CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 203441/S-002
`
`GATTEX
`
`
`Trade Name:
`
`Teduglutide [rDNA origin]
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`NPS Pharmaceuticals, Inc.
`
`June 26, 2014
`
` 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.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 203441/S-002
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`X
`X
`
`
`X
`X
`
`
`X
`X
`
`X
`X
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`APPLICA TION NUMBER:
`NDA 203441/S-002
`NDA 203441/S-002
`
`
`
`
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 203441/S-002
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
` NPS Pharmaceuticals, Inc.
`
`
`
` Attention: Diane C. Fiorenza, RAC
`
` Senior Director, Regulatory Affairs
`
`550 Hills Drive 3rd Floor
`
`
`
`
`Bedminster, New Jersey 07921
`
`
`
`
`Dear Ms. Fiorenza:
`
`
`
`
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received August 28,
`
`
`
`
`
`
`2013, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`
`Gattex (teduglutide [rDNA origin]) for subcutaneous injection, 5 mg.
`
`
`We acknowledge receipt of your amendments dated October 28, 2013, November 20, 2013,
`January 14, 2014, February 10, 2014, February 25, 2014, March 12, 2014, May 6, 2014, May 21,
`
`2014, May 28, 2014, June 5, 2014, June 11, 2014, June 19, 2014, and June 25, 2014.
`
`
`
`
`This Prior Approval supplemental new drug application provides for the following changes to
`
`the Package Insert:
`
`
`
`
`
`
`• Section 5 WARNINGS AND PRECAUTIONS- Assorted minor editorial changes
`
`
`
`
`• Section 6 ADVERSE REACTIONS- Revision to incorporate results from the complete
`
`
`study report
`
`
`• Section 8 USE IN SPECIFIC POPULATIONS- Revision of 8.5 to reflect additional
`
`
`
`
`patient exposures
`
`
`
`
`• Section 11 DESCRIPTION- Assorted minor editorial changes
`
`
`• Section 13 NONCLINICAL TOXICOLOGY - Revision to incorporate final results of 2­
`
`
`
`
`year mouse carcinogenicity study
`
`• Section 14 CLINICAL STUDIES- Revisions to incorporate results from the complete
`
`
`
`
`study report
`
`
`• Section 17 PATIENT COUNSELING INFORMATION- Minor editorial change
`
`
`
`
`
`
`This supplemental new drug application also provides for proposed modifications to the
`
`
`
`approved risk evaluation and mitigation strategy (REMS).
`
`
`APPROVAL & LABELING
`
`
`
`
`We have completed our review of this supplemental application, as amended. It is approved,
`
`
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`
`Reference ID: 3532895
`
`

`

`
`
`
`
` NDA 203441/S-002
`
` Page 2
`
`
`
` text.
`
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`
`
`
`
`
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`
`
`
`automated drug registration and listing system (eLIST), as described at
`
`
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, Medication
`
`
`Guide, text for the Instructions for Use), with the addition of any labeling changes in pending
`
`
`
`“Changes Being Effected” (CBE) supplements, as well as annual reportable changes not
`
`
`
`included in the enclosed labeling.
`
`
`
`
`
` Information on submitting SPL files using eList may be found in the guidance for industry titled
` “SPL Standard for Content of Labeling Technical Qs and As at
`
`
`
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`
`
`
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`
`
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`
`
`
`
`
`changes approved in this supplemental application, as well as annual reportable changes and
`
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`
`
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`
`should provide appropriate annotations, including supplement number(s) and annual report
`
`
`
`
`
`
`
`date(s).
`
`
`We request that the labeling approved today be available on your website within 10 days of
`
`
`receipt of this letter.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`
`
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`
`
`
`administration are required to contain an assessment of the safety and effectiveness of the
`
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`
`
`deferred, or inapplicable.
`
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`
`
`
`
`
`from this requirement.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`
`
`The REMS for Gattex was originally approved on December 21, 2012. The REMS consists of a
`
`
`
`
`
`Reference ID: 3532895
`
`

`

`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
` NDA 203441/S-002
`
` Page 3
`
`
` communication plan, elements to assure safe use, and a timetable for submission of assessments
`
`
`
`
` of the REMS. Your proposed modifications to the REMS consist of:
` revisions to the Dear Healthcare Professional and Dear Professional Society Letters to
`
`
`
`
`•
`
`
`
` reflect the updated title of the patient and caregiver counseling guide,
` revisions to the Prescriber Education Slide Deck to reflect information from the
`
`
` completion of three major Gattex clinical trials, and
`
`
`
`
`
` revisions to the Patient and Caregiver Counseling Guide to focus on the Gattex REMS
`
` key safety messages, and to provide for improved readability, including renaming the
`
`
`
` Patient and Caregiver Counseling Guide to What You Need to Know About Gattex
`
`
`
` Treatment: A Patient and Caregiver Counseling Guide.
`
`
`
`
`
`
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
`
`
`
`
`application with elements to assure safe use from using any element to block or delay approval
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`
` result in enforcement action.
`
`
`
`
`
`Your proposed modified REMS, submitted on June 19, 2014, and appended to this letter, is
`
`approved.
`
`
`The timetable for submission of assessments of the REMS will remain the same as that approved
`
`on December 21, 2012.
`
`
`
`
`
`There are no changes to the REMS assessment plan described in our December 21, 2012 letter.
`
`
`
`In addition to the assessments submitted according to the timetable included in the approved
`
`REMS, you must submit a REMS assessment when you submit a supplemental application for a
`
`
`new indication for use as described in section 505-1(g)(2)(A) of the FDCA.
`
`
`
`
`If the assessment instruments and methodology for your REMS assessments are not included in
`
`
`the REMS supporting document, or if you propose changes to the submitted assessment
`
`
`instruments or methodology, you should update the REMS supporting document to include
`
`
`
`specific assessment instrument and methodology information at least 90 days before the
`
`
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`
`new document that references previous REMS supporting document submission(s) for
`
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`
`
`
`submission containing the assessment instruments and methodology with the following wording
`
`in bold capital letters at the top of the first page of the submission:
`
`
`
`
`
`NDA 203441 REMS CORRESPONDENCE
`
`
`(insert concise description of content in bold capital letters, e.g.,
`
`
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`
`
`METHODOLOGY)
`
`
`
`
`Reference ID: 3532895
`
`

`

`
`
` NDA 203441/S-002
`
` Page 4
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
` Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`
` contact us to discuss what will be required in the authorized generic drug REMS submission.
`
`
`
`
`
`Prominently identify the submission containing the REMS assessments or proposed
`
`
`
`
`modifications of the REMS with the following wording in bold capital letters at the top of the
`
`
`first page of the submission as appropriate:
`
`
`
`
`
`
`
`NDA 2034412 REMS ASSESSMENT
`
`
`
`NEW SUPPLEMENT FOR NDA 2034412
`
`
`PROPOSED REMS MODIFICATION
`
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`
`FOR NDA 2034412
`
`REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`
`
`
`
`
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`
`
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion (OPDP)
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`
`
`
`
`FDA 2253 is available at
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`
`
`Information and Instructions for completing the form can be found at
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`
`
`
`more information about submission of promotional materials to the Office of Prescription Drug
`
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`REPORTING REQUIREMENTS
`
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`(21 CFR 314.80 and 314.81).
`
`Reference ID: 3532895
`
`

`

` NDA 203441/S-002
`
` Page 5
`
`
`
` We request that you submit all cases of fluid overload and increased absorption of oral
`
`
`
` concomitant drugs with a serious outcome as 15-day “Alert Reports” to the FDA.
`
`
`
`
`
`If you have any questions, call Jennifer Sarchet, Regulatory Project Manager, at 240-402-4275.
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Joyce A. Korvick, MD., MPH
`
`
`Deputy Director for Safety
`
`Division of Gastroenterology and Inborn Errors
`
`Products
`
`
`Office of Drug Evaluation III
`
`Center for Drug Evaluation and Research
`
`
`
`
`
`ENCLOSURE(S):
`
`
`Content of Labeling
`
`REMS
`
`
`
`Reference ID: 3532895
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOYCE A KORVICK
`06/26/2014
`
`Reference ID: 3532895
`
`

`

` CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`APPLICA TION NUMBER:
`NDA 203441/S-002
`NDA 203441/S-002
`
`
`
`
`
`LABELING
`LABELING
`
`

`

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

`

`
` FULL PRESCRIBING INFORMATION
`
`1
`
`
`
`
`
`INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`
`
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` GATTEX® (teduglutide [rDNA origin]) for injection is indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on
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` parenteral support. [see Clinical Pharmacology (12.2)]
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`DOSAGE AND ADMINISTRATION
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`2.1 Dosing Information
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`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
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`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.
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`2.2 Monitoring to Assess Safety
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`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
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`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
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`no less frequently than every 5 years. If a polyp is found, adherence to current polyp follow-up guidelines is recommended.
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`Patients should undergo initial laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) within 6 months prior to starting treatment with
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`GATTEX. Subsequent laboratory assessments are recommended every 6 months. If clinically meaningful elevation is seen, further diagnostic workup is
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`recommended as clinically indicated (ie, imaging of the biliary tract, liver, or pancreas). [see Warnings and Precautions (5.1) (5.5)]
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`2.3 Dosage Modifications in Renal Impairment
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`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
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`Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]
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`2.4 Discontinuation of Treatment
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`Discontinuation of treatment with GATTEX may result in fluid and electrolyte imbalance. Therefore, patients’ fluid and electrolyte status should be carefully
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`monitored.
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`2.5
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`DOSAGE FORMS AND STRENGTHS
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`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
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`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.
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`CONTRAINDICATIONS
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`None.
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Acceleration of Neoplastic Growth
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`Based on the pharmacologic activity and findings in animals, GATTEX has the potential to cause hyperplastic changes including neoplasia. In patients at
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`increased risk for malignancy, the clinical decision to use GATTEX should be considered only if the benefits outweigh the risks. In patients with active
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`gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), GATTEX therapy should be discontinued. In patients with active non-gastrointestinal
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`malignancy, the clinical decision to continue GATTEX should be made based on risk-benefit considerations. [see Clinical Pharmacology (12.1) and Nonclinical
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`Toxicology (13.1)]
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`Preparation for Administration
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`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
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`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
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`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
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`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
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`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
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`Supplied/Storage and Handling (16.2)]
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`Colorectal Polyps
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`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
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`starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies
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`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)]
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`Small Bowel Neoplasia
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`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
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`found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued. [see Nonclinical Toxicology (13.1)]
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`Intestinal Obstruction
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`Intestinal obstruction has been reported in clinical trials. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued
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`while the patient is clinically managed. GATTEX may be restarted when the obstructive presentation resolves, if clinically indicated. [see Adverse Reactions
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`(6.1)]
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`5.2
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`Reference ID: 3532895
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` 5.3 Biliary and Pancreatic Disease
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`Gallbladder and Biliary Tract Disease
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`Cholecystitis, cholangitis, and cholelithiasis, have been reported in clinical studies. For identification of the onset or worsening of gallbladder/biliary disease,
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`patients should undergo laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting GATTEX, and at least every 6 months
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`while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or
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`biliary tract is recommended; and the need for continued GATTEX treatment should be reassessed. [see Adverse Reactions (6.1)]
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`Pancreatic Disease
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`Pancreatitis has been reported in clinical studies. For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of
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`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
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`meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended; and the need for continued GATTEX treatment should be
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`reassessed. [see Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)]
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`Fluid Overload
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`Fluid overload and congestive heart failure have been observed in clinical trials, which were felt to be related to enhanced fluid absorption associated with
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`GATTEX. If fluid overload occurs, parenteral support should be adjusted and GATTEX treatment should be reassessed, especially in patients with underlying
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`cardiovascular disease. If significant cardiac deterioration develops while on GATTEX, the need for continued GATTEX treatment should be reassessed. [see
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`Adverse Reactions (6.1)]
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`Increased Absorption of Concomitant Oral Medication
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`Altered mental status in association with GATTEX has been observed in patients on benzodiazepines in clinical trials. Patients on concomitant oral drugs (e.g.,
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`benzodiazepines, phenothiazines) requiring titration or with a narrow therapeutic index may require dose adjustment while on GATTEX. [see Adverse Reactions
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`(6.2)]
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`ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical
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`trials and may not reflect the rates observed in clinical practice.
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`5.4
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`5.5
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`6
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`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
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`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
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`0.10 mg/kg/day).
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`The most commonly reported (≥ 10%) adverse reactions in subjects treated with GATTEX across all clinical studies (N = 595) were: abdominal pain (31 3%);
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`injection site reactions (21.8%); nausea (18.8%); headaches (16.3%); abdominal distension (14.8%); upper respiratory tract infection (11.9%).
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`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
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`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.
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`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)
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`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
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`underlying disease and/or parenteral nutrition.
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` Table 1: Adverse reactions in ≥5% of GATTEX-treated SBS subjects and
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` more frequent than placebo: Studies 1 and 3
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` Placebo
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` n (%)
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` Adverse Reaction
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` 16 ( 27.1)
` 8 ( 13.6)
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` 12 ( 20.3)
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` 1 ( 1.7)
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` 6 ( 10.2)
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` 4 ( 6.8)
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` 4 ( 6.8)
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` 3 ( 5.1)
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` 2 ( 3.4)
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` 1 ( 1.7)
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` Abdominal Pain
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` Upper Respiratory Tract Infection
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` Nausea
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` Abdominal Distension
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` Vomiting
` Fluid Overload
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` Flatulence
` Hypersensitivity
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` Appetite Disorders
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` Sleep Disturbances
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` Cough
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` Skin Hemorrhage
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` Subjects with Stoma
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` Gastrointestinal Stoma Complication
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` 3 (13.6)a
` 13 (41.9)a
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` aPercentage based on 53 subjects with a stoma (n = 22 placebo; n = 31 GATTEX
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`In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and GATTEX study groups experienced an injection site reaction.
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` GATTEX
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` n (%)
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` 9 ( 11.7)
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` 7 ( 9.1)
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`Reference ID: 3532895
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`Adverse Reactions of Special Interest
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`6.2
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`6.3
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`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
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`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
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`was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to GATTEX. Two subjects had extensive smoking histories,
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`and were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of GATTEX exposure, respectively.
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`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-
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`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
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`(inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 11 polyp cases occurred in the extension studies − 2
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`colorectal villous adenomas (onset at 6 and 7 months i