Adverse reactions : תופעות לוואי

4.8      Undesirable effects

Summary of the safety profile
Adverse reactions were retrieved from 2 placebo-controlled clinical studies with Gattex in 109 patients with SBS treated with doses of 0.05 mg/kg/day and 0.10 mg/kg/day for up to 24 weeks.
Approximately 52% of the patients treated with Gattex experienced adverse reactions (versus 36% of the patients given placebo). The most commonly reported adverse reactions were abdominal pain and distension (45%), respiratory tract infections (28%) (including nasopharyngitis, influenza, upper respiratory tract infection, and lower respiratory tract infection), nausea (26%), injection site reactions (26%), headache (16%), and vomiting (14%). Approximately 38% of the treated patients with a stoma experienced gastrointestinal stoma complications. The majority of these reactions were mild or moderate.

No new safety signals have been identified in patients exposed to 0.05 mg/kg/day of teduglutide for up to 30 months in a long-term open-label extension study.

Tabulated list of adverse reactions
Adverse reactions are listed below by MedDRA system organ class and by frequency. Frequencies are defined as very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

All adverse reactions identified in post-marketing experience are italicised.

Frequency         Very common              Common              Uncommon              Not known 
System Organ
Class
Infections and         Respiratory tract       Influenza-like infestations              infection*               illness
Immune system                                                                            Hypersensitivity disorders
Metabolism and                              Decreased appetite nutrition disorders                          Fluid overload
Psychiatric                                      Anxiety disorders                                       Insomnia
Nervous system             Headache disorders
Cardiac disorders                            Congestive heart failure
Vascular disorders                                                     Syncope Respiratory,                                     Cough thoracic and                                    Dyspnoea mediastinal disorders
Gastrointestinal          Abdominal          Colorectal polyp      Duodenal polyp         Gastric polyp disorders                 distension         Colonic stenosis
Abdominal pain         Flatulence
Nausea               Intestinal
Vomiting             obstruction
Pancreatic duct stenosis
Pancreatitis†
Small intestinal stenosis
Hepatobiliary                                 Cholecystitis disorders                                   Cholecystitis acute

General disorders            Injection site      Oedema peripheral                               Fluid retention and administration             reaction‡ site conditions
Injury, poisoning           Gastrointestinal and procedural            stoma complication complications
*Includes the following preferred terms: Nasopharyngitis, Influenza, Upper respiratory tract infection, and Lower respiratory tract infection.
†
Includes the following preferred terms: Pancreatitis, Pancreatitis acute, and Pancreatitis chronic.
‡
Includes the following preferred terms: Injection site haematoma, Injection site erythema, Injection site pain, Injection site swelling and Injection site haemorrhage.


Description of selected adverse reactions
Immunogenicity
Consistent with the potentially immunogenic properties of medicinal products containing peptides, administration of Gattex may potentially trigger the development of antibodies. Based on integrated data from two trials in adults with SBS (a 6-month randomised placebo-controlled trial, followed by a 24-month open-label trial), the development of anti-teduglutide antibodies in subjects who received subcutaneous administration of 0.05 mg/kg teduglutide 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. In phase 3 studies with SBS patients who received Gattex for ≥2 years, 28% of patients developed antibodies against E.coli protein (residual host cell protein from the manufacture). The antibody formation has not been associated with clinically relevant safety findings, reduced efficacy or changed pharmacokinetics of Gattex.

Injection site reactions
Injection site reactions occurred in 26% of SBS patients treated with teduglutide, compared to 5% of patients in the placebo arm. The reactions included injection site haematoma, injection site erythema and injection site pain, injection site swelling and injection site haemorrhage (see also section 5.3).
The majority of reactions were moderate in severity and no occurrences led to drug discontinuation.

C-reactive protein
Modest increases of C-reactive protein of approximately 25 mg/l have been observed within the first seven days of teduglutide treatment, which decreased continuously under ongoing daily injections.
After 24 weeks of teduglutide treatment, patients showed small overall increase in C-reactive protein of approximately 1.5 mg/l on average. These changes were neither associated with any changes in other laboratory parameters nor with any reported clinical symptoms. There were no clinically relevant mean increases of C-reactive protein from baseline following long-term treatment with teduglutide for up to 30 months.

Paediatric population
In one completed clinical study, there were 37 paediatric subjects (aged 1 to 14 years) enrolled and exposed to teduglutide for a duration of 12 weeks. No subject discontinued the study due to an adverse event. Overall, the safety profile of teduglutide in children and adolescents (ages 1-17 years) was similar to that in adults.

The following terms were reported at a higher frequency in paediatric subjects when compared to adults: fatigue (very common), painful defaecation (very common), and dizziness (common).
However, the safety database in children is limited.

Long-term safety data are not yet available for this paediatric population. No data are available for children under 1 year of age.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.


Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com