Loargys

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 therapy and after extended duration of therapy. Initiate LOARGYS 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 LOARGYS 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. Initiate LOARGYS 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 LOARGYS, and immediately initiate appropriate medical treatment, including use of epinephrine. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity : If a severe hypersensitivity reaction occurs, discontinue LOARGYS and immediately initiate appropriate medical treatment, including epinephrine. ( 5.1 ) 5.1 Hypersensitivity Reactions Including Anaphylaxis Life-threatening hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with enzyme replacement therapies (ERTs) including LOARGYS. Hypersensitivity reactions that were mild to moderate in severity occurred in 13% (6/48) of LOARGYS-treated patients in clinical trials [see Adverse Reactions ( 6 )] . Hypersensitivity reactions have included facial swelling, rash, flushing and dyspnea. The reactions generally occurred with the first few doses, but may also occur later in treatment. LOARGYS-treated patients who developed anti-drug antibodies (ADA) generally had a greater incidence of hypersensitivity reactions compared to those who did not develop ADA [see Adverse Reactions ( 6.1 )] . Anaphylaxis has occurred during the early course of ERT and after extended duration of ERT. Administration of LOARGYS should be supervised by a healthcare provider knowledgeable in the management of hypersensitivity reactions including anaphylaxis. Consider pre‑medication with an antihistamine. Corticosteroids can be considered in patients who have previously developed a hypersensitivity reaction. Initiate LOARGYS 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 LOARGYS and immediately initiate appropriate medical treatment, including use of epinephrine. Consider the risks and benefits of re-administering LOARGYS following a severe hypersensitivity reaction (including anaphylaxis). Caution should be exercised upon rechallenge. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur. • If a mild or moderate hypersensitivity reaction occurs, consider treatment with antihistamines and/or corticosteroids. For intravenous administration, consider temporarily holding the infusion or slowing the infusion rate.

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] . Most common adverse reactions (>10%) are vomiting, pyrexia, infusion associated reactions and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Immedica at toll-free phone 1-844-627-4687 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 safety of LOARGYS was evaluated in a randomized, double-blind, placebo-controlled trial in pediatric and adult patients with ARG1-D (Trial 1). Additional safety information was derived from Trial 2, a Phase 1 open-label trial that evaluated 16 patients between the ages of 5 to 31 years to assess safety, PK and PD of LOARGYS, and Trial 3, an open-label extension including 14 patients from Trial 2. Adverse Reactions from Trial 1 (Double-Blind Period) A total of 21 patients between the ages of 2 and 28 years of age, at enrollment, received intravenous LOARGYS dosages up to 0.2 mg/kg once weekly and 11 patients received placebo for 24 weeks [see Clinical Studies ( 14 )] . Table 1 summarizes the adverse reactions reported in ≥ 2 LOARGYS-treated patients and at a higher incidence in LOARGYS-treated patients compared to placebo-treated patients in Trial 1. Table 1: Common Adverse Reactions a in Pediatric and Adult Patients with ARG1-D in Trial 1 a Common adverse reactions were those that occurred in ≥ 2 LOARGYS-treated patients and at a higher incidence in LOARGYS-treated patients compared to placebo-treated patients. b Infusion-associated reactions are defined as reactions occurring within 4 hours after the infusion and included pruritus, arm swelling, and abdominal pain in LOARGYS-treated patients. c Includes reactions that were classified as hypersensitivity during the trial and reactions that were assessed as hypersensitivity based on symptoms and temporal relationship with drug. Adverse Reaction LOARGYS N = 21 n (%) Placebo N = 11 n (%) Vomiting 7 (33) 3 (27) Pyrexia 4 (19) 1 (9) Infusion Associated Reaction b 3 (14) 1 (9) Constipation 3 (14) 1 (9) Dizziness 2 (10) 0 Fall 2 (10) 0 Hypersensitivity c 2 (10) 0 Nasopharyngitis 2 (10) 0 Rhinorrhoea 2 (10) 0 Alanine aminotransferase increased 2 (10) 0 Aspartate aminotransferase increased 2 (10) 0 Description of Selected Adverse Reactions Hypersensitivity Reactions : Hypersensitivity reactions with symptoms including facial swelling, rash, flushing and dyspnea were reported in 13% (6/48) of LOARGYS-treated patients during clinical trials [see Warnings and Precautions ( 5.1 )] . Injection Site Reactions : Injection site reactions were reported in 14% (6/44) of patients after subcutaneous LOARGYS administration during the open-label extension periods in Trial 1 and Trial 3. Signs and symptoms included pain, erythema, swelling, irritation, and rash at the injection site. Immunogenicity: Anti-Drug Antibody-Associated Adverse Reactions Across Trials 1, 2, and 3, in patients with ARG1-D, the incidence of hypersensitivity reactions was 42% (5/12) in LOARGYS-treated patients who developed anti-drug antibodies (ADA) (i.e., anti-pegzilarginase-nbln antibodies and/or anti-PEG antibodies) and 3% (1/36) in those who were ADA-negative [see Clinical Pharmacology ( 12.6 )] .

<table ID="_Ref223113352" width="50%" cellpadding="7.2pt" styleCode="Noautorules"><caption>Table 1: Common Adverse Reactions^a in Pediatric and Adult Patients with ARG1-D in Trial 1</caption><col width="24%"/><col width="16%"/><col width="16%"/><tfoot><tr><td align="left" valign="top" colspan="3">^a Common adverse reactions were those that occurred in &#x2265; 2 LOARGYS-treated patients and at a higher incidence in LOARGYS-treated patients compared to placebo-treated patients. ^b Infusion-associated reactions are defined as reactions occurring within 4 hours after the infusion and included pruritus, arm swelling, and abdominal pain in LOARGYS-treated patients. ^c Includes reactions that were classified as hypersensitivity during the trial and reactions that were assessed as hypersensitivity based on symptoms and temporal relationship with drug.</td></tr></tfoot><tbody><tr><td valign="bottom" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="right" valign="bottom" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">LOARGYS N = 21 n (%)</content></paragraph></td><td align="right" valign="bottom" styleCode="Rrule Botrule Lrule Toprule "><paragraph><content styleCode="bold">Placebo N = 11 n (%)</content></paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Vomiting </paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>7 (33)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>3 (27)</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Pyrexia </paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>4 (19)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>1 (9)</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Infusion Associated Reaction^b</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>3 (14)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>1 (9)</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Constipation</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>3 (14)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>1 (9)</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Dizziness </paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>2 (10)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>0</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Fall </paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>2 (10)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>0</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Hypersensitivity^c</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>2 (10)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>0</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Nasopharyngitis </paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>2 (10)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>0</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Rhinorrhoea </paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>2 (10)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>0</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Lrule Botrule "><paragraph>Alanine aminotransferase increased</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>2 (10)</paragraph></td><td align="right" valign="top" styleCode="Rrule Lrule Toprule Botrule "><paragraph>0</paragraph></td></tr><tr><td valign="top" styleCode="Rrule Botrule Lrule Toprule "><paragraph>Aspartate aminotransferase increased</paragraph></td><td align="right" valign="top" styleCode="Rrule Botrule Lrule Toprule "><paragraph>2 (10)</paragraph></td><td align="right" valign="top" styleCode="Rrule Botrule Lrule Toprule "><paragraph>0</paragraph></td></tr></tbody></table>