•
`
`
`•
`
`
`
`•
`
`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: 06/2014
`
`
`
`
`
`
`-------------------------------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
`
`
`
`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Information
`
`
`
`2.2 Monitoring to Assess Safety
`
`
`2.3 Dosage Modifications in Renal Impairment
`
`
`
`2.4 Discontinuation of Treatment
`
`
`2.5 Preparation for Administration
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Acceleration of Neoplastic Growth
`
`
`5.2
`Intestinal Obstruction
`
`
`5.3 Biliary and Pancreatic Disease
`
`
`5.4 Fluid Overload
`
`
`5.5
`Increased Absorption of Concomitant Oral Medication
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2
`Immunogenicity
`
`
`6.3 Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Potential for Increased Absorption of Oral Medications
`
`
`
`7.2 Concomitant Drug Therapy
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`
`
`
`8.7 Hepatic Impairment
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Study 1 (Placebo-controlled) and Study 2 (Open-label extension
`
`of Study 1)
`
`
`14.2 Study 3 (Placebo-controlled) and Study 4 (Blinded uncontrolled
`
`extension of Study 3)
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`
`16.2 Storage and Handling
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`17.1 Acceleration of Neoplastic Growth
`
`
`17.2
`Intestinal Obstruction
`
`
`
`17.3 Gallbladder and Bile Duct Disease
`
`
`17.4 Pancreatic Disease
`
`
`17.5 Cardiovascular Disease
`
`
`
`
`
`17.6 Risks Resulting from Increased Absorption of Concomitant Oral
`
`Medication
`
`Instructions
`
`
`17.7
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
` 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)
`
`
`•
`
`
`
`
`
`Reference ID: 3532895
`
`Page 1
`
`

`
`
` FULL PRESCRIBING INFORMATION
`
`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)]
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`2
`
`
`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
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`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)]
`
`
`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)]
`
`
`
`
`
`
`
`
`
`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)]
`
`
`
`
`
`
`
`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)]
`
`
`3
`
`
`4
`
`
`
`
`
`
`
`
`5.2
`
`
`
`
`Reference ID: 3532895
`
`Page 2
`
`

`
`
`
`
` 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)]
`
`
`
`
`
`
`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)]
`
`
`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)]
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`5.4
`
`
`
`
`5.5
`
`
`
`6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`
`
` Placebo
`
` (N=59)
`
` n (%)
`
`
`
` Adverse Reaction
`
`
`
`
`
`
`
`
` 16 ( 27.1)
` 8 ( 13.6)
`
`
` 12 ( 20.3)
`
`
`
` 1 ( 1.7)
`
` 6 ( 10.2)
`
` 4 ( 6.8)
`
`
`
` 4 ( 6.8)
`
`
` 3 ( 5.1)
`
`
` 2 ( 3.4)
`
` 0
`
`
` 0
` 1 ( 1.7)
`
`
`
`
` Abdominal Pain
`
` Upper Respiratory Tract Infection
`
` Nausea
`
` Abdominal Distension
`
` Vomiting
` Fluid Overload
`
`
` Flatulence
` Hypersensitivity
`
`
` Appetite Disorders
`
` Sleep Disturbances
`
` Cough
`
` Skin Hemorrhage
`
`
` Subjects with Stoma
`
` Gastrointestinal Stoma Complication
`
`
` 3 (13.6)a
` 13 (41.9)a
`
` aPercentage 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.
`
`
`
`
`
`
`
` GATTEX
`
`
` 0.05mg/kg/day
`
` (N=77)
`
` n (%)
`
` 29 ( 37.7)
`
` 20 ( 26.0)
`
` 19 ( 24.7)
`
`
` 15 ( 19.5)
` 9 ( 11.7)
`
`
`
` 9 ( 11.7)
`
` 7 ( 9.1)
`
`
`
` 6 ( 7.8)
`
`
` 5 ( 6.5)
`
`
` 4 ( 5.2)
`
`
` 4 ( 5.2)
`
`
` 4 ( 5.2)
`
`
`
`Reference ID: 3532895
`
`Page 3
`
`

`
`
`
`
`
`
`
`
`Adverse Reactions of Special Interest
`
`
`6.2
`
`
`6.3
`
`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.
`
`
`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.
`
`
`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.
`
`
`
`
`
`
`
`
`
`Reference ID: 3532895
`
`Page 4
`
`

`
`
`
`
` 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.
`
`
`
`
`Reference ID: 3532895
`
`Page 5
`
`

`
`
`
`
`
`
`
`
`
`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