Linzess

1 INDICATIONS AND USAGE LINZESS is indicated for the treatment of: • irritable bowel syndrome with constipation (IBS-C) in adults and pediatric patients 7 years of age and older • chronic idiopathic constipation (CIC) in adults • functional constipation (FC) in pediatric patients 6 years of age and older LINZESS is a guanylate cyclase-C agonist indicated for treatment of: Irritable bowel syndrome with constipation (IBS-C) in adults and pediatric patients 7 years of age and older. ( 1 ) Chronic idiopathic constipation (CIC) in adults. ( 1 ) Functional constipation (FC) in pediatric patients 6 years of age and older. ( 1 )

6 ADVERSE REACTIONS Most common adverse reactions (≥2%) reported in adult patients with IBS-C or CIC are: diarrhea, abdominal pain, flatulence and abdominal distension. ( 6.1 ) Most common adverse reaction (≥2%) reported in pediatric patients with FC or IBS-C is diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie, Inc. at 1-800-678-1605 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Demographic characteristics were comparable between treatment groups in all studies [see Clinical Studies ( 14.1 , 14.2 , 14.3 , 14.4 )] . Irritable Bowel Syndrome with Constipation (IBS-C) in Adults Most Common Adverse Reactions The data described below reflect exposure to LINZESS in the two placebo-controlled clinical trials involving 1605 adult patients with IBS-C (Trials 1 and 2) [see Clinical Studies ( 14.1 )] . Patients were randomized to receive placebo or 290 mcg LINZESS once daily on an empty stomach for up to 26 weeks. Table 1 provides the incidence of adverse reactions reported in at least 2% of IBS-C patients in the LINZESS treatment 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 (1 and 2) in Adult Patients with IBS-C Adverse Reactions LINZESS 290 mcg [N=807] % Placebo [N=798] % Gastrointestinal Diarrhea Abdominal pain b Flatulence Abdominal distension 20 7 4 2 3 5 2 1 Infections and Infestations Viral Gastroenteritis 3 1 Nervous System Disorders Headache 4 3 a: Reported in at least 2% of LINZESS-treated patients and at an incidence greater than placebo b: “Abdominal pain” term includes abdominal pain, upper abdominal pain, and lower abdominal pain. Adverse reactions in an additional placebo-controlled trial in 614 IBS-C patients randomized to placebo or LINZESS 290 mcg once daily on an empty stomach for 12 weeks (Trial 6) were similar to those in Table 1. Diarrhea Diarrhea was the most commonly reported adverse reaction of the LINZESS-treated patients in the pooled IBS-C pivotal placebo-controlled trials. In these trials, 20% of LINZESS-treated patients reported diarrhea compared to 3% of placebo-treated patients. Severe diarrhea was reported in 2% of the LINZESS-treated patients versus less than 1% of the placebo-treated patients, and 5% of LINZESS-treated patients discontinued due to diarrhea vs less than 1% of placebo-treated patients. The majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment [see Warnings and Precautions ( 5.2 )] . Adverse Reactions Leading to Discontinuation In placebo-controlled trials in patients with IBS-C, 9% of patients treated with LINZESS and 3% of patients treated with placebo discontinued prematurely due to adverse reactions. In the LINZESS-treatment group, the most common reasons for discontinuation due to adverse reactions were diarrhea (5%) and abdominal pain (1%). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain. Adverse Reactions Leading to Dose Reductions In the open-label, long-term trials, 2147 patients with IBS-C received 290 mcg of LINZESS daily for up to 18 months. In these trials, 29% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. Less Common Adverse Reactions Defecation urgency, fecal incontinence, vomiting, and gastroesophageal reflux disease were reported in <2% of patients in the LINZESS-treatment group and at an incidence greater than in the placebo treatment group. Chronic Idiopathic Constipation (CIC) in Adults Most Common Adverse Reactions The data described below reflect exposure to LINZESS in the two double-blind placebo-controlled clinical trials of 1275 adult patients with CIC (Trials 3 and 4) [see Clinical Studies ( 14.3 )] . Patients were randomized to receive placebo or 145 mcg LINZESS or 290 mcg LINZESS once daily on an empty stomach, for at least 12 weeks. Table 2 provides the incidence of adverse reactions reported in at least 2% of CIC patients in the 145 mcg LINZESS treatment group and at an incidence that was greater than in the placebo treatment group. Table 2: Most Common Adverse Reactions a in the Two Placebo-controlled Trials (3 and 4) in Adult Patients with CIC Adverse Reactions LINZESS 145 mcg [N=430] % Placebo [N=423] % Gastrointestinal Diarrhea Abdominal pain b Flatulence Abdominal distension 16 7 6 3 5 6 5 2 Infections and Infestations Upper respiratory tract infection Sinusitis 5 3 4 2 a: Reported in at least 2% of LINZESS-treated patients and at an incidence greater than placebo b: “Abdominal pain” term includes abdominal pain, upper abdominal pain, and lower abdominal pain. The safety of a 72 mcg dose was evaluated in an additional placebo-controlled trial in which 1223 patients were randomized to LINZESS 72 mcg, 145 mcg, or placebo once daily for 12 weeks (Trial 5). In Trial 5, adverse reactions that occurred at a frequency of ≥ 2% in LINZESS-treated patients (N=411 in each LINZESS 72 mcg and 145 mcg group) and at a higher rate than placebo (N=401) were: Diarrhea (LINZESS 72 mcg 19%; LINZESS 145 mcg 22%; placebo 7%) Abdominal distension (LINZESS 72 mcg 2%; LINZESS 145 mcg 1%; placebo < 1%) Diarrhea In Trials 3 and 4 (pooled) and Trial 5, diarrhea was the most commonly reported adverse reaction in LINZESS-treated patients in the CIC placebo-controlled studies. In all trials, the majority of reported cases of diarrhea started within the first 2 weeks of LINZESS treatment. Severe diarrhea was reported in less than 1% of the 72 mcg LINZESS-treated patients (Trial 5), in 2% of the 145 mcg LINZESS-treated patients (Trials 3, 4, and 5), and less than 1% of the placebo-treated patients (Trials 3, 4, and 5) [see Warnings and Precautions ( 5.2 )] . Adverse Reactions Leading to Discontinuation In placebo-controlled trials in patients with CIC, 3% of patients treated with 72 mcg (Trial 5) and between 5% and 8% (Trials 3, 4, and 5) of patients treated with 145 mcg of LINZESS discontinued prematurely due to adverse reactions compared to between less than 1% and 4% (Trials 3, 4, and 5) of patients treated with placebo. In patients treated with 72 mcg LINZESS, the most common reason for discontinuation due to adverse reactions was diarrhea (2% in Trial 5) and, in patients treated with 145 mcg LINZESS, the most common reasons for discontinuation due to adverse reactions were diarrhea (between 3% and 5% in Trials 3, 4, and 5) and abdominal pain (1% in Trials 3 and 4). In comparison, less than 1% of patients in the placebo group withdrew due to diarrhea or abdominal pain (Trials 3, 4, and 5). Adverse Reactions Leading to Dose Reductions In the open-label, long-term trials, 1129 patients with CIC received 290 mcg of LINZESS daily for up to 18 months. In these trials, 27% of patients had their dose reduced or suspended secondary to adverse reactions, the majority of which were diarrhea or other GI adverse reactions. Less Common Adverse Reactions Defecation urgency, fecal incontinence, dyspepsia, and viral gastroenteritis were reported in less than 2% of patients in the LINZESS treatment group and at an incidence greater than in the placebo treatment group. Functional Constipation (FC) in Pediatric Patients 6 Years of Age and Older The safety of LINZESS 72 mcg once daily was evaluated in pediatric patients 6 to 17 years of age with FC in a 12-week double-blind, placebo-controlled clinical trial (Trial 7) [see Clinical Studies ( 14.4 )] . There were 164 patients per treatment group. Diarrhea was the most common adverse reaction and was reported in 4% of LINZESS-treated patients compared to 2% of placebo-treated patients. One patient in the LINZESS-treated group reported severe diarrhea and discontinued treatment. No patient in the placebo-treated group discontinued treatment due to severe diarrhea. Most reported cases of diarrhea started within the first 2 weeks of LINZESS treatment [see Warnings and Precautions ( 5.2 )] . Other adverse reactions reported at a higher incidence in the LINZESS group than the placebo group included nausea (2 patients) and abdominal discomfort and dehydration (1 patient each). IBS- C in Pediatric Patients 7 Years of Age and Older The safety of LINZESS 145 mcg once daily was evaluated in 55 pediatric patients 7 to 17 years of age with IBS-C in a 12-week double-blind, parallel-group clinical trial (Trial 8) [see Clinical Studies ( 14.2 )] . The safety profile in pediatric patients treated with LINZESS was similar to the safety profile from trials in adults with IBS-C and CIC and in pediatric patients with FC. Diarrhea was the most common adverse reaction reported in 7% of 145 mcg LINZESS-treated pediatric patients. Most reported cases of diarrhea started within the first 2 weeks of LINZESS treatment [see Warnings and Precautions ( 5.2 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of LINZESS. 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 : Anaphylaxis, angioedema, rash (including hives or urticaria) Gastrointestinal reactions: Hematochezia, nausea, rectal hemorrhage