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

2.5 Discontinuation of Treatment

Discontinuation of treatment with GATTEX may result in fluid and electrolyte imbalance. Monitor fluid and electrolyte status in patients who discontinue GATTEX treatment [see Warnings and Precautions (5.4)].

2.6 Preparation Instructions

• Reconstitute each vial of GATTEX by slowly injecting the 0.5 mL of preservative-free Sterile Water for Injection provided in the prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution.
• Allow the vial containing GATTEX and water to stand for approximately 30 seconds and then gently roll the vial between the palms for about 15 seconds. Do not shake the vial.
• Allow the mixed contents to stand for about 2 minutes. Inspect the vial for any undissolved powder. If undissolved powder is observed, gently roll the vial again until all material is dissolved. Do not shake the vial.
• 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.

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.

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

5.4 Fluid Imbalance and Fluid Overload

5.5 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)].

6.1 Clinical Trials Experience

6.2 Immunogenicity

As with all peptides, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to teduglutide in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness in pediatric patients less than 1 year of age have not been established.

The safety and effectiveness of GATTEX have been established in pediatric patients 1 year to less than 17 years of age who are dependent on parenteral support for the treatment of SBS. Use of GATTEX in this population is supported by evidence from adequate and well-controlled studies in adults, with additional efficacy, safety, pharmacokinetic and pharmacodynamic data in pediatric patients 1 year to less than 17 years of age [see Dosage and Administration (2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. These data were derived from two studies of 24-week (Study 5) and 12-week (NCT01952080) duration in which 41 pediatric patients were treated with GATTEX in the following groups: 1 infant (1 year to less than 2 years), 37 children (2 years to less than 12 years) and 3 adolescents (12 years to less than 17 years).

In these 2 studies and the corresponding extension studies (Study 6 and NCT02949362), 29 pediatric patients were administered GATTEX prospectively for up to 94 weeks [see Clinical Studies (14.2)]. Adverse reactions in pediatric patients were similar to those seen in adults [see Adverse Reactions (6.1)].

8.5 Geriatric Use

Of the 134 patients with SBS that were treated with GATTEX at the recommended dosage of 0.05 mg/kg/day in the clinical studies, 19 patients were 65 years or older while 5 patients were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

In adult subjects with moderate to severe renal impairment or end-stage renal disease (ESRD) (creatinine clearance <60 mL/min), the exposure to teduglutide increased with the degree of renal impairment [see Clinical Pharmacology (12.3)]. Reduce the dosage of GATTEX by half in both pediatric and adult patients with eGFR less than 60 mL/min/1.73 m2 [see Dosage and Administration (2.3)].

8.7 Hepatic Impairment

GATTEX has not been studied in patients with severe hepatic impairment (Child-Pugh grade C). No dosage adjustment is recommended for patients with mild and moderate hepatic impairment (Child-Pugh grade A and B) [see Clinical Pharmacology (12.3)].

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

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic potential of GATTEX was assessed in 2-year subcutaneous carcinogenicity studies in rats and mice. In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10, and 35 mg/kg/day (about 15, 41, and 199 times the exposures [AUC] achieved at 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. In a 2-year carcinogenicity study in Crl:CD1(ICR) mice at subcutaneous doses of 1, 3.5, and 12.5 mg/kg/day (about 32, 66, and 244 times the exposures [AUC] achieved at the recommended daily human dose of 0.05 mg/kg, respectively), teduglutide caused a significant increase in papillary adenomas in the gall bladder; it also caused adenocarcinomas in the jejunum in male mice at the high dose of 12.5 mg/kg/day.

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 25 mg/kg twice daily (50 mg/kg/day or at least 202 times the clinical exposure (AUC) at 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.

14.1 Treatment of SBS in Adults

Study 1 (Placebo-controlled) and Study 2 (Open-label Extension of Study 1)

Study 1 (CL0600-020, NCT00798967)

The efficacy, safety, and tolerability of GATTEX was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center clinical study (Study 1) in adults with SBS who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. For 8 weeks (or less) prior to randomization, investigators optimized the PN/I.V. volume of all patients. Optimization was followed by a 4-week to 8-week period of fluid stabilization. Patients then were randomized (1:1) to placebo (n=43) or GATTEX 0.05 mg/kg/day (n=43). Study treatment was administered subcutaneously once daily for 24 weeks. PN/I.V. volume adjustments (up to 30% decrease) and clinical assessments were made at 2, 4, 8, 12, 20, and 24 weeks.

The primary efficacy endpoint was based on a clinical response, defined as a patient achieving at least 20% reduction in weekly PN/I.V. volume from Baseline (immediately before randomization) to both Weeks 20 and 24.

The mean age of patients was 50 years. Mean duration of PN/I.V. dependency prior to enrollment was 6 years (range 1 to 26 years). The most common reasons for intestinal resection leading to SBS were vascular disease (34%, 29/85), Crohn's Disease (21%, 18/85), and "other" (21%, 18/85). Stoma was present in 45% (38/85) of patients, and the most common type was jejunostomy/ileostomy (82%, 31/38). The mean length of remaining small intestine was 77.3±64.4 cm (range: 5 to 343 cm). The colon was not in continuity in 44% (37/85) patients. At baseline, the mean (± SD) prescribed days per week for PN/I.V. infusion was 5.73 (±1.59) days.

The percentages of treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomized patients. Sixty-three percent (27/43) of GATTEX-treated patients versus 30% (13/43) of placebo-treated patients were considered responders (p=0.002).

At Week 24, the mean reduction in weekly PN/I.V. volume was 4.4 Liters for GATTEX-treated patients (from pre-treatment baseline of 12.9 Liters) versus 2.3 Liters for placebo-treated patients (from pre-treatment baseline of 13.2 Liters/week) (p<0.001).

Twenty-one patients on GATTEX (54%) versus 9 on placebo (23%) achieved at least a one-day reduction in PN/I.V. support.

The mean changes from Baseline in PN/I.V. volume by visit are shown in Figure 2.

Figure 2: Change (±95% CI) in PN/I.V. volume (L/week)

Study 2 (CL0600-021, NCT00930644)

Study 2 was a 2-year open-label extension of Study 1 in which 88 patients received GATTEX 0.05 mg/kg/day. Ninety-seven percent (76/78) of patients who completed Study 1 elected to enroll in Study 2 (37 received GATTEX; 39 received Placebo). An additional 12 patients entered Study 2, who had been optimized and stabilized but not randomized in Study 1 because of closed enrollment.

30 months exposure

Thirty GATTEX patients completed a total duration of 30 months (Study 1 followed by Study 2 treatment). Of these, 28 patients (93%) achieved a 20% or greater reduction of parenteral support (PS). Of responders in Study 1 who had completed 2 additional years of continuous treatment with GATTEX, 96% (21/22) sustained their response to GATTEX. The mean reduction in PN/I.V. (n=30) was 7.55 L/week (a 66% reduction from baseline). Ten patients were weaned off their PN/I.V. support while on GATTEX treatment for 30 months. Patients were maintained on GATTEX even if no longer requiring PN/I.V. support. These 10 patients had required PN/I.V. support for 1.2 to 15.5 years, and prior to GATTEX had required between 3.5 L/week and 13.4 L/week of PN/I.V. support. At the end of study, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively.

24 months exposure

Of the 39 placebo-treated patients from Study 1 entering Study 2, 29 completed 24 months of treatment with GATTEX. The mean reduction in PN/I.V. was 3.11 L/week (an additional 28.3% reduction) from the start of Study 2. Sixteen (55%) of the 29 completers achieved a 20% or greater reduction of PS. At the end of the study, 14 (48%), 7 (24%) and 5 (17%) achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively. Two patients were weaned off their PN/I.V. support while on GATTEX. Of the 12 patients entering Study 2 directly, 6 completed 24 months of treatment with GATTEX. Similar effects were seen. One of the six patients was weaned off their PN/I.V. support while on GATTEX.

14.2 Treatment of SBS in Pediatric Patients

One-vial kits are pre-assembled and ready to be used:

GATTEX 5 mg One-vial Kit (NDC 68875-0103-1):

• One single-dose vial of 5 mg teduglutide (NDC 68875-0101-1)
• One disposable prefilled syringe containing 0.5 mL Sterile Water for Injection USP for reconstitution, with a separate needle (23G × 1½ in) to attach to the syringe
• One sterile disposable 1-mL syringe with needle (27G × 1/2 in) for dosing
• Four alcohol swabs

Storage and Handling of One-Vial Kit

Prior to Dispensing:

• Store GATTEX 5 mg Strength one-vial kits refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use beyond the expiration date on the label.

After Dispensing by the Pharmacist:

• Store GATTEX 5 mg Strength one-vial kits at room temperature up to 25°C (77°F). Do not freeze. Dispense with a 90-day "use by" dating.

GATTEX is also supplied in 30-vial cartons to be assembled by the dispensing pharmacist into a 30-vial kit by transferring the trays containing 30 vials from a Carton of Drug Vials into a Carton of Ancillary Supplies:

GATTEX 5 mg Carton of Drug Vials (NDC 68875-0101-2):

• Thirty single-dose vials of GATTEX 5 mg (NDC 68875-0101-1)
• Carton of Ancillary Supplies:
  • Thirty disposable prefilled syringes containing diluent (0.5 mL Sterile Water for Injection USP) for reconstitution
  • Thirty separate needles (23G × 1½ in) to attach to the syringes for reconstitution
  • Thirty sterile disposable 1-mL syringes with needle (27G × 1/2 in)
  • Sixty alcohol swabs

The final assembled 30-Vial Kit should contain the items:

GATTEX 5 mg Strength 30-Vial Kit (NDC 68875-0102-1):

• Thirty single-dose vials of 5 mg teduglutide (NDC 68875-0101-1)
• Thirty disposable prefilled syringes containing 0.5 mL Sterile Water for Injection USP for reconstitution, with 30 separate needles (23G × 1½ in) to attach to the syringes
• Thirty sterile disposable 1-mL syringes with needle (27G × 1/2 in) for dosing
• Sixty alcohol swabs

Storage and Handling of 30-Vial Cartons and 30-Vial Kits

Prior to Dispensing:

• Store GATTEX 5 mg vials refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use beyond the expiration date on the label.
• Store the Carton of Ancillary Supplies at room temperature up to 25°C (77°F).

After Dispensing by the Pharmacist:

• Store GATTEX 5 mg Strength 30-vial kits at room temperature up to 25°C (77°F). Do not freeze. Dispense with a 90-day "use by" dating.

Acceleration of Neoplastic Growth

Advise patients and their caregivers that they will need to undergo clinical examinations and repeated colonoscopies (or alternate imaging/diagnostics, such as fecal occult blood testing) during treatment with GATTEX to monitor for the development of polyps and/or neoplasia of the GI tract [see Warnings and Precautions (5.1)].

Intestinal Obstruction

Advise patients and their caregivers to immediately contact their healthcare provider if they experience any symptoms suggestive of intestinal or stomal obstruction [see Warnings and Precautions (5.2)].

Biliary and Pancreatic Disease

Advise patients and their caregivers that laboratory assessments will be done periodically while on GATTEX to monitor for the onset or worsening of gallbladder, biliary and pancreatic disease, and to report immediately to their healthcare provider if they develop symptoms suggestive of cholecystitis, cholangitis, cholelithiasis or pancreatic disease [see Warnings and Precautions (5.3)].

Fluid Overload

Advise patients and their caregivers to immediately contact their healthcare provider if they develop fluid overload or symptoms of congestive heart failure while on GATTEX [see Warnings and Precautions (5.4)].

Fluid Imbalance

Advise patients and their caregivers of the risk of fluid and electrolyte imbalance with discontinuation of GATTEX, and to contact their healthcare provider if they develop symptoms suggestive of electrolyte imbalances [see Warnings and Precautions (5.4)].

Increased Absorption of Concomitant Oral Medication

Instruct patients and their caregivers to report to their healthcare provider any concomitant oral medications that they are taking in order to assess any potential for increased absorption during GATTEX treatment of those oral medications requiring titration or with a narrow therapeutic index [see Warnings and Precautions (5.5)].

Lactation

Advise women that breastfeeding is not recommended during treatment with GATTEX [see Use in Specific Populations (8.2)].