tential 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 findings in animals, 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. colorectal polyps colorectal polyps were identified during the clinical studies [see adverse reactions (6.1) ] . in adults, within 6 months prior to starting treatment with gattex, perform colonoscopy of the entire colon with removal of polyps. a follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of gattex. perform subsequent colonoscopies every 5 years or more often as needed. if a polyp is found, adherence to current polyp follow-up guidelines is recommended. if colorectal cancer is diagnosed, discontinue gattex therapy. in children and adolescents, perform fecal occult blood testing prior to initiating treatment with gattex. colonoscopy/sigmoidoscopy is required if there is unexplained blood in the stool. perform subsequent fecal occult blood testing annually in children and adolescents while they are receiving gattex. colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of treatment, every 5 years thereafter while on continuous treatment with gattex, and if they have new or unexplained gastrointestinal bleeding [see dosage and administration (2.1) ] . small bowel neoplasia based on tumor findings in the rat and mouse carcinogenicity studies, monitor patients clinically for small bowel neoplasia [see nonclinical toxicology (13.1) ] . if a benign neoplasm is found, it should be removed. in case of small bowel cancer, 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) ] .

nt 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. within 6 months prior to starting treatment with gattex: adults : perform a colonoscopy of the entire colon with removal of polyps [see warnings and precautions (5.1) ] . pediatric patients : perform fecal occult blood testing; if there is unexplained blood in the stool, perform colonoscopy/sigmoidoscopy [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 schedule in adults a follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of gattex. if no polyp is found, subsequent colonoscopies 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 schedule in pediatric patients perform subsequent fecal occult blood testing annually in children and adolescents while they are receiving gattex. colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of treatment, every 5 years thereafter while on continuous treatment with gattex, and if they have new or unexplained gastrointestinal bleeding [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.

n 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 immunogenicity as with all peptides, there is potential for immunogenicity. the detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. for these reasons, comparison of the incidence of antibodies to teduglutide in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. adults based on integrated data from two studies in adults with sbs (a 6-month randomized placebo-controlled study, followed by a 24-month open-label study), the development of anti-teduglutide antibodies in patients who received subcutaneous administration of 0.05 mg/kg gattex once daily was 3% (2/60) at month 3, 17% (13/77) at month 6, 24% (16/67) at month 12, 33% (11/33) at month 24, and 48% (14/29) at month 30. anti-teduglutide antibodies were cross-reactive to native glucagon-like peptide (glp-2) in 5 of the 6 patients (83%) who had anti-teduglutide antibodies and were tested for cross-reactivity. in the same two studies, a total of 36 patients were tested for neutralizing antibodies: one patient developed borderline positive neutralizing antibody responses at month 24 of the extension study. the antibody formation has not been associated with clinically relevant safety findings, reduced efficacy or changed pharmacokinetics of gattex. pediatric patients 1 year to less than 17 years of age in pediatric patients who received subcutaneous administration of 0.05 mg/kg gattex once daily for 24 weeks, the rate of anti-teduglutide antibody formation at month 6 was 19% (5/26) and was similar to the rate of antibody formation in adult patients (17%). of the 5 pediatric patients who had developed antibodies to teduglutide at month 6, 2 patients had neutralizing antibodies. however, with the longer duration of treatment, the rate of anti-teduglutide formation at month 12 was higher in pediatric patients with 54% (14/26), compared to that of adults (24%). of the 14 pediatric patients who had developed antibodies to teduglutide at month 12, 1 patient had neutralizing antibodies. among the small number of pediatric patients who developed anti-teduglutide antibodies, no association with adverse events or lack of efficacy was observed.

pulation, 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). 8.2 lactation risk summary there is no information regarding the presence of gattex in human milk, the effects of gattex on the breastfed infant, or the effects of gattex on milk production. teduglutide is present in the milk of lactating rats ( see data ). systemic exposure of teduglutide to a breastfed infant is expected to be low. however, because of the potential for serious adverse reactions in a breastfed infant, including tumorigenicity [see nonclinical toxicology (13.1) ] , advise patients that breastfeeding is not recommended during treatment with gattex. data in a milk excretion study in the rat, a single subcutaneous dose of 25 mg/kg of teduglutide (81 times the recommended daily human dose of 0.05 mg/kg based on body surface area) was administered to lactating female rats at day 12 postpartum. the maximum concentration of teduglutide in the milk corresponded to 0.9% and 2.9% of the plasma concentration at 1.5 and 4 hours after dosing, respectively. 8.4 pediatric use 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. 8.5 geriatric use 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) ] . 8.6 renal impairment in adult subjects with moderate to severe renal impairment or end-stage renal disease (esrd) (creatinine clearance <60 ml/min), the exposure to teduglutide increased with the degree of renal impairment [see clinical pharmacology (12.3) ] . reduce the dosage of gattex by half in both pediatric and adult patients with egfr less than 60 ml/min/1.73 m 2 [see dosage and administration (2.3) ] . 8.7 hepatic impairment gattex has not been studied in patients with severe hepatic impairment (child-pugh grade c). no dosage adjustment is recommended for patients with mild and moderate hepatic impairment (child-pugh grade a and b) [see clinical pharmacology (12.3) ] .

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).

ies 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.

r, dose-ranging study. all subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750 to 1000 ml/day, and increased villus height and crypt depth of the intestinal mucosa. cardiac electrophysiology at a dose 5 times the recommended dose, gattex did not prolong the qt interval to any clinically relevant extent. 12.3 pharmacokinetics absorption in healthy subjects, gattex administered subcutaneously had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at 3 to 5 hours after administration. following a 0.05 mg/kg subcutaneous dose in sbs subjects, the median peak teduglutide concentration (c max ) was 36 ng/ml and the median area under the curve at steady state (auc tau ) was 0.15 µg∙hr/ml. no accumulation of teduglutide was observed following repeated subcutaneous administrations. the c max and auc of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg (up to 8 times the recommended dose of gattex). distribution in healthy subjects, teduglutide has a volume of distribution (103 ml/kg) similar to blood volume. elimination metabolism the metabolic pathway of teduglutide was not investigated in humans. however, teduglutide is expected to be degraded into small peptides and amino acids via catabolic pathways, similar to the catabolism of endogenous glp-2. excretion in healthy subjects, teduglutide plasma clearance was approximately 123 ml/hr/kg which is similar to the gfr suggesting that teduglutide is primarily cleared by the kidney. teduglutide has a mean terminal half-life (t 1/2 ) of approximately 2 hours in healthy subjects and 1.3 hours in sbs subjects. use in specific populations geriatric patients no differences were observed between healthy subjects younger than 65 years and those older than 65 years. experience in subjects 75 years and above is limited. pediatric patients following subcutaneous administration, similar steady state c max of teduglutide across age groups was demonstrated by population pharmacokinetics modeling (see table 2 ). however, lower auc was seen in pediatric patients 1 to 17 years of age as compared with adults and increases with increasing age. table 2: teduglutide pharmacokinetic parameters following subcutaneous dosing of gattex 0.05 mg/kg by age groups age parameters (mean ± sd) c max, ss (ng/ml) auc ss (ng∙h/ml) cl/f (l/h) t 1/2 (h) 12 to 17 years (n=3) 29.7 ± 8.4 154 ± 17.6 13.0 ± 2.3 1.0 ± 0.01 1 to 11 years (n=37) 33.5 ± 11.5 128 ± 56.7 7.45 ± 2.1 0.7 ± 0.2 male and female patients no clinically relevant gender differences were observed. patients with renal impairment in adult subjects with moderate to severe renal impairment or end stage renal disease (esrd) (creatinine clearance <60 ml/min), the c max and auc 0-inf of teduglutide increased with the degree of renal impairment following a single subcutaneous dose of 10 mg gattex. teduglutide exposure increased by a factor of 1.6, 1.4, and 2.1 (c max ) and 1.5, 1.7, and 2.6 (auc 0-inf ) in subjects with moderate, severe renal impairment and esrd, respectively, compared to healthy subjects [see dosage and administration (2.3) , use in specific populations (8.6) ] . patients with hepatic impairment subjects with moderate hepatic impairment (child-pugh class b) had an approximately 10 to 15% lower teduglutide c max and auc compared to healthy matched control subjects after a single subcutaneous dose of 20 mg gattex. this reduction in teduglutide exposure is not thought to be clinically meaningful. gattex was not studied in subjects with severe hepatic impairment (child-pugh class c). drug interaction studies clinical interaction studies were not performed. no inhibition or induction of the cytochrome p450 enzyme system has been observed based on in vitro studies although the relevance of in vitro studies to an in vivo setting is unknown.

bolism of endogenous glp-2. excretion in healthy subjects, teduglutide plasma clearance was approximately 123 ml/hr/kg which is similar to the gfr suggesting that teduglutide is primarily cleared by the kidney. teduglutide has a mean terminal half-life (t 1/2 ) of approximately 2 hours in healthy subjects and 1.3 hours in sbs subjects. use in specific populations geriatric patients no differences were observed between healthy subjects younger than 65 years and those older than 65 years. experience in subjects 75 years and above is limited. pediatric patients following subcutaneous administration, similar steady state c max of teduglutide across age groups was demonstrated by population pharmacokinetics modeling (see table 2 ). however, lower auc was seen in pediatric patients 1 to 17 years of age as compared with adults and increases with increasing age. table 2: teduglutide pharmacokinetic parameters following subcutaneous dosing of gattex 0.05 mg/kg by age groups age parameters (mean ± sd) c max, ss (ng/ml) auc ss (ng∙h/ml) cl/f (l/h) t 1/2 (h) 12 to 17 years (n=3) 29.7 ± 8.4 154 ± 17.6 13.0 ± 2.3 1.0 ± 0.01 1 to 11 years (n=37) 33.5 ± 11.5 128 ± 56.7 7.45 ± 2.1 0.7 ± 0.2 male and female patients no clinically relevant gender differences were observed. patients with renal impairment in adult subjects with moderate to severe renal impairment or end stage renal disease (esrd) (creatinine clearance <60 ml/min), the c max and auc 0-inf of teduglutide increased with the degree of renal impairment following a single subcutaneous dose of 10 mg gattex. teduglutide exposure increased by a factor of 1.6, 1.4, and 2.1 (c max ) and 1.5, 1.7, and 2.6 (auc 0-inf ) in subjects with moderate, severe renal impairment and esrd, respectively, compared to healthy subjects [see dosage and administration (2.3) , use in specific populations (8.6) ] . patients with hepatic impairment subjects with moderate hepatic impairment (child-pugh class b) had an approximately 10 to 15% lower teduglutide c max and auc compared to healthy matched control subjects after a single subcutaneous dose of 20 mg gattex. this reduction in teduglutide exposure is not thought to be clinically meaningful. gattex was not studied in subjects with severe hepatic impairment (child-pugh class c). drug interaction studies clinical interaction studies were not performed. no inhibition or induction of the cytochrome p450 enzyme system has been observed based on in vitro studies although the relevance of in vitro studies to an in vivo setting is unknown.

t, 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.

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.

ased on a clinical response, defined as a patient achieving at least 20% reduction in weekly pn/i.v. volume from baseline (immediately before randomization) to both weeks 20 and 24. the mean age of patients was 50 years. mean duration of pn/i.v. dependency prior to enrollment was 6 years (range 1 to 26 years). the most common reasons for intestinal resection leading to sbs were vascular disease (34%, 29/85), crohn's disease (21%, 18/85), and "other" (21%, 18/85). stoma was present in 45% (38/85) of patients, and the most common type was jejunostomy/ileostomy (82%, 31/38). the mean length of remaining small intestine was 77.3±64.4 cm (range: 5 to 343 cm). the colon was not in continuity in 44% (37/85) patients. at baseline, the mean (± sd) prescribed days per week for pn/i.v. infusion was 5.73 (±1.59) days. the percentages of treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomized patients. sixty-three percent (27/43) of gattex-treated patients versus 30% (13/43) of placebo-treated patients were considered responders (p=0.002). at week 24, the mean reduction in weekly pn/i.v. volume was 4.4 liters for gattex-treated patients (from pre-treatment baseline of 12.9 liters) versus 2.3 liters for placebo-treated patients (from pre-treatment baseline of 13.2 liters/week) (p<0.001). twenty-one patients on gattex (54%) versus 9 on placebo (23%) achieved at least a one-day reduction in pn/i.v. support. the mean changes from baseline in pn/i.v. volume by visit are shown in figure 2. figure 2: change (±95% ci) in pn/i.v. volume (l/week) figure 2 study 2 (cl0600-021, nct00930644) study 2 was a 2-year open-label extension of study 1 in which 88 patients received gattex 0.05 mg/kg/day. ninety-seven percent (76/78) of patients who completed study 1 elected to enroll in study 2 (37 received gattex; 39 received placebo). an additional 12 patients entered study 2, who had been optimized and stabilized but not randomized in study 1 because of closed enrollment. 30 months exposure thirty gattex patients completed a total duration of 30 months (study 1 followed by study 2 treatment). of these, 28 patients (93%) achieved a 20% or greater reduction of parenteral support (ps). of responders in study 1 who had completed 2 additional years of continuous treatment with gattex, 96% (21/22) sustained their response to gattex. the mean reduction in pn/i.v. (n=30) was 7.55 l/week (a 66% reduction from baseline). ten patients were weaned off their pn/i.v. support while on gattex treatment for 30 months. patients were maintained on gattex even if no longer requiring pn/i.v. support. these 10 patients had required pn/i.v. support for 1.2 to 15.5 years, and prior to gattex had required between 3.5 l/week and 13.4 l/week of pn/i.v. support. at the end of study, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved a reduction of 1, 2, or 3 days per week in pn/i.v. support, respectively. 24 months exposure of the 39 placebo-treated patients from study 1 entering study 2, 29 completed 24 months of treatment with gattex. the mean reduction in pn/i.v. was 3.11 l/week (an additional 28.3% reduction) from the start of study 2. sixteen (55%) of the 29 completers achieved a 20% or greater reduction of ps. at the end of the study, 14 (48%), 7 (24%) and 5 (17%) achieved a reduction of 1, 2, or 3 days per week in pn/i.v. support, respectively. two patients were weaned off their pn/i.v. support while on gattex. of the 12 patients entering study 2 directly, 6 completed 24 months of treatment with gattex. similar effects were seen. one of the six patients was weaned off their pn/i.v. support while on gattex. study 3 (placebo-controlled) and study 4 (blinded uncontrolled extension of study 3) study 3 (cl0600-004, nct00081458) study 3 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study in adults with sbs who were dependent on parenteral nutrition/intravenous (pn/i.v.) support for at least 12 months and required pn at least 3 times per week. after a period of optimization and stabilization similar to study 1, patients were randomized to receive 24 weeks of one of the following treatment regimens: gattex 0.05 mg/kg/day (n=35), gattex 0.1 mg/kg/day (twice the recommended dose) (n=33), or placebo (n=16). gattex 0.1 mg/kg/day is not a recommended dosage [see dosage and administration (2.2) ] . the treatment groups were compared using the intent-to-treat population of this study which was defined as all randomized patients who were administered at least one dose of study drug. this population contained one less patient in the 0.1 mg/kg/day dose group hence n=32 in this group for all analyses. the primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose. further evaluation of pn/i.v. volume reduction using the endpoint of response (defined as at least 20% reduction in pn/i.v. fluid from baseline to weeks 20 and 24) showed that 46% of patients on gattex 0.05 mg/kg/day responded versus 6% on placebo. patients on gattex in both dose groups experienced a 2.5 l/week reduction in ps requirements versus 0.9 l/week for placebo at 24 weeks. two patients in the gattex 0.05 mg/kg/day dose group were weaned off ps by week 24. study 4 (cl0600-005, nct00172185) study 4 was a blinded, uncontrolled extension of study 3, in which 65 patients from study 3 received gattex for up to an additional 28 weeks of treatment. of responders in study 3 who entered study 4, 75% sustained response on gattex after one year of treatment. in the gattex 0.05 mg/kg/day dose group, a 20% or greater reduction of ps was achieved in 68% (17/25) of patients. the mean reduction of weekly pn/i.v. volume was 4.9 l/week (52% reduction from baseline) after one year of continuous gattex treatment. the patients who had been completely weaned off pn/i.v. support in study 3 remained off ps through study 4. during study 4, an additional patient from study 3 was weaned off ps. 14.2 treatment of sbs in pediatric patients study 5 (ted-c14-006, nct02682381) study 5 was a 24-week, multicenter study conducted in 59 pediatric patients aged 1 year through 17 years with sbs who were dependent on ps. patients chose whether to receive gattex or standard of care (soc). patients who chose to receive gattex treatment were subsequently randomized in a double-blind manner to 0.025 mg/kg/day (n=24) or 0.05 mg/kg/day (n=26), while 9 patients enrolled in the soc arm. randomization to the gattex dose groups was stratified by age. patients treated with 0.05 mg/kg had a mean age of 6 years at baseline. the most common reasons for intestinal resection leading to sbs were gastroschisis (54%, 14/26), midgut volvulus (23%, 6/26), and necrotizing enterocolitis (12%, 3/26). stoma was present in 19% (5/26) of patients, and the most common type was jejunostomy (80%, 4/5). the mean length of remaining small intestine was 47 (±28) cm (range: 9 to 120 cm). in the 25 patients who had remaining colon, the colon was in continuity in 22 patients. at baseline, the mean ps volume was 60 (±29) ml/kg/day (range: 24 to 133 ml/kg/day) [8 (±4) l/week (range: 3 to 19 l/week)] and mean ps infusion time was 7 (±1) days/week (range: 5 to 7 days/week) and 11 (±3) hours/day (range: 7 to 20 hours/day). results described in table 3 correspond to the recommended gattex dosage of 0.05 mg/kg subcutaneously once daily. table 3 summary of efficacy endpoints at week 24 results based on patient diary data, itt population for study 5 – patients treated with gattex 0.05 mg/kg/day (n = 26) efficacy endpoints results reduction in ps volume of at least 20%, n/n (%) 18/26 (69%) achieved enteral autonomy, n/n (%) 3/26 (12%) reduction in ps infusion of ≥1 day/week, n/n (%) 10/26 (38%) change in ps volume from baseline (ml/kg/day), mean (sd) and [mean% (sd)] -23 (18) ml/kg/day [-42% (29%)] study 6 (shp633-304, nct02954458) study 6 was a prospective, open-label, long-term extension study of pediatric patients who completed study 5. in the extension study, patients received additional treatment with gattex 0.05 mg/kg subcutaneously once daily if they deteriorated or stopped improving after discontinuation of prior gattex treatment. of the 15 patients who initially responded in study 5 and enrolled in study 6, 13 patients (87%) required additional treatment with gattex. efficacy results at the end of the first 24-week treatment period in study 6 (total treatment for a mean of 40 weeks) were similar to those achieved at the end of 24 weeks treatment in study 5. one additional patient treated with 0.05 mg/kg in study 5 eventually achieved enteral autonomy during follow-up in study 6.

sing 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 (22g × 1½ in) to attach to the syringes for reconstitution thirty sterile disposable 1-ml syringes with needle (26g × 5/8 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 (22g × 1½ in) to attach to the syringes thirty sterile disposable 1-ml syringes with needle (26g × 5/8 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.

re 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) ] .