2.1 Recommended Dose

The recommended dose is 60 Units/kg of body weight administered once every 2 weeks as a 60–120 minute intravenous infusion.

Patients currently being treated with imiglucerase for Type 1 Gaucher disease can be switched to ELELYSO. Patients previously treated on a stable dose of imiglucerase are recommended to begin treatment with ELELYSO at that same dose when they switch from imiglucerase to ELELYSO.

Dosage adjustments can be based on achievement and maintenance of each patient's therapeutic goals. Clinical studies have evaluated dose ranges from 11 Units/kg to 73 Units/kg every other week.

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. The initial infusion rate should be 1.3 mL/min. After patient tolerability to the infusion rate is established, the rate of infusion may be increased to 2.3 mL/min. The total volume of the infusion solution should be delivered over a period of no less than 1 hour.

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 techniques. ELELYSO should be prepared using low-protein-binding containers and administered with a low-protein-binding infusion set equipped with an in-line, low-protein-binding 0.2 micrometer filter.

2.2 Instructions for Use

ELELYSO should be reconstituted, diluted, and administered under the supervision of a healthcare professional.

Prepare and use 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) x 60 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 volume of 5.3 mL and a withdrawal 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 particular matter is present.

d.

Withdraw 5 mL of reconstituted solution from each vial and dilute with 0.9% Sodium Chloride Injection, USP, to a final volume of 100 – 200 mL. Mix gently. DO NOT SHAKE. Since this is a protein solution, slight flocculation (described as translucent fibers) occurs occasionally after dilution.

As ELELYSO contains no preservative, the product should be used immediately once reconstituted. If immediate use is not possible, the reconstituted or the diluted product may be stored for up to 24 hours at 2 to 8°C (36 to 46°F). Do not freeze. Protect from light. Discard any unused product.

5.1 Anaphylaxis

As with any intravenous protein product, severe allergic reactions are possible. Anaphylaxis has been reported in patients treated with ELELYSO [see Adverse Reactions ( 6.1)]. If anaphylaxis occurs, ELELYSO should be immediately discontinued, and appropriate medical treatment should be initiated.

In patients who have experienced anaphylaxis during infusion with ELELYSO, caution should be exercised upon rechallenge; appropriate medical support should be readily available [see Adverse Reactions ( 6)].

5.2 Allergic and Infusion Reactions

Infusion reactions (including allergic reactions), defined as a reaction occurring within 24 hours of the infusion, were the most commonly observed reactions in patients (44%–46%) treated with ELELYSO in clinical studies [see Adverse Reactions (6)]. The most commonly observed symptoms of infusion reactions were headache (16%), chest pain or discomfort (6%), asthenia (7%), fatigue (5%), urticaria (7%), erythema (5%), increased blood pressure (5%), back pain and arthralgia (7%), and flushing (6%). Other infusion or allergic reactions included, angioedema, wheezing, dyspnea, coughing, cyanosis, and hypotension. Most of these reactions were mild and did not require treatment intervention.

Base the management of infusion reactions on the type and severity of the reaction, e.g., slowing the infusion rate or treatment with medications such as antihistamines and antipyretics.

Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where symptomatic treatment was required. Patients were not routinely pre-medicated prior to infusion of ELELYSO during clinical studies.

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.

The data described below reflect exposure to ELELYSO in 60 patients ages 13 to 74 years who received ELELYSO at doses ranging from 11 to 73 Units/kg every two weeks in 3 clinical studies, and included 31 males and 29 females. Thirty-two patients were naïve to ERT (Study 1) and 28 were switched from imiglucerase to ELELYSO (Study 2) [see Clinical Studies ( 14)]. Study 3 includes patients continuing treatment from Study 1 and Study 2. Twenty-four patients were treated for longer than 2 years and 4 patients were treated longer than 3 years.

Important adverse reactions including anaphylaxis, allergic reactions, and infusion reactions are described elsewhere in the label [see Warnings and Precautions ( 5.1)]. One patient experienced a Type III immune-mediated skin reaction. The most common adverse reactions requiring interventions were infusion reactions [see Warnings and Precautions ( 5.2)].

Table 2 is a listing of adverse reactions that occurred in 10% or greater of patients.

The types and incidences of adverse reactions with up to 24 months of treatment in Study 3 were similar to Study 1 and Study 2.

In addition to those listed in Table 2, less commonly reported adverse reactions (>2%) observed in clinical trials include fatigue, pain, pharyngolaryngeal pain, pruritus, diarrhea, dizziness, nausea, bone pain, abdominal pain, erythema, flushing, edema peripheral, muscle spasms, paresthesia, dyspnea, throat irritation, asthenia, chest discomfort, infusion site pain, alanine aminotransferase increased, musculoskeletal discomfort, musculoskeletal pain, insomnia, rash and skin irritation.

6.2 Immunogenicity

As with all therapeutic proteins, patients have developed IgG anti-drug antibodies (ADA) to ELELYSO. In Study 1, seventeen of 32 treatment naïve patients (17/32, 53%) who were administered ELELYSO every two weeks developed ADA post-treatment (defined as ADA positive at one or more post-treatment time points). Two additional patients were antibody positive at baseline; one patient withdrew after developing an allergic reaction with the first dose of ELELYSO and the second patient had increasing antibody titers with continued treatment. In Study 2, four of 28 patients (4/28, 14%) switched from imiglucerase treatment to ELELYSO treatment once every two weeks developed ADA after the switch. One additional patient who switched from imiglucerase in Study 2 was positive at baseline but did not develop increased ADA titers after ELELYSO treatment. The relevance of ADA to therapeutic response and adverse events is currently unclear.

Using neutralizing antibody assays of limited sensitivity, two treatment naïve patients (at 24 months of ELELYSO treatment) and one patient switched from imiglucerase (at 9 months of ELELYSO treatment) were determined to be positive for neutralizing activity in an in vitro enzyme inhibition assay and were negative in a cell based assay. For these patients there was no demonstrated association between positive neutralizing antibody assay results and therapeutic response. The significance of these findings is unknown at this time.

It is unknown if the presence of ADA to taliglucerase alfa is associated with a higher risk of infusion reactions. Patients who develop infusion or immune reactions with ELELYSO treatment should be monitored for ADA to ELELYSO. Additionally, patients with an immune reaction to other enzyme replacement therapies who are switching to ELELYSO should be monitored for ADA to ELELYSO.

Immunogenicity 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.

8.1 Pregnancy

8.3 Nursing Mothers

There are no data from studies in lactating women. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ELELYSO is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of ELELYSO in pediatric patients have not be established. One 8 year-old pediatric patient experienced a serious adverse reaction (gastroenteritis).

8.5 Geriatric Use

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

12.1 Mechanism of Action

ELELYSO catalyzes the hydrolysis of glucocerebroside to glucose and ceramide. In clinical trials, ELELYSO reduced spleen and liver size, and improved anemia and thrombocytopenia.

12.3 Pharmacokinetics

In Gaucher disease patients treated with 30 or 60 Units/kg (N=29), pharmacokinetics were determined with the first dose and at 38 weeks.

The pharmacokinetics of taliglucerase alfa appeared to be nonlinear with a greater than dose-proportional increase in exposure at the doses studied. The median systemic clearance (CL) values were approximately 30 L/hr and 20 L/hr for the 30 and 60 Units/kg, respectively. The median volume of distribution at steady state (Vss) ranged from 7.30 to 11.7 L for both dose groups. At the end of infusion, taliglucerase alfa serum concentrations fell rapidly with a median terminal half life of 18.9 to 28.7 minutes for both dose groups.

No significant accumulation or change in taliglucerase alfa pharmacokinetics over time from Weeks 1 to 38 was observed with repeated doses of 30 or 60 Units/kg.

Based on the limited data, there were no significant pharmacokinetic differences between male and female patients in the study.

13.1 Carcinogenesis, Mutagenesis and 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).

14.1 Study 1: Trial of ELELYSO as Initial Therapy

The safety and efficacy of ELELYSO was assessed in 31 adult patients with Type 1 Gaucher disease. The trial was a 9-month multi-center, double blind, randomized study in patients with Gaucher disease-related enlarged spleens (greater than 8 times normal) and thrombocytopenia (less than 120,000 /mm3). Sixteen patients had enlarged livers and ten patients had anemia at baseline. All patients were naive to ERT. Patients with severe neurological symptoms were excluded from the study. Patient age ranged from 19–74 years (mean age 36 years) and 48% were male. Patients were randomized to receive ELELYSO at a dose of either 30 Units/kg (n=15) or 60 Units/kg (n=16).

At baseline, mean % body weight (%BW) and multiples of normal (MN) spleen volumes were 3.1 and 3.3 (%BW) and 15.4 and 16.7 (MN) for the 30 Units/kg and 60 Units/kg dose groups, respectively. Similarly, liver volumes were 4.2 and 3.8 (%BW) and 1.7 and 1.5 (MN). Hemoglobin concentrations were 12.2 and 11.4 g/dL and platelet counts were 75,320 and 65,038 /mm3, for the 30 Units/kg and 60 Units/kg dose groups, respectively. For all studies, liver and spleen volumes were measured by MRI. The changes in clinical parameters after nine months of treatment are shown in Table 3. The observed change from baseline in the primary endpoint, spleen volume, was considered to be clinically meaningful in light of the natural history of untreated Gaucher disease.

Twenty-six previously treatment naive patients continued to be treated with ELELYSO in an extension of this study (Study 3) in a blinded manner for a total treatment duration of 24 months. For the respective 30 and 60 Units/kg dose groups, mean (SD) spleen volume (%BW) decrease -1.4 (0.6) and -2.0 (2.0); hemoglobin increased 1.3 (0.7) g/dL and 2.4 (2.3) g/dL; liver volume (%BW) decreased -1.1 (0.5) and -1.0 (0.7); and platelet count increased 28,433 (31,996) /mm3 and 72,029 (68,157) /mm3.

14.2 Study 2: Trial in Patients Switching from Imiglucerase to ELELYSO

The safety and efficacy of ELELYSO was assessed in 25 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 doses ranging from 11 Units/kg to 60 Units/kg for a minimum of 2 years. Patients were also required to be clinically stable and to have a stable biweekly dose of imiglucerase for at least 6 months prior to enrollment. Patient age ranged from 13–66 years (mean age 45 years including pediatric) and 46% 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. Adjustment of dosage was allowed by study criteria if needed in order to maintain clinical parameters (i.e., hemoglobin, platelet count, spleen volume, and liver volume). One patient required a dose increase (from 9.5 Units/kg to 19 Units/kg at week 24) for a platelet count of 92,000 /mm3 at week 22, and responded with a platelet count of 170,000 /mm3 at month 9.

Organ volumes and hematologic values remained stable on average through 9 months of ELELYSO treatment. At baseline, spleen volume %BW was 1.1% and MN was 5.5; liver volume %BW was 2.4% and MN was 1.0; mean (SD) hemoglobin was 13.6 (1.57) g/dL; and mean platelet count was 160,447 (79,086) /mm3. At the nine month endpoint, spleen volume %BW was 1.0% and MN was 5.1; live volume %BW was 2.3% and MN was 0.9; mean hemoglobin was 13.4 (1.6) and mean platelet count was 165,654 (94,038) /mm3.

Store ELELYSO at 2 to 8°C (36 to 46°F). Protect vials from light.