Gattex

Description

The active ingredient in GATTEX (teduglutide) for injection is teduglutide, which is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified by recombinant DNA technology. The chemical composition of teduglutide is L-histidyl-L-glycyl-L-aspartyl-Lglycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-Lisoleucyl-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-Lthreonyl-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-dose vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for reconstitution and administration by subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.434 mg dibasic sodium phosphate heptahydrate, 3.88 mg L-histidine, 15 mg mannitol, and 0.644 mg monobasic sodium phosphate monohydrate as excipients. No preservatives are present.

At the time of administration, the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for subcutaneous injection upon reconstitution.

Indications

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

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].
• Pediatric patients: Perform fecal occult blood testing; if there is unexplained blood in the stool, perform colonoscopy/sigmoidoscopy [see WARNINGS AND PRECAUTIONS].
• Obtain baseline laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase) [see WARNINGS AND PRECAUTIONS].

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.

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].

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].

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].

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].

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].

Preparation Instructions

Do not shake the vial.

• 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.
• 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.

How Supplied

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.

Storage And Handling

GATTEX (teduglutide) for injection is supplied as 5 mg of teduglutide as a white, lyophilized powder for reconstitution in a sterile, single-dose glass vial with 0.5 mL Sterile Water for Injection in a single-dose prefilled syringe. The product to be dispensed is either a one-vial kit or a 30-vial kit.

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 (22G x 1½ in) to attach to the syringe
• One sterile disposable 1-mL syringe with needle (26G x 5/8 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 (22G x 1½ in) to attach to the syringes for reconstitution
  • Thirty sterile disposable 1-mL syringes with needle (26G x 5/8 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 (22G x 1½ in) to attach to the syringes
• Thirty sterile disposable 1-mL syringes with needle (26G x 5/8 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.

Distributed by: Takeda Pharmaceuticals America, Inc. Lexington, MA 02421 USA. Revised: Oct 2022

Side Effects

The following serious adverse reactions are described elsewhere in the labeling:

• Acceleration of Neoplastic Growth [see WARNINGS AND PRECAUTIONS]
• Intestinal Obstruction [see WARNINGS AND PRECAUTIONS]
• Biliary and Pancreatic Disease [see WARNINGS AND PRECAUTIONS]
• Fluid Imbalance and Fluid Overload [see WARNINGS AND PRECAUTIONS]

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

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, Clinical Studies]. 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].

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].

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].

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.

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].

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].

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.

Drug Interactions

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].

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.

WarningS

Included as part of the “PRECAUTIONS” Section

Precautions

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, Nonclinical Toxicology]. 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]. 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].

Small Bowel Neoplasia

Based on tumor findings in the rat and mouse carcinogenicity studies, monitor patients clinically for small bowel neoplasia [see Nonclinical Toxicology]. If a benign neoplasm is found, it should be removed. In case of small bowel cancer, discontinue GATTEX therapy.

Intestinal Obstruction

Intestinal obstruction has been reported in clinical studies [see ADVERSE REACTIONS] 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.

Biliary And Pancreatic Disease

Gallbladder And Biliary Tract Disease

Cholecystitis, cholangitis, and cholelithiasis have been reported in clinical studies [see ADVERSE REACTIONS] 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]. 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.

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]. 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].

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].

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

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].

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].

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].

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].

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].

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].

Lactation

Advise women that breastfeeding is not recommended during treatment with GATTEX [see Use In Specific Populations].

Nonclinical Toxicology

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.

Use In Specific Populations

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).

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], advise patients that breastfeeding is not recommended during treatment with GATTEX.

Data

In a milk excretion study in the rat, a single subcutaneous dose of 25 mg/kg of teduglutide (81 times the recommended daily human dose of 0.05 mg/kg based on 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.

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, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies]. 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]. Adverse reactions in pediatric patients were similar to those seen in adults [see ADVERSE REACTIONS].

Juvenile Animal Toxicity Data

In a juvenile toxicity study, teduglutide was administered to juvenile minipigs at subcutaneous doses of 0.5, 2.5 and 12.5 mg/kg twice daily (1, 5, and 25 mg/kg/day) from post-natal day 7 and continuing for 90 days). Exposures (AUC) at these doses were at least 12-, 25-, and 170-fold the pediatric clinical exposure for ages 1 year to 11 years at 0.05 mg/kg, respectively, and 10-, 21-, and 141-fold the pediatric clinical exposure for ages 12 years to 17 years at 0.05 mg/kg, respectively.

In juvenile minipigs, subcutaneous teduglutide caused intestinotrophic effects, gall bladder mucosal hyperplasia, bile duct mucosal hyperplasia, and injection site reactions, similar to those observed in adult animals.

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].

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]. 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].

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].

Overdose

The maximum dose of GATTEX studied during clinical development was 80 mg/day for 8 days. No unexpected systemic adverse reactions were seen. In the event of overdose, the patient should be carefully monitored by the medical professional.

Contraindications

None.

Clinical Pharmacology

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).

Pharmacodynamics

Intestinal Fluid Absorption

The ability of GATTEX to improve intestinal absorption was studied in 17 adult subjects with Short Bowel Syndrome (N=2-3 per dose group) using daily doses of 0.03, 0.1, 0.15 mg/kg (doses ranging from 0.6 to 3 times the recommended dose) in a 21-day, open-label, multi-center, dose-ranging study. All subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750 to 1000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.

Cardiac Electrophysiology

At a dose 5 times the recommended dose, GATTEX did not prolong the QT interval to any clinically relevant extent.

Pharmacokinetics

Absorption

In healthy subjects, GATTEX administered subcutaneously had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at 3 to 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 at steady state (AUCtau) was 0.15 μg•hr/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations.

The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg (up to 8 times the recommended dose of GATTEX).

Distribution

In healthy subjects, teduglutide has a volume of distribution (103 mL/kg) similar to blood volume.

Elimination

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.

Excretion

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 (t_1/2) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects.

Use In Specific Populations

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.

Pediatric Patients

Following subcutaneous administration, similar steady state Cmax of teduglutide across age groups was demonstrated by population pharmacokinetics modeling (see Table 2). However, lower AUC was seen in pediatric patients 1 to 17 years of age as compared with adults and increases with increasing age.

Table 2: Teduglutide Pharmacokinetic Parameters Following Subcutaneous Dosing of GATTEX 0.05 mg/kg by Age Groups

Male And Female Patients

No clinically relevant gender differences were observed.

Patients With Renal Impairment

In adult subjects with moderate to severe renal impairment or end stage renal disease (ESRD) (creatinine clearance <60 mL/min), the Cmax and AUC0-inf of teduglutide increased with the degree of renal impairment following a single subcutaneous dose of 10 mg GATTEX. Teduglutide exposure increased by a factor of 1.6, 1.4, and 2.1 (Cmax) and 1.5, 1.7, and 2.6 (AUC0-inf) in subjects with moderate, severe renal impairment and ESRD, respectively, compared to healthy subjects [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].

Patients With Hepatic Impairment

Subjects with moderate hepatic impairment (Child-Pugh Class B) had an approximately 10 to 15% lower teduglutide Cmax and AUC compared to healthy matched control subjects after a single subcutaneous dose of 20 mg GATTEX. This reduction in teduglutide exposure is not thought to be clinically meaningful. GATTEX was not studied in subjects with severe hepatic impairment (Child-Pugh Class C).

Drug Interaction Studies

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.

Clinical Studies

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.

Study 3 (Placebo-Controlled) And Study 4 (Blinded Uncontrolled Extension Of Study 3)

Study 3 (CL0600-004, NCT00081458)

Study 3 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study 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. After a period of optimization and stabilization similar to Study 1, patients were randomized to receive 24 weeks of one of the following treatment regimens: GATTEX 0.05 mg/kg/day (n=35), GATTEX 0.1 mg/kg/day (twice the recommended dose) (n=33), or placebo (n=16). GATTEX 0.1 mg/kg/day is not a recommended dosage [see DOSAGE AND ADMINISTRATION]. The treatment groups were compared using the intent-to-treat population of this study which was defined as all randomized patients who were administered at least one dose of study drug. This population contained one less patient in the 0.1 mg/kg/day dose group hence n=32 in this group for all analyses. The primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose. Further evaluation of PN/I.V. volume reduction using the endpoint of response (defined as at least 20% reduction in PN/I.V. fluid from Baseline to Weeks 20 and 24) showed that 46% of patients on GATTEX 0.05 mg/kg/day responded versus 6% on placebo. Patients on GATTEX in both dose groups experienced a 2.5 L/week reduction in PS requirements versus 0.9 L/week for placebo at 24 weeks. Two patients in the GATTEX 0.05 mg/kg/day dose group were weaned off PS by Week 24.

Study 4 (CL0600-005, NCT00172185)

Study 4 was a blinded, uncontrolled extension of Study 3, in which 65 patients from Study 3 received GATTEX for up to an additional 28 weeks of treatment. Of responders in Study 3 who entered Study 4, 75% sustained response on GATTEX after one year of treatment. In the GATTEX 0.05 mg/kg/day dose group, a 20% or greater reduction of PS was achieved in 68% (17/25) of patients. The mean reduction of weekly PN/I.V. volume was 4.9 L/week (52% reduction from baseline) after one year of continuous GATTEX treatment. The patients who had been completely weaned off PN/I.V. support in Study 3 remained off PS through Study 4. During Study 4, an additional patient from Study 3 was weaned off PS.

Treatment Of SBS In Pediatric Patients

Study 5 (TED-C14-006, NCT02682381)

Study 5 was a 24-week, multicenter study conducted in 59 pediatric patients aged 1 year through 17 years with SBS who were dependent on PS. Patients chose whether to receive GATTEX or standard of care (SOC). Patients who chose to receive GATTEX treatment were subsequently randomized in a double-blind manner to 0.025 mg/kg/day (n=24) or 0.05 mg/kg/day (n=26), while 9 patients enrolled in the SOC arm. Randomization to the GATTEX dose groups was stratified by age.

Patients treated with 0.05 mg/kg had a mean age of 6 years at baseline. The most common reasons for intestinal resection leading to SBS were gastroschisis (54%, 14/26), midgut volvulus (23%, 6/26), and necrotizing enterocolitis (12%, 3/26). Stoma was present in 19% (5/26) of patients, and the most common type was jejunostomy (80%, 4/5). The mean length of remaining small intestine was 47 (±28) cm (range: 9 to 120 cm). In the 25 patients who had remaining colon, the colon was in continuity in 22 patients. At baseline, the mean PS volume was 60 (±29) mL/kg/day (range: 24 to 133 mL/kg/day) [8 (±4) L/week (range: 3 to 19 L/week)] and mean PS infusion time was 7 (±1) days/week (range: 5 to 7 days/week) and 11 (±3) hours/day (range: 7 to 20 hours/day).

Results described in Table 3 correspond to the recommended GATTEX dosage of 0.05 mg/kg subcutaneously once daily.

Table 3 Summary of Efficacy Endpoints at Week 24* for Study 5 – Patients treated with GATTEX 0.05 mg/kg/day (N = 26)

Study 6 (SHP633-304, NCT02954458)

Study 6 was a prospective, open-label, long-term extension study of pediatric patients who completed Study 5. In the extension study, patients received additional treatment with GATTEX 0.05 mg/kg subcutaneously once daily if they deteriorated or stopped improving after discontinuation of prior GATTEX treatment. Of the 15 patients who initially responded in Study 5 and enrolled in Study 6, 13 patients (87%) required additional treatment with GATTEX. Efficacy results at the end of the first 24-week treatment period in Study 6 (total treatment for a mean of 40 weeks) were similar to those achieved at the end of 24 weeks treatment in Study 5. One additional patient treated with 0.05 mg/kg in Study 5 eventually achieved enteral autonomy during follow-up in Study 6.