Teduglutide

The active ingredient in GATTEX (teduglutide) for injection is teduglutide, which is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified by recombinant DNA technology. The chemical composition of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid. The structural formula is: Figure 1: Structural formula of teduglutide Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear, colorless to light-straw–colored liquid. Each single-dose vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for reconstitution and administration by subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.434 mg dibasic sodium phosphate heptahydrate, 3.88 mg L-histidine, 15 mg mannitol, and 0.644 mg monobasic sodium phosphate monohydrate as excipients. No preservatives are present. At the time of administration, the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a single-dose prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for subcutaneous injection upon reconstitution. Chemical Structure

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 )

GATTEX (teduglutide) for injection is supplied as 5 mg of teduglutide as a white, lyophilized powder for reconstitution in a sterile, single-dose glass vial with 0.5 mL Sterile Water for Injection in a single-dose prefilled syringe. The product to be dispensed is either a one-vial kit or a 30-vial kit. One-vial kits are pre-assembled and ready to be used: GATTEX 5 mg One-vial Kit (NDC 68875-0103-1): One single-dose vial of 5 mg teduglutide (NDC 68875-0101-1) One disposable prefilled syringe containing 0.5 mL Sterile Water for Injection USP for reconstitution, with a separate needle (23G × 1½ in) to attach to the syringe One sterile disposable 1 mL syringe with needle (27G × 1/2 in) for dosing Four alcohol swabs Storage and Handling of One-Vial Kit Prior to Dispensing: Store GATTEX 5 mg Strength one-vial kits refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use beyond the expiration date on the label. After Dispensing by the Pharmacist: Store GATTEX 5 mg Strength one-vial kits at room temperature up to 25°C (77°F). Do not freeze. Dispense with a 90-day "use by" dating. GATTEX is also supplied in 30-vial cartons to be assembled by the dispensing pharmacist into a 30-vial kit by transferring the trays containing 30 vials from a Carton of Drug Vials into a Carton of Ancillary Supplies : GATTEX 5 mg Carton of Drug Vials (NDC 68875-0101-2): Thirty single-dose vials of GATTEX 5 mg (NDC 68875-0101-1) Carton of Ancillary Supplies : Thirty disposable prefilled syringes containing diluent (0.5 mL Sterile Water for Injection USP) for reconstitution Thirty separate needles (23G × 1½ in) to attach to the syringes for reconstitution Thirty sterile disposable 1 mL syringes with needle (27G × 1/2 in) Sixty alcohol swabs The final assembled 30-Vial Kit should contain the items: GATTEX 5 mg Strength 30-Vial Kit (NDC 68875-0102-1): Thirty single-dose vials of 5 mg teduglutide (NDC 68875-0101-1) Thirty disposable prefilled syringes containing 0.5 mL Sterile Water for Injection USP for reconstitution, with 30 separate needles (23G × 1½ in) to attach to the syringes Thirty sterile disposable 1 mL syringes with needle (27G × 1/2 in) for dosing Sixty alcohol swabs Storage and Handling of 30-Vial Cartons and 30-Vial Kits Prior to Dispensing: Store GATTEX 5 mg vials refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use beyond the expiration date on the label. Store the Carton of Ancillary Supplies at room temperature up to 25°C (77°F). After Dispensing by the Pharmacist: Store GATTEX 5 mg Strength 30-vial kits at room temperature up to 25°C (77°F). Do not freeze. Dispense with a 90-day "use by" dating.

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 Preparation Instructions Reconstitute each vial of GATTEX by slowly injecting the 0.5 mL of preservative-free Sterile Water for Injection provided in the prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Allow the vial containing GATTEX and water to stand for approximately 30 seconds and then gently roll the vial between the palms for about 15 seconds. Do not shake the vial. Allow the mixed contents to stand for about 2 minutes. Inspect the vial for any undissolved powder. If undissolved powder is observed, gently roll the vial again until all material is dissolved. Do not shake the vial. Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored solution, which should be free from particulates. If there is any discoloration or particulates, discard the solution. A maximum of 0.38 mL of the reconstituted solution, containing 3.8 mg of teduglutide, can be withdrawn from the vial for dosing. If the product remains undissolved after the second attempt, do not use. Storage of the reconstituted solution Administer within 3 hours after reconstitution. Discard any unused portion. Do not shake or freeze the reconstituted solution. For single use only.

None. None. ( 4 )

Acceleration of Neoplastic Growth : In case of intestinal malignancy, discontinue GATTEX. The decision to continue GATTEX in patients with non-gastrointestinal malignancy should be made based on benefit risk considerations. ( 5.1 ) In adult patients, colonoscopy and upper GI endoscopy (or alternate imaging) is recommended after 1 year of treatment. Perform subsequent colonoscopies and upper GI endoscopes (or alternate imaging) no less frequently than every 5 years. ( 5.1 ) In pediatric patients, perform fecal occult blood testing annually. Colonoscopy/sigmoidoscopy is recommended after 1 year of treatment and every 5 years thereafter on treatment. Consider upper GI endoscopy (or alternate imaging) during treatment with GATTEX. ( 5.1 ) Intestinal Obstruction : In patients who develop intestinal or stomal obstruction, temporarily discontinue GATTEX pending further clinical evaluation and management. ( 5.2 ) Biliary and Pancreatic Disease : Obtain bilirubin, alkaline phosphatase, lipase, amylase every 6 months. If clinically meaningful changes are seen, further evaluation is recommended including imaging, and reassess continued GATTEX treatment. ( 5.3 ) Fluid Overload, Including Congestive Heart Failure : If fluid overload occurs, adjust parenteral support, and reassess continued GATTEX treatment. ( 5.4 ) Potential for Increased Absorption of Oral Medications : Monitor patients on concomitant oral medications (e.g., benzodiazepines) for adverse reactions related to the concomitant drug; dosage reduction of the other drug may be required. ( 5.5 , 7.1 ) 5.1 Acceleration of Neoplastic Growth Based on the pharmacologic activity and tumor findings in the rat and mouse carcinogenicity studies, GATTEX has the potential to cause hyperplastic changes including neoplasia [see Clinical Pharmacology ( 12.1 ), Nonclinical Toxicology ( 13.1 )] . In patients at increased risk for malignancy, the clinical decision to use GATTEX should be considered only if the benefits outweigh the risks. In patients who develop active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic) while on GATTEX, discontinue GATTEX treatment. In patients who develop active non-gastrointestinal malignancy while on GATTEX, the clinical decision to continue GATTEX should be made based on benefit-risk considerations. Gastrointestinal Polyps Intestinal polyps were identified during the clinical studies. Postmarketing cases of colorectal, gastric, and small intestinal (duodenum, ileum, and jejunum) polyps have been reported postmarketing [see Adverse Reactions ( 6.1 , 6.2 )] . Adult Patients Within 6 months prior to starting treatment with GATTEX, perform colonoscopy and upper GI endoscopy with removal of polyps. A follow-up colonoscopy and upper GI endoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Perform subsequent colonoscopies and upper GI endoscopies (or alternate imaging) every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. If gastrointestinal cancer is diagnosed, discontinue GATTEX therapy. Pediatric Patients Within 6 months prior to starting treatment with GATTEX, perform fecal occult blood testing; if there is new or unexplained blood in the stool, perform colonoscopy/sigmoidoscopy and an upper GI endoscopy. 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. Colonoscopy/sigmoidoscopy is recommended for all pediatric patients after 1 year of treatment and every 5 years thereafter while on continuous treatment with GATTEX [see Dosage and Administration ( 2.1 )] . Consider upper GI endoscopy (or alternate other imaging) during treatment with GATTEX. If gastrointestinal cancer is diagnosed, discontinue GATTEX therapy. 5.2 Intestinal Obstruction Intestinal obstruction has been reported in clinical studies [see Adverse Reactions ( 6.1 )] and postmarketing. In patients who develop intestinal or stomal obstruction, temporarily discontinue GATTEX while the patient is clinically managed. GATTEX may be restarted when the obstructive presentation resolves, if clinically indicated. 5.3 Biliary and Pancreatic Disease Gallbladder and Biliary Tract Disease Cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies [see Adverse Reactions ( 6.1 )] and postmarketing. For identification of the onset or worsening of gallbladder/biliary disease, obtain laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or biliary tract is recommended; and reassess the need for continued GATTEX treatment. Pancreatic Disease Pancreatitis has been reported in clinical studies [see Adverse Reactions ( 6.1 )] . For identification of onset or worsening of pancreatic disease, obtain laboratory assessments of lipase and amylase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended; and reassess the need for continued GATTEX treatment. 5.4 Fluid Imbalance and Fluid Overload Fluid Overload Fluid overload and congestive heart failure have been observed in clinical studies, which were deemed to be related to enhanced fluid absorption associated with GATTEX [see Adverse Reactions ( 6.1 )] . If fluid overload occurs, adjust parenteral support and reassess GATTEX treatment, especially in patients with underlying cardiovascular disease. If significant cardiac deterioration develops while on GATTEX, reassess the need for continued GATTEX treatment. Fluid and Electrolyte Imbalance Discontinuation of treatment with GATTEX may also result in fluid and electrolyte imbalance. Monitor fluid and electrolyte status in patients who discontinue treatment with GATTEX [see Dosage and Administration ( 2.5 )]. 5.5 Increased Absorption of Concomitant Oral Medication In the adult placebo-controlled studies, an analysis of episodes of cognition and attention disturbances was performed for patients on benzodiazepines. One patient receiving prazepam concomitantly with GATTEX 0.05 mg/kg once daily experienced a dramatic deterioration in mental status progressing to coma during the first week of GATTEX therapy. The patient was admitted to the ICU and the prazepam blood concentration was >300 mcg/L. GATTEX and prazepam were discontinued, and coma resolved 5 days later. Monitor patients receiving concomitant oral drugs requiring titration or with a narrow therapeutic index, for adverse reactions due to potential increased absorption of the concomitant drug. The concomitant drug may require a reduction in dosage [see Drug Interactions ( 7.1 )] .

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Acceleration of Neoplastic Growth Advise adult patients and their caregivers that the patient will need to undergo clinical examinations, repeated colonoscopies and upper GI endoscopies (or alternate imaging) before and during treatment with GATTEX to monitor for the development of polyps and/or neoplasia of the GI tract. Advise pediatric patients and their caregivers that the patient will need to undergo clinical examinations, fecal occult blood testing before and during treatment and colonoscopies after 1 year of treatment, every 5 years thereafter while on continuous treatment with GATTEX or if they have new or unexplained gastrointestinal bleeding. Advise pediatric patients and their caregivers that an upper GI endoscopy will be performed if there is any new or unexplained blood in the stool [see Warnings and Precautions ( 5.1 )] . Intestinal Obstruction Advise patients and their caregivers to immediately contact their healthcare provider if they experience any symptoms suggestive of intestinal or stomal obstruction [see Warnings and Precautions ( 5.2 )] . Biliary and Pancreatic Disease Advise patients and their caregivers that laboratory assessments will be done periodically while on GATTEX to monitor for the onset or worsening of gallbladder, biliary and pancreatic disease, and to report immediately to their healthcare provider if they develop symptoms suggestive of cholecystitis, cholangitis, cholelithiasis or pancreatic disease [see Warnings and Precautions ( 5.3 )] . Fluid Overload Advise patients and their caregivers to immediately contact their healthcare provider if they develop fluid overload or symptoms of congestive heart failure while on GATTEX [see Warnings and Precautions ( 5.4 )] . Fluid Imbalance Advise patients and their caregivers of the risk of fluid and electrolyte imbalance with discontinuation of GATTEX, and to contact their healthcare provider if they develop symptoms suggestive of electrolyte imbalances [see Warnings and Precautions ( 5.4 )] . Increased Absorption of Concomitant Oral Medication Instruct patients and their caregivers to report to their healthcare provider any concomitant oral medications that they are taking in order to assess any potential for increased absorption during GATTEX treatment of those oral medications requiring titration or with a narrow therapeutic index [see Warnings and Precautions ( 5.5 )] . Lactation Advise women that breastfeeding is not recommended during treatment with GATTEX [see Use in Specific Populations ( 8.2 )] .

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.

Carcinogenic potential of GATTEX was assessed in 2-year subcutaneous carcinogenicity studies in rats and mice. In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10, and 35 mg/kg/day (about 15, 41, and 199 times the exposures [AUC] achieved at the recommended daily human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in the incidences of adenomas in the bile duct and jejunum of male rats. In a 2-year carcinogenicity study in Crl:CD1(ICR) mice at subcutaneous doses of 1, 3.5, and 12.5 mg/kg/day (about 32, 66, and 244 times the exposures [AUC] achieved at the recommended daily human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary adenomas in the gall bladder; it also caused adenocarcinomas in the jejunum in male mice at the high dose of 12.5 mg/kg/day. Teduglutide was negative in the Ames test, chromosomal aberration test in Chinese hamster ovary cells, and in vivo mouse micronucleus assay. Teduglutide at subcutaneous doses up to 25 mg/kg twice daily (50 mg/kg/day or at least 202 times the clinical exposure (AUC) at the recommended daily human dose of 0.05 mg/kg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Risk Summary Available data from case reports with GATTEX use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant women with short bowel syndrome are at risk for malnutrition, which is associated with adverse maternal and fetal outcomes (see Clinical Considerations ) . In animal reproduction studies, no effects on embryo-fetal development were observed with the subcutaneous administration of teduglutide to pregnant rats and rabbits during organogenesis at exposures up to 686 and 657 times, respectively, the clinical exposure at the recommended human dose (based on AUC) ( 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 U.S. 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. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Pregnant women with short bowel syndrome are at risk for malnutrition. Severe malnutrition in pregnant women is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. Data Animal Data Reproduction studies have been performed in pregnant rats at subcutaneous doses of teduglutide up to 25 mg/kg twice daily (50 mg/kg/day) (about 686 times the clinical exposure (AUC) at the recommended daily human dose of 0.05 mg/kg) and in pregnant rabbits at subcutaneous doses up to 25 mg/kg twice daily (50 mg/kg/day) (about 657 times the clinical exposure (AUC) at the recommended daily human dose of 0.05 mg/kg) during the period of organogenesis. These studies did not reveal any evidence of impaired fertility or harm to the fetus due to teduglutide. In a pre- and postnatal development study in rats (gestation day 7 to lactation day 20), teduglutide did not show any significant adverse effects on pre- and postnatal development at doses up to 25 mg/kg twice daily (50 mg/kg/day) (about 343 times the clinical exposure (AUC) at the recommended daily human dose of 0.05 mg/kg).

The safety and effectiveness in pediatric patients less than 1 year of age have not been established. The safety and effectiveness of GATTEX have been established in pediatric patients 1 year to less than 17 years of age who are dependent on parenteral support for the treatment of SBS. Use of GATTEX in this population is supported by evidence from adequate and well-controlled studies in adults, with additional efficacy, safety, pharmacokinetic and pharmacodynamic data in pediatric patients 1 year to less than 17 years of age [see Dosage and Administration ( 2 ), Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . These data were derived from two studies of 24-week (Study 5) and 12-week (NCT01952080) duration in which 41 pediatric patients were treated with GATTEX in the following groups: 1 infant (1 year to less than 2 years), 37 children (2 years to less than 12 years) and 3 adolescents (12 years to less than 17 years). In these 2 studies and the corresponding extension studies (Study 6 and NCT02949362), 29 pediatric patients were administered GATTEX prospectively for up to 94 weeks [see Clinical Studies ( 14.2 )] . Adverse reactions in pediatric patients were similar to those seen in adults [see Adverse Reactions ( 6.1 )] . Juvenile Animal Toxicity Data In a juvenile toxicity study, teduglutide was administered to juvenile minipigs at subcutaneous doses of 0.5, 2.5 and 12.5 mg/kg twice daily (1, 5, and 25 mg/kg/day) from post-natal day 7 and continuing for 90 days). Exposures (AUC) at these doses were at least 12-, 25-, and 170-fold the pediatric clinical exposure for ages 1 year to 11 years at 0.05 mg/kg, respectively, and 10-, 21-, and 141-fold the pediatric clinical exposure for ages 12 years to 17 years at 0.05 mg/kg, respectively. In juvenile minipigs, subcutaneous teduglutide caused intestinotrophic effects, gall bladder mucosal hyperplasia, bile duct mucosal hyperplasia, and injection site reactions, similar to those observed in adult animals.

Of the 134 patients with SBS that were treated with GATTEX at the recommended dosage of 0.05 mg/kg/day in the clinical studies, 19 patients were 65 years or older while 5 patients were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology ( 12.3 )] .

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 group), 4 colorectal tubular adenomas (onset between 24 and 29 months in GATTEX 0.05 mg/kg/day dose group), 1 serrated adenoma (onset at 24 months in GATTEX 0.05 mg/kg/day dose group), 1 colorectal polyp biopsy not done (onset at 24 months in GATTEX 0.05 mg/kg/day dose group), 1 rectal inflammatory polyp (onset at 10 months in the GATTEX 0.05 mg/kg/day dose group, and 1 small duodenal polyp (onset at 3 months in GATTEX 0.05 mg/kg/day dose group) [see Warnings and Precautions ( 5.1 )] . In the pediatric clinical studies (up to 69 weeks of exposure), there was one case of cecal polyp that was not biopsied and was not seen on repeat colonoscopy. Gastrointestinal Obstruction Overall, in the adult clinical studies, 12 patients with SBS experienced one or more episodes of intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The 6 patients in the placebo-controlled studies were all on GATTEX: 3/77 (4%) on GATTEX 0.05 mg/kg/day and 3/32 (9%) on GATTEX 0.1 mg/kg/day (twice the recommended dose). No cases of intestinal obstruction occurred in the placebo group. Onset ranged from 1 day to 6 months. In the adult extension studies, 6 additional patients (all on GATTEX 0.05 mg/kg/day) were diagnosed with intestinal obstruction/stenosis with onsets ranging from 6 days to 19 months. Two of the 6 patients from the placebo-controlled studies experienced recurrence of obstruction in the extension studies. Of all 8 patients with an episode of intestinal obstruction/stenosis in these extension studies, 2 patients required endoscopic dilation and 1 required surgical intervention) [see Warnings and Precautions ( 5.2 )] . In the pediatric clinical studies (up to 69 weeks of exposure), there was 1 serious adverse reaction of obstruction. Teduglutide was temporarily withheld, obstruction resolved without additional intervention, and there was no recurrence once teduglutide was restarted. Gallbladder, Biliary and Pancreatic Disease For gallbladder and biliary disease in the adult placebo-controlled studies, 3 patients with SBS were diagnosed with cholecystitis, all of whom had a prior history of gallbladder disease and were in the GATTEX 0.05 mg/kg/day dose group. No cases were reported in the placebo group. One of these 3 cases had gallbladder perforation and underwent cholecystectomy the next day. The remaining 2 cases underwent elective cholecystectomy at a later date. In the adult extension studies, 4 patients had an episode of acute cholecystitis; 3 patients had new-onset cholelithiasis; and 1 patient experienced cholestasis secondary to an obstructed biliary stent. For pancreatic disease in the adult placebo-controlled studies, 1 patient (GATTEX 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed after 4 months of GATTEX. In the adult extension studies, 1 patient was diagnosed with chronic pancreatitis; and 1 patient was diagnosed with acute pancreatitis) [see Warnings and Precautions ( 5.3 )] . Fluid Overload In the adult placebo-controlled studies, peripheral edema was reported in 2/59 (3%) of patients on placebo and 8/77 (10%) patients on GATTEX; fluid overload was reported in 1/77 (1%) patient in the GATTEX group; no cases of fluid overload were seen in the placebo arm. There were 2 cases of congestive heart failure (CHF, 3%) in the GATTEX arm, 1 of which was reported as a serious adverse event and the other as non-serious. The serious case had onset at 6 months and was possibly associated with previously undiagnosed hypothyroidism and/or cardiac dysfunction [see Warnings and Precautions ( 5.4 )] . Other Less Common Adverse Reactions Reported in less than 5% of patients treated with GATTEX: Gastrointestinal disorders: Colonic stenosis, Pancreatic duct stenosis, Small intestinal stenosis Respiratory, thoracic and mediastinal disorders: Dyspnea 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of teduglutide. 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. Gastrointestinal Neoplasia : colorectal polyps, gastric polyps, small intestinal polyps (duodenum, ileum, and jejunum) Injection Site Reactions : injection site induration, inflammation, pruritus, urticaria, and warmth

The maximum dose of GATTEX studied during clinical development was 80 mg/day for 8 days. No unexpected systemic adverse reactions were seen. In the event of overdose, the patient should be carefully monitored by the medical professional.