Linaclotide

LINZESS (linaclotide) is a guanylate cyclase-C (GC-C) agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide). The molecular formula of linaclotide is C 59 H 79 N 15 O 21 S 6 and its molecular weight is 1526.8. The amino acid sequence for linaclotide is shown below: Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin capsules. LINZESS is available as 72 mcg, 145 mcg and 290 mcg capsules for oral administration. The inactive ingredients of LINZESS 72 mcg capsules include: calcium chloride dihydrate, L-histidine, microcrystalline cellulose, polyvinyl alcohol, and talc. The components of the capsule shell include gelatin and titanium dioxide. The inactive ingredients of LINZESS 145 mcg and 290 mcg capsules include: calcium chloride dihydrate, hypromellose, L-leucine, and microcrystalline cellulose. The components of the capsule shell include gelatin and titanium dioxide. LINZESS (linaclotide) is a guanylate cyclase-C (G-CC) agonist. Linaclotide is a 14-amino acid peptide with the following chemical name: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide).

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 )

How Supplied LINZESS Capsule Strength Description Packaging NDC number 72 mcg White to off-white opaque hard gelatin capsules with gray imprint “FL 72” Bottle of 30 0456-1203-30 145 mcg White to off-white opaque hard gelatin capsules with gray imprint "FL 145" Bottle of 30 0456-1201-30 290 mcg White to off-white opaque hard gelatin capsules with gray imprint "FL 290" Bottle of 30 0456-1202-30 Storage Store at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles tightly closed in a dry place.

The recommended dosage in adults is: IBS-C : 290 mcg orally once daily. ( 2.1 ) CIC : 145 mcg orally once daily or 72 mcg orally once daily based on individual presentation or tolerability. ( 2.1 ) The recommended dosage in pediatric patients: 7 years of age and older with IBS-C : 145 mcg orally once daily. ( 2.1 ) 6 years of age and older with FC : 72 mcg orally once daily. ( 2.1 ) Administration Instructions ( 2.2 ): Take on empty stomach at least 30 minutes prior to a meal at approximately the same time each day. Do not crush or chew LINZESS capsule or capsule contents. For patients who have difficulty swallowing capsules whole or those with a nasogastric or gastrostomy tube, see full prescribing information for instructions for opening the capsule and administering with applesauce or water. 2.1 Recommended Dosage Irritable Bowel Syndrome with Constipation (IBS-C) : The recommended dosage of LINZESS is: • Adults : 290 mcg orally once daily • Pediatric patients 7 years of age and older : 145 mcg orally once daily Chronic Idiopathic Constipation (CIC) in Adults The recommended dosage of LINZESS in adults is 145 mcg orally once daily. A dosage of 72 mcg once daily may be used based on individual presentation or tolerability. Functional Constipation (FC) in Pediatric Patients 6 Years of Age and Older The recommended dosage of LINZESS in pediatric patients 6 years of age and older is 72 mcg orally once daily. 2.2 Preparation and Administration Instructions • Take LINZESS on an empty stomach, at least 30 minutes prior to a meal, at approximately the same time each day. • If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the same time. • Do not crush or chew LINZESS capsule or capsule contents. • Swallow LINZESS capsule whole. • For patients who are unable to swallow the capsule whole, LINZESS capsules can be opened and administered orally in either applesauce or with water or administered with water via a nasogastric or gastrostomy tube. Sprinkling of LINZESS beads on other soft foods or in other liquids has not been tested. Oral Administration in Applesauce: Place one teaspoonful of room-temperature applesauce into a clean container. Open the capsule. Sprinkle the entire contents (beads) on applesauce. Consume the entire contents immediately. Do not chew the beads. Do not store the bead-applesauce mixture for later use. Oral Administration in Water: Pour approximately 30 mL of room-temperature bottled water into a clean cup. Open the capsule. Sprinkle the entire contents (beads) into the water. Gently swirl beads and water for at least 20 seconds. Swallow the entire mixture of beads and water immediately. Add another 30 mL of water to any beads remaining in cup, swirl for 20 seconds, and swallow immediately. Do not store the bead-water mixture for later use. Note: The drug is coated on the surface of the beads and will dissolve off the beads into the water. The beads will remain visible and will not dissolve. Therefore, it is not necessary to consume all the beads to deliver the complete dose. Administration with Water via a Nasogastric or Gastrostomy Tube: Open the capsule and empty the beads into a clean container with 30 mL of room-temperature bottled water. Mix by gently swirling beads for at least 20 seconds. Draw-up the beads and water mixture into an appropriately sized catheter-tipped syringe and apply rapid and steady pressure (10 mL/10 seconds) to dispense the syringe contents into the tube. Add another 30 mL of water to any beads remaining in the container and repeat the process. After administering the bead-water mixture, flush nasogastric/ gastrostomy tube with a minimum of 10 mL of water. Note: It is not necessary to flush all the beads through to deliver the complete dose.

LINZESS is contraindicated in: Patients less than 2 years of age due to the risk of serious dehydration [see Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.4 )] . Patients with known or suspected mechanical gastrointestinal obstruction. Patients less than 2 years of age. ( 4 , 5.1 , 8.4 ) Patients with known or suspected mechanical gastrointestinal obstruction. ( 4 )

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 Less Than 2 Years of Age LINZESS is contraindicated in patients less than 2 years of age. In neonatal mice (human age equivalent of approximately 0 to 28 days), linaclotide increased fluid secretion as a consequence of age-dependent elevated GC-C agonism which was associated with increased mortality within the first 24 hours due to dehydration. There was no age-dependent trend in GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age; however, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences in these patients [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.4 ) ] . 5. 2 Diarrhea In adults, diarrhea was the most common adverse reaction of LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar between the IBS-C and CIC populations. Severe diarrhea was reported in 2% of adult patients with IBS-C or CIC treated with LINZESS 145 mcg or 290 mcg once daily, and in <1% of adult patients with CIC treated with LINZESS 72 mcg once daily [see Adverse Reactions ( 6.1 )] . In pediatric patients, diarrhea was also the most common adverse reaction of LINZESS-treated patients in IBS-C and FC clinical trials. In two double-blind trials, diarrhea was reported in 4% of pediatric patients 6 to 17 years of age with FC treated with LINZESS 72 mcg once daily, and 7% and 8% of pediatric patients 7 to 17 years of age with IBS-C treated with LINZESS 145 mcg and 290 mcg once daily, respectively. In clinical trials, severe diarrhea was reported in one pediatric patient with FC treated with LINZESS 72 mcg once daily [see Adverse Reactions ( 6.1 )] and in one pediatric patient with IBS-C treated with LINZESS at a dosage higher than the recommended 145 mcg once daily dosage for IBS-C. In post-marketing experience, severe diarrhea associated with dizziness, syncope, hypotension and electrolyte abnormalities (hypokalemia and hyponatremia) requiring hospitalization or intravenous fluid administration have been reported in patients treated with LINZESS. If severe diarrhea occurs, suspend dosing and rehydrate the patient.

Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Advise patients: Diarrhea To stop LINZESS and contact their healthcare provider if they experience unusual or severe abdominal pain, and/or severe diarrhea, especially if in combination with hematochezia or melena [see Warnings and Precautions ( 5.2 )] . Accidental Ingestion Accidental ingestion of LINZESS in children especially in patients less than 2 years of age may result in severe diarrhea and dehydration. Instruct patients to take steps to store LINZESS securely and out of reach of children, and to dispose of unused LINZESS [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 , 5.2 )]. Administration and Handling Instructions To take LINZESS once daily on an empty stomach at least 30 minutes prior to a meal at approximately the same time each day [see Dosage and Administration ( 2.2 )]. If a dose is missed, skip the missed dose and take the next dose at the regular time. Do not take 2 doses at the same time. To swallow LINZESS capsules whole. Do not crush or chew capsules or capsule contents. For patients who are unable to swallow the capsule whole, LINZESS capsules can be opened and administered orally in either applesauce or with bottled water or administered with water via a nasogastric or gastrostomy tube, as described in the Medication Guide. To keep LINZESS in the original container. Do not subdivide or repackage. Protect from moisture. Do not remove desiccant from the container. Keep bottles closed tightly in a dry place . Marketed by: AbbVie, Inc. North Chicago, IL 60064 Ironwood Pharmaceuticals, Inc. Boston, MA, 02110 © 2025 AbbVie and Ironwood Pharmaceuticals, Inc. All rights reserved. LINZESS and its design are registered trademarks of Ironwood Pharmaceuticals, Inc. For more information, go to www.LINZESS.com or call 1-800-678-1605. 20096895

Carcinogenesis In 2-year carcinogenicity studies, linaclotide was not tumorigenic in rats at doses up to 3500 mcg/kg/day or in mice at doses up to 6000 mcg/kg/day. The maximum recommended human dose is approximately 5 mcg/kg/day based on a 60-kg body weight. Limited systemic exposure to linaclotide and its active metabolite was achieved at the tested dose levels in animals, whereas no detectable exposure occurred in humans. Therefore, animal and human doses should not be compared directly for evaluating relative exposure. Mutagenesis Linaclotide was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay or in the in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes. Impairment of Fertility Linaclotide had no effect on fertility or reproductive function in male and female rats at oral doses of up to 100,000 mcg/kg/day.

8. 1 Pregnancy Risk Summary Linaclotide and its active metabolite are negligibly absorbed systemically following oral administration [see Clinical Pharmacology ( 12.3 )] , and maternal use is not expected to result in fetal exposure to the drug. The available data on LINZESS use in pregnant women are not sufficient to inform any drug-associated risk for major birth defects and miscarriage. In animal developmental studies, no effects on embryo-fetal development were observed with oral administration of linaclotide in rats and rabbits during organogenesis at doses much higher than the maximum recommended human dosage. Severe maternal toxicity associated with effects on fetal morphology were observed in mice ( see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data The potential for linaclotide to cause harm to embryo-fetal development was studied in rats, rabbits and mice. In pregnant mice, oral dose levels of at least 40,000 mcg/kg/day given during organogenesis produced severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. Oral doses of 5,000 mcg/kg/day did not produce maternal toxicity or any adverse effects on embryo-fetal development in mice. Oral administration of up to 100,000 mcg/kg/day in rats and 40,000 mcg/kg/day in rabbits during organogenesis produced no maternal toxicity and no effects on embryo-fetal development. Additionally, oral administration of up to 100,000 mcg/kg/day in rats during organogenesis through lactation produced no developmental abnormalities or effects on growth, learning and memory, or fertility in the offspring through maturation. The maximum recommended human dose is approximately 5 mcg/kg/day, based on a 60-kg body weight. Limited systemic exposure to linaclotide was achieved in animals during organogenesis (AUC = 40, 640, and 25 ng•hr/mL in rats, rabbits, and mice, respectively, at the highest dose levels). Linaclotide and its active metabolite are not measurable in human plasma following administration of the recommended clinical dosages. Therefore, animal and human doses should not be compared directly for evaluating relative exposure.

LINZESS is contraindicated in patients less than 2 years of age due to the risk of serious dehydration. In nonclinical studies, deaths occurred within 24 hours in neonatal mice (human age equivalent of approximately 0 to 28 days) following oral administration of linaclotide which increased fluid secretion as a consequence of age-dependent elevated GC-C agonism resulting in rapid and severe dehydration (see Juvenile Animal Toxicity Data ) . In a clinical GC-C ontogeny study in children 6 months to less than 18 years of age (N=99) to measure GC-C mRNA expression levels in duodenal and colonic samples to evaluate the risk of diarrhea and severe dehydration due to GC-C agonism, there was insufficient data on GC-C intestinal expression to assess the risk of developing diarrhea and its potentially serious consequences in children less than 2 years of age [see Warnings and Precautions ( 5.1 )] . Functional Constipation (FC) The safety and effectiveness of LINZESS for the treatment of FC have been established in pediatric patients 6 years of age and older. Use of LINZESS for this indication is supported by evidence from adequate and well-controlled studies in adults and pediatric patients 6 to 17 years of age. The safety of LINZESS in adult and pediatric patients in these clinical studies was similar [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.4 )] . The safety and effectiveness of LINZESS for the treatment of FC have not been established in pediatric patients less than 6 years of age. Irritable Bowel Syndrome with Constipation (IBS-C) The safety and effectiveness of LINZESS for the treatment of IBS-C have been established in pediatric patients 7 years of age and older. Use of LINZESS for this indication is supported by evidence from adequate and well-controlled studies in adults and pediatric patients 7 to 17 years of age. The safety of LINZESS in adult and pediatric patients in these clinical studies was similar [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14.2 )] . The safety and effectiveness of LINZESS for the treatment of IBS-C have not been established in pediatric patients less than 7 years of age. Juvenile Animal Toxicity Data In toxicology studies in neonatal mice, oral administration of linaclotide at 10 mcg/kg/day caused deaths on post-natal day 7 (human age equivalent of approximately 0 to 28 days). These deaths were due to rapid and severe dehydration produced by significant fluid shifts into the intestinal lumen resulting from GC-C agonism in neonatal mice [see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 )] . Tolerability to linaclotide increases with age in juvenile mice. In 2-week-old mice, linaclotide was well tolerated at a dose of 50 mcg/kg/day, but deaths occurred after a single oral dose of 100 mcg/kg. In 3-week-old mice, linaclotide was well tolerated at 100 mcg/kg/day, but deaths occurred after a single oral dose of 600 mcg/kg.

Irritable Bowel Syndrome with Constipation (IBS-C) Of 2219 IBS-C patients in the placebo-controlled clinical studies of LINZESS (Trials 1, 2, and 6), 154 (7%) were 65 years of age and over, while 34 (2%) were 75 years and over. Clinical studies of LINZESS did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. Chronic Idiopathic Constipation (CIC) Of 2498 CIC patients in the placebo-controlled clinical studies of LINZESS (Trials 3, 4, and 5), 273 (11%) were 65 years of age and over, while 56 (2%) were 75 years and over. Clinical studies of LINZESS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

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

Single LINZESS doses of 2897 mcg were administered to 22 healthy subjects; the safety profile in these subjects was consistent with that in the overall LINZESS-treated population, with diarrhea being the most commonly reported adverse reaction.