`
`
`
`
`(bilirubin, alkaline
`
`
`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 adults and pediatric patients 1 year of age and older with
`
`
`
`Short Bowel Syndrome (SBS) who are dependent on parenteral support.
`
`(1)
`
`
`
`
`----------------------- DOSAGE AND ADMINISTRATION -----------------------
`Important Administration Information
`GATTEX is for adult self-administration or caregiver administration.
`
`Self-administration in pediatric patients has not been tested. Use of the
`
`
`GATTEX 5 mg kit is not recommended in pediatric patients weighing
`
`less than 10 kg.
`Within 6 months prior to initiating treatment with GATTEX:
`
`Adults: Perform a colonoscopy with removal of polyps. (2.1, 5.1)
`
`
`
`
`Pediatric patients: Perform fecal occult blood testing; if there is
`
`
`
`
`perform
`unexplained
`blood
`the
`in
`stool,
`
`
`
`
`colonoscopy/sigmoidoscopy. (2.1, 5.1)
`
`
`laboratory assessments
` Obtain baseline
`
`
`
`phosphatase, lipase and amylase). (2.1, 5.3)
`
`Dosage and Administration
`For subcutaneous use only. (2.2)
`
`
`
`
`The recommended dosage of GATTEX for both adults and
`
`
`
`
`pediatric patients is 0.05 mg/kg once daily by subcutaneous
`
`
`injection. (2.2)
`
`Alternate sites between 1 of the 4 quadrants of the abdomen, or
`
`into alternating thighs or alternating arms. (2.2)
`
`Dosage Adjustment for Renal Impairment
`
`For adult and pediatric patients with moderate and severe renal
`
`
`
`impairment and end-stage renal disease (estimated glomerular
`
`
`
`filtration rate less than 60 mL/min/1.73 m2) 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 single-dose prefilled syringe. (3)
`
`
`------------------------------- CONTRAINDICATIONS-------------------------------
`
`
`
`None. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS -----------------------
`
`
`
`Acceleration of Neoplastic Growth: In adults and pediatric patients,
`
`
`
`
`colonoscopy is recommended after 1 year of treatment. Perform
`
`
`
`subsequent colonoscopies no less frequently than every 5 years.
`
`
`
`
`
`In case of intestinal malignancy, discontinue GATTEX. The
`decision to continue GATTEX in patients with non-gastrointestinal
`
`malignancy should be made based on benefit-risk considerations.
`
`
`
`(5.1)
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`
`2 DOSAGE AND ADMINISTRATION
`
`
`Important Administration Information
`2.1
`2.2 Recommended Dosage and Administration for Adults and
`Pediatric Patients 1 Year of Age and Older
`
`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
`
`Intestinal Obstruction
`5.2
`5.3 Biliary and Pancreatic Disease
`
`5.4 Fluid Imbalance and Fluid Overload
`Increased Absorption of Concomitant Oral Medication
`5.5
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`Immunogenicity
`6.2
`
`7 DRUG INTERACTIONS
`
`7.1 Potential for Increased Absorption of Oral Medications
`
`
`
`Reference ID: 4738888
`
`Revised: 01/2021
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`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
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`14.1 Treatment of SBS in Adults
`14.2 Treatment of SBS in Pediatric Patients
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`

`

` FULL PRESCRIBING INFORMATION
`
`1
`INDICATIONS AND USAGE
`GATTEX® is indicated for the treatment of adults and pediatric patients 1 year of age and older with
`
`
`
`
`
`Short Bowel Syndrome (SBS) who are dependent on parenteral support.
`DOSAGE AND ADMINISTRATION
`2
`2.1
`Important Administration Information
`
`GATTEX is for adult self-administration or caregiver administration. Self-administration in pediatric
`
`patients has not been tested.
`
`Use of the GATTEX 5 mg kit is not recommended in pediatric patients weighing less than 10 kg.
`
`
`Within 6 months prior to starting treatment with GATTEX:
` Adults: Perform a colonoscopy of the entire colon with removal of polyps [see Warnings and
`
`
`
`Precautions (5.1)].
` Pediatric patients: Perform fecal occult blood testing; if there is unexplained blood in the stool,
`
`
`
`perform colonoscopy/sigmoidoscopy [see Warnings and Precautions (5.1)].
` Obtain baseline laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase)
`
`
`
`[see Warnings and Precautions (5.3)].
`2.2 Recommended Dosage and Administration for Adults and Pediatric Patients 1 Year of Age
`
`and Older
`GATTEX is for subcutaneous injection only. Not for intravenous or intramuscular administration.
`
`
`The recommended dosage of GATTEX is 0.05 mg/kg once daily administered by subcutaneous
`injection.
`
`
`If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses
`on the same day.
`
`
`
`
`
`Alternation of sites for subcutaneous injection is recommended, and can include the thighs, upper
`
`arms, and the abdomen.
`2.3 Dosage Adjustment for Renal Impairment
`
`The recommended dosage in adult and pediatric patients with moderate and severe renal impairment
`
`
`
`and end-stage renal disease (estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2) is
`0.025 mg/kg once daily [see Use in Specific Populations (8.6)].
`
`2.4 Monitoring to Assess Safety
`Colonoscopy Schedule in Adults
`A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. If
`
`
`
`
`no polyp is found, subsequent colonoscopies should be done no less frequently than every 5 years. If a
`
`
`
`polyp is found, adherence to current polyp follow-up guidelines is recommended [see Warnings and
`Precautions (5.1)].
`Colonoscopy Schedule in Pediatric Patients
`
`Perform subsequent fecal occult blood testing annually in children and adolescents while they are
`receiving GATTEX.
`
`Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of
`treatment, every 5 years thereafter while on continuous treatment with GATTEX, and if they have new or
`
`unexplained gastrointestinal bleeding [see Warnings and Precautions (5.1)].
`
`Laboratory Testing
`
`Laboratory assessments are recommended every 6 months. If any clinically meaningful elevation is
`seen, further diagnostic workup is recommended as clinically indicated (i.e., imaging of the biliary tract,
`liver, or pancreas) [see Warnings and Precautions (5.1), (5.3)].
`
`Reference ID: 4738888
`
`

`

`
`
`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
`
`
`3
`
` Reconstitute each vial of GATTEX by slowly injecting the 0.5 mL of preservative-free Sterile Water
`
`
`for Injection provided in the prefilled syringe. A 10 mg/mL sterile solution is obtained after
`
`
`
`
`reconstitution.
` Allow the vial containing GATTEX and water to stand for approximately 30 seconds and then
`
`
`
`
`gently roll the vial between the palms for about 15 seconds. Do not shake the vial.
`
` Allow the mixed contents to stand for about 2 minutes. Inspect the vial for any undissolved
`
`
`
`powder. If undissolved powder is observed, gently roll the vial again until all material is dissolved.
`
`
`
`Do not shake the vial.
` Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored solution, which should
`
`
`
`
`
`be free from particulates. If there is any discoloration or particulates, discard the solution.
`
` A maximum of 0.38 mL of the reconstituted solution, containing 3.8 mg of teduglutide, can be
`
`
`
`
`
`
`withdrawn from the vial for dosing.
`
`If the product remains undissolved after the second attempt, do not use.
`
`
`
`Storage of the reconstituted solution
`
`
` Administer within 3 hours after reconstitution. Discard any unused portion.
`
`
` Do not shake or freeze the reconstituted solution.
`
` For single use only.
`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 single-dose prefilled syringe.
`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 studies [see Adverse Reactions (6.1)]. In adults,
`
`
`
`within 6 months prior to starting treatment with GATTEX, perform colonoscopy of the entire colon with
`
`
`
`removal of polyps. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of
`
`
`
`GATTEX. Perform subsequent colonoscopies every 5 years or more often as needed. If a polyp is found,
`
`adherence to current polyp follow-up guidelines is recommended. If colorectal cancer is diagnosed,
`
`
`
`
`discontinue GATTEX therapy.
`In children and adolescents, perform fecal occult blood testing prior to initiating treatment with
`
`
`GATTEX. Colonoscopy/sigmoidoscopy is required if there is unexplained blood in the stool. Perform
`
`
`subsequent fecal occult blood testing annually in children and adolescents while they are receiving
`
`GATTEX. Colonoscopy/sigmoidoscopy is recommended for all children and adolescents after 1 year of
`
`treatment, every 5 years thereafter while on continuous treatment with GATTEX, and if they have new or
`
`unexplained gastrointestinal bleeding [see Dosage and Administration (2.1)].
`
`Reference ID: 4738888
`
`3
`
`
`

`

`
`
`Small Bowel Neoplasia
`Based on tumor findings in the rat and mouse carcinogenicity studies, monitor patients clinically for
`
`
`
`small bowel neoplasia [see Nonclinical Toxicology (13.1)]. If a benign neoplasm is found, it should be
`
`
`
`removed. In case of small bowel cancer, discontinue GATTEX therapy.
`5.2
`Intestinal Obstruction
`
`
`
`Intestinal obstruction has been reported in clinical studies [see Adverse Reactions (6.1)] and
`
`
`postmarketing. In patients who develop intestinal or stomal obstruction, temporarily discontinue GATTEX
`
`
`while the patient is clinically managed. GATTEX may be restarted when the obstructive presentation
`resolves, if clinically indicated.
`5.3 Biliary and Pancreatic Disease
`Gallbladder and Biliary Tract Disease
`
`
`Cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies [see Adverse
`
`
`Reactions (6.1)] and postmarketing. For identification of the onset or worsening of gallbladder/biliary
`
`
`
`
`disease, obtain laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting
`
`
`
`GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically
`
`
`
`meaningful changes are seen, further evaluation including imaging of the gallbladder and/or biliary tract is
`recommended; and reassess the need for continued GATTEX treatment.
`
`Pancreatic Disease
`
`
`Pancreatitis has been reported in clinical studies [see Adverse Reactions (6.1)]. For identification of
`
`
`onset or worsening of pancreatic disease, obtain laboratory assessments of lipase and amylase within
`
`
`
`
`6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if
`
`
`needed. If clinically meaningful changes are seen, further evaluation such as imaging of the pancreas is
`recommended; and reassess the need for continued GATTEX treatment.
`
`5.4 Fluid Imbalance and Fluid Overload
`
`Fluid Overload
`
`
`
`Fluid overload and congestive heart failure have been observed in clinical studies, which were
`
`
`
`deemed to be related to enhanced fluid absorption associated with GATTEX [see Adverse Reactions (6.1)].
`If fluid overload occurs, adjust parenteral support and reassess GATTEX treatment, especially in patients
`
`
`
`with underlying cardiovascular disease. If significant cardiac deterioration develops while on GATTEX,
`reassess the need for continued GATTEX treatment.
`
`Fluid and Electrolyte Imbalance
`Discontinuation of treatment with GATTEX may also result in fluid and electrolyte imbalance. Monitor
`
`fluid and electrolyte status in patients who discontinue treatment with GATTEX [see Dosage and
`
`
`
`Administration (2.5)].
`
`
`Increased Absorption of Concomitant Oral Medication
`
`In the adult placebo-controlled studies, an analysis of episodes of cognition and attention
`
`
`disturbances was performed for patients on benzodiazepines. One patient receiving prazepam
`
`
`
`concomitantly with GATTEX 0.05 mg/kg once daily experienced a dramatic deterioration in mental status
`
`
`progressing to coma during the first week of GATTEX therapy. The patient was admitted to the ICU and
`
`
`
`the prazepam blood concentration was >300 mcg/L. GATTEX and prazepam were discontinued, and coma
`
`resolved 5 days later.
`
`
`
`Monitor patients receiving concomitant oral drugs requiring titration or with a narrow therapeutic
`
`
`index, for adverse reactions due to potential increased absorption of the concomitant drug. The concomitant
`drug may require a reduction in dosage [see Drug Interactions (7.1)].
`
`5.5
`
`Reference ID: 4738888
`
`4
`
`
`

`

`
`
`6
`ADVERSE REACTIONS
`
`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
`
`Adults
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates
`observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed
`
`
`in clinical practice.
`
`The rates of adverse reactions in 136 adult patients with SBS participating in two randomized,
`
`
`placebo-controlled, 24-week, double-blind clinical studies (Study 1 and Study 3) are summarized in
`
`Table 1. Only those reactions with a rate of at least 5% in the GATTEX group, and greater than placebo
`
`
`
`
`
`
`group, are summarized in Table 1.
`
`
`
`Table 1: Common Adverse Reactions* in Adult Patients with SBS in
`Placebo-Controlled Studies: 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
`
`
`Reference ID: 4738888
`
`5
`
`
`

`

`
`
`Adverse Reactions in the Subset of Patients with a Stoma
`
`Among the 53 patients with a stoma in the placebo-controlled studies (Study 1 and Study 3), the
`
`
`
`
`
`
`percentage of patients with gastrointestinal stoma complication was 42% (13/31) for patients receiving
`
`
`
`
`
`GATTEX 0.05 mg/kg/day and 14% (3/22) for patients receiving placebo.
`
`Pediatric Patients 1 Year to Less Than 17 Years of Age
`
`
`
`In two clinical studies of 24-week and 12-week duration, 41 pediatric patients aged 1 year to less than
`
`17 years were treated with GATTEX 0.05 mg/kg/day [see Use in Specific Populations (8.4), Clinical Studies
`(14.2)]. Overall, the safety profile of GATTEX was similar to that in adults. In the long-term extension studies
`with mean exposure of 41 weeks, no new safety signals were identified.
`Less Common Adverse Reactions
`
`Adverse Reactions of Special Interest
`Malignancy
`
`
`Three patients were diagnosed with malignancy in the SBS clinical studies in adults, all of whom were
`
`
`
`
`
`
`male and had received GATTEX 0.05 mg/kg/day in Study 2. One patient had a history of abdominal
`
`
`radiation for Hodgkin’s disease two decades prior to receiving GATTEX and prior liver lesion on CT scan,
`
`
`
`and was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to
`
`
`
`GATTEX. Two patients had extensive smoking histories and were diagnosed with lung cancers (squamous
`
`
`and non-small cell) after 12 months and 3 months of GATTEX exposure, respectively [see Warnings and
`
`Precautions (5.1)].
`Intestinal Polyps
`
`In the adult clinical studies, 14 patients with SBS were diagnosed with polyps of the GI tract after
`
`
`
`
`initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (2%) of patients on placebo and
`
`
`
`1/109 (1%) of patients on GATTEX 0.05 mg/kg/day were diagnosed with intestinal polyps (inflammatory
`
`
`stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 12 polyp cases
`
`
`
`
`
`
`occurred in the extension studies  2 colorectal villous adenomas (onset at 6 and 7 months in GATTEX
`
`
`
`0.1 mg/kg/day (twice
`the recommended dose) and 0.05 mg/kg/day dose groups, respectively),
`
`2 hyperplastic polyps (onset 6 months in GATTEX 0.1 mg/kg/day dose group and 24 months in GATTEX
`
`
`
`
`
`0.05 mg/kg/day dose group), 4 colorectal tubular adenomas (onset between 24 and 29 months in GATTEX
`
`
`
`0.05 mg/kg/day dose group), 1 serrated adenoma (onset at 24 months in GATTEX 0.05 mg/kg/day dose
`
`group), 1 colorectal polyp biopsy not done (onset at 24 months in GATTEX 0.05 mg/kg/day dose group),
`
`
`1 rectal inflammatory polyp (onset at 10 months in the GATTEX 0.05 mg/kg/day dose group, and 1 small
`
`duodenal polyp (onset at 3 months in GATTEX 0.05 mg/kg/day dose group) [see Warnings and Precautions
`
`(5.1)].
`
`In the pediatric clinical studies (up to 69 weeks of exposure), there was one case of cecal polyp that
`was not biopsied and was not seen on repeat colonoscopy.
`
`Gastrointestinal Obstruction
`
`
`Overall, in the adult clinical studies, 12 patients with SBS experienced one or more episodes of
`
`
`intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The
`
`6 patients in the placebo-controlled studies were all on GATTEX: 3/77 (4%) on GATTEX 0.05 mg/kg/day
`
`
`
`and 3/32 (9%) on GATTEX 0.1 mg/kg/day (twice the recommended dose). No cases of intestinal
`
`
`
`
`
`
`
`
`obstruction occurred in the placebo group. Onset ranged from 1 day to 6 months. In the adult extension
`
`studies, 6 additional patients (all on GATTEX 0.05 mg/kg/day) were diagnosed with
`intestinal
`
`
`obstruction/stenosis with onsets ranging from 6 days to 19 months. Two of the 6 patients from the
`
`placebo-controlled studies experienced recurrence of obstruction in the extension studies. Of all 8 patients
`
`
`with an episode of intestinal obstruction/stenosis in these extension studies, 2 patients required endoscopic
`
`dilation and 1 required surgical intervention) [see Warnings and Precautions (5.2)].
`
`
`In the pediatric clinical studies (up to 69 weeks of exposure), there was 1 serious adverse reaction of
`
`
`obstruction. Teduglutide was temporarily withheld, obstruction resolved without additional intervention, and
`there was no recurrence once teduglutide was restarted.
`
`
`Reference ID: 4738888
`
`6
`
`
`

`

`
`
`6.2
`
`Gallbladder, Biliary and Pancreatic Disease
`For gallbladder and biliary disease in the adult placebo-controlled studies, 3 patients with SBS were
`
`
`
`diagnosed with cholecystitis, all of whom had a prior history of gallbladder disease and were in the GATTEX
`
`
`0.05 mg/kg/day dose group. No cases were reported in the placebo group. One of these 3 cases had
`
`
`
`gallbladder perforation and underwent cholecystectomy the next day. The remaining 2 cases underwent
`
`elective cholecystectomy at a later date. In the adult extension studies, 4 patients had an episode of acute
`
`cholecystitis; 3 patients had new-onset cholelithiasis; and 1 patient experienced cholestasis secondary to
`
`
`
`
`an obstructed biliary stent. For pancreatic disease in the adult placebo-controlled studies, 1 patient
`
`
`(GATTEX 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed after 4 months of GATTEX.
`
`
`
`
`In the adult extension studies, 1 patient was diagnosed with chronic pancreatitis; and 1 patient was
`diagnosed with acute pancreatitis) [see Warnings and Precautions (5.3)].
`
`Fluid Overload
`
`
`In the adult placebo-controlled studies, peripheral edema was reported in 2/59 (3%) of patients on
`
`
`placebo and 8/77 (10%) patients on GATTEX; fluid overload was reported in 1/77 (1%) patient in the
`
`
`GATTEX group; no cases of fluid overload were seen in the placebo arm. There were 2 cases of congestive
`
`
`heart failure (CHF, 3%) in the GATTEX arm, 1 of which was reported as a serious adverse event and the
`
`
`
`
`other as non-serious. The serious case had onset at 6 months and was possibly associated with previously
`undiagnosed hypothyroidism and/or cardiac dysfunction [see Warnings and Precautions (5.4)].
`Other Less Common Adverse Reactions
`Reported in less than 5% of patients treated with GATTEX:
`Gastrointestinal disorders: Colonic stenosis, Pancreatic duct stenosis, Small intestinal stenosis
`
`
`Respiratory, thoracic and mediastinal disorders: Dyspnea
`
`Immunogenicity
`
`
`
`As with all peptides, there is potential for immunogenicity. The detection of antibody formation is
`
`
`
`highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of
`antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors
`
`including assay methodology, sample handling, timing of sample collection, concomitant medications, and
`
`underlying disease. For these reasons, comparison of the incidence of antibodies to teduglutide in the
`
`
`
`studies described below with the incidence of antibodies in other studies or to other products may be
`
`misleading.
`Adults
`
`
`
`
`
`
`Based on integrated data from two studies in adults with SBS (a 6-month randomized
`
`placebo-controlled study, followed by a 24-month open-label study), the development of anti-teduglutide
`
`
`antibodies in patients who received subcutaneous administration of 0.05 mg/kg GATTEX once daily was
`
`
`3% (2/60) at Month 3, 17% (13/77) at Month 6, 24% (16/67) at Month 12, 33% (11/33) at Month 24, and
`48% (14/29) at Month 30. Anti-teduglutide antibodies were cross-reactive to native glucagon-like peptide
`
`
`(GLP-2) in 5 of the 6 patients (83%) who had anti-teduglutide antibodies and were tested for cross-reactivity.
`
`
`In the same two studies, a total of 36 patients were tested for neutralizing antibodies: one patient developed
`
`
`borderline positive neutralizing antibody responses at month 24 of the extension study. The antibody
`
`
`formation has not been associated with clinically relevant safety findings, reduced efficacy or changed
`pharmacokinetics of GATTEX.
`Pediatric Patients 1 Year to Less than 17 Years of Age
`
`
`In pediatric patients who received subcutaneous administration of 0.05 mg/kg GATTEX once daily
`for 24 weeks, the rate of anti-teduglutide antibody formation at Month 6 was 19% (5/26) and was similar to
`
`
`
`
`the rate of antibody formation in adult patients (17%). Of the 5 pediatric patients who had developed
`
`
`
`antibodies to teduglutide at Month 6, 2 patients had neutralizing antibodies. However, with the longer
`duration of treatment, the rate of anti-teduglutide formation at Month 12 was higher in pediatric patients with
`
`54% (14/26), compared to that of adults (24%). Of the 14 pediatric patients who had developed antibodies
`
`to teduglutide at Month 12, 1 patient had neutralizing antibodies.
`
`
`
`Among the small number of pediatric patients who developed anti-teduglutide antibodies, no
`
`association with adverse events or lack of efficacy was observed.
`
`Reference ID: 4738888
`
`7
`
`
`

`

`
`
`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. Altered mental status has been observed in patients taking GATTEX and
`
`
`
`benzodiazepines in the adult clinical studies [see Warnings and Precautions (5.5)].
`
`
`Monitor patients on concomitant oral drugs requiring titration or with a narrow therapeutic index for
`
`adverse reactions related to the concomitant drug while on GATTEX. The concomitant drug may require a
`
`reduction in dosage.
`
`
`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
`
`and fetal outcomes (see Clinical Considerations). In animal reproduction studies, no effects on embryo-fetal
`
`
`development were observed with the subcutaneous administration of teduglutide to pregnant rats and
`
`
`rabbits during organogenesis at exposures up to 686 and 657 times, respectively, the clinical exposure at
`
`the recommended human dose (based on AUC) (see Data).
`
`
`
`The estimated background risk of major birth defects and miscarriage for the indicated population is
`
`
`unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the
`
`
`
`U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically
`recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
`Clinical Considerations
`Disease-associated maternal and/or embryo/fetal risk
`
`Pregnant women with short bowel syndrome are at risk for malnutrition. Severe malnutrition in
`
`pregnant women is associated with preterm delivery, low birth weight, intrauterine growth restriction,
`congenital malformations and perinatal mortality.
`
`Data
`Animal Data
`
`
`
`
`
`Reproduction studies have been performed in pregnant rats at subcutaneous doses of teduglutide
`
`up to 25 mg/kg twice daily (50 mg/kg/day) (about 686 times the clinical exposure (AUC) at the
`
`
`
`recommended daily human dose of 0.05 mg/kg) and in pregnant rabbits at subcutaneous doses up to
`
`
`
`
`
`25 mg/kg twice daily (50 mg/kg/day) (about 657 times the clinical exposure (AUC) at the recommended
`
`
`
`
`daily human dose of 0.05 mg/kg) during the period of organogenesis. These studies did not reveal any
`
`
`
`
`evidence of impaired fertility or harm to the fetus due to teduglutide. In a pre- and postnatal development
`
`
`
`study in rats (gestation day 7 to lactation day 20), teduglutide did not show any significant adverse effects
`
`
`
`
`on pre- and postnatal development at doses up to 25 mg/kg twice daily (50 mg/kg/day) (about 343 times
`
`the clinical exposure (AUC) at the recommended daily human dose of 0.05 mg/kg).
`
`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.
`
`Reference ID: 4738888
`
`8
`
`
`

`

`
`
`Data
`
`
`
`In a milk excretion study in the rat, a single subcutaneous dose of 25 mg/kg of teduglutide (81 times
`
`the recommended daily human dose of 0.05 mg/kg based on body surface area) was administered to
`
`
`lactating female rats at Day 12 postpartum. The maximum concentration of teduglutide in the milk
`corresponded to 0.9% and 2.9% of the plasma concentration at 1.5 and 4 hours after dosing, respectively.
`8.