Linzess

Indications and Usage ( 1 ) 5/2026 Dosage and Administration, Recommended Dosage ( 2.1 ) 5/2026 Warnings and Precautions, Diarrhea ( 5.2 ) 5/2026

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 2 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 2 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION 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 ) 2 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 2 Years of Age and Older The recommended dosage of LINZESS in pediatric patients 2 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.

3 DOSAGE FORMS AND STRENGTHS LINZESS capsules are white to off-white opaque: 72 mcg; gray imprint “FL 72” 145 mcg; gray imprint “FL 145” 290 mcg; gray imprint “FL 290” Capsules: 72 mcg, 145 mcg and 290 mcg ( 3 )

4 CONTRAINDICATIONS 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 )

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 7 to 17 years of age with IBS-C and 6 to 17 years of age with FC is diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie, Inc. at 1-800-633-9110 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 , 14.5 )] . 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. IBS- C in Pediatric Patients 7 Years of Age and Older The safety of LI …

8 USE IN SPECIFIC POPULATIONS 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. 8.2 Lactation Risk Summary Linaclotide and its active metabolite were not detected in the milk of lactating women (see Data). In adults, concentrations of linaclotide and its active metabolite were below the limit of quantitation in plasma following multiple doses of LINZESS [see Clinical Pharmacology ( 12.3 ) ] . Maternal use of LINZESS is not expected to result in exposure to linaclotide or its active metabolite in breastfed infants. There is no information on the effects of linaclotide or its active metabolite on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LINZESS and any potential adverse effects on the breastfed infant from LINZESS or from the underlying maternal condition. Data Following oral administration of 72 mcg, 145 mcg, or 290 mcg of LINZESS once daily for 3 days to breastfeeding mothers taking linaclotide therapeutically, the concentrations of linaclotide and its metabolite were below the limits of quantitation (<0.25 ng/mL and <1 ng/mL, respectively) in all breast milk samples collected over 24 hours. 8.4 Pediatric Use 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 increase …

12.1 Mechanism of Action Linaclotide is structurally related to human guanylin and uroguanylin and functions as a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. In an animal model of visceral pain, linaclotide reduced abdominal muscle contraction and decreased the activity of pain-sensing nerves by increasing extracellular cGMP.

11 DESCRIPTION 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).

10 OVERDOSAGE 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 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.