Trulance Immediate release

WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS TRULANCE is contraindicated in patients less than 6 years of age; in nonclinical studies in young juvenile mice, administration of a single oral dose of plecanatide caused deaths due to dehydration [see Contraindications (4) , Use in Specific Populations (8.4) ] . Avoid use of TRULANCE in patients 6 years to less than 18 years of age [see Warnings and Precautions (5.1) , Use in Specific Populations (8.4) ] . The safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age [see Use in Specific Populations (8.4) ] . WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS See full prescribing information for complete boxed warning. TRULANCE is contraindicated in patients less than 6 years of age; in young juvenile mice, plecanatide caused death due to dehydration. ( 4 , 8.4 ) Avoid use of TRULANCE in patients 6 years to less than 18 years of age. ( 5.1 , 8.4 ) The safety and effectiveness of TRULANCE have not been established in patients less than 18 years of age. ( 8.4 )

5 WARNINGS AND PRECAUTIONS Diarrhea: Patients may experience severe diarrhea. If severe diarrhea occurs, suspend dosing and rehydrate the patient. ( 5.2 ) 5.1 Risk of Serious Dehydration in Pediatric Patients TRULANCE is contraindicated in patients less than 6 years of age. The safety and effectiveness of TRULANCE in patients less than 18 years of age have not been established. In young juvenile mice (human age equivalent of approximately 1 month to less than 2 years), plecanatide increased fluid-secretion into the intestines as a consequence of stimulation of guanylate cyclase-C (GC-C), resulting in mortality in some mice within the first 24 hours, apparently due to dehydration. Due to increased intestinal expression of GC-C, patients less than 6 years of age may be more likely than patients 6 years of age and older to develop severe diarrhea and its potentially serious consequences. Avoid the use of TRULANCE in patients 6 years to less than 18 years of age. Although there were no deaths in older juvenile mice, given the deaths in younger mice and the lack of clinical safety and efficacy data in pediatric patients, avoid the use of TRULANCE in patients 6 years to less than 18 years of age [see Contraindications (4) , Warnings and Precautions (5.2) , Use in Specific Populations (8.4) ] . 5.2 Diarrhea Diarrhea was the most common adverse reaction in four placebo-controlled clinical trials, two in patients with CIC and two in patients with IBS-C. Severe diarrhea was reported in 0.6% of patients in two trials in patients with CIC and in 0.6% of patients in the two trials in patients with IBS-C [see Adverse Reactions (6.1) ] . If severe diarrhea occurs, suspend dosing and rehydrate the patient.

6 ADVERSE REACTIONS Most common adverse reaction (≥2%) is diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Salix Pharmaceuticals at 1-800-321-4576 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Demographic characteristics were comparable between the TRULANCE and placebo groups in all studies [see Clinical Studies (14) ] . Chronic Idiopathic Constipation (CIC) The safety data described below reflect data from 1,733 adult patients with CIC randomized in two double-blind, placebo-controlled clinical trials (Study 1 and Study 2) to receive placebo or 3 mg of TRULANCE once daily for 12 weeks. Most Common Adverse Reactions Table 1 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the TRULANCE-treated group and at an incidence that was greater than in the placebo group. Table 1: Most Common Adverse Reactions a in Two Placebo-Controlled Trials of TRULANCE [Study 1 and Study 2] in Patients with CIC Adverse Reaction TRULANCE, 3 mg (N = 863) % Placebo (N = 870) % a: Reported in at least 2% of TRULANCE-treated patients with CIC and at an incidence greater than placebo. b: Verbatim reports of diarrhea were recorded as adverse reactions; reports of loose stools and increase in stool frequency were recorded as adverse reactions if they were also reported to be bothersome to the patient. Diarrheaᵇ 5 1 Diarrhea The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 0.6% of TRULANCE-treated patients compared to 0.3% of placebo-treated patients. Severe diarrhea was reported to occur within the first 3 days of treatment [see Warnings and Precautions (5.2) ] . Adverse Reactions Leading to Discontinuation Discontinuations due to adverse reactions occurred in 4% of TRULANCE-treated patients and 2% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 2% of TRULANCE-treated patients and 0.5% of placebo-treated patients withdrew due to diarrhea . Less Common Adverse Reactions Adverse reactions reported in less than 2% of TRULANCE-treated patients and at an incidence greater than placebo were: sinusitis, upper respiratory tract infection, abdominal distension, flatulence, abdominal tenderness, and increased liver biochemical tests (2 patients with alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal and 3 patients with aspartate aminotransferase (AST) greater than 5 times the upper limit of normal). Irritable Bowel Syndrome with Constipation (IBS-C) The safety data described below reflect data from 1,449 adults patients with IBS-C randomized in two double-blind, placebo-controlled clinical trials (Study 3 and Study 4) to receive placebo or 3 mg TRULANCE once daily for 12 weeks. Most Common Adverse Reactions Table 2 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients treated with TRULANCE and at an incidence that was greater than in the placebo group. Table 2: Most Common Adverse Reactions a in Two Placebo-Controlled Trials of TRULANCE [Study 3 and Study 4] in Patients with IBS-C Adverse Reaction TRULANCE, 3 mg (N = 723) % Placebo (N = 726) % a: Reported in at least 2% of TRULANCE-treated patients with IBS-C and at an incidence greater than placebo. b: Verbatim reports of diarrhea were recorded as adverse reactions; reports of loose stools and increase in stool frequency were recorded as adverse reactions if they were also reported to be bothersome to the patient. Diarrhea b 4.3 1 Diarrhea The majority of reported cases of diarrhea occurred within 4 weeks of treatment initiation. Severe diarrhea was reported in 1% of TRULANCE-treated patients compared to 0.1% of placebo-treated patients [see Warnings and Precautions (5.2) ] . Severe diarrhea was reported to occur within the first day of treatment. Adverse Reactions Leading to Discontinuation Discontinuations due to adverse reactions occurred in 2.5% of TRULANCE-treated patients and 0.4% of placebo-treated patients. The most common adverse reaction leading to discontinuation was diarrhea: 1.2% of TRULANCE-treated patients and 0% of placebo-treated patients withdrew due to diarrhea . Less Common Adverse Reactions Adverse reactions reported in 1% or more but less than 2% of TRULANCE-treated patients and at an incidence greater than placebo were: nausea, nasopharyngitis, upper respiratory tract infection, urinary tract infection, and dizziness. Two patients reported increased liver biochemical tests (alanine aminotransferase (ALT) greater than 5 to 15 times the upper limit of normal). 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TRULANCE. 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 TRULANCE exposure. Hypersensitivity Reactions : skin itching, hives, rash Vomiting

<table ID="_RefID0EQBAE" width="98.04%"><caption>Table 1: Most Common Adverse Reactions ^ain Two Placebo-Controlled Trials of TRULANCE [Study 1 and Study 2] in Patients with CIC </caption><col width="29%"/><col width="24%"/><col width="47%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Adverse Reaction</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">TRULANCE, 3 mg</content> <content styleCode="bold">(N = 863)</content> <content styleCode="bold">%</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 870)</content> <content styleCode="bold">%</content></th></tr></thead><tfoot><tr><td align="left" colspan="3" styleCode="Botrule" valign="top">^a:Reported in at least 2% of TRULANCE-treated patients with CIC and at an incidence greater than placebo. </td></tr><tr><td align="left" colspan="3" styleCode="Botrule" valign="top">^b:Verbatim reports of diarrhea were recorded as adverse reactions; reports of loose stools and increase in stool frequency were recorded as adverse reactions if they were also reported to be bothersome to the patient. </td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Diarrhea&#x1D47;</paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>5</paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>

<table ID="_RefID0EAGAE" width="100%"><caption>Table 2: Most Common Adverse Reactions ^ain Two Placebo-Controlled Trials of TRULANCE [Study 3 and Study 4] in Patients with IBS-C </caption><col width="40%"/><col width="32%"/><col width="28%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Adverse Reaction</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">TRULANCE, 3 mg</content> <content styleCode="bold">(N = 723)</content> <content styleCode="bold">%</content></th><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 726)</content> <content styleCode="bold">%</content></th></tr></thead><tfoot><tr><td align="left" colspan="3" styleCode="Botrule" valign="top">^a:Reported in at least 2% of TRULANCE-treated patients with IBS-C and at an incidence greater than placebo. </td></tr><tr><td align="left" colspan="3" styleCode="Botrule" valign="top">^b:Verbatim reports of diarrhea were recorded as adverse reactions; reports of loose stools and increase in stool frequency were recorded as adverse reactions if they were also reported to be bothersome to the patient. </td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Diarrhea ^b</paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>4.3</paragraph></td><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>