table 4: Mean (SDSD = standard deviation) Changes in Clinical Parameters from Baseline to 9 Months in Treatment-Naïve Adults with Type 1 Gaucher Disease Initiating Therapy with ELELYSO (N=31)Clinical Parameter30 units/kgThe recommended ELELYSO dosage in treatment-naïve adult patients is 60 units/kg every other week. ELELYSO 30 units/kg every other week is not a recommended dosage. [see Dosage and Administration (2.1)] (n=15)Mean (SD)60 units/kg (n=16)Mean (SD)Spleen Volume (%BW%BW = percentage of body weight)Baseline3.1 (1.5)3.3 (2.7)Month 92.2 (1.3)2.1 (1.9)Change-0.9 (0.4)-1.3 (1.1)Spleen Volume (MNMN = multiples of normal)Baseline15.4 (7.7)16.7 (13.4)Month 911.1 (6.3)10.4 (9.4)Change-4.5 (2.1)-6.6 (5.4)Liver Volume (%BW)Baseline4.2 (0.9)3.8 (1.0)Month 93.6 (0.7)3.1 (0.7)Change-0.6 (0.5)-0.6 (0.4)Liver Volume (MN)Baseline1.7 (0.4)1.5 (0.4)Month 91.4 (0.3)1.2 (0.3)Change-0.2 (0.2)-0.3 (0.2)Platelet Count (mm3)Baseline75,320 (40,861)65,038 (28,668)Month 986,747 (50,989)106,531 (53,212)Change11,427 (20,214)41,494 (47,063)Hemoglobin (g/dl)Baseline12.2 (1.7)11.4 (2.6)Month 914.0 (1.4)13.6 (2.0)Change1.6 (1.4)2.2 (1.4)Twenty-six of the 31 patients in this 9-month clinical trial continued blinded treatment with ELELYSO in an extension trial for a total treatment duration of 24 months. The following data are the changes in clinical parameters from baseline to Month 24 for the 30 units/kg (n=12) and 60 units/kg (n=14) dose groups, respectively: mean (SD) spleen volume (%BW) decreased by 1.4 (0.6) and 2.0 (2.0), in MN by 6.8 (3.0) and 10.2 (9.8); hemoglobin increased by 1.3 (1.7) g/dL and 2.4 (2.3) g/dL; liver volume (%BW) decreased by 1.1 (0.5) and 1.0 (0.7), in MN by 0.4 (0.2) and 0.4 (0.3 and platelet count increased 28,433 (31,996) /mm3 and 72,029 (68,157) /mm3. Twenty-three of the 26 patients who continued open-label treatment with ELELYSO for additional 12 months demonstrated stability in these clinical parameters.

Clinical Trial in Patients 16 years and YoungerThe safety and efficacy of ELELYSO were assessed in 9 pediatric patients with Type 1 Gaucher disease. The trial was a 12-month, multi-center, double-blind, randomized study in treatment-naïve patients. Patients were 2 to 13 years of age (mean age 8.1 years), and 67% were male. Patients were randomized to receive ELELYSO at a dosage of either 30 units/kg (n=4) or 60 units/kg (n=5) every other week. The recommended ELELYSO dosage in treatment-naïve pediatric patients is 60 units/kg every other week. ELELYSO 30 units/kg every other week is not a recommended dosage [see Dosage and Administration (2.1)].The following data are the changes [median (Q1, Q3)] in clinical parameters from baseline to Month 12 for the 60 units/kg dose group (n=5): spleen volume decreased from 18.4 (14.2, 35.1) MN to 11.0 (8.3, 14.5) MN; hemoglobin increased from 11.1 (9.2, 11.3) g/dL to 11.7 (11.5, 12.9) g/dL; liver volume decreased from 2.1 (2.0, 2.3) MN to 1.6 (1.5, 1.9) MN; platelet count increased from 80,000 (79,000, 87,000)/mm3 to 131,000 (119,000, 215,000)/mm3.Nine pediatric patients in the 12-month clinical trial continued blinded treatment with ELELYSO in an extension trial for a total treatment duration of 24 months. The following data are the changes [median (Q1, Q3)] in clinical parameters from baseline to Month 24 for the 60 units/kg dose group (n=5): spleen volume decreased by 19.0 (8.3, 41.2) MN; hemoglobin increased by 2.5 (1.9, 3.0) g/dL; liver volume decreased by 0.8 (0.6, 1.1) MN; and platelet count increased by 76,000 (67,000, 100,000)/mm3.

Hypersensitivity Reactions Including AnaphylaxisAdvise patients and caregivers that reactions related to administration and infusion may occur during and after ELELYSO 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 medical care should signs and symptoms occur. Inform patients that they should be carefully re-evaluated for treatment with ELELYSO if serious hypersensitivity reactions, including anaphylaxis, occur. Reduction of the infusion rate and/or pre-treatment with antihistamines, antipyretics and/or corticosteroids may prevent subsequent reactions [see Warnings and Precautions (5.1)].

Licensed from Protalix BiotherapeuticsLAB-0610-7.0

2.2 Preparation Instructions

  • ELELYSO should be reconstituted, diluted, and administered under the supervision of a healthcare professional.Each vial of ELELYSO provides 200 units of taliglucerase alfa and is intended for single use only. Do not use the vial more than one time. The reconstitution and dilution steps must be completed using aseptic technique.ELELYSO should be reconstituted with Sterile Water for Injection and diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 mL to 200 mL, and delivered by intravenous infusion. Prepare ELELYSO according to the following steps. Use aseptic technique. a.Determine the number of vials to be reconstituted based on the patient's weight and the recommended dose of 60 units/kg, using the following calculations (1–3):(1)Total dose in units = Patient's weight (kg) × dose (units/kg)(2)Total number of vials = Total dose in units divided by 200 units/vial(3)Round up to the next whole vial.b.Remove the required number of vials from the refrigerator. Do not leave these vials at room temperature longer than 24 hours prior to reconstitution. Do not heat or microwave these vials.c.Reconstitute each vial of ELELYSO with 5.1 mL of Sterile Water for Injection to yield a reconstituted product with a concentration of 40 units/mL and an extractable volume of 5 mL. Upon reconstitution, mix vials gently. DO NOT SHAKE. Prior to further dilution, visually inspect the solution in the vials; the solution should be clear and colorless. Do not use if the solution is discolored or if foreign particulate matter is present.d.Withdraw the calculated dose of drug from the appropriate number of vials and dilute with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 to 200 mL.i.For pediatric patients, a final volume of 100 to 120 mL should be used.ii.For adult patients, a final volume of 130 to 150 mL may be used. However, if the volume of reconstituted product alone is equal to or greater than 130 to 150 mL, then the final volume should not exceed 200 mL.e.Mix gently. DO NOT SHAKE. Since this is a protein solution, slight flocculation (described as translucent fibers) occurs occasionally after dilution.

2.3 Administration Instructions

  • After reconstitution and dilution, the preparation should be administered via intravenous infusion and filtered through an in-line low protein-binding 0.2 μm filter.For pediatric patients: An initial infusion rate of 1 mL/minute should be used. After tolerability to ELELYSO is established, the infusion rate may be increased, but should not exceed the maximum recommended infusion rate of 2 mL/minute. The total volume of the infusion should be delivered over a minimum of 60 minutes.For adult patients: An initial infusion rate of 1.2 mL/minute should be used. After tolerability to ELELYSO is established, the infusion rate may be increased, but should not exceed the maximum recommended infusion rate of 2.2 mL/minute. The total volume of the infusion should be delivered over a minimum of 60 minutes.As ELELYSO contains no preservative, the product should be used immediately once reconstituted. If immediate use is not possible, the reconstituted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light or up to 4 hours at 20 to 25 °C (68 to 77 °F) without protection from light. The diluted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light. Storage of the reconstituted product and the diluted product should not exceed a total of 24 hours. Do not freeze. Discard any unused product.

3 Dosage Forms And Strengths

For injection: 200 units, lyophilized powder in single-use vials for reconstitution.

4 Contraindications

None.

5.1 Hypersensitivity Reactions Including Anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have occurred in some patients treated with ELELYSO. In clinical trials, 2 of 72 (3%) patients treated with ELELYSO experienced signs and symptoms consistent with anaphylaxis. Signs and symptoms of these patients included urticaria, hypotension, flushing, wheezing, chest tightness, nausea, vomiting, and dizziness. These reactions occurred during ELELYSO infusion. In clinical trials with ELELYSO, 21 of 72 (29%) patients experienced hypersensitivity reactions, including anaphylaxis. Signs and symptoms of hypersensitivity reactions included pruritus, angioedema, flushing, erythema, rash, nausea, vomiting, cough, chest tightness, and throat irritation. These reactions have occurred up to 3 hours after the start of infusion [see Adverse Reactions (6.1)].Due to the potential for anaphylaxis, appropriate medical support should be readily available when ELELYSO is administered. Observe patients closely for an appropriate period of time after administration of ELELYSO, taking into account the time to onset of anaphylaxis seen in clinical trials. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. If anaphylaxis occurs, ELELYSO should be immediately discontinued, and appropriate medical treatment should be initiated.Management of hypersensitivity reactions should be based on the severity of the reaction and include slowing or temporary interruption of the infusion and/or administration of antihistamines, antipyretics, and/or corticosteroids for mild reactions. Pretreatment with antihistamines and/or corticosteroids may prevent subsequent hypersensitivity reactions. Patients were not routinely premedicated prior to infusion of ELELYSO during clinical studies. If severe hypersensitivity reactions occur, immediately stop the infusion of ELELYSO and initiate appropriate treatment. Consider the risks and benefits of re-administering ELELYSO in patients who have experienced a severe reaction associated with ELELYSO. Caution should be exercised upon rechallenge, and appropriate medical support should be readily available [see Adverse Reactions (6.3)].

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 practice.

6.2 Immunogenicity

As with all therapeutic proteins, patients may develop anti-drug antibodies (ADA) to ELELYSO. In clinical trials of treatment-naïve adults, 17 (53%) of 32 patients developed ADA during treatment with ELELYSO, and 2 (6%) of 32 patients tested positive for ADA at baseline prior to ELELYSO treatment. Of the 17 patients who developed ADA during ELELYSO treatment, 6 patients (35%) developed hypersensitivity reactions, 2 of whom met criteria for anaphylaxis. Two of the 17 patients who developed ADA during ELELYSO treatment discontinued treatment due to hypersensitivity reactions, one of whom had met criteria for anaphylaxis. Of the 2 patients who tested positive for ADA prior to initiation of ELELYSO treatment, one patient developed a hypersensitivity reaction during the first dose of ELELYSO and withdrew from the study. The second patient did not experience a hypersensitivity reaction.In a clinical trial of treatment-naïve pediatric patients, 2 (22%) of 9 patients developed ADA during treatment with ELELYSO, and one of 9 patients was ADA-positive prior to initiation of ELELYSO. Two of these 3 patients experienced hypersensitivity reactions (1 who developed ADA during treatment and became negative after Week 12 and 1 who was ADA-positive at baseline and became ADA negative after Week 8) and continued treatment with ELELYSO. The third patient who developed ADA during treatment and continued to be ADA-positive until study completion at Week 52 did not experience a hypersensitivity reaction.In clinical trials of 31 patients (26 adult and 5 pediatric patients) who switched from imiglucerase to ELELYSO treatment, 5 adults (16% of patients) developed ADA during treatment with ELELYSO. Four additional patients (13%, 2 adults and 2 children) tested positive for ADA at baseline but became ADA-negative after the switch to ELELYSO; one of these adult patients subsequently developed ADA to ELELYSO. Two adult patients (1 patient who developed ADA after the switch and 1 who was ADA positive at baseline) experienced hypersensitivity reactions. Both patients continued treatment with ELELYSO. The relationship between ADA and hypersensitivity reactions is not fully understood. Monitoring for ADA to ELELYSO may be useful in ADA positive patients or in patients who have experienced hypersensitivity reactions to ELELYSO or other enzyme replacement therapies.Twenty-nine of the 30 adult and pediatric patients who tested positive for ADA were tested for neutralizing antibodies capable of inhibiting the enzymatic activity of ELELYSO. Neutralizing antibodies were detected in 5 (17.2%) of 29 patients, 3 treatment-naïve adult patients, 1 treatment-naïve pediatric patient, and 1 adult patient who switched from imiglucerase. Due to limited available data, it is not possible to determine a relationship between the presence of neutralizing antibodies and therapeutic response with ELELYSO. 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 medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to ELELYSO with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ELELYSO in countries where it is marketed. Because these reactions include those reported voluntarily from a population of uncertain size in addition to those from postmarketing studies, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Gastrointestinal disorders: Vomiting, diarrheaGeneral disorders and administration site conditions: FatigueImmune system disorders: Anaphylaxis [see Warning and Precautions (5.1)], Type III immune-mediated fixed drug eruptionMusculoskeletal and connective tissue disorders: Back pain

8.4 Pediatric Use

The use of ELELYSO for treatment of pediatric patients with Type 1 Gaucher disease is supported by evidence of effectiveness from adequate and well-controlled trials of ELELYSO in adults, with additional pharmacodynamic data from 5 pediatric patients and pharmacokinetic data from 9 pediatric patients who participated in clinical trials [see Clinical Studies (14.1, 14.2), Clinical Pharmacology (12.3)]. Data from 14 pediatric patients were included in the safety evaluation [see Adverse Reactions (6.1)]. There are insufficient data to inform dosing in patients less than 4 years of age.Pediatric patients experienced a higher frequency of vomiting during ELELYSO treatment (4 of 9 treatment-naïve patients) than adult patients, and this may be a symptom of hypersensitivity reaction. The frequencies of other adverse reactions were similar between pediatric and adult patients [see Adverse Reactions (6.1)].

8.5 Geriatric Use

During clinical trials, 8 patients aged 65 or older were treated with ELELYSO. Clinical trials of ELELYSO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

11 Description

Taliglucerase alfa, a hydrolytic lysosomal glucocerebroside-specific enzyme for intravenous infusion, is a recombinant active form of the lysosomal enzyme, β-glucocerebrosidase, which is expressed in genetically modified carrot plant root cells cultured in a disposable bioreactor system (ProCellEx®). β-Glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide. ELELYSO is produced by recombinant DNA technology using plant cell culture (carrot). Purified taliglucerase alfa is a monomeric glycoprotein containing 4 N-linked glycosylation sites (Mr = 60,800). Taliglucerase alfa differs from native human glucocerebrosidase by two amino acids at the N terminal and up to 7 amino acids at the C terminal. Taliglucerase alfa is a glycosylated protein with oligosaccharide chains at the glycosylation sites having terminal mannose sugars. These mannose-terminated oligosaccharide chains of taliglucerase alfa are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease. ELELYSO is supplied as a sterile, non-pyrogenic, lyophilized product. The quantitative composition of each 200 unit vial is D-mannitol (206.7 mg), polysorbate 80 (0.56 mg), sodium citrate (30.4 mg), and taliglucerase alfa (212 units). Citric acid may be added to adjust the pH at the time of manufacture.A Unit is the amount of enzyme that catalyzes the hydrolysis of 1 micromole of the synthetic substrate para-nitrophenyl-β-D-glucopyranoside (pNP-Glc) per minute at 37°C. After reconstitution with Sterile Water for Injection, taliglucerase alfa concentration is 40 units/mL [see Dosage and Administration (2)]. Reconstituted solutions have a pH of approximately 6.0.

12.1 Mechanism Of Action

Gaucher disease is an autosomal recessive disorder caused by mutations in the human glucocerebrosidase gene, which results in a reduced activity of the lysosomal enzyme glucocerebrosidase. Glucocerebrosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency results in accumulation of substrate glucocerebroside primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells," which accumulate in the liver, spleen and bone marrow.ELELYSO, a long term enzyme replacement therapy, is a recombinant analog of human lysosomal glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, reducing the amount of accumulated glucocerebroside. ELELYSO uptake into cellular lysosomes is mediated by binding of ELELYSO mannose oligosaccharide chains to specific mannose receptors on the cell surface leading to internalization and subsequent transport to the lysosomes.

12.3 Pharmacokinetics

Pharmacokinetics of taliglucerase alfa were evaluated in 38 patients (29 adult and 9 pediatric patients) who received intravenous infusions of ELELYSO 30 units/kg or 60 units/kg every other week. ELELYSO 30 units/kg is not a recommended dose in treatment-naïve Gaucher disease patients [see Dosage and Administration (2.1)]. The pharmacokinetic parameters in adult and pediatric patients are summarized in Table 3.In adult Type 1 Gaucher disease patients treated with ELELYSO 30 units/kg or 60 units/kg (N=29) every other week as initial therapy, pharmacokinetics were determined with the first dose and at Week 38 of treatment. The pharmacokinetics of taliglucerase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure at the doses studied. No significant accumulation or change in taliglucerase alfa pharmacokinetics over time from Weeks 1 to 38 was observed with repeated dosages of 30 units/kg or 60 units/kg every other week. Based on the limited data, there were no significant pharmacokinetic differences between male and female patients in this study.The pharmacokinetics of taliglucerase alfa were evaluated in 9 pediatric patients 4 to 17 years of age with Type 1 Gaucher disease who were treated with ELELYSO for 10 to 27 months. Six of the 9 patients were treatment-naïve, and 3 patients were switched from imiglucerase. In both the 30 units/kg and 60 units/kg dose groups, clearance values in pediatric patients were similar to those in adult patients. AUC values in pediatric patients were lower than AUC values in adult patients, due to weight-based dosing of taliglucerase alfa and lower body weights in pediatric patients.Table 3: Taliglucerase Alfa Pharmacokinetic Parameters after Repeated Dosing in Adult and Pediatric Patients with Type 1 Gaucher DiseasePediatric Patients (N=9)Median (Range)Adult Patients at Week 38 (N=29)Median (Range)30 units/kgn = 560 units/kgn = 430 units/kgn = 1460 units/kgn = 15Age (years)15 (10, 17)11 (4, 16)35 (19, 74)33 (19, 58)Weight (kg)44.3 (22.8, 71.0)28.6 (16.5, 50.4)72.5 (51.5, 99.5)73.5 (58.5, 87.0)n = 14AUC0–∞ (ng*h/mL)Values were derived from concentration data expressed in ng/mL 1416 (535, 1969)2984 (1606, 4273)2007 (1007, 10092)6459 (2548, 21020)T1/2 (min)37.1 (22.5, 56.8)32.5 (18.0, 42.9)18.9 (9.20, 57.9)28.7 (11.3, 104)CL (L/h)30.5 (17.4, 37.8)15.8 (11.7, 24.9)30.5 (6.79, 68.0)18.5 (6.20, 37.9)Vss (L)14.9 (10.1, 35.6)8.80 (3.75, 21.4)11.7 (2.3, 22.7)10.7 (1.4, 18.5)

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 taliglucerase alfa. In a male and female fertility study in rats, taliglucerase alfa did not cause any significant adverse effect on male or female fertility parameters up to a maximum dose of 55 mg/kg/day (about 5 times the recommended human dose of 60 units/kg based on the body surface area).

14.2 Clinical Trial In Patients Switching From Imiglucerase Treatment To Elelyso

The safety and efficacy of ELELYSO were assessed in 31 patients (26 adult and 5 pediatric patients) with Type 1 Gaucher disease who were switched from imiglucerase to ELELYSO. The trial was a 9-month, multi-center, open-label, single arm study in patients who had been receiving treatment with imiglucerase at dosages ranging from 9.5 units/kg to 60 units/kg every other week for a minimum of 2 years. Patients were required to be clinically stable and have a stable biweekly dose of imiglucerase for at least 6 months prior to enrollment. Patients were 6 to 66 years of age (mean age 42 years, including pediatric patients), and 55% were male. Imiglucerase therapy was stopped, and treatment with ELELYSO was administered every other week at the same number of units as each patient's previous imiglucerase dose. If needed, adjustment of dosage was allowed during the study in order to maintain stability of clinical parameters (i.e., spleen volume, liver volume, platelet count, and hemoglobin). Mean (SD) organ volumes and hematologic values remained stable through 9 months of ELELYSO treatment. At baseline, spleen volume was 5.2 (4.5) MN, liver volume was 1.0 (0.3) MN, platelet count was 161,137 (73,387)/mm3, and hemoglobin was 13.5 (1.4) g/dL. After 9 months of ELELYSO treatment, spleen volume was 4.8 (4.6) MN, liver volume was 1.0 (0.2) MN, platelet count was 161,167 (80,820)/mm3, and hemoglobin was 13.4 (1.5) g/dL. ELELYSO dose remained unchanged in 30 of 31 patients. One patient required a dose increase at Week 24 (from 9.5 units/kg to 19 units/kg) for a platelet count of 92,000/mm3 at Week 22, which subsequently increased to 170,000/mm3 at Month 9.Eighteen of the 26 adult patients who completed the 9-month clinical trial continued treatment with ELELYSO in an open-label extension trial for additional 27 months (total treatment 36 months). Patients maintained stability in clinical parameters (spleen volume, liver volume, platelet count and hemoglobin); however only 10 of 18 adult patients completed 27 months of ELELYSO treatment in the extension trial and only 7 patients had their spleen and liver volumes assessed at 36 months.Five pediatric patients in the 9-month clinical trial who continued open-label treatment with ELELYSO for additional 24 months demonstrated stability in these clinical parameters.

16 How Supplied/Storage And Handling

ELELYSO is supplied as a lyophilized powder in single use vials. Each vial contains 200 units of ELELYSO.NDC 0069-0106-01, 200 units per vial

Storage And Handling

Store ELELYSO under refrigeration at 2° C to 8° C (36° F to 46° F). Do not freeze. Protect vials from light.As ELELYSO contains no preservative, the product should be used immediately once reconstituted. If immediate use is not possible, the reconstituted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light or up to 4 hours at 20 to 25 °C (68 to 77 °F) without protection from light. The diluted product may be stored for up to 24 hours at 2 to 8 °C (36 to 46 °F) under protection from light. Storage of the reconstituted product and the diluted product should not exceed a total of 24 hours. Do not freeze. Discard any unused product.

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