linaclotide 0.29 MG Oral Capsule [Linzess]

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 )

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.

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 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 in clinical trials of patients 7 to 17 years of age with IBS-C and 6 to 17 years of age with FC treated with LINZESS [see Adverse Reactions ( 6.1 )]. • In a double-blind trial of patients 7 to 17 years of age with IBS-C, diarrhea was reported in 7% and 8% of patients treated with LINZESS 145 mcg and 290 mcg once daily, respectively. One severe case of diarrhea was reported in the IBS-C trial at a dosage higher than the recommended LINZESS 145 mcg once daily dosage for IBS-C. • In a double-blind trial of patients 6 to 17 years of age with FC treated with LINZESS 72 mcg once daily, diarrhea was reported in 4% of patients, and one case of severe diarrhea was reported. 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.

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 )

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.