FDA label d9ba5424-69f3-7d3e-e053-2995a90a1b3e

5 WARNINGS AND PRECAUTIONS Cardiovascular Ischemic Events, Including Major Adverse Cardiovascular Events (MACE) : The potential risks of treatment must be balanced with expectations in improvements in symptoms of IBS-C. Discontinue ZELNORM treatment in patients who experience a myocardial infarction, stroke, transient ischemic attack or angina. ( 4 ) Evaluate the risks and benefits of continued treatment in patients who develop clinical or other evidence of cardiovascular ischemic heart disease and/or experience changes in health status that could increase cardiovascular risk during treatment. ( 4 , 5.1 ) Ischemic Colitis : Monitor for rectal bleeding, bloody diarrhea, and new or worsening abdominal pain and discontinue ZELNORM if symptoms develop. ( 5.2 ) Volume Depletion Associated with Diarrhea : Avoid use in patients with severe diarrhea. Instruct patients to discontinue ZELNORM and contact their healthcare provider if severe diarrhea, hypotension or syncope occur. ( 5.3 ) Suicidal Ideation and Behavior : Monitor patients for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment. Instruct patients to immediately discontinue ZELNORM and contact their healthcare provider if their depression is persistently worse or they are experiencing emergent suicidal thoughts or behaviors. ( 5.4 ) 5.1 Cardiovascular Ischemic Events, Including Major Adverse Cardiovascular Events (MACE) Stroke, MI, and cardiovascular death (major adverse cardiovascular events [MACE]) have been reported in adults taking ZELNORM who had an increased risk of developing an adverse cardiovascular event based on their medical history [see Adverse Reactions (6.1) ] . ZELNORM is contraindicated in patients with a history of MI, stroke, TIA, or angina [see Contraindications (4) ] . Assess female patients less than 65 years of age for a history of cardiovascular disease and cardiovascular risk factors prior to treatment with ZELNORM [see Adverse Reactions (6.1) ] . The potential risks of treatment must be balanced with expectations in improvements in symptoms of IBS-C. Discontinue ZELNORM in patients who experience an MI, stroke, TIA, or angina [see Contraindications (4) ]. Evaluate the risks and benefits of continued use of ZELNORM in patients who develop clinical or other evidence of cardiovascular ischemic heart disease (e.g., coronary artery disease) and/or experience changes in health status that could increase cardiovascular risk during treatment with ZELNORM. 5.2 Ischemic Colitis Ischemic colitis and other forms of intestinal ischemia have been reported postmarketing in patients receiving ZELNORM [see Adverse Reactions (6.2) ] . In some cases, hospitalization was required. Discontinue ZELNORM in patients who develop symptoms of ischemic colitis, such as rectal bleeding, bloody diarrhea, or new or worsening abdominal pain. Evaluate patients experiencing these symptoms promptly and perform appropriate diagnostic testing. Do not reinitiate ZELNORM in patients who develop findings consistent with ischemic colitis or other forms of intestinal ischemia [see Contraindications (4) ] . 5.3 Volume Depletion Associated with Diarrhea Diarrhea is one of the most common adverse reactions in ZELNORM-treated patients from the pooled IBS-C double-blind placebo-controlled trials. Diarrhea resulted in discontinuation in 1.6% of ZELNORM-treated patients compared to 0% in placebo [see Adverse Reactions (6) ] . In post-marketing experience, serious consequences of diarrhea including hypovolemia, hypotension, and syncope have been reported in patients treated with ZELNORM. In some cases, these complications have required hospitalization for rehydration. Avoid use of ZELNORM in patients who are currently experiencing or frequently experience diarrhea. Instruct patients to discontinue ZELNORM and contact their healthcare provider if severe diarrhea, hypotension, or syncope occur. 5.4 Suicidal Ideation and Behavior Suicide, suicidal attempt and ideation, and self-injurious behavior have been reported in clinical trials of IBS-C and other gastrointestinal motility disorders . The frequency of suicidal ideation or attempts with tegaserod treatment (8 patients out of 10,003) was higher than placebo (1 patient out of 5,425) [see Adverse Reactions (6.1) ] . Suicidal ideation/behavior in clinical trials was proportionately more frequent among patients receiving antidepressant medication. Monitor all ZELNORM-treated patients for clinical worsening of depression and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment. Counsel family members and caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Instruct patients to immediately discontinue ZELNORM and contact their healthcare provider if their depression is persistently worse or they are experiencing emergent suicidal thoughts or behaviors.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail elsewhere in the labeling: Cardiovascular Ischemic Events, including MACE [see Warnings and Precautions (5.1) ] Ischemic Colitis [see Warnings and Precautions (5.2) ] Volume Depletion Associated with Diarrhea [see Warnings and Precautions (5.3) ] Suicidal Ideation and Behavior [see Warnings and Precautions (5.4) ] Most common adverse reactions (>2%) are headache, abdominal pain, nausea, diarrhea, flatulence, dyspepsia, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact US WorldMeds at 1-855-697-9232 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. Common Adverse Reactions In three clinical trials 2,343 female patients less than 65 years of age with IBS-C received ZELNORM 6 mg twice daily or placebo. The majority of patients were Caucasian. Table 1 provides the incidence of common adverse reactions reported in >2% of IBS-C patients in the ZELNORM treatment group and at an incidence that was greater than in the placebo group. Table 1. Most Common Adverse Reactions Reported in >2% of ZELNORM-treated patients and at an incidence greater than placebo in Three Placebo-Controlled Trials of ZELNORM in Female IBS-C Patients Less than 65 Years of Age Adverse Reactions ZELNORM 6 mg twice daily Placebo [N = 1,184] % [N = 1,159] % Headache 14 10 Abdominal Pain Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, abdominal tenderness, epigastric pain or discomfort 11 10 Nausea 8 7 Diarrhea 8 3 Flatulence 6 5 Dyspepsia 4 3 Dizziness 4 3 Diarrhea The majority (84%) of the ZELNORM patients reporting diarrhea had a single episode. In most cases, diarrhea occurred within the first week of treatment. Typically, diarrhea resolved with continued therapy. Diarrhea resulted in discontinuation in 1.6% of ZELNORM-treated patients compared to 0% in placebo [see Warnings and Precautions (5.3) ] . Less Common Adverse Reactions The following is a list of less common adverse reactions reported in ≤ 2% of patients in clinical trials of IBS-C on ZELNORM but more frequently than placebo: Blood and Lymphatic System Disorders: Anemia Ear and Labyrinth Disorders: Vertigo Gastrointestinal Disorders: Rectal hemorrhage General Disorders and Administration Site Conditions: Asthenia Investigations: Increased blood creatine phosphokinase Metabolism and Nutrition Disorders: Increased appetite Musculoskeletal and Connective Tissue Disorders: Arthropathy, tendonitis Nervous System Disorders: Migraine Adverse Reactions of Special Interest ZELNORM is recommended for use in female patients with IBS-C, and is not recommended for other motility disorders [see Indications and Dosage (1) ]. Major Adverse Cardiovascular Events (MACE) A retrospective analysis of the pooled clinical trial database data (involving 18,645 patients, both male and female) of 29 placebo-controlled trials of IBS-C and other gastrointestinal motility disorders of at least four weeks duration was conducted. An external adjudication of the reported cardiovascular ischemic (CVI) events identified an imbalance in patients taking ZELNORM (13 events, 0.1%) compared to placebo (1 event, 0.01%). A second external adjudication was conducted with additional patient-level information, and used a comprehensive pre-specified methodology regarding both case selection and assessment. This adjudication confirmed seven CVI events (0.06%) on ZELNORM compared to one event (0.01%) on placebo. An imbalance in MACE events (defined as cardiovascular death, non-fatal MI, non-fatal stroke) was observed in patients taking ZELNORM compared to placebo, as reported in both external adjudications. All events occurred in male and female patients with a history of cardiovascular ischemic disease and/or more than one cardiovascular risk factor. A summary of the event rates from both adjudications is provided in Table 2. The rate of MACE events for ZELNORM-treated patients ranged from 0.03% to 0.06% in the overall population and 0.01% to 0.03% in the female population less than 65 years of age without a history of cardiovascular ischemic disease compared to zero in the placebo-treated group. Table 2. Number of MACE Events Confirmed in Two External Adjudications of the Clinical Trial Database Females < 65 Years of Age All Patients (Male and Female) Without a History of Cardiovascular Ischemic Disease Defined as prior MI, stroke, transient ischemic attack, angina, etc. Without a History of Cardiovascular Ischemic Disease and One or Fewer Cardiovascular Risk Factors Defined as active smoking, current hypertension/history of antihypertensive treatment, current hyperlipidemia/history of lipid lowering medication, history of diabetes mellitus, age ≥55 years, or obesity (BMI >30 kg/m 2). ZELNORM (N=11,614) n (%) Placebo (N=7,031) n (%) ZELNORM (N=9,547) n (%) Placebo (N=5,748) n (%) ZELNORM (N=7,785) n (%) Placebo (N=4,686) n (%) First External Adjudication 7 Five females less than 65 years, one male less than 65 years and one male greater than 65 years of age (0.06%) 0 3 Cardiovascular death, MI and stroke; all three patients had > one cardiovascular risk factor at baseline (0.03%) 0 0 0 Second External Adjudication 4 Three females less than 65 years of age and one male greater than 65 years of age (0.03%) 0 1 Cardiovascular death (one of the three cases confirmed in the 1 st external adjudication) (0.01%) 0 0 0 Suicidal Ideation/Behavior Two ZELNORM-treated patients committed suicide, one in a controlled study of IBS-C and one during open label treatment for another motility disorder. In 27 placebo-controlled trials, assessing tegaserod at a total daily dose of 4 mg to 50 mg (up to four times the recommended daily dose), or placebo for the treatment of IBS-C or other gastrointestinal motility disorders, the frequency of suicidal ideation/behavior with tegaserod treatment (8 events/10,003, or 0.08%) was higher than placebo (1 event/5,425, or 0.02%). Events on ZELNORM included one completed suicide, two suicide attempts, four cases of self-injurious behavior, and one case of suicidal ideation. There was one suicide attempt on placebo. Of the eight ZELNORM-treated patients who experienced an event, all were less than 65 years of age, seven were female and three had IBS-C. The patient who committed suicide was a female, less than 65 years of age with IBS-C, taking ZELNORM 2 mg twice daily. Abdominal Surgeries, Including Cholecystectomy An increase in abdominal surgeries was observed on ZELNORM (9 patients out of 2,965 or 0.3%) versus placebo (3 patients out of 1,740 or 0.2%) in clinical trials of men and women treated with ZELNORM for IBS-C. The increase was primarily due to a numerical imbalance in cholecystectomies reported in patients treated with ZELNORM (5 patients out of 2,965 or 0.17%) versus placebo (1 patient out of 1,740 or 0.06%). A causal relationship between abdominal surgeries and ZELNORM has not been established. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ZELNORM. 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. Ischemic colitis, mesenteric ischemia, gangrenous bowel and rectal bleeding [see Warnings and Precautions (5.2) ] Severe diarrhea resulting in syncope, hypotension, hypovolemia, electrolyte disorders [see Warnings and Precautions (5.3) ] Sphincter of Oddi spasm, bile duct stone, cholecystitis with elevated transaminases, elevation in ALT, AST and bilirubin, hepatitis [see Contraindications (4) ] Alopecia Hypersensitivity reactions, including anaphylaxis [see Contraindications (4) ]

<table width="75%"><caption>Table 1. Most Common Adverse Reactions <footnote ID="K978">Reported in &gt;2% of ZELNORM-treated patients and at an incidence greater than placebo</footnote> in Three Placebo-Controlled Trials of ZELNORM in Female IBS-C Patients Less than 65 Years of Age </caption><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" valign="bottom">Adverse Reactions</th><th styleCode="Rrule">ZELNORM 6 mg twice daily </th><th styleCode="Rrule">Placebo</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">[N = 1,184] % </th><th styleCode="Rrule">[N = 1,159] % </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">14</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal Pain <footnote ID="K1037">Includes abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, abdominal tenderness, epigastric pain or discomfort</footnote></td><td styleCode="Rrule">11</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">8</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">8</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Flatulence</td><td styleCode="Rrule">6</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3</td></tr><tr><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3</td></tr></tbody></table>

<table width="75%"><caption>Table 2. Number of MACE Events Confirmed in Two External Adjudications of the Clinical Trial Database</caption><col width="15%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="15%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><thead><tr><th rowspan="2" styleCode="Botrule Lrule Rrule"/><th colspan="2" styleCode="Rrule"/><th colspan="4" styleCode="Botrule Rrule">Females &lt; 65 Years of Age</th></tr><tr styleCode="Botrule"><th colspan="2" styleCode="Rrule">All Patients (Male and Female) </th><th colspan="2" styleCode="Rrule">Without a History of Cardiovascular Ischemic Disease <footnote ID="t2f1">Defined as prior MI, stroke, transient ischemic attack, angina, etc.</footnote></th><th colspan="2" styleCode="Rrule">Without a History of Cardiovascular Ischemic Disease <footnoteRef IDREF="t2f1"/> and One or Fewer Cardiovascular Risk Factors <footnote ID="K1290">Defined as active smoking, current hypertension/history of antihypertensive treatment, current hyperlipidemia/history of lipid lowering medication, history of diabetes mellitus, age &#x2265;55 years, or obesity (BMI &gt;30 kg/m 2). </footnote></th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">ZELNORM (N=11,614) n (%) </th><th styleCode="Rrule">Placebo (N=7,031) n (%) </th><th styleCode="Rrule">ZELNORM (N=9,547) n (%) </th><th styleCode="Rrule">Placebo (N=5,748) n (%) </th><th styleCode="Rrule">ZELNORM (N=7,785) n (%) </th><th styleCode="Rrule">Placebo (N=4,686) n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">First External Adjudication</td><td styleCode="Rrule">7 <footnote ID="K1337">Five females less than 65 years, one male less than 65 years and one male greater than 65 years of age</footnote> (0.06%) </td><td styleCode="Rrule">0</td><td styleCode="Rrule">3 <footnote ID="K1347">Cardiovascular death, MI and stroke; all three patients had &gt; one cardiovascular risk factor at baseline</footnote> (0.03%) </td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr><td styleCode="Lrule Rrule">Second External Adjudication</td><td styleCode="Rrule">4 <footnote ID="K1367">Three females less than 65 years of age and one male greater than 65 years of age</footnote> (0.03%) </td><td styleCode="Rrule">0</td><td styleCode="Rrule">1 <footnote ID="K1377">Cardiovascular death (one of the three cases confirmed in the 1 st external adjudication) </footnote> (0.01%) </td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr></tbody></table>