Regulatory Decision Summary for Ivozfo

In support of this Supplement to a New Drug Submission (SNDS) Submission Relying on Third-Party Data (SRTD) for Ivozfo, the sponsor submitted third-party publications – including observational studies based on real-world evidence (RWE), experimental studies, and systematic reviews and meta-analyses – and the European Medicines Agency (EMA) Referral Assessment Report. The Non-Interventional Study–Fosfomycin (NIS-FOM) was considered pivotal due to the variety of indications covered, the broad microbiological spectrum involved, the robustness of the clinical data, the quality of evidence, and the large sample size. It was the largest prospective non-interventional study conducted at the time of review with IV fosfomycin.

The primary efficacy endpoint was the number of patients who achieved clinical success (i.e., clinical cure or clinical improvement). The secondary efficacy endpoints were the number of patients with microbiological success (i.e., eradication of the underlying pathogens), improvement of infection, unaltered infection, clinical treatment failure, and microbiological treatment failure. The primary and secondary efficacy endpoints were met in the study. Therefore, the efficacy of IV fosfomycin, alone or in combination, was clearly established at the proposed dosing regimens when the infection was caused by either susceptible or “problematic” pathogens. This supported an altered list of infection-related indications.

Overall, IV fosfomycin was well tolerated by most patients, including children and neonates. There was no death related to fosfomycin in the study. The most common fosfomycin-induced adverse events were hypernatremia, hypokalemia, and diarrhea. Other common adverse drug reactions included skin allergies, gastrointestinal disorders, injection site phlebitis, and dysgeusia. The majority of adverse events observed with Ivozfo were mild and transient. All adverse events were adequately addressed in the Product Monograph.

The main safety issues associated with Ivozfo are the risk of sodium overload and electrolyte disturbances, mainly hypernatremia and hypokalemia. This is of particular concern in patients with cardiac insufficiency or renal impairment or hepatic dysfunction. Precautionary monitoring of plasma electrolytes, low-sodium diet and potassium supplementation during Ivozfo therapy are risk mitigation measures outlined in the Product Monograph.

Other submitted third-party published studies confirmed the effective and safe use of IV fosfomycin.

After reviewing the revised Risk Management Plan, the related Canadian addendum, and the latest Periodic Safety Update Reports (PSURs) submitted, the Marketed Health Products Directorate (MHPD) recommended routine post-market monitoring of the drug by the sponsor.

Following the review of the submitted efficacy and safety data, the overall benefit-harm-uncertainty profile of Ivozfo is considered favorable when the drug is administered to patients under the conditions specified in the labelling. Therefore, the revised indications and dosing regimens of Ivozfo are recommended for authorization in adults and children, including neonates.