injection, powder, lyophilized, for solution
[Pfizer Laboratories Div Pfizer Inc]
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ELELYSO safely and effectively. See full prescribing information for ELELYSO.
ELELYSO (taliglucerase alfa) for injection, for intravenous use
Initial U.S. Approval: 2012
INDICATIONS AND USAGE
ELELYSO™ (taliglucerase alfa) for injection is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy (ERT) for patients with a confirmed diagnosis of Type 1 Gaucher disease. (1)
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
The most common adverse reactions during clinical studies were infusion reactions (6.1). Other commonly observed adverse reactions in ≥10% of patients were URTI/nasopharyngitis, pharyngitis/throat infection, headache, arthralgia, influenza/flu, UTI/pyelonephritis, back pain, extremity pain (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at (1-800-438-1985) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
ELELYSO™ (taliglucerase alfa) for injection is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy (ERT) for patients with a confirmed diagnosis of Type 1 Gaucher disease.
2 DOSAGE AND ADMINISTRATION
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.
- 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):
- Total dose in Units = Patient's weight (kg) x 60 Units/kg
- Total number of vials = Total dose in Units divided by 200 Units/vial
- Round up to the next whole vial.
- 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.
- 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.
- 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 WARNINGS AND PRECAUTIONS
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 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 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.
|Study 1||Study 2|
|Infusion reaction||14 (44%)||13 (46%)|
|URTI/Nasopharyngitis||7 (22%)||5 (18%)|
|Pharyngitis/Throat infection||6 (19%)||1 (4%)|
|Headache||6 (19%)||3 (11%)|
|Arthralgia||4 (13%)||3 (11%)|
|Influenza/Flu||4 (13%)||1 (4%)|
|UTI/Pyelonephritis||3 (9%)||3 (11%)|
|Back pain||1 (3%)||3 (11%)|
|Extremity pain||0||3 (11%)|
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.
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 USE IN SPECIFIC POPULATIONS
Reproduction studies with taliglucerase alfa have been performed in pregnant rats at intravenous doses up to 55 mg/kg/day (about 5 times the recommended human dose of 60 Units/kg based on the body surface area) and in pregnant rabbits at intravenous doses up to 27.8 mg/kg/day (about 5 times the recommended human dose of 60 Units/kg based on the body surface area). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to taliglucerase alfa. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ELELYSO should be used during pregnancy only if clearly needed.
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).
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. 220.127.116.11) 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 the taliglucerase alfa concentration is 40 Units/mL [see Dosage and Administration ( 2)]. Reconstituted solutions have a pH of approximately 6.0.
12 CLINICAL PHARMACOLOGY
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.
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 NONCLINICAL TOXICOLOGY
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 CLINICAL STUDIES
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.
|Clinical Parameter||30 Units/kg |
|Change in Spleen Volume||%BW Mean (SD)||-0.9 (0.4)||-1.3 (1.1)|
|MN Mean (SD)||-4.5 (2.1)||-6.6 (5.4)|
|Change in Hemoglobin||g/dL Mean (SD)||1.6 (1.4)||2.2 (1.4)|
|Change in Liver Volume||%BW Mean (SD)||-0.6 (0.5)||-0.6 (0.4)|
|MN Mean (SD)||-0.2 (0.2)||-0.3 (0.2)|
|Change in Platelet Count||/mm3 Mean (SD)||11,427 (20,214)||41,494 (47,063)|
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.
16 HOW SUPPLIED/STORAGE AND HANDLING
ELELYSO™ is available as a lyophilized powder, 200 Units per vial (NDC 0069 0106 01)
17 PATIENT COUNSELING INFORMATION
- Inform patients that ELELYSO is administered under the supervision of a healthcare professional as an intravenous infusion every other week. The infusion typically takes 60 to 120 minutes.
- Advise patients that ELELYSO may cause severe allergic reactions or infusion reactions. Patients should be counseled that they should be carefully re-evaluated for treatment with ELELYSO if serious allergic reactions occur. Patients should also be counseled that infusion reactions can usually be managed by slowing the infusion rate, treatment with medications such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with decreased infusion rate. Patients should also be counseled that pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions [see Warnings and Precautions (5.1,5.2)].
- Advise patients to report any adverse reactions while on ELELYSO treatment.
Principal Display Panel
Manufactured and Distributed by:
Division of Pfizer Inc.
New York, NY 10017
Licensed from Protalix Biotherapeutics
PRINCIPAL DISPLAY PANEL - 200 Unit Vial Label
For intravenous infusion only
Single-use vial. Discard any
taliglucerase alfa injection, powder, lyophilized, for solution
|Labeler - Pfizer Laboratories Div Pfizer Inc (134489525)|
|Registrant - Pfizer Inc (113480771)|
|Pharmacia and Upjohn Company||829076566||MANUFACTURE(0069-0106), PACK(0069-0106)|