Teduglutide

12.1 Mechanism of Action Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine. GLP-2 is known to increase intestinal and portal blood flow and inhibit gastric acid secretion. Teduglutide binds to the glucagon-like peptide-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in the local release of multiple mediators including insulin-like growth factor (IGF)-1, nitric oxide and keratinocyte growth factor (KGF).

1 INDICATIONS AND USAGE GATTEX ® is indicated for the treatment of adults and pediatric patients 1 year of age and older with Short Bowel Syndrome (SBS) who are dependent on parenteral support . GATTEX ® is a glucagon-like peptide-2 (GLP-2) analog indicated for the treatment of adults and pediatric patients 1 year of age and older with Short Bowel Syndrome (SBS) who are dependent on parenteral support. ( 1 )

2 DOSAGE AND ADMINISTRATION Important Administration Information GATTEX is for adult self-administration or caregiver administration. Self-administration in pediatric patients has not been tested. Use of the GATTEX 5 mg kit is not recommended in pediatric patients weighing less than 10 kg. ( 2.1 ) Evaluation Testing within 6 Months Prior to Starting GATTEX Adult Patients : Perform a colonoscopy and upper GI endoscopy with removal of polyps. ( 2.1 , 5.1 ) Pediatric Patients : Perform fecal occult blood testing. If new or unexplained blood in the stool, perform colonoscopy/sigmoidoscopy and upper GI endoscopy. ( 2.1 , 5.1 ) Adult and Pediatric Patients : Obtain baseline laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase). ( 2.1 , 5.3 ) Dosage and Administration For subcutaneous use only. ( 2.2 ) The recommended dosage of GATTEX for both adults and pediatric patients is 0.05 mg/kg once daily by subcutaneous injection. ( 2.2 ) Alternate sites between 1 of the 4 quadrants of the abdomen, or into alternating thighs or alternating arms. ( 2.2 ) Dosage Adjustment for Renal Impairment For adult and pediatric patients with moderate and severe renal impairment and end-stage renal disease (estimated glomerular filtration rate less than 60 mL/min/1.73 m 2 ) the recommended dosage is 0.025 mg/kg once daily. ( 2.3 ) Discontinuation When treatment is discontinued, monitor for fluid and electrolyte imbalances. ( 2.5 , 5.4 ) Preparation See full prescribing information for instructions on reconstitution. ( 2.6 ) 2.1 Important Administration Information GATTEX is for adult self-administration or caregiver administration. Self-administration in pediatric patients has not been tested. Use of the GATTEX 5 mg kit is not recommended in pediatric patients weighing less than 10 kg. Evaluation and testing prior to starting treatment with GATTEX: Within 6 months prior to treatment: Adult patients Perform a colonoscopy and an upper gastrointestinal (GI) endoscopy with removal of polyps [see Warnings and Precautions ( 5.1 )] . Obtain baseline laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) [see Warnings and Precautions ( 5.3 )] . Pediatric patients Perform fecal occult blood testing; if there is new or unexplained blood in the stool, perform colonoscopy/sigmoidoscopy and an upper GI endoscopy [see Warnings and Precautions ( 5.1 )] . Obtain baseline laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) [see Warnings and Precautions ( 5.3 )] . 2.2 Recommended Dosage and Administration for Adults and Pediatric Patients 1 Year of Age and Older GATTEX is for subcutaneous injection only. Not for intravenous or intramuscular administration. The recommended dosage of GATTEX is 0.05 mg/kg once daily administered by subcutaneous injection. If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses on the same day. Alternation of sites for subcutaneous injection is recommended, and can include the thighs, upper arms, and the abdomen. 2.3 Dosage Adjustment for Renal Impairment The recommended dosage in adult and pediatric patients with moderate and severe renal impairment and end-stage renal disease (estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m 2 ) is 0.025 mg/kg once daily [see Use in Specific Populations ( 8.6 )] . 2.4 Monitoring to Assess Safety Colonoscopy and Upper GI Endoscopy in Adults A follow-up colonoscopy and upper GI endoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. If no polyp is found, subsequent colonoscopies and upper GI endoscopies (or alternate imaging) should be done no less frequently than every 5 years. If a polyp is found, adherence to current polyp follow-up guidelines is recommended [see Warnings and Precautions ( 5.1 )] . Colonoscopy and Upper GI Endoscopy in Pediatric Patients Perform subsequent fecal occult blood testing annually in pediatric patients while they are receiving GATTEX. If there is new or unexplained blood in the stool, perform colonoscopy/sigmoidoscopy and an upper GI endoscopy [see Warnings and Precautions ( 5.1 )] . Colonoscopy/sigmoidoscopy is recommended for all pediatric patients after 1 year of treatment and every 5 years thereafter while on continuous treatment with GATTEX. Consider upper GI endoscopy (or alternate other imaging) during treatment with GATTEX [see Warnings and Precautions ( 5.1 )] . Laboratory Testing Laboratory assessments are recommended every 6 months. If any clinically meaningful elevation is seen, further diagnostic workup is recommended as clinically indicated (i.e., imaging of the biliary tract, liver, or pancreas) [see Warnings and Precautions ( 5.1 ), ( 5.3 )] . 2.5 Discontinuation of Treatment Discontinuation of treatment with GATTEX may result in fluid and electrolyte imbalance. Monitor fluid and electrolyte status in patients who discontinue GATTEX treatment [see Warnings and Precautions ( 5.4 )] . 2.6

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Acceleration of Neoplastic Growth [see Warnings and Precautions ( 5.1 )] Intestinal Obstruction [see Warnings and Precautions ( 5.2 )] Biliary and Pancreatic Disease [see Warnings and Precautions ( 5.3 )] Fluid Imbalance and Fluid Overload [see Warnings and Precautions ( 5.4 )] Most common adverse reactions (≥10%) are: abdominal pain, nausea, upper respiratory tract infection, abdominal distension, injection site reaction, vomiting, fluid overload, and hypersensitivity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Adults Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. The rates of adverse reactions in 136 adult patients with SBS participating in two randomized, placebo-controlled, 24-week, double-blind clinical studies (Study 1 and Study 3) are summarized in Table 1 . Only those reactions with a rate of at least 5% in the GATTEX group, and greater than placebo group, are summarized in Table 1 . Table 1: Common Adverse Reactions Reported at a rate of at least 5% in the GATTEX group, and greater than the placebo group. in Adult Patients with SBS in Placebo-Controlled Studies: Studies 1 and 3 Adverse Reaction Placebo (N=59) (%) GATTEX 0.05 mg/kg Once Daily (N=77) (%) Abdominal pain Includes: Abdominal pain, upper abdominal pain, lower abdominal pain 22 30 Nausea 20 23 Upper respiratory tract infection Includes: Upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, laryngitis, rhinitis, viral upper respiratory tract infection 12 21 Abdominal distension 2 20 Injection site reaction Includes: Injection site hematoma, injection site erythema, injection site pain, injection site swelling, injection site hemorrhage, injection site discoloration, injection site reaction, injection site rash 12 13 Vomiting 10 12 Fluid Overload Includes: Fluid overload, peripheral edema, edema, generalized edema, fluid retention and jugular vein distension 7 12 Hypersensitivity Includes: Erythema, rash, dermatitis allergic, pruritus, rash macular, drug eruption, eyelid edema, flushing 7 10 Flatulence 7 9 Decreased appetite 3 7 Influenza Includes: Influenza, influenza-like illness 2 7 Skin hemorrhage Includes: Hematoma, abdominal wall hematoma, post procedural hematoma, umbilical hematoma, blood blister 2 5 Cough 0 5 Sleep disturbances Includes: Insomnia (3 patients) and hypersomnia (1 patient) 0 5 Adverse Reactions in the Subset of Patients with a Stoma Among the 53 patients with a stoma in the placebo-controlled studies (Study 1 and Study 3), the percentage of patients with gastrointestinal stoma complication was 42% (13/31) for patients receiving GATTEX 0.05 mg/kg/day and 14% (3/22) for patients receiving placebo. Pediatric Patients 1 Year to Less Than 17 Years of Age In two clinical studies of 24-week and 12-week duration, 41 pediatric patients aged 1 year to less than 17 years were treated with GATTEX 0.05 mg/kg/day [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.2 )] . Overall, the safety profile of GATTEX was similar to that in adults. In the long-term extension studies with mean exposure of 41 weeks, no new safety signals were identified. Less Common Adverse Reactions Adverse Reactions of Special Interest Malignancy Three patients were diagnosed with malignancy in the SBS clinical studies in adults, all of whom were male and had received GATTEX 0.05 mg/kg/day in Study 2. One patient had a history of abdominal radiation for Hodgkin's disease two decades prior to receiving GATTEX and prior liver lesion on CT scan, and was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to GATTEX. Two patients had extensive smoking histories and were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of GATTEX exposure, respectively [see Warnings and Precautions ( 5.1 )] . Intestinal Polyps In the adult clinical studies, 14 patients with SBS were diagnosed with polyps of the GI tract after initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (2%) of patients on placebo and 1/109 (1%) of patients on GATTEX 0.05 mg/kg/day were diagnosed with intestinal polyps (inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 12 polyp cases occurred in the extension studies – 2 colorectal villous adenomas (onset at 6 and 7 months in GATTEX 0.1 mg/kg/day (twice the recommended dose) and 0.05 mg/kg/day dose groups, respectively), 2 hyperplastic polyps (onset 6 months in GATTEX 0.1 mg/kg/day dose group and 24 months in GATTEX 0.05 mg/kg/day dose grou

7 DRUG INTERACTIONS 7.1 Potential for Increased Absorption of Oral Medications Based upon the pharmacodynamic effect of GATTEX, there is a potential for increased absorption of concomitant oral medications. Altered mental status has been observed in patients taking GATTEX and benzodiazepines in the adult clinical studies [see Warnings and Precautions ( 5.5 )] . Monitor patients on concomitant oral drugs requiring titration or with a narrow therapeutic index for adverse reactions related to the concomitant drug while on GATTEX. The concomitant drug may require a reduction in dosage.