SIDE EFFECTS

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

 In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and GATTEX study groups experienced an injection site reaction.

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.

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.

Read the entire FDA prescribing information for Gattex (Teduglutide [rDNA origin] for Injection) »