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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, 595 subjects were exposed to at least one dose of GATTEX (249 patient-years of exposure; mean duration of exposure was 22 weeks). Of the 595 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 subjects treated with GATTEX across all clinical studies (N = 595) were: abdominal pain (31.3%); injection site reactions (21.8%); nausea (18.8%); headaches (16.3%); abdominal distension (14.8%); upper respiratory tract infection (11.9%).
The rates of adverse reactions in subjects with SBS participating in 2 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% (n=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
|Abdominal Pain||16 ( 27.1)||29 ( 37.7)|
|Upper Respiratory Tract Infection||8 ( 13.6)||20 ( 26.0)|
|Nausea||12 ( 20.3)||19 ( 24.7)|
|Abdominal Distension||1 ( 1.7)||15 ( 19.5)|
|Vomiting||6 ( 10.2)||9 ( 11.7)|
|Fluid Overload||4( 6.8)||9 ( 11.7)|
|Flatulence||4( 6.8)||7( 9.1)|
|Hypersensitivity||3 ( 5.1)||6 ( 7.8)|
|Appetite Disorders||2( 3.4)||5 ( 6.5)|
|Sleep Disturbances||0||4( 5.2)|
|Skin Hemorrhage||1 ( 1.7)||4( 5.2)|
|Subjects with Stoma|
|Gastrointestinal Stoma Complication||3 (13.6)a||13 (41.9)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.
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, 13 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 11 polyp cases occurred in the extension studies - 2 colorectal villous adenomas (onset at 6 and 7 months in GATTEX 0.10 and 0.05 mg/kg/day dose groups, respectively), 2 hyperplastic polyp (onset 6 months in GATTEX 0.10 mg/kg/day dose group and 24 months in GATTEX 0.05 mg/kg/day dose group), 3 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).
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 19 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, 2 subjects required endoscopic dilation and 1 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, 4 subjects had an episode of acute cholecystitis; 3 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.
Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of GATTEX may trigger the development of antibodies. Based on data from two trials in adults with SBS (a 6-month randomized placebo-controlled trial, followed by a 24-month open-label trial), the incidence of anti-teduglutide antibody was 3% (2/60) at Month 3, 18% (13/74) at Month 6, 25% (18/71) at Month 12, 31% (10/32) at Month 24 and 48% (14/29) at Month 30 in subjects who received subcutaneous administration of 0.05 mg/kg GATTEX once daily. The anti-teduglutide antibodies were cross-reactive to native glucagon-like peptide (GLP-2) in 5 of the 6 subjects (83%) who had anti-teduglutide antibodies. Anti-teduglutide antibodies appear to have no impact on short term (up to 2.5 years) efficacy and safety although the long-term impact is unknown.
In the same two trials, a total of 36 subjects were tested for neutralizing antibodies: 9 of these subjects had no neutralizing antibodies, and the remaining 27 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.
The following adverse reactions have been identified during post-approval use of GATTEX. 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 GATTEX exposure.
Cardiac disorders: Cardiac Arrest, Cardiac
Failure Nervous system disorders: Cerebral Hemorrhage
Read the Gattex (teduglutide [rdna origin] for injection) Side Effects Center for a complete guide to possible side effects
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]
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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 7/10/2014
Additional Gattex Information
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