`
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203441Orig1s000
`LABELING
`
`
`
`
`
`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)
`
`•
`
`•
`
`
`---------------------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`can then be withdrawn from the vial.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)
`50% dosage reduction recommended in patients with moderate to severe
`renal impairment (2.3) (8.6) (12.3)
`
`•
`
`•
`
`•
`
`discontinue GATTEX. The clinical decision to continue GATTEX in
`patients with non-gastrointestinal malignancy should be made based on
`risk and benefit considerations. (5.1)
`Intestinal obstruction. In patients who develop obstruction, GATTEX
`should be temporarily discontinued pending further clinical evaluation
`and management. (5.2)
`Biliary and pancreatic disease. Patients should undergo laboratory
`assessment (bilirubin, alkaline phosphatase, lipase, amylase) before
`starting GATTEX. Subsequent laboratory tests should be done every 6
`months. If clinically meaningful changes are seen, further evaluation is
`recommended including imaging, and continued treatment with
`GATTEX should be reassessed. (5.3)
`Fluid overload. There is a potential for fluid overload while on
`GATTEX. If fluid overload occurs, especially in patients with
`cardiovascular disease, parenteral support should be appropriately
`adjusted, and GATTEX treatment reassessed. (5.4)
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`The most common adverse reactions (≥ 10%) across all studies with
`GATTEX are abdominal pain, injection site reactions, nausea,
`headaches, abdominal distension, upper respiratory tract infection. In
`addition, vomiting and fluid overload were reported in the SBS studies
`(1 and 3) at rates ≥ 10%. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact NPS
`Pharmaceuticals at 1-855-5GATTEX (1-855-542-8839) or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`•
`GATTEX has the potential to increase absorption of concomitant oral
`medications. Careful monitoring and possible dose adjustment of oral
`medications that require titration or have a narrow therapeutic index is
`recommended. (5.5) (7.1)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`•
`The safety and efficacy of GATTEX in pediatric patients have not
`been established. (8.4)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`-------------------------------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
`_______________________________________________________________________________________________________________________________________
`8.7 Hepatic Impairment
`FULL PRESCRIBING INFORMATION: CONTENTS*
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Study 1 (Placebo-controlled) and Study 2 (Open-label extension
`of Study 1)
`14.2 Study 3 (Placebo-controlled) and Study 4 (Blinded uncontrolled
`extension of Study 3)
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage and Handling
`17 PATIENT COUNSELING INFORMATION
`17.1 Acceleration of Neoplastic Growth
`17.2
`Intestinal Obstruction
`17.3 Gallbladder and Bile Duct Diseases
`17.4 Pancreatic Diseases
`17.5 Cardiovascular Disease
`17.6 Risks Resulting from Increased Absorption of Concomitant Oral
`Medication
`Instructions
`
`
`
`
`
`
`
`
`
`Revised: 12/2012
`
`17.7
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
` 1
`
`INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Dosing Information
`2.2 Monitoring to Assess Safety
`2.3 Dosage Modifications in Renal Impairment
`2.4 Discontinuation of Treatment
`2.5 Preparation for Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Acceleration of Neoplastic Growth
`5.2
`Intestinal Obstruction
`5.3 Biliary and Pancreatic Disease
`5.4 Fluid Overload
`5.5
`Increased Absorption of Concomitant Oral Medication
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Immunogenicity
`7 DRUG INTERACTIONS
`7.1 Potential for Increased Absorption of Oral Medications
`7.2 Concomitant Drug Therapy
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`
`Reference ID: 3235717
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
` 1
`
`
`
`
`
`INDICATIONS AND USAGE
`
`GATTEX® (teduglutide [rDNA origin]) for injection is indicated for the treatment of adult patients with Short Bowel Syndrome (SBS) who are dependent on
`parenteral support. [see Clinical Pharmacology 12.2].
`
`DOSAGE AND ADMINISTRATION
`
` 2
`
`
`
`
`2.1 Dosing Information
`The recommended daily dose of GATTEX is 0.05 mg/kg body weight administered by subcutaneous injection once daily. Alternation of sites for subcutaneous
`injection is recommended, and can include the thighs, arms, and the quadrants of the abdomen. GATTEX should not be administered intravenously or
`intramuscularly. If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses on the same day.
`
`2.2 Monitoring to Assess Safety
`A colonoscopy (or alternate imaging) of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A
`follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. If no polyp is found, subsequent colonoscopies should be done
`no less frequently than every 5 years. If a polyp is found, adherence to current polyp follow-up guidelines is recommended.
`
`Patients should undergo initial laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) within 6 months prior to starting treatment with
`GATTEX. Subsequent laboratory assessments are recommended every 6 months. If clinically meaningful elevation is seen, further diagnostic workup is
`recommended as clinically indicated (ie, imaging of the biliary tract, liver, or pancreas). [see Warnings and Precautions (5.1) (5.5)]
`
`2.3 Dosage Modifications in Renal Impairment
`Reduce the dose by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min), and end-stage renal disease [see Use
`in Specific Populations (8.6) and Clinical Pharmacology (12.3)]
`
`2.4 Discontinuation of Treatment
`Discontinuation of treatment with GATTEX may result in fluid and electrolyte imbalance. Therefore, patients’ fluid and electrolyte status should be carefully
`monitored.
`
`
`
`2.5
`
` 3
`
`
`
`4
`
`
`
`
`
`
`
`5.2
`
`Preparation for Administration
`Reconstitute each vial of GATTEX by slowly injecting the 0.5 mL of preservative-free Sterile Water for Injection provided in the prefilled syringe. Allow the
`vial containing GATTEX and water to stand for approximately 30 seconds and then gently roll the vial between your palms for about 15 seconds. Do not shake
`the vial. Allow the mixed contents to stand for about 2 minutes. Inspect the vial for any undissolved powder. If undissolved powder is observed, gently roll the
`vial again until all material is dissolved. Do not shake the vial. If the product remains undissolved after the second attempt, do not use. GATTEX does not
`contain any preservatives and is for single-use only. Discard any unused portion. The product should be used within 3 hours after reconstitution. [see How
`Supplied/Storage and Handling (16.2)]
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`For Injection: Each single-use glass vial contains a dose of 5 mg teduglutide as a lyophilized powder that upon reconstitution with the 0.5 mL Sterile Water for
`Injection provided in the prefilled syringe delivers a maximum of 0.38 mL of the reconstituted sterile solution which contains 3.8 mg of teduglutide.
`
`CONTRAINDICATIONS
`None.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Acceleration of Neoplastic Growth
`Based on the pharmacologic activity and findings in animals, GATTEX has the potential to cause hyperplastic changes including neoplasia. In patients at
`increased risk for malignancy, the clinical decision to use GATTEX should be considered only if the benefits outweigh the risks. In patients with active
`gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), GATTEX therapy should be discontinued. In patients with active non-gastrointestinal
`malignancy, the clinical decision to continue GATTEX should be made based on risk-benefit considerations. [see Clinical Pharmacology (12.1) and Nonclinical
`Toxicology (13.1)]
`
`Colorectal Polyps
`Colorectal polyps were identified during the clinical trials. Colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to
`starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies
`should be done every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of diagnosis
`of colorectal cancer, GATTEX therapy should be discontinued. [see Adverse Reactions (6.1)]
`
`Small Bowel Neoplasia
`Based on benign tumor findings in the rat carcinogenicity study, patients should be monitored clinically for small bowel neoplasia. If a benign neoplasm is
`found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued. [see Nonclinical Toxicology (13.1)]
`
`Intestinal Obstruction
`Intestinal obstruction has been reported in clinical trials. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued
`while the patient is clinically managed. GATTEX may be restarted when the obstructive presentation resolves, if clinically indicated. [see Adverse Reactions
`(6.1)]
`
`
`5.3 Biliary and Pancreatic Disease
`
`
`
`
`Reference ID: 3235717
`
`
`
`
`
`
`
`
`
`
`
`5.4
`
`
`
`5.5
`
`
`
` 6
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Gallbladder and Biliary Tract Disease
`Cholecystitis, cholangitis, and cholelithiasis, have been reported in clinical studies. For identification of the onset or worsening of gallbladder/biliary disease,
`patients should undergo laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting GATTEX, and at least every 6 months
`while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or
`biliary tract is recommended; and the need for continued GATTEX treatment should be reassessed. [see Adverse Reactions (6.1)]
`
`Pancreatic Disease
`Pancreatitis has been reported in clinical studies. For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of
`lipase and amylase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically
`meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended; and the need for continued GATTEX treatment should be
`reassessed. [see Adverse Reactions (6.1) and Nonclinical Toxicology (13.1)]
`
`Fluid Overload
`Fluid overload and congestive heart failure have been observed in clinical trials, which were felt to be related to enhanced fluid absorption associated with
`GATTEX. If fluid overload occurs, parenteral support should be adjusted and GATTEX treatment should be reassessed, especially in patients with underlying
`cardiovascular disease. If significant cardiac deterioration develops while on GATTEX, the need for continued GATTEX treatment should be reassessed. [see
`Adverse Reactions (6.1) ]
`
`Increased Absorption of Concomitant Oral Medication
`Altered mental status in association with GATTEX has been observed in patients on benzodiazepines in clinical trials. Patients on concomitant oral drugs (e.g.,
`benzodiazepines, phenothiazines) requiring titration or with a narrow therapeutic index may require dose adjustment while on GATTEX. [see Adverse Reactions
`(6.2)]
`
` ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical
`trials and may not reflect the rates observed in clinical practice.
`
`Across all clinical studies, 566 subjects were exposed to at least one dose of GATTEX (190 patient-years of exposure; mean duration of exposure was 17 weeks).
`Of the 566 subjects, 173 subjects were treated in Phase 3 SBS studies (134/173 [77%] at the dose of 0.05 mg/kg/day and 39/173 [23%] at the dose of
`0.10 mg/kg/day).
`
`The most commonly reported (≥ 10%) adverse reactions in patients treated with GATTEX across all clinical studies (n = 566) were: abdominal pain (30.0%);
`injection site reactions (22.4%); nausea (18.2%); headaches (15.9%); abdominal distension (13.8%); upper respiratory tract infection (11.8%).
`
`The rates of adverse reactions in subjects 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. The majority of these reactions were mild or moderate. Of subjects receiving GATTEX at the recommended dose of 0.05 mg/kg/day, 88.3% (N=68/77)
`experienced an adverse reaction, as compared to 83.1% (49/59) for placebo. Many of these adverse reactions have been reported in association with the
`underlying disease and/or parenteral nutrition.
`
`Table 1: Adverse reactions in ≥5% of GATTEX-treated SBS subjects and
`more frequent than placebo: Studies 1 and 3
`Placebo
`(N=59)
`n (%)
`
`Adverse Reaction
`
`GATTEX
`0.05mg/kg/day
`(N=77)
`n (%)
`29 ( 37.7)
`20 ( 26.0)
`19 ( 24.7)
`15 ( 19.5)
`9 ( 11.7)
`9 ( 11.7)
`7 ( 9.1)
`6 ( 7.8)
`5 ( 6.5)
`4 ( 5.2)
`4 ( 5.2)
`4 ( 5.2)
`
`Abdominal Pain
`Upper Respiratory Tract Infection
`Nausea
`Abdominal Distension
`Vomiting
`Fluid Overload
`Flatulence
`Hypersensitivity
`Appetite Disorders
`Sleep Disturbances
`Cough
`Skin Hemorrhage
`Subjects with Stoma
`Gastrointestinal Stoma Complication
`13 (41.9)a
`3 (13.6)a
`aPercentage based on 53 subjects with a stoma (N = 22 placebo; N = 31
`GATTEX 0.05 mg/kg/day)
`In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and GATTEX study groups experienced an injection site reaction.
`
`16 ( 27.1)
`8 ( 13.6)
`12 ( 20.3)
`1 ( 1.7)
`6 ( 10.2)
`4 ( 6.8)
`4 ( 6.8)
`3 ( 5.1)
`2 ( 3.4)
`0
`0
`1 ( 1.7)
`
`Adverse Reactions of Special Interest
`
`Malignancy. Three subjects were diagnosed with malignancy in the clinical studies, all of whom were male and had received GATTEX 0.05 mg/kg/day in
`Study 2. One subject had a history of abdominal radiation for Hodgkin’s disease two decades prior to receiving GATTEX and prior liver lesion on CT scan, and
`was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to GATTEX. Two subjects had extensive smoking histories,
`and were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of GATTEX exposure, respectively.
`
`
`
`Reference ID: 3235717
`
`
`
`
`
`6.2
`
`
`Colorectal Polyps. In the clinical studies, 6 subjects were diagnosed with polyps of the G.I. tract after initiation of study treatment. In the SBS placebo-
`controlled studies, 1/59 (1.7%) of subjects on placebo and 1/109 (0.9%) of subjects on GATTEX 0.05 mg/kg/day were diagnosed with intestinal polyps
`(inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 4 polyp cases occurred in the extension studies − two
`colorectal villous adenomas (onset at 6 and 7 months in GATTEX 0.10 and 0.05 mg/kg/day dose groups, respectively), one hyperplastic polyp (onset 6 months
`in GATTEX 0.10 mg/kg/day dose group), and one small duodenal polyp (onset at 3 months in GATTEX 0.05 mg/kg/day dose group).
`
`Gastrointestinal Obstruction. Overall, 12 subjects experienced one or more episodes of intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6
`in the extension studies. The 6 subjects in the placebo-controlled trials were all on GATTEX: 3/77 (3.9%) on GATTEX 0.05 mg/kg/day and 3/32 (9.4%) on
`GATTEX 0.10 mg/kg/day. No cases of intestinal obstruction occurred in the placebo group. Onsets ranged from 1 day to 6 months. In the extension studies, 6
`additional subjects (all on GATTEX 0.05 mg/kg/day) were diagnosed with intestinal obstruction/stenosis with onsets ranging from 6 days to 7 months. Two of
`the 6 subjects from the placebo-controlled trials experienced recurrence of obstruction in the extension studies. Of all 8 subjects with an episode of intestinal
`obstruction/stenosis in these extension studies, 1 subject required endoscopic dilation and none required surgical intervention.
`
`Gallbladder, Biliary and Pancreatic Disease. For gallbladder and biliary disease in the placebo-controlled studies, 3 subjects were diagnosed with cholecystitis,
`all of whom had a prior history of gallbladder disease and were in the GATTEX 0.05 mg/kg/day dose group. No cases were reported in the placebo group. One
`of these 3 cases had gallbladder perforation and underwent cholecystectomy the next day. The remaining 2 cases underwent elective cholecystectomy at a later
`date. In the extension studies, 3 subjects had an episode of acute cholecystitis; 2 subjects had new-onset cholelithiasis; and 1 subject experienced cholestasis
`secondary to an obstructed biliary stent. For pancreatic disease in the placebo-controlled studies, 1 subject (GATTEX 0.05 mg/kg/day dose group) had a
`pancreatic pseudocyst diagnosed after 4 months of GATTEX. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and 1 subject was
`diagnosed with acute pancreatitis.
`
`Fluid Overload. In the placebo-controlled trials, fluid overload was reported in 4/59 (6.8%) of subjects on placebo and 9/77 (11.7%) subjects on GATTEX
`0.05 mg/kg/day. Of the 9 cases in the GATTEX group, there were 2 cases of congestive heart failure (CHF), 1 of whom was reported as a serious adverse event
`and the other as non-serious. The serious case had onset at 6 months, and was possibly associated with previously undiagnosed hypothyroidism and/or cardiac
`dysfunction.
`
`Concomitant Oral Medication. GATTEX can increase the absorption of concomitant oral medications such as benzodiazepines and psychotropic agents. In the
`placebo-controlled trials, an analysis of episodes of cognition and attention disturbances was performed for subjects on benzodiazepines. One of the subjects in
`the GATTEX 0.05 mg/kg/day group (on prazepam) experienced dramatic deterioration in mental status progressing to coma during her first week of GATTEX
`therapy. She was admitted to the ICU where her benzodiazepine level was >300 mcg/L. GATTEX and prazepam were discontinued, and coma resolved 5 days
`later.
`
`Immunogenicity
`
`Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of GATTEX may trigger the development of
`antibodies. In a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center, clinical trial (Study 1) in adults with SBS, the
`incidence of anti-GATTEX antibody was 0% (0/16) at Week 12 and 18% (6/34) at Week 24 in subjects who received subcutaneous administration of 0.05 mg/kg
`GATTEX once daily. The anti-GATTEX antibodies were cross-reactive to native glucagon-like peptide (GLP-2) in five of the six subjects (83%) who had anti-
`GATTEX antibodies. In the extension study (Study 2), the immunogenicity incidence rate increased over time to 27% (14/51) at 12 months and 38% (13/34) at
`18 months. Anti-GATTEX antibodies appear to have no impact on short term (up to 1.5 years) efficacy and safety although the long-term impact is unknown.
`
` A
`
` total of 40 subjects were tested for neutralizing antibodies − 20 of these subjects had no neutralizing antibodies, and the remaining 20 subjects had no
`detectable neutralizing antibodies although, the presence of teduglutide at low levels in these study samples could have resulted in false negatives (no
`neutralizing antibody detected although present).
`
`Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay
`methodology, sample handling, timing of sample collection, concomitant medication, and underlying diseases. For these reasons, comparison of the incidence of
`antibodies to GATTEX with the incidence of antibodies to other products may be misleading.
`
`
`7 DRUG INTERACTIONS
`
`7.1
`
`Potential for Increased Absorption of Oral Medications
`Based upon the pharmacodynamic effect of GATTEX, there is a potential for increased absorption of concomitant oral medications, which should be considered
`if these drugs require titration or have a narrow therapeutic index. [see Warnings and Precautions (5.5)]
`
`
`7.2 Concomitant Drug Therapy
`Clinical interaction studies were not performed. No inhibition or induction of the cytochrome P450 enzyme system has been observed based on in vitro studies
`although the relevance of in vitro studies to an in vivo setting is unknown.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`Pregnancy Category B
`Reproduction studies with teduglutide have been performed in pregnant rats at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily
`human dose of 0.05 mg/kg) and in rabbits at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg).
`These studies did not reveal any evidence of impaired fertility or harm to the fetus due to teduglutide. A pre- and postnatal development study in rats showed no
`evidence of any adverse effect on pre- and postnatal development at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human
`dose of 0.05 mg/kg). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of
`human response, teduglutide should be used during pregnancy only if clearly needed.
`
`
`8.3 Nursing Mothers
`It is unknown whether teduglutide is excreted in human milk. Teduglutide is excreted in the milk of lactating rats, and the highest concentration in the milk was
`2.9% of the plasma concentration following a single subcutaneous injection of 25 mg/kg. Because many drugs are excreted in human milk; because of the
`potential for serious adverse reactions to nursing infants from teduglutide and because of the potential for tumorigenicity shown for teduglutide in rats, a decision
`should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. [see Nonclinical
`Toxicology (13.1)]
`
`
`Reference ID: 3235717
`
`
`
`
`
`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 566 subjects treated with teduglutide, 43 subjects were 65 years or older, whereas
`6 subjects were 75 years of age or older. In the SBS studies, no overall differences in safety or efficacy were observed between these subjects and younger
`subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of
`some older individuals cannot be ruled out. [see Clinical Pharmacology (12.3)]
`
`
`8.6 Renal Impairment
`Reduce the dose of GATTEX by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min) and end-stage renal
`disease (ESRD) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]
`
`
`8.7 Hepatic Impairment
`GATTEX has not been formally studied in subjects with severe hepatic impairment. No dosage adjustment is necessary for patients with mild and moderate
`hepatic impairment based on a study conducted in Child-Pugh grade B subjects. [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]
`
`
`10 OVERDOSAGE
`The maximum dose of GATTEX studied during clinical development was 80 mg/day for 8 days. In the event of overdose, the patient should be carefully
`monitored by the medical professional.
`
`
`11 DESCRIPTION
`The active ingredient in GATTEX (teduglutide [rDNA origin]) for injection is teduglutide (rDNA origin), which is a 33 amino acid glucagon-like peptide-2 (GLP-
`2) analog manufactured using a strain of Escherichia coli modified by recombinant DNA technology. The chemical name of teduglutide is L-histidyl-L-glycyl-L-
`aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-
`leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-
`isoleucyl-L-threonyl-L-aspartic acid. The structural formula is:
`
`
`
`Figure 1: Structural formula of teduglutide
`
`Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear, colorless to light-straw–colored liquid.
`
`Each single-use vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. In addition to the active
`pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate
`monohydrate, 3.434 mg dibasic sodium phosphate heptahydrate as excipients. No preservatives are present.
`
`At the time of administration the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a prefilled syringe. A
`10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for
`subcutaneous injection upon reconstitution.
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine. GLP-2 is known to
`increase intestinal and portal blood flow, and inhibit gastric acid secretion. Teduglutide binds to the glucagon-like peptide-2 receptors located in intestinal
`subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors
`results in the local release of multiple mediators including insulin-like growth factor (IGF)-1, nitric oxide and keratinocyte growth factor (KGF).
`
`12.2 Pharmacodynamics
`The ability of GATTEX to improve intestinal absorption was studied in 17 adult subjects with Short Bowel Syndrome using daily doses of 0.03, 0.10,
`0.15 mg/kg (N=2-3 per dose group) in a 21-day, open-label, multi-center, dose-ranging study. All subcutaneous (abdomen) doses studied, except 0.03 mg/kg
`once daily, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750-1000 mL/day, and increased villus height and crypt depth of
`the intestinal mucosa.
`
`
` At a dose 5 times the maximum recommended dose, teduglutide did not prolong the QTc interval to any clinically relevant extent.
`
`12.3 Pharmacokinetics
`
`Absorption:
`In healthy subjects, GATTEX administered subcutaneously had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at
`3-5 hours after administration. Following a 0.05 mg/kg subcutaneous dose in SBS subjects, the median peak teduglutide concentration (Cmax) was 36 ng/mL and
`the median area under the curve (AUC0-inf) was 0.15 µg•hr/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations.
`
`Distribution:
`In healthy subjects, teduglutide has a volume of distribution (103 mL/kg) similar to blood volume.
`
`Metabolism:
`The metabolic pathway of teduglutide was not investigated in humans. However, teduglutide is expected to be degraded into small peptides and amino acids via
`catabolic pathways, similar to the catabolism of endogenous GLP-2.
`
`
`Reference ID: 3235717
`
`
`
`
`
`
`Elimination:
`In healthy subjects, teduglutide plasma clearance was approximately 123 mL/hr/kg which is similar to the GFR suggesting that teduglutide is primarily cleared
`by the kidney. Teduglutide has a mean terminal half-life (t1/2) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects.
`
`Dose Linearity:
`The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg GATTEX.
`
`Hepatic Impairment:
`Subjects with moderate hepatic impairment had lower teduglutide Cmax and AUC (10 ~15%) compared to healthy matched control subjects after a single
`subcutaneous dose of 20 mg GATTEX. Teduglutide PK was not assessed in subjects with severe hepatic impairment.
`
`Renal Impairment:
`In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-inf increased with the degree of renal
`impairment following a single subcutaneous administration of 10 mg teduglutide. Teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC0-inf) in
`ESRD subjects compared to healthy subjects.
`
`Geriatric Patients:
`No differences were observed between healthy subjects younger than 65 years and those older than 65 years. Experience in subjects 75 years and above is
`limited.
`
`Gender:
`No clinically relevant gender differences were observed.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily
`human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in the incidences of adenomas in the bile duct and jejunum of male
`rats.
`Teduglutide was negative in the Ames test, chromosomal aberration test in Chinese hamster ovary cells, and in vivo mouse micronucleus assay.
`Teduglutide at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) was found to have no adverse
`effect on fertility and reproductive performance of male and female rats.
`14 CLINICAL STUDIES
`14.1 Study 1