VPRIV

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS Patients treated with enzyme replacement therapies have experienced life-threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement and after extended duration of therapy. Initiate VPRIV in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue VPRIV and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1) ] . WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS See full prescribing information for complete boxed warning. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. ( 5.1 ) Initiate VPRIV in a healthcare setting with appropriate medical monitoring and support measures, including access to cardiopulmonary resuscitation equipment. ( 5.1 ) If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue VPRIV and immediately initiate appropriate medical treatment, including use of epinephrine. ( 5.1 )

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)

<table width="75%"><caption>Table 1: Adverse Reactions Observed in &#x2265;10% of Adult and Pediatric Patients with Type 1 Gaucher Disease Treated with VPRIV in the Pooled 5 Clinical Studies</caption><col width="60%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" valign="middle">Adverse Reaction</th><th styleCode="Rrule" valign="middle">Na&#xEF;ve to ERT N = 54 Number of patients (%)</th><th styleCode="Rrule">Switched from imiglucerase to VPRIV N = 40 Number of patients (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypersensitivity reaction<footnote>Denotes any event considered related to and occurring within up to 24 hours of VPRIV infusion, including one case of anaphylaxis.</footnote></td><td styleCode="Rrule">28 (52)</td><td styleCode="Rrule">9 (23)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">19 (35)</td><td styleCode="Rrule">12 (30)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">12 (22)</td><td styleCode="Rrule">3 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">12 (22)</td><td styleCode="Rrule">5 (13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">10 (19)</td><td styleCode="Rrule">6 (15)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">9 (17)</td><td styleCode="Rrule">7 (18)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Joint pain (knee)</td><td styleCode="Rrule">8 (15)</td><td styleCode="Rrule">3 (8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia/Fatigue</td><td styleCode="Rrule">8 (15)</td><td styleCode="Rrule">5 (13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Activated partial thromboplastin time prolonged</td><td styleCode="Rrule">6 (11)</td><td styleCode="Rrule">2 (5)</td></tr><tr><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">3 (6)</td><td styleCode="Rrule">4 (10)</td></tr></tbody></table>