替度鲁肽GATTEX KIT(TEDUGLUTIDE RECOMBINANT)POWDER;SUBCUTANEOUS获FDA批准用于治疗需要额外胃肠外营养的成人短肠综合征（SBS）患者 12月21日，美国食品与药物管理局（FDA）批准了替度鲁肽(teduglutide)用于治疗需要额外胃肠外营养的成人短肠综合征（SBS）患者。 替度鲁肽是一种有助于改善肠道液体和营养物质吸收的注射剂，每日应用一次。该药是第三个FDA批准需要营养支持的成人SBS的治疗药物。其余两种药物——生长激素（somatropin）和谷氨酰胺(glutamine)分别于2003年和2004年获准。今年6月，欧洲药品管理局（EMA）也推荐批准替度鲁肽(teduglutide)用于治疗成人短肠综合征。 接受替度鲁肽治疗的患者发生肠道癌症和息肉，肠梗阻，胆囊、胆道和胰腺疾病的潜在危险增加。为确保患者应用替度鲁肽的获益大于其潜在风险，FDA通过风险评估和减轻策略批准了该药。为研究替度鲁肽的长期安全性，FDA已要求厂家在常规临床环境下使SBS患者应用替度鲁肽的上市后研究，以进一步评估该药增加潜在致结直肠癌和其他疾病风险。该研究中的患者将随访至少10年。 两项临床试验和延伸试验评估了替度鲁肽的安全性、有效性和耐受性。试验中的患者被随机分为接受替度鲁肽治疗组和安慰剂组。评估治疗20—24周后每周胃肠外营养容量至少降低20%的患者数（临床反应）和治疗24周后胃肠外营养平均降低容量。结果显示，接受替度鲁肽治疗的患者中有46%和63%达到了临床反应，而安慰剂组的患者这一百分比为6%和30%。胃肠外营养在替度鲁肽治疗组平均降低了2.5 L/周和4.4 L/周，安慰剂组为0.9 L/周和2.3 L/周。 延伸试验随访了接受额外的28周替度鲁肽治疗的患者。结果显示，连续替度鲁肽治疗1年后患者胃肠外营养容量平均降低4.9 L/周和5.2 L/周。延伸试验中有6例患者在接受替度鲁肽治疗时摆脱了胃肠外营养支持治疗。 试验中接受替度鲁肽治疗的患者最常见的不良反应包括腹痛，注射部位反应，恶心，头痛，腹胀和上呼吸道感染。 完整说明资料附件：https://www.shirecontent.com/PI/PDFS/Gattex_USA_ENG.pdf HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use GATTEX safely and effectively. See full prescribing information for GATTEX. GATTEX (teduglutide [rDNA origin]), for injection, for subcutaneous use Initial U.S. Approval: 2012 INDICATIONS AND USAGE GATTEX® (teduglutide [rDNA origin]) for injection is a glucagon-like peptide-2 (GLP-2) analog indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on parenteral support. (1) DOSAGE AND ADMINISTRATION The recommended once daily dose of GATTEX is 0.05 mg/kg. (2.1) Administer by subcutaneous injection; alternate sites between 1 of the 4 quadrants of the abdomen, or into alternating thighs or alternating arms. (2.1) For subcutaneous injection only. (2.1) For single-use only. Use within 3 hours after reconstitution, discard any unused portion. (2.5) 50% dosage reduction recommended in patients with moderate to severe renal impairment. (2.3) (8.6) (12.3) DOSAGE FORMS AND STRENGTHS For injection: Each single-use glass vial containing 5 mg of teduglutide as a white, lyophilized powder for reconstitution with 0.5 mL Sterile Water for Injection provided in a prefilled syringe. (3) Reconstitution with the 0.5 mL Sterile Water for Injection provided in the prefilled syringe results in a 10 mg/mL solution. A maximum of 0.38 mL of reconstituted solution which contains 3.8 mg of teduglutide can then be withdrawn from the vial. (3) (16.1) CONTRAINDICATIONS None (4) WARNINGS AND PRECAUTIONS Neoplastic growth. There is a risk for acceleration of neoplastic growth. Colonoscopy of the entire colon with removal of polyps should be done before initiating treatment with GATTEX and is recommended after 1 year. Subsequent colonoscopies should be done as needed, but no less frequently than every 5 years. In case of intestinal malignancy discontinue GATTEX. The clinical decision to continue GATTEX in patients with non-gastrointestinal malignancy should be made based on risk and benefit considerations. (5.1) Intestinal obstruction. In patients who develop obstruction, GATTEX should be temporarily discontinued pending further clinical evaluation and management. (5.2) Biliary and pancreatic disease. Patients should undergo laboratory assessment (bilirubin, alkaline phosphatase, lipase, amylase) before starting GATTEX. Subsequent laboratory tests should be done every 6 months. If clinically meaningful changes are seen, further evaluation is recommended including imaging, and continued treatment with GATTEX should be reassessed. (5.3) Fluid overload. There is a potential for fluid overload while on GATTEX. If fluid overload occurs, especially in patients with cardiovascular disease, parenteral support should be appropriately adjusted, and GATTEX treatment reassessed. (5.4) ADVERSE REACTIONS The most common adverse reactions (≥ 10%) across all studies with GATTEX are abdominal pain, injection site reactions, nausea, headaches, abdominal distension, upper respiratory tract infection. In addition, vomiting and fluid overload were reported in the SBS studies (1 and 3) at rates ≥ 10%. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact NPS Pharmaceuticals at 1-855-5GATTEX (1-855-542-8839) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS GATTEX has the potential to increase absorption of concomitant oral medications. Careful monitoring and possible dose adjustment of oral medications that require titration or have a narrow therapeutic index is recommended. (5.5) (7.1) USE IN SPECIFIC POPULATIONS The safety and efficacy of GATTEX in pediatric patients have not been established. (8.4) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 6/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE GATTEX® (teduglutide [rDNA origin]) for injection is indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on parenteral support. [see Clinical Pharmacology (12.2)] 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended daily dose of GATTEX is 0.05 mg/kg body weight administered by subcutaneous injection once daily. Alternation of sites for subcutaneous injection is recommended, and can include the thighs, arms, and the quadrants of the abdomen. GATTEX should not be administered intravenously or intramuscularly. 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. 2.2 Monitoring to Assess Safety A colonoscopy (or alternate imaging) of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. 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. Patients should undergo initial laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) within 6 months prior to starting treatment with GATTEX. Subsequent laboratory assessments are recommended every 6 months. If clinically meaningful elevation is seen, further diagnostic workup is recommended as clinically indicated (ie, imaging of the biliary tract, liver, or pancreas). [see Warnings and Precautions (5.1) (5.5)] 2.3 Dosage Modifications in Renal Impairment Reduce the dose by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min), and end-stage renal disease. [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)] 2.4 Discontinuation of Treatment Discontinuation of treatment with GATTEX may result in fluid and electrolyte imbalance. Therefore, patients' fluid and electrolyte status should be carefully monitored. 2.5 Preparation for Administration Reconstitute each vial of GATTEX by slowly injecting the 0.5 mL of preservative-free Sterile Water for Injection provided in the prefilled syringe. Allow the vial containing GATTEX and water to stand for approximately 30 seconds and then gently roll the vial between your 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. If the product remains undissolved after the second attempt, do not use. GATTEX does not contain any preservatives and is for single-use only. Discard any unused portion. The product should be used within 3 hours after reconstitution. [see How Supplied/Storage and Handling (16.2)] 3 DOSAGE FORMS AND STRENGTHS For Injection: Each single-use glass vial contains a dose of 5 mg teduglutide as a lyophilized powder that upon reconstitution with the 0.5 mL Sterile Water for Injection provided in the prefilled syringe delivers a maximum of 0.38 mL of the reconstituted sterile solution which contains 3.8 mg of teduglutide. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 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. 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 with active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), GATTEX therapy should be discontinued. In patients with active non-gastrointestinal malignancy, the clinical decision to continue GATTEX should be made based on risk-benefit considerations. [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)] Colorectal Polyps Colorectal polyps were identified during the clinical trials. Colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be done every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of diagnosis of colorectal cancer, GATTEX therapy should be discontinued. [see Adverse Reactions (6.1)] Small Bowel Neoplasia Based on tumor findings in the rat and mouse carcinogenicity studies, patients should be monitored clinically for small bowel neoplasia. If a benign neoplasm is found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued. [see Nonclinical Toxicology (13.1)] 5.2 Intestinal Obstruction Intestinal obstruction has been reported in clinical trials. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued while the patient is clinically managed. GATTEX may be restarted when the obstructive presentation resolves, if clinically indicated. [see Adverse Reactions (6.1)] 5.3 Biliary and Pancreatic Disease Gallbladder and Biliary Tract Disease Cholecystitis, cholangitis, and cholelithiasis, have been reported in clinical studies. For identification of the onset or worsening of gallbladder/biliary disease, patients should undergo 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 the need for continued GATTEX treatment should be reassessed. [see Adverse Reactions (6.1)] Pancreatic Disease Pancreatitis has been reported in clinical studies. For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment 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 the need for continued GATTEX treatment should be reassessed. [see Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)] 5.4 Fluid Overload Fluid overload and congestive heart failure have been observed in clinical trials, which were felt to be related to enhanced fluid absorption associated with GATTEX. If fluid overload occurs, parenteral support should be adjusted and GATTEX treatment should be reassessed, especially in patients with underlying cardiovascular disease. If significant cardiac deterioration develops while on GATTEX, the need for continued GATTEX treatment should be reassessed. [see Adverse Reactions (6.1)] 5.5 Increased Absorption of Concomitant Oral Medication Altered mental status in association with GATTEX has been observed in patients on benzodiazepines in clinical trials. Patients on concomitant oral drugs (e.g., benzodiazepines, phenothiazines) requiring titration or with a narrow therapeutic index may require dose adjustment while on GATTEX. [see Adverse Reactions (6.2)] 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 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. Across all clinical studies, 595 subjects were exposed to at least one dose of GATTEX (249 patient-years of exposure; mean duration of exposure was 22 weeks). Of the 595 subjects, 173 subjects were treated in Phase 3 SBS studies (134/173 [77%] at the dose of 0.05 mg/kg/day and 39/173 [23%] at the dose of 0.10 mg/kg/day). The most commonly reported (≥ 10%) adverse reactions in subjects treated with GATTEX across all clinical studies (N = 595) were: abdominal pain (31.3%); injection site reactions (21.8%); nausea (18.8%); headaches (16.3%); abdominal distension (14.8%); upper respiratory tract infection (11.9%). The rates of adverse reactions in subjects with SBS participating in 2 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. The majority of these reactions were mild or moderate. Of subjects receiving GATTEX at the recommended dose of 0.05 mg/kg/day, 88.3% (n=68/77) experienced an adverse reaction, as compared to 83.1% (n=49/59) for placebo. Many of these adverse reactions have been reported in association with the underlying disease and/or parenteral nutrition. Table 1: Adverse reactions in ≥5% of GATTEX-treated SBS subjects and more frequent than placebo: Studies 1 and 3 Adverse Reaction Placebo (N=59) n (%) GATTEX 0.05mg/kg/day (N=77) n (%) Abdominal Pain 16 ( 27.1) 29 ( 37.7) Upper Respiratory Tract Infection 8 ( 13.6) 20 ( 26.0) Nausea 12 ( 20.3) 19 ( 24.7) Abdominal Distension 1 ( 1.7) 15 ( 19.5) Vomiting 6 ( 10.2) 9 ( 11.7) Fluid Overload 4 ( 6.8) 9 ( 11.7) Flatulence 4 ( 6.8) 7 ( 9.1) Hypersensitivity 3 ( 5.1) 6 ( 7.8) Appetite Disorders 2 ( 3.4) 5 ( 6.5) Sleep Disturbances 0 4 ( 5.2) Cough 0 4 ( 5.2) Skin Hemorrhage 1 ( 1.7) 4 ( 5.2) Subjects with Stoma Gastrointestinal Stoma Complication 3 (13.6) 13 (41.9) Percentage based on 53 subjects with a stoma (n = 22 placebo; n = 31 GATTEX 0.05 mg/kg/day) In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and GATTEX study groups experienced an injection site reaction. Adverse Reactions of Special Interest Malignancy Three subjects were diagnosed with malignancy in the clinical studies, all of whom were male and had received GATTEX 0.05 mg/kg/day in Study 2. One subject 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 subjects 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. Colorectal Polyps In the clinical studies, 13 subjects were diagnosed with polyps of the G.I. tract after initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (1.7%) of subjects on placebo and 1/109 (0.9%) of subjects 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 11 polyp cases occurred in the extension studies – 2 colorectal villous adenomas (onset at 6 and 7 months in GATTEX 0.10 and 0.05 mg/kg/day dose groups, respectively), 2 hyperplastic polyp (onset 6 months in GATTEX 0.10 mg/kg/day dose group and 24 months in GATTEX 0.05 mg/kg/day dose group), 3 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). Gastrointestinal Obstruction Overall, 12 subjects experienced one or more episodes of intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The 6 subjects in the placebo-controlled trials were all on GATTEX: 3/77 (3.9%) on GATTEX 0.05 mg/kg/day and 3/32 (9.4%) on GATTEX 0.10 mg/kg/day. No cases of intestinal obstruction occurred in the placebo group. Onsets ranged from 1 day to 6 months. In the extension studies, 6 additional subjects (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 subjects from the placebo-controlled trials experienced recurrence of obstruction in the extension studies. Of all 8 subjects with an episode of intestinal obstruction/stenosis in these extension studies, 2 subjects required endoscopic dilation and 1 required surgical intervention. Gallbladder, Biliary and Pancreatic Disease For gallbladder and biliary disease in the placebo-controlled studies, 3 subjects 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 extension studies, 4 subjects had an episode of acute cholecystitis; 3 subjects had new-onset cholelithiasis; and 1 subject experienced cholestasis secondary to an obstructed biliary stent. For pancreatic disease in the placebo-controlled studies, 1 subject (GATTEX 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed after 4 months of GATTEX. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and 1 subject was diagnosed with acute pancreatitis. Fluid Overload In the placebo-controlled trials, fluid overload was reported in 4/59 (6.8%) of subjects on placebo and 9/77 (11.7%) subjects on GATTEX 0.05 mg/kg/day. Of the 9 cases in the GATTEX group, there were 2 cases of congestive heart failure (CHF), 1 of whom 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. Concomitant Oral Medication GATTEX can increase the absorption of concomitant oral medications such as benzodiazepines and psychotropic agents. In the placebo-controlled trials, an analysis of episodes of cognition and attention disturbances was performed for subjects on benzodiazepines. One of the subjects in the GATTEX 0.05 mg/kg/day group (on prazepam) experienced dramatic deterioration in mental status progressing to coma during her first week of GATTEX therapy. She was admitted to the ICU where her benzodiazepine level was >300 mcg/L. GATTEX and prazepam were discontinued, and coma resolved 5 days later. 6.2 Immunogenicity Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of GATTEX may trigger the development of antibodies. Based on data from two trials in adults with SBS (a 6-month randomized placebo-controlled trial, followed by a 24-month open-label trial), the incidence of anti-teduglutide antibody was 3% (2/60) at Month 3, 18% (13/74) at Month 6, 25% (18/71) at Month 12, 31% (10/32) at Month 24 and 48% (14/29) at Month 30 in subjects who received subcutaneous administration of 0.05 mg/kg GATTEX once daily. The anti-teduglutide antibodies were cross-reactive to native glucagon-like peptide (GLP-2) in 5 of the 6 subjects (83%) who had anti-teduglutide antibodies. Anti-teduglutide antibodies appear to have no impact on short term (up to 2.5 years) efficacy and safety although the long-term impact is unknown. In the same two trials, a total of 36 subjects were tested for neutralizing antibodies: 9 of these subjects had no neutralizing antibodies, and the remaining 27 subjects had no detectable neutralizing antibodies although, the presence of teduglutide at low levels in these study samples could have resulted in false negatives (no neutralizing antibody detected although present). Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying diseases. For these reasons, comparison of the incidence of antibodies to GATTEX with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of GATTEX. 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 GATTEX exposure. Cardiac disorders: Cardiac Arrest, Cardiac Failure Nervous system disorders: Cerebral Hemorrhage 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, which should be considered if these drugs require titration or have a narrow therapeutic index. [see Warnings and Precautions (5.5)] 7.2 Concomitant Drug Therapy 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. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category B Risk Summary Adequate and well controlled studies with GATTEX have not been conducted in pregnant women. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of subcutaneous teduglutide at doses up to 1000 times the recommended human dose in both rats and rabbits. Because animal reproductive studies are not always predictive of human response, GATTEX should be used during pregnancy only if clearly needed. Data Animal data In animal studies, no effects on embryo-fetal development were observed in pregnant rats given subcutaneous teduglutide at doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) or pregnant rabbits given subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). 8.3 Nursing Mothers It is not known whether GATTEX is present in human milk. Teduglutide is excreted in the milk of lactating rats, and the highest concentration measured in milk was 2.9% of the plasma concentration following a single subcutaneous injection of 25 mg/kg. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions to nursing infants from GATTEX and because of the potential for tumorigenicity shown for teduglutide in mice and rats, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. [see Nonclinical Toxicology (13.1)] 8.4 Pediatric Use Safety and efficacy in pediatric patients have not been established. 8.5 Geriatric Use No dose adjustment is necessary in patients above the age of 65 years. Of the 595 subjects treated with teduglutide, 43 subjects were 65 years or older, whereas 6 subjects were 75 years of age or older. In the SBS studies, no overall differences in safety or efficacy were observed between these subjects and younger subjects, 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 Reduce the dose of GATTEX by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min) and end-stage renal disease (ESRD). [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)] 8.7 Hepatic Impairment GATTEX has not been formally studied in subjects with severe hepatic impairment. No dosage adjustment is necessary for patients with mild and moderate hepatic impairment based on a study conducted in Child-Pugh grade B subjects. [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)] 10 OVERDOSAGE The maximum dose of GATTEX studied during clinical development was 80 mg/day for 8 days. In the event of overdose, the patient should be carefully monitored by the medical professional. 11 DESCRIPTION The active ingredient in GATTEX (teduglutide [rDNA origin]) for injection is teduglutide (rDNA origin), 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-use vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate monohydrate, 3.434 mg dibasic sodium phosphate heptahydrate 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 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. 12 CLINICAL PHARMACOLOGY 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). 12.2 Pharmacodynamics The ability of GATTEX to improve intestinal absorption was studied in 17 adult subjects with Short Bowel Syndrome using daily doses of 0.03, 0.10, 0.15 mg/kg (N=2-3 per dose group) in a 21-day, open-label, multi-center, 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 750-1000 mL/day, and increased villus height and crypt depth of the intestinal mucosa. At a dose 5 times the maximum recommended dose, teduglutide did not prolong the QTc 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 3-5 hours after administration. Following a 0.05 mg/kg subcutaneous dose in SBS subjects, the median peak teduglutide concentration (Cmax) was 36 ng/mL and the median area under the curve (AUC0-inf) was 0.15 µg∙hr/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations. Distribution In healthy subjects, teduglutide has a volume of distribution (103 mL/kg) similar to blood volume. 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. Elimination 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 (t1/2) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects. Dose Linearity The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg GATTEX. Hepatic Impairment Subjects with moderate hepatic impairment had lower teduglutide Cmax and AUC (10 ~15%) compared to healthy matched control subjects after a single subcutaneous dose of 20 mg GATTEX. Teduglutide PK was not assessed in subjects with severe hepatic impairment. Renal Impairment In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-inf increased with the degree of renal impairment following a single subcutaneous administration of 10 mg teduglutide. Teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC0-inf) in ESRD subjects compared to healthy subjects. 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. Gender No clinically relevant gender differences were observed. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 60, 200 and 700 times 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 20, 70 and 250 times 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 (about 250 times the recommended human dose). 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 50 mg/kg/day (about 1000 times 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. 14 CLINICAL STUDIES 14.1 Study 1 (Placebo-controlled) and Study 2 (Open-label extension of Study 1) Study 1 The efficacy, safety, and tolerability of GATTEX was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center clinical trial (Study 1) 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. For 8 weeks (or less) prior to randomization, investigators optimized the PN/I.V. volume of all subjects. Optimization was followed by a 4-week to 8-week period of fluid stabilization. Subjects then were randomized (1:1) to placebo (n=43) or GATTEX 0.05 mg/kg/day (n=43). Study treatment was administered subcutaneously once daily for 24 weeks. PN/I.V. volume adjustments (up to 30% decrease) and clinical assessments were made at 2, 4, 8, 12, 20, and 24 weeks. The primary efficacy endpoint was based on a clinical response, defined as a subject 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 subjects was 50.3 years. Mean duration of PN/I.V. dependency prior to enrollment was 6.25 years (range 1-25.8 years). The most common reasons for intestinal resection leading to SBS were vascular disease (34.1%, 29/85), Crohn's Disease (21.2%, 18/85), and "other" (21.2%, 18/85). Stoma was present in 44.7% (38/85) of subjects, and the most common type was jejunostomy/ileostomy (81.6%, 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 43.5% (37/85) subjects. 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. 63% (27/43) of GATTEX-treated subjects versus 30% (13/43) of placebo-treated subjects 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 subjects (from pre-treatment baseline of 12.9 Liters) versus 2.3 Liters for placebo-treated subjects (from pre-treatment baseline of 13.2 Liters/week) (p<0.001). Twenty-one subjects on GATTEX (53.8%) versus 9 on placebo (23.1%) 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) Study 2 Study 2 was a 2-year open-label extension of Study 1 in which 88 subjects received GATTEX 0.05 mg/kg/day. Ninety-seven percent (76/78) of subjects who completed Study 1 elected to enroll in Study 2 (37 received GATTEX; 39 received Placebo). An additional 12 subjects entered Study 2, who had been optimized and stabilized but not randomized in Study 1 because of closed enrollment. 30 months exposure Thirty GATTEX subjects completed a total duration of 30 months (Study 1 followed by Study 2 treatment). Of these, 28 subjects (93%) achieved a 20% or greater reduction of parenteral support. 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 65.6% reduction from baseline). Ten subjects were weaned off their PN/I.V. support while on GATTEX treatment for 30 months. Subjects were maintained on GATTEX even if no longer requiring PN/I.V. support. These 10 subjects 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 month exposure Of the 39 placebo subjects 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 (55.2%) of the 29 completers achieved a 20% or greater reduction of parenteral support. At the end of study, 14 (48.3%), 7 (24.1%) and 5 (17.2%) achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively. Two subjects were weaned off their PN/I.V. support while on GATTEX. Of the 12 subjects entering Study 2 directly, 6 completed 24 months of treatment with GATTEX. Similar effects were seen. One of the six subjects was weaned off their PN/I.V. support while on GATTEX. 14.2 Study 3 (Placebo-controlled) and Study 4 (Blinded uncontrolled extension of Study 3) Study 3 Study 3 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study in adults with Short Bowel Syndrome 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, subjects were randomized to receive 24 weeks of one of the following treatment regimens: GATTEX 0.05 mg/kg/day (n=35), GATTEX 0.10 mg/kg/day dose (n=33), or placebo (n=16). 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 0.10 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 subjects on GATTEX 0.05 mg/kg/day responded versus 6% on placebo. Subjects on GATTEX at both dose levels experienced a 2.5 L/week reduction in parenteral support requirements versus 0.9 L/week for placebo at 24 weeks. Two subjects in the GATTEX 0.05 mg/kg/day dose group were weaned off parenteral support by Week 24. Study 4 Study 4 was a blinded, uncontrolled extension of Study 3, in which 65 subjects 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 parenteral support was achieved in 68% (17/25) of subjects. 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 subjects who had been completely weaned off PN/I.V. support in Study 3 remained off parenteral support through Study 4. During Study 4, an additional subject from Study 3 was weaned off parenteral support. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied GATTEX® (teduglutide [rDNA origin]) for injection is supplied in a sterile, single-use glass vial containing 5 mg of teduglutide as a white, lyophilized powder to be reconstituted with 0.5 mL Sterile Water for Injection. The product to be dispensed is either a one-vial kit or a 30-vial kit. The one-vial kit is pre-assembled and ready to be used. The 30-vial kit is to be assembled by a pharmacist with the following two cartons: Carton of Drug Vials (NDC 68875-0101-2): Thirty single-use vials of drug (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 pharmacist in a dispensing pharmacy will assemble a 30-vial kit by transferring the trays containing 30 vials from a Carton of Drug Vials into a Carton of Ancillary Supplies. The final patient kits should contain the items listed as follows: 30-vial kit (NDC 68875-0102-1): Thirty single-use vials of drug (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 One-vial kit (NDC 68875-0103-1): One single-use vial of drug (NDC 68875-0101-1) One disposable prefilled syringe containing 0.5 mL Sterile Water for Injection USP for reconstitution, with a separate needle (22G × 1½ in) to attach to the syringe One sterile disposable 1-mL syringe with needle (26G × 5/8 in) for dosing Four alcohol swabs Reconstitution with 0.5 mL of preservative-free Sterile Water for Injection, provided in a prefilled syringe, is required prior to subcutaneous administration of the drug. Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored 10 mg/mL solution, which should be free from particulates. Upon reconstitution with the 0.5 mL Sterile Water for Injection provided in the prefilled syringe, a maximum of 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn from the vial for dosing. 16.2 Storage and Handling Prior to Dispensing: Store refrigerated at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze. Do not use beyond the expiration date on the label. Store at room temperature up to 25°C (77°F) for the Cartons of Ancillary Supplies. Instruction for the Pharmacist: Prior to Dispensing: Store at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze. Dispensing Instructions: Dispense with a 90-day "use by" dating and specify "Store at room temperature up to 25°C (77°F). Do not freeze." Dispense Medication Guide to each patient. Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored solution, which should be free from particulates. The drug should be completely dissolved before the solution is withdrawn from the vial. Do not shake or freeze the reconstituted solution. If the product remains undissolved after the second attempt, do not use. GATTEX does not contain any preservatives and is for single-use only. Any unused portion should be discarded. The product should be used within 3 hrs after reconstitution. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=66b69c1e-b25c-44d3-b5ff-1c1de9a516fa