FDA label 29010ef0-4da9-ebe7-e063-6294a90a7380

5 WARNINGS AND PRECAUTIONS Risk of Persistent or Worsening Diarrhea Complicated by Fever and/or Bloody Stool: AEMCOLO was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Discontinue use if diarrhea gets worse or persists more than 48 hours, and consider alternative antibacterial therapy. ( 1. 5.1 ) Clostridium difficile -associated Diarrhea : Evaluate if diarrhea occurs after therapy or does not improve or worsens during therapy. ( 5.2 ) 5.1 Risk of Persistent or Worsening of Diarrhea Complicated by Fever and/or Bloody Stool AEMCOLO was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool. Patients with these conditions treated with AEMCOLO had prolonged time to last unformed stool (TLUS). The effectiveness of AEMCOLO in travelers' diarrhea caused by pathogens other than E. coli has not been demonstrated. AEMCOLO is not recommended for use in patients with diarrhea accompanied by fever or bloody stools or due to pathogens other than noninvasive strains of E. coli [see Indications and Usage (1) , Clinical Studies (14) ]. Discontinue AEMCOLO if diarrhea gets worse or persists more than 48 hours and consider alternative antibacterial therapy. 5.2 Clostridium difficile -Associated Diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile may cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, specific antibacterial treatment of C. difficile , and/or surgical evaluation should be instituted as clinically indicated. 5.3 Development of Drug-Resistant Bacteria Prescribing AEMCOLO in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS Most common adverse reactions (incidence > 2%) are headache and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact RedHill Biopharma Inc. at 833-ADR-HILL (833-237-4455) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of oral AEMCOLO 388 mg twice daily was assessed in 619 adults with travelers' diarrhea in two controlled clinical trials (Trial 1 and Trial 2) with 96% of patients receiving three or four days of treatment. These patients had a mean age of 36.2 years (range 18 to 87 years) with 7% ≥ 65 years old; 49% were male, 84% were White, and 4% were Hispanic. Discontinuation of AEMCOLO due to adverse reactions occurred in 1% of patients. The most frequent adverse reactions leading to discontinuation of AEMCOLO were abdominal pain (0.5%) and pyrexia (0.3%). In Trial 1 (placebo-controlled), the adverse reaction that occurred in at least 2% of AEMCOLO-treated patients (n = 199) and with an incidence higher than in the placebo group was constipation (3.5% AEMCOLO, 1.5% placebo) In Trial 2 (active comparator), the adverse reaction that occurred in at least 2% of AEMCOLO-treated patients (n = 420) and with an incidence higher than in the ciprofloxacin group was headache (3.3% AEMCOLO, 1.9% ciprofloxacin) Adverse reactions reported in <2% of patients receiving AEMCOLO 388 mg twice daily with a higher incidence than the comparator group was dyspepsia.