7.2)].
5.4 Clostridium difficile-Associated Diarrhea (CDAD)
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterialagents, including imipenem/cilastatin plus relebactam, and may range in severity from mild diarrhea tofatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowthof C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producingstrains of C. difficile cause increased morbidity and mortality, as these infections can be refractory toantimicrobial therapy and may require colectomy. CDAD must be considered in all patients who presentwith diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has beenreported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile mayneed to be discontinued. Appropriate fluid and electrolyte management, protein supplementation,antibacterial drug treatment of C. difficile, and surgical eva luation should be instituted as clinicallyindicated.
5.5 Development of Drug-Resistant Bacteria
Prescribing RECARBRIO in the absence of a proven or strongly suspected bacterial infection orprophylactic indication is unlikely to provide benefit to the patient and increases the risk of thedevelopment of drug-resistant bacteria.
6 ADVERSE REACTIONS
The following serious adverse reactions are described in greater detail in the Warnings and Precautionssection.
Hypersensitivity Reactions [see Warnings and Precautions (5.1)]
Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions(5.2)]
Increased Seizure Potential Due to Interaction with Valproic Acid [see Warnings and Precautions(5.3)]
Clostridium difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed inthe clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug andmay not reflect the rates observed in practice.
Overview of the Safety eva luation of RECARBRIO
Safety was primarily eva luated in two active-controlled, double-blind dose-ranging trials (Trials 1 and 2).
In the cUTI trial (Trial 1, NCT01505634) and cIAI trial (Trial 2, NCT01506271), patients in the treatmentarms were treated with either imipenem 500 mg/cilastatin 500 mg and relebactam 250 mg or imipenem500 mg/cilastatin 500 mg and relebactam 125 mg (not an approved dose), and patients in the control armwere treated with imipenem 500 mg/cilastatin 500 mg plus placebo (IV normal saline). Across Trials 1 and2, the mean duration of IV therapy in patients treated with imipenem/cilastatin plus relebactam 250 mgwas approximately 7 days.
Clinical Trial Experience in Patients with cUTI including pyelonephritis
Trial 1 included 198 adult patients treated with imipenem/cilastatin and relebactam (99 patients each withimipenem 500 mg/cilastatin 500 mg plus relebactam 125 mg or relebactam 250 mg) and 100 patientstreated with imipenem 500 mg/cilastatin 500 mg, administered intravenously over 30 minutes every6 hours. After a minimum of 4 days of IV therapy, patients could be switched to oral ciprofloxacin (500 mgdaily every 1 |
