Gattex Drug Information

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.

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.

Evaluation and testing prior to starting treatment with GATTEX: Within 6 months prior to treatment: Adult patients Perform a colonoscopy and an upper gastrointestinal (GI) endoscopy with removal of polyps. Obtain baseline laboratory assessments (bilirubin, alkaline phosphatase, lipase and amylase). Pediatric patients Perform fecal occult blood testing; if there is new or unexplained blood in the stool, perform colonoscopy/sigmoidoscopy and an upper GI endoscopy.

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 m 2 ) is 0.025 mg/kg once daily.

Monitoring to Assess Safety Colonoscopy and Upper GI Endoscopy in Adults A follow-up colonoscopy and upper GI endoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. If no polyp is found, subsequent colonoscopies and upper GI endoscopies (or alternate imaging) should be done no less frequently than every 5 years. If a polyp is found, adherence to current polyp follow-up guidelines is recommended.

Colonoscopy and Upper GI Endoscopy in Pediatric Patients Perform subsequent fecal occult blood testing annually in pediatric patients while they are receiving GATTEX. Colonoscopy/sigmoidoscopy is recommended for all pediatric patients after 1 year of treatment and every 5 years thereafter while on continuous treatment with GATTEX. Consider upper GI endoscopy (or alternate other imaging) during treatment with GATTEX.

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).

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.

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. 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.

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. Only those reactions with a rate of at least 5% in the GATTEX group, and greater than placebo group, are summarized in Table 1. 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. 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 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. No cases of intestinal obstruction occurred in the placebo group. Onset ranged from 1 day to 6 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. 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. 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. 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

Postmarketing Experience

The following adverse reactions have been identified during post approval use of teduglutide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Neoplasia: colorectal polyps, gastric polyps, small intestinal polyps (duodenum, ileum, and jejunum) Injection Site Reactions: injection site induration, inflammation, pruritus, urticaria, and warmth

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. 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.

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 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).

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.

Adverse reactions in pediatric patients were similar to those seen in adults. 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.

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.