FDA label ed35fe39-7e44-646f-e053-2995a90a7347

6. ADVERSE REACTIONS Most common adverse reactions (≥ 3%) are upper respiratory tract infection, flatulence, diarrhea, increased blood creatinine phosphokinase, abdominal distension, and increased blood pressure. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Braintree Laboratories, Inc. at 1-800-874-6756 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies 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 PIZENSY in 807 patients with CIC in a six-month placebo-controlled trial (Study 1), a three-month active-controlled trial (Study 2) [see Clinical Studies (14) ] , and a one-year uncontrolled safety study (NCT02819310). Of the 298 patients in the one-year uncontrolled study, 55 patients were enrolled from Study 1 or Study 2. Most Common Adverse Reactions: Table 1 provides the incidence of adverse reactions in Study 1 reported in at least 3% of patients in the PIZENSY treatment group and at higher incidence than placebo. Table 1: Common Adverse Reactions 1 Reported in Adult Patients with CIC in Study 1 1 reported in at least 3% of patients and greater than placebo 2 74 of 291 patients in the PIZENSY group at least temporarily reduced their dose 3 Upper respiratory tract infection includes the terms viral upper respiratory tract infection and nasopharyngitis. 4 Increased blood creatinine phosphokinase includes the term blood creatinine phosphokinase myocardial band (MB) increased. 5 Increased blood pressure includes the term Hypertension PIZENSY 2 N=291 (%) Placebo N=302 (%) Upper Respiratory Tract Infection 3 9 6 Flatulence 8 3 Diarrhea 4 3 Increased blood creatinine phosphokinase 4 4 3 Abdominal Distension 3 1 Increased blood pressure 5 3 1 In Study 2, the safety profile of PIZENSY was similar to Study 1. In the 1-year uncontrolled safety study, adverse reactions reported in patients receiving PIZENSY (N=298) with an incidence of at least 3% that are not represented in Table 1 include urinary tract infection (5%) and abdominal pain (3%). Adverse Reaction of Special Interest - Severe Diarrhea In Study 1, severe diarrhea was reported in 2 (1%) PIZENSY-treated patients compared to no patients in the placebo group. Adverse Reactions Leading to Discontinuation In Study 1, 11/291 (4%) PIZENSY-treated patients discontinued due to adverse reactions, compared to 10/302 (3%) of patients in the placebo group. The most common adverse reactions leading to discontinuation in PIZENSY-treated patients (1% each) were elevated creatinine kinase, flatulence, diarrhea and increased blood pressure. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of lactitol outside of the United States. 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. hypersensitivity reactions, including rash and pruritus

<table ID="t1" width="100%"><caption>Table 1: Common Adverse Reactions ¹ Reported in Adult Patients with CIC in Study 1 </caption><col width="34.85%" align="left"/><col width="30.49%" align="left"/><col width="34.65%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">¹ reported in at least 3% of patients and greater than placebo </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">² 74 of 291 patients in the PIZENSY group at least temporarily reduced their dose </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">³ Upper respiratory tract infection includes the terms viral upper respiratory tract infection and nasopharyngitis. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">⁴ Increased blood creatinine phosphokinase includes the term blood creatinine phosphokinase myocardial band (MB) increased. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="First Footnote">⁵ Increased blood pressure includes the term Hypertension </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Botrule Lrule Rrule Toprule"/><td align="center" styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">PIZENSY ²</content></paragraph><paragraph><content styleCode="bold">N=291</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N=302</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule Toprule"> Upper Respiratory Tract Infection ³</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">9</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">6</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule Toprule"> Flatulence</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">8</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule Toprule"> Diarrhea</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">4</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule Toprule"> Increased blood creatinine phosphokinase ⁴</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">4</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule Toprule"> Abdominal Distension</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule Toprule"> Increased blood pressure ⁵</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td></tr></tbody></table>