`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) for injection, for subcutaneous use
`
`Initial U.S. Approval: 2012
`
`
` ----------------------------INDICATIONS AND USAGE----------------------------
`GATTEX® 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 -----------------------
`Important Administration Information
`Within 6 months prior to initiating treatment with GATTEX:
`
`Perform a colonoscopy (or alternate imaging) of the entire colon
`
`
`
`
`with removal of polyps. (2.1, 2.4, 5.1)
`
`(bilirubin, alkaline
`laboratory assessments
` Obtain baseline
`
`
`phosphatase, lipase and amylase). (2.1, 2.4, 5.3)
`
`Dosage and Administration
`For subcutaneous use only. (2.2)
`
`
`
`
`The recommended dosage of GATTEX is 0.05 mg/kg once daily
`
`
`by subcutaneous injection. (2.2)
`
`Alternate sites between 1 of the 4 quadrants of the abdomen, or
`
`into alternating thighs or alternating arms. (2.2)
`
`Dosage Adjustment for Renal Impairment
`
`For patients with moderate and severe renal impairment and
`
`
`
`than
`end-stage
`regnal disease
`(creatinine clearance
`less
`
`60 mL/min) 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)
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`
`
`
`For injection: 5 mg teduglutide in a single-dose vial supplied with
`
`0.5 mL Sterile Water for Injection in a prefilled syringe. (3)
`
`
` ------------------------------- CONTRAINDICATIONS-------------------------------
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`
`2 DOSAGE AND ADMINISTRATION
`
`
`Important Administration Information
`2.1
`2.2 Recommended Dosage and Administration
`2.3 Dosage Adjustment for Renal Impairment
`
`2.4 Monitoring to Assess Safety
`2.5 Discontinuation of Treatment
`
`2.6 Preparation Instructions
`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 Imbalance and Fluid Overload
`Increased Absorption of Concomitant Oral Medication
`5.5
` ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`Immunogenicity
`6.2
`
` DRUG INTERACTIONS
`
`7.1 Potential for Increased Absorption of Oral Medications
`8 USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`
`
`6
`
`7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`None (4)
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`
`
`Acceleration of Neoplastic Growth: Colonoscopy is recommended
`
`
`
`after 1 year of treatment and with subsequent colonoscopies as
`needed, but no less frequently than every 5 years. In case of
`intestinal malignancy, discontinue GATTEX. The clinical decision
`
`in patients with non-gastrointestinal
`to continue GATTEX
`malignancy should be made based on benefit-risk considerations.
`
`(5.1)
`
`Intestinal Obstruction: In patients who develop intestinal or stomal
`obstruction, temporarily discontinue GATTEX pending further
`
`clinical evaluation and management. (5.2)
`
`Biliary and Pancreatic Disease: Obtain bilirubin, alkaline
`
`phosphatase,
`lipase, amylase every 6 months.
`If clinically
`meaningful changes are seen, further evaluation is recommended
`including imaging, and reassess continued GATTEX treatment.
`
`(5.3)
`
`Fluid Overload, Including Congestive Heart Failure: If fluid
`overload occurs, adjust parenteral support, and
`reassess
`continued GATTEX treatment. (5.4)
`
`Potential for Increased Absorption of Oral Medications: Monitor
`
`patients on concomitant oral medications (e.g., benzodiazepines)
`for adverse reactions related to the concomitant drug; dosage
`
`reduction of the other drug may be required. (5.5, 7.1)
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`Most common adverse reactions (≥10%) are: abdominal pain, nausea,
`upper respiratory tract infection, abdominal distension, injection site
`
`reaction, vomiting, fluid overload, and hypersensitivity. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Shire-NPS
`
`Pharmaceuticals, Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088
`
`or www.fda.gov/medwatch.
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`Lactation: Breastfeeding not recommended. (8.2)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`
`
`
`Revised: 12/2018
`
`
`8.1
` Pregnancy
`8.2
` Lactation
`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
` NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
` CLINICAL STUDIES
`
`(Placebo-controlled) and Study 2
` Study 1
`14.1
`
`
`Extension of Study 1)
`
`(Placebo-controlled) and Study 4
` Study 3
`
`
`Uncontrolled Extension of Study 3)
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`13
`
`14
`
`14.2
`
`(Open-label
`
`
`(Blinded
`
`
`
`Reference ID: 4365346
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`GATTEX® is indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are
`
`
`dependent on parenteral support.
`
`DOSAGE AND ADMINISTRATION
`2
`Important Administration Information
`2.1
`Within 6 months prior to starting treatment with GATTEX:
`
`
` Perform a colonoscopy (or alternate imaging) of the entire colon with removal of polyps [see
`Warnings and Precautions (5.1)].
`
`
`
` Obtain baseline laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase)
`[see Warnings and Precautions (5.3)].
`
`
`2.2 Recommended Dosage and Administration
`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, arms,
`and the quadrants of the abdomen.
`2.3 Dosage Adjustment for Renal Impairment
`
`The recommended dosage in patients with moderate and severe renal impairment and end-stage
`
`renal disease (creatinine clearance less than 60 mL/min) is 0.025 mg/kg once daily [see Use in Specific
`Populations (8.6)].
`
`2.4 Monitoring to Assess Safety
`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.
`
`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.
`
`If the product remains undissolved after the second attempt, do not use.
`
`Inspect the reconstituted GATTEX solution for particulate matter and discoloration prior to
`administration. GATTEX is a clear, colorless to light straw-colored solution. If there is any
`
`discoloration or particulates, discard the solution.
`
`
` Administer within 3 hours after reconstitution. Discard any unused portion.
`
`
`
` Do not shake or freeze the reconstituted solution.
`
`
` For single use only.
`
`
`
`
`
`
`
`Reference ID: 4365346
`
`

`

`
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`For Injection: 5 mg teduglutide as a white lyophilized powder for reconstitution in a single-dose vial
`
`supplied with 0.5 mL Sterile Water for Injection in a prefilled syringe and delivers a maximum of 0.38 mL
`
`of the reconstituted sterile solution which contains 3.8 mg of teduglutide.
`
`CONTRAINDICATIONS
`4
`
`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 [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 trials [see Adverse Reactions (6.1)]. Within
`6 months prior to starting treatment with GATTEX, perform colonoscopy of the entire colon with removal
`of polyps [see Dosage and Administration (2.1)]. 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.
`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.
`
`Intestinal Obstruction
`5.2
`
`Intestinal obstruction has been reported in clinical trials [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.
`
`Reference ID: 4365346
`
`3
`
`
`

`

`
`
`
`
` 5.4 Fluid Imbalance and Fluid Overload
`
` Fluid Overload
`
`Fluid overload and congestive heart failure have been observed in clinical trials, 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)].
`
`Increased Absorption of Concomitant Oral Medication
`5.5
`
`In the placebo-controlled trials, 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)].
`
`ADVERSE REACTIONS
`6
`
`The following serious adverse reactions are described elsewhere in the labeling:
`
`
`Acceleration of Neoplastic Growth [see Warnings and Precautions (5.1)]
`
`
`
`Intestinal Obstruction [see Warnings and Precautions (5.2)]
`
`
`Biliary and Pancreatic Disease [see Warnings and Precautions (5.3)]
`
`
`
`
`Fluid Imbalance and Fluid Overload [see Warnings and Precautions (5.4)]
`
`
`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.
`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.
`
`Reference ID: 4365346
`
`4
`
`
`

`

`Table 1: Common Adverse Reactions* in Adult Patients with SBS in
`
`Placebo-Controlled Trials: Studies 1 and 3
`
`
`
` Placebo
`
` (N=59)
`(%)
`
`GATTEX
`
`0.05 mg/kg
`
`Once Daily
`
`(N=77)
`(%)
`
`22
`Abdominal pain1
`
` 30
`
`20
`Nausea
`23
`12
`Upper respiratory tract infection2
`
` 21
`2
`
` Abdominal distension
`
` 20
`12
`Injection site reaction3
`
` 13
`10
`Vomiting
` 12
`
`7
` 12
`Fluid Overload4
`7
`Hypersensitivity5
`
` 10
`
`7
`Flatulence
`9
`
`3
`Decreased appetite
` 7
`2
`
` 7
`Influenza6
`2
`Skin hemorrhage7
`
` 5
`0
`Cough
`
` 5
`0
`
`
` 5
`Sleep disturbances8
`* Reported at a rate of at least 5% in the GATTEX group, and greater than the placebo group.
`
`
`1 Includes: Abdominal pain, upper abdominal pain, lower abdominal pain
`
`2 Includes: Upper respiratory tract infection, nasopharyngitis, pharyngitis, sinusitis, laryngitis,
`
`rhinitis, viral upper respiratory tract infection
`
`3 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
`4 Includes: Fluid overload, peripheral edema, edema, generalized edema, fluid retention and
`jugular vein distension
`5 Includes Erythema, rash, dermatitis allergic, pruritus, rash macular, drug eruption, eyelid edema,
`flushing
`6 Includes: Influenza, influenza-like illness
`
`7 Includes: Hematoma, abdominal wall hematoma, post procedural hematoma, umbilical
`hematoma, blood blister
`
`8 Includes: Insomnia (3 patients) and hypersomnia (1 patient)
`
`
`
`
`
` Adverse Reaction
`
`
`
`
`
`
`
`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.
`Less Common Adverse Reactions
`
`Adverse Reactions of Special Interest
`Malignancy
`Three patients were diagnosed with malignancy in the SBS clinical trials, 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 clinical trials, 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
`
`Reference ID: 4365346
`
`

`

`
`
` 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
`
`the recommended dose) and 0.05 mg/kg/day dose groups, respectively),
`0.1 mg/kg/day (twice
`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)].
`
`Gastrointestinal Obstruction
`
`Overall, 12 patients with SBS experienced one or more episodes of intestinal obstruction/stenosis:
`the
`6 in SBS placebo-controlled studies and 6 in
`the extension studies. The 6 patients
`in
`
`placebo-controlled trials 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 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 trials 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)].
`
`Gallbladder, Biliary and Pancreatic Disease
`For gallbladder and biliary disease in the 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 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 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 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 placebo-controlled trials, 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
`
`Reference ID: 4365346
`
`6
`
`
`

`

`
`
`studies described below with the incidence of antibodies in other studies or to other products may be
`misleading.
`
`
`trials
`two
`from
`integrated data
`Based on
`in adults with SBS (a 6-month randomized
`
`placebo-controlled trial, followed by a 24-month open-label trial), 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 trials, a total of 36 patients were tested for neutralizing antibodies: one
`patient developed borderline positive neutralizing antibody responses at month 24 of the extension trial.
`
`The antibody formation has not been associated with clinically relevant safety findings, reduced efficacy
`or changed pharmacokinetics of GATTEX.
`
`DRUG INTERACTIONS
`7
`7.1 Potential for Increased Absorption of Oral Medications
`
`Based upon the pharmacodynamic effect of GATTEX, there is a potential for increased absorption
`
`of concomitant oral medications. Altered mental status has been observed in patients taking GATTEX
`
`and benzodiazepines in clinical trials [see Warnings and Precautions (5.5)].
`Monitor patients on concomitant oral drugs requiring titration or with a narrow therapeutic index for
`
`adverse reactions related to the concomitant drug while on GATTEX. The concomitant drug may require
`
`a reduction in dosage.
`
`
`8
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Risk Summary
`
`Available data from case reports with GATTEX use in pregnant women have not identified a
`drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Pregnant
`women with short bowel syndrome are at risk for malnutrition, which is associated with adverse maternal
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`
`and fetal outcomes (see Clinical Considerations). In animal reproduction studies, no effects on
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`embryo-fetal development were observed with the subcutaneous administration of teduglutide to pregnant
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`rats and rabbits during organogenesis at exposures up to 686 times the clinical exposure at the
`
`recommended human dose (based on AUC) (see Data).
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
`U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
`recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
`Clinical Considerations
`Disease-associated maternal and/or embryo/fetal risk
`
`Pregnant women with short bowel syndrome are at risk for malnutrition. Severe malnutrition in
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`pregnant women is associated with preterm delivery, low birth weight, intrauterine growth restriction,
`congenital malformations and perinatal mortality.
`
`Data
`Animal Data
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`Reproduction studies have been performed in pregnant rats at subcutaneous doses of teduglutide
`
`up to 50 mg/kg/day (resulting in exposures of 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
`50 mg/kg/day (resulting in exposures of 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 50 mg/kg/day (about 161 times the recommended daily
`
`human dose of 0.05 mg/kg, based on body surface area [BSA]).
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` 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 BSA) 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
`
`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 134 patients that
`
`were treated with GATTEX at the recommended dose of 0.05 mg/kg/day in the SBS safety and efficacy
`
`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 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 dose of GATTEX by half in these patients
`[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)].
`10 OVERDOSAGE
`
`The maximum dose of GATTEX studied during clinical development was 80 mg/day for 8 days. No
`
`unexpected systemic adverse reactions were seen. In the event of overdose, the patient should be
`
`carefully monitored by the medical professional.
`11 DESCRIPTION
`
`The active ingredient in GATTEX (teduglutide) for injection is teduglutide, which is a 33 amino acid
`
`glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified by
`recombinant DNA technology. The chemical composition of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L­
`glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L­
`isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-
`L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L­
`
`threonyl-L-aspartic acid. The structural formula is:
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` Figure 1: Structural formula of teduglutide
`
`Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear,
`
` colorless to light-straw–colored liquid.
`Each single-dose vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for
`
`reconstitution and administration by subcutaneous injection. In addition to the active pharmaceutical
`ingredient (teduglutide), each vial of GATTEX contains 3.434 mg dibasic sodium phosphate
`
`heptahydrate, 3.88 mg L-histidine, 15 mg mannitol, and 0.644 mg monobasic sodium phosphate
`monohydrate as excipients. No preservatives are present.
`
`At the time of administration, the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for
`
`Injection, which is provided in a 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
`
`Intestinal Fluid Absorption
`The ability of GATTEX to improve intestinal absorption was studied in 17 adult subjects with Short
`Bowel Syndrome (N=2-3 per dose group) using daily doses of 0.03, 0.1, 0.15 mg/kg (doses ranging from
`0.6 to 3 times the recommended dose) in a 21-day, open-label, multi-center, dose-ranging study. All
`
`in enhanced
`subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, resulted
`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 c