The FDA Center for Drug Evaluation and Research (CDER) has published a warning on the use of medicinal products containing semaglutide regarding the occurrence of acute gallbladder injury, and data on use during pregnancy and lactation.
Section “Warnings and precautions”
New subsection added
Acute gallbladder disease
In studies of GLP-1 receptor agonists and in the post-marketing period, cases of acute gallbladder injury (cholelithiasis or cholecystitis) have been reported. In placebo-controlled studies, cases of cholelithiasis were reported in 1,5% and 0,4% of patients receiving semaglutide at a dose of 0,5 mg and 1 mg, respectively. No cases of cholelithiasis were observed in patients receiving placebo. If cholelithiasis is suspected, gallbladder examinations and appropriate clinical follow-up are indicated.
“Adverse reactions” section
The following was added:
Acute gallbladder disease [see Warnings and Precautions]
Subsection “Study results”
Additions underlined
In a clinical study with 959 patients who received semaglutide 1 mg or semaglutide 2 mg once weekly as an add-on to metformin with or without sulfonylurea treatment for 40 weeks, no new safety signals were identified.
In the study of semaglutide at doses of 1 and 2 mg, gastrointestinal adverse reactions occurred more frequently among patients who received semaglutide 2 mg (34,0%) compared with those who received semaglutide 1 mg (30,8%).
Subsection “Post-marketing experience”
Additions underlined
Hepatobiliary system: cholecystitis, cholecystectomy
Section “Use in specific population groups”
Subsection “Pregnancy”
Additions and/or changes are underlined
Risk summary
In pregnant rats given semaglutide during organogenesis, embryofetal mortality, structural abnormalities and alterations in growth, and maternal toxicity were observed at clinical exposure based on AUC. In rabbits and cynomolgus monkeys given semaglutide during organogenesis, early pregnancy losses or structural abnormalities were observed at clinical exposure (rabbit) and at 2-fold the MRHD (Maximum Recommended Human Dose) (monkey). These findings coincided with marked maternal body weight loss in both animal species (see Data).
In the embryonic development study in pregnant rabbits, subcutaneous doses of 0,0010, 0,0025 or 0,0075 mg/kg/day (0,02-, 0,2- and 1,2-fold the MRHD) were administered throughout organogenesis from day 6 to day 19 of pregnancy. Pharmacologically mediated decreases in maternal body weight gain and food consumption were observed at all dose levels. Early pregnancy loss and an increased incidence of minor visceral (kidney, liver) and skeletal (sternum) fetal anomalies were observed at a dose greater than or equal to 0,0025 mg/kg/day, during clinically relevant exposure.
In the embryonic development study in pregnant cynomolgus monkeys, doses of 0,015, 0,075 and 0,15 mg/kg twice weekly (0,5-, 3- and 8-fold the MRHD) were administered subcutaneously throughout organogenesis, from day 16 to day 50 of pregnancy. Pharmacologically mediated marked initial loss of maternal body weight and decreased body weight gain and food consumption coincided with the occurrence of sporadic anomalies (vertebrae, sternum, ribs) at a dose of greater than or equal to 0,075 mg/kg twice weekly (greater than or equal to 3-fold human exposure).
In the pre- and postnatal development study in pregnant cynomolgus monkeys, subcutaneous doses of 0,015, 0,075 and 0,15 mg/kg twice weekly (0,3-, 2- and 4-fold the MRHD) were administered from day 16 to day 140 of pregnancy. Pharmacologically mediated marked initial loss of maternal body weight and decreased body weight gain and food consumption coincided with increased early pregnancy loss and led to the birth of slightly smaller offspring at a dose of 0,075 mg/kg twice weekly (greater than or equal to 2-fold human exposure).
Update of recommendations for patients
Additions underlined
Your dose of semaglutide and other diabetes medications may change due to:
changes in the level of physical activity or exercise, weight gain or loss, increased stress, illness, changes in diet, fever, injury, infection, surgery, or other medicines you are taking.
If you have taken too much semaglutide, call your healthcare provider or go immediately to the nearest hospital emergency department.
What are the possible side effects of semaglutide?
Semaglutide may cause serious side effects, including:
- gallbladder problems. Gallbladder problems have occurred in some people who take semaglutide. Tell your healthcare provider right away if you have symptoms of gallbladder problems, which may include:
- pain in the upper abdomen (abdominal cavity)
- fever
- yellowing of the skin or eyes (jaundice)
- clay-colored stool
INFORMATION ON PATIENT COUNSELING
Additions underlined
Acute gallbladder disease
Inform patients about the potential risk of developing gallstone disease or cholecystitis. Instruct patients to contact their doctor if gallstone disease or cholecystitis is suspected for appropriate clinical monitoring [see the section “Warnings and Precautions”].
The original text of the notice can be found at https://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges/index.cfm?event=searchdetail.page&DrugNameID=2183#
