VPRIV

1 INDICATIONS AND USAGE VPRIV is indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease. VPRIV is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy (ERT) for patients with type 1 Gaucher disease. ( 1 )

2 DOSAGE AND ADMINISTRATION Administration of VPRIV should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis ( 2.1 ) Recommended Starting Dose in Adults and Pediatric Patients 4 Years of Age or Older: Patients Naïve to Enzyme Replacement Therapy: 60 Units/kg ( 2.2 ) Patients being treated with stable imiglucerase dosages for Gaucher disease: Can switch to VPRIV at previous imiglucerase dose two weeks after last imiglucerase dose ( 2.3 ) Determine number of vials to be reconstituted based on patient's actual weight and prescribed dose ( 2.4 ) Supplied VPRIV lyophilized powder must be reconstituted with Sterile Water for Injection ( 2.4 ) Reconstituted VPRIV solution must be diluted in 100 mL of 0.9% Sodium Chloride Injection prior to intravenous infusion ( 2.4 ) Administer the diluted VPRIV solution through an in-line low protein-binding 0.2 or 0.22 µm filter ( 2.5 ) 2.1 Recommendations Prior to VPRIV treatment Administration of VPRIV should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis [see Warnings and Precautions (5.1) ] . Initiate VPRIV in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment [see Warnings and Precautions (5.1)] . 2.2 Recommended Starting Dosage in Patients Naïve to Enzyme Replacement Therapy The recommended starting VPRIV dosage in naïve adults and naïve pediatric patients 4 years of age and older is 60 Units/kg administered every other week as a 60-minute intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each patient's therapeutic goals. 2.3 Switching from Imiglucerase to VPRIV Adults and pediatric patients 4 years of age and older currently being treated on a stable dosage of imiglucerase for type 1 Gaucher disease may be switched to VPRIV by starting treatment with VPRIV at the previous imiglucerase dosage two weeks after the last imiglucerase dose. VPRIV should be administered under the supervision of a healthcare professional as a 60-minute intravenous infusion. The dosage can be adjusted based on achievement and maintenance of each patient's therapeutic goals. 2.4 Reconstitution of the VPRIV Lyophilized Powder VPRIV is a lyophilized powder, which requires reconstitution and dilution, using sterile technique, prior to intravenous infusion. VPRIV should be prepared as follows: (a) Determine the number of vials to be reconstituted based on the individual patient's weight and the prescribed dose. (b) Inject 4.3 mL of Sterile Water for Injection, USP into a vial containing VPRIV lyophilized powder. (c) Mix gently. DO NOT SHAKE. The reconstituted VPRIV solution will have a 100 Units/mL concentration (400 Units VPRIV in 4 mL of solution). (d) If additional vials are needed, repeat steps (b) and (c). (e) Visually inspect the reconstituted VPRIV solution in the vials. The solution should be clear to slightly opalescent and colorless. Do not use if the solution is discolored or if foreign particulate matter is present. (f) With a single syringe, withdraw the calculated dose of drug from the appropriate number of vials. Using a separate syringe, withdraw air from a bag of 100 mL of 0.9% Sodium Chloride Injection suitable for intravenous administration. Then dilute the calculated dose of VPRIV directly into the 0.9% Sodium Chloride Injection. Mix gently. DO NOT SHAKE. Slight flocculation (described as white irregular shaped particles) may occasionally occur. Diluted solution with slight flocculation is acceptable for administration. (g) Because VPRIV contains no preservatives, use the reconstituted VPRIV solution and the diluted VPRIV solution immediately. If immediate use is not possible, the reconstituted VPRIV solution or the diluted VPRIV solution may be stored for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze and protect from light. Complete the infusion within 24 hours of reconstitution of vials. (h) Vials are for one-time use and only for one patient. Discard any unused solution. 2.5 Important Administration Instructions Administer the diluted VPRIV solution through an in-line low protein-binding 0.2 or 0.22 µm filter over 60 minutes. Do not infuse VPRIV with other products in the same infusion tubing because the compatibility of a VPRIV solution with other products has not been evaluated. 2.6 Premedication to Reduce Risk of Subsequent Hypersensitivity Reactions Consider pre-treatment with antihistamines and/or corticosteroids in patients who exhibited symptoms of hypersensitivity associated with prior velaglucerase alfa product infusions. Appropriate medical support should be readily available when VPRIV is administered [see Warnings and Precautions (5.1) ].

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS See boxed warning ( 5.1 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with enzyme replacement therapies, including VPRIV. VPRIV-treated patients have had these reactions occur in clinical studies and postmarketing experience [see Adverse Reactions (6.1) and Clinical studies (14) ] . Hypersensitivity reactions were the most commonly observed adverse reactions in patients treated with VPRIV in clinical studies. Patients were not routinely pre-medicated prior to infusion of VPRIV during clinical studies. The most commonly observed symptoms of hypersensitivity reactions were: headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and pyrexia/body temperature increased. Generally the reactions were mild and, in treatment-naïve patients, onset occurred mostly during the first 6 months of treatment and tended to occur less frequently with time. Additional hypersensitivity reactions of chest discomfort, dyspnea, pruritus and vomiting have been reported in post-marketing experience. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Administration of VPRIV should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Initiate VPRIV in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. The management of hypersensitivity reactions should be based on the severity of the reaction, e.g., slowing the infusion rate, treatment with medications such as antihistamines, antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusion time. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue VPRIV and immediately initiate appropriate medical treatment, including use of epinephrine. In cases where patients have exhibited symptoms of hypersensitivity to velaglucerase alfa or excipients in the drug product or to other enzyme replacement therapy, pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur.

6 ADVERSE REACTIONS Most common adverse reactions (≥10%) are: hypersensitivity reactions, headache, dizziness, abdominal pain, nausea, back pain, joint pain, prolonged activated PTT, fatigue/asthenia, and pyrexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 of 94 patients with type 1 Gaucher disease who received VPRIV at doses ranging from 15 Units/kg to 60 Units/kg every other week in 5 clinical studies. Fifty-four (54) patients were naïve to enzyme replacement therapy (ERT) and received VPRIV for 9 months and 40 patients switched from imiglucerase to VPRIV treatment and received VPRIV for 12 months [see Clinical Studies (14) ] . Patients were between 4 and 71 years old at time of first treatment with VPRIV, and included 46 male and 48 female patients. The most serious adverse reactions in patients treated with VPRIV were hypersensitivity reactions [see Warnings and Precautions (5.1) ] . The most commonly reported adverse reactions (occurring in ≥10% of patients) that were considered related to VPRIV are shown in Table 1. The most common adverse reactions were hypersensitivity reactions. Table 1: Adverse Reactions Observed in ≥10% of Adult and Pediatric Patients with Type 1 Gaucher Disease Treated with VPRIV in the Pooled 5 Clinical Studies Adverse Reaction Naïve to ERT N = 54 Number of patients (%) Switched from imiglucerase to VPRIV N = 40 Number of patients (%) Hypersensitivity reaction Denotes any event considered related to and occurring within up to 24 hours of VPRIV infusion, including one case of anaphylaxis. 28 (52) 9 (23) Headache 19 (35) 12 (30) Dizziness 12 (22) 3 (8) Pyrexia 12 (22) 5 (13) Abdominal pain 10 (19) 6 (15) Back pain 9 (17) 7 (18) Joint pain (knee) 8 (15) 3 (8) Asthenia/Fatigue 8 (15) 5 (13) Activated partial thromboplastin time prolonged 6 (11) 2 (5) Nausea 3 (6) 4 (10) Less common adverse reactions affecting more than one patient (>2% in the treatment-naïve group and >3% in patients switched from imiglucerase to VPRIV treatment) were bone pain, tachycardia, rash, urticaria, flushing, hypertension, and hypotension. Adverse Reactions in Pediatric Patients The safety profile of VPRIV was similar between pediatric patients (ages 4 to 17 years) and adult patients. Adverse reactions more commonly seen in pediatric patients compared to adult patients include (>10% difference): rash, aPTT prolonged, and pyrexia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to VPRIV in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. In clinical studies, 1 of 54 (2%) enzyme treatment-naïve patients treated with VPRIV developed IgG antibodies to VPRIV. One additional patient developed IgG antibodies to VPRIV during an extension study. In both patients, the IgG antibodies to VPRIV were determined to be neutralizing in an in vitro assay. The presence of IgG antibodies to VPRIV was not associated with hypersensitivity reactions. It is unknown if the presence of IgG antibodies to VPRIV is associated with a higher risk of infusion reactions. Patients with an immune response to other enzyme replacement therapies who are switching to VPRIV should continue to be monitored for antibodies to VPRIV. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VPRIV. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders: vomiting (in some cases vomiting can be serious, requiring hospitalization and/or drug discontinuation)

8.1 Pregnancy Risk Summary Available data on use of velaglucerase alfa in pregnant women includes more than 300 pregnancies reported from the pharmacovigilance database and published observational cohort studies, including the international Gaucher Disease registry. While available data cannot definitively establish or exclude the absence of a velaglucerase alfa associated risk during pregnancy, these data have not identified an association with use of velaglucerase alfa during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies no fetal harm was observed in rats or rabbits when velaglucerase alfa was administered intravenously during organogenesis at doses with exposures up to 1.8 times and 4.3 times, respectively, the recommended human daily dose (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, and other adverse outcomes. In the U.S. general population, the estimated major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and Embryo/Fetal Risk Women with Type 1 Gaucher disease have an increased risk of spontaneous abortion, especially 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 pregnancy, and thrombocytopenia which can lead to excessive bleeding. Data Animal Data Embryo-fetal development studies with velaglucerase alfa have been performed during the period of organogenesis in pregnant rats (gestation days 7 through 17) and rabbits (gestation days 6 through 18). In pregnant rats intravenous doses up to 17 mg/kg (102 mg/m 2 , about 1.8 times the recommended human dose of 60 Units/kg or 1.5 mg/kg or 55.5 mg/m 2 based on the body surface area) were administered two to three times weekly. In pregnant rabbits intravenous doses up to 20 mg/kg (240 mg/m 2 , about 4.3 times the recommended human dose of 60 Units/kg based on the body surface area) were administered two to three times weekly. These studies did not reveal any evidence of impaired fertility or harm to the fetus due to velaglucerase alfa. In a pre- and postnatal development study, velaglucerase alfa was administered intravenously to pregnant rats twice weekly from gestation day 6 to lactation day 19. There was no evidence of any adverse effect on pre- and postnatal development at doses up to 17 mg/kg/day (102 mg/m 2 , about 1.8 times the recommended human dose of 60 Units/kg based on the body surface area).