Regulatory Decision Summary for Xfusor

The purpose of this New Drug Submission was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Xfusor, filed by Formative Pharma Inc.

The submission was filed for Xfusor (ropivacaine hydrochloride), 2 milligrams per millilitre (mg/mL) (5 millilitre per hour [mL/h] continuous infiltration for 48 hours), for the indications of continuous peripheral nerve block infiltration for postoperative pain management in adults, and continuous wound infiltration for postoperative pain management in adults.

Upon review of the submitted data package, Health Canada authorized Xfusor as filed.

The submission was filed as a Submission Relying on Third-Party Data according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience).

This New Drug Submission (NDS) was filed as a Submission Relying on Third Party Data (SRTD) for Xfusor (Ropivacaine hydrochloride) to be used for continuous peripheral nerve block infiltration for postoperative pain management in adults, and continuous wound infiltration (CWI) for postoperative pain management in adults.

Following the initial review, a Notice of Non-Compliance (NON) was issued, primarily due to uncertainties related to impurities and other minor quality concerns. The Response to the NON (R-NON), addressed all identified deficiencies, and the submission met all of the conditions and requirements in the SRTD Guidance document.

The Regulatory Decision Recommendation was based on all elements presented in the R-NON, including literature-based clinical and non-clinical studies, a human factors study, evidence addressing the uncertainties raised in the NON letter, chemistry, manufacturing, and controls studies, medical device studies, as well as non-clinical studies conducted by the sponsor. In addition, foreign regulatory labels and reviews on the use of ropivacaine in other jurisdictions, as well as additional literature-based clinical and non-clinical studies identified by Health Canada were included in the assessment.

Efficacy

Naropin (ropivacaine hydrochloride) has been approved in the European Union (EU), the United Kingdom (UK) and Australia for the proposed indications since 1996. In 2017, the EU, UK and Australia authorized Ropivacaine Readyfusor, which uses a pump to deliver ropivacaine, as a generic version of Naropin. Xfusor is almost identical to Ropivacaine Readyfusor, except for the use of a second-generation version of the pump, referred to as the "Gen2 pump." While both pumps operate on the same principle, the Gen2 pump was developed to reduce the overall size, enhance manufacturing capabilities, and improve the sterilization process and impurity profile of the finished product. Aside from differences in the pump design, Xfusor and Ropivacaine Readyfusor are identical in the ropivacaine formulation and dose (2 milligrams per millilitre [mg/mL]), and Xfusor proposed indications are virtually identical to those approved for Ropivacaine Readyfusor. In Canada, while the formulation and strength of Xfusor and Naropin are the same, Xfusor could not be approved as a generic version of Naropin because the indications authorized for Naropin in Canada differ slightly from those authorized in foreign jurisdictions. However, the experience gained with the internationally approved indications for Naropin, spanning up to 30 years, as well as the experience with Readyfusor, provided significant support for the safety and efficacy of the proposed indications for Xfusor in Canada.

To further support the safety and efficacy assessment for Xfusor, the sponsor included a total of 13 literature studies (Randomized Controlled Trials [RCTs]) in 11 meta-analyses. However, these meta-analyses were not used for the efficacy assessment as each analysis included data supporting both proposed indications, which did not allow for the assessment of each indication on its own. Instead, the 13 RCTs were considered individually for their relative pertinence within each indication for post-operative pain management.

Taken together, the international experience, the published literature and the potential benefit of new products for non-opioid analgesics, were considered adequate to support efficacy of Xfusor.

Safety

The toxicology profile of ropivacaine at the proposed doses is known. An up to date assessment of general toxicology, genotoxicity, carcinogenicity, local tolerance, and toxicity of impurities did not reveal any new or unexpected findings. Regarding reproductive and developmental toxicity, an in vitro study indicated that reduced myometrial contractions may be a potential risk associated with local anesthetics if used during labour. Adequate labelling of the risks related to labour and delivery were already included in the Product Monograph (PM), however, Health Canada added a brief paragraph to outline the potential risk of reduced myometrial contractions in the pharmacodynamic section. All other toxicology-related issues were known and deemed adequately addressed in the PM.

The clinical pharmacology of ropivacaine is well known and no new safety concerns arose from an updated assessment. The clinical pharmacology aspects of Xfusor, including the known drug interactions are adequately addressed in the proposed PM.

The clinical safety profile of ropivacaine is well known and an assessment focused on the safety profile of ropivacaine marketed in foreign jurisdictions for the proposed Xfusor indications did not reveal any new or unexpected findings. In addition, published literature studies were evaluated for any additional safety information related to administration of ropivacaine by continuous infiltration. The labelling of both foreign and Canadian ropivacaine products was consulted to ensure adequate labelling of safety information for the Xfusor PM.

Due to a possible signal for impaired wound healing resulting from an in vitro study, Health Canada retrieved a study conducted in humans which had retrospectively assessed whether ropivacaine delayed the process of wound healing or increased the risk of infection following hepatobiliary pancreatic surgery. The study found an initial and temporary decrease in wound maturation in the ropivacaine-exposed group. However, this difference did not persist in the long term, and it should be noted that these findings may be related to the catheter rather than ropivacaine itself. While clear clinical evidence of irreversible wound healing impairment was not found, the in vitro results were added to the Pharmacodynamic section of the PM, and a warning was added to the Warnings and Precautions section.

In addition, a warning was added to the PM conveying the risk of falls due to the occurrence of 3 falls exclusively in the ropivacaine group in one of the studies.

Overall, the safety profile of Xfusor for the continuous peripheral nerve block infiltration and CWI indications was considered acceptable based on the total available evidence from the use of ropivacaine, provided it is used as described in the final agreed-upon PM for this NDS.

A Risk Management Plan for Xfusor was considered to be acceptable with minor changes. The sponsor will be requested to submit a Periodic Safety Update Report/Periodic Benefit-Risk Evaluation Report one year after market entry in Canada, to allow further characterization of the safety profile associated with the use of the drug in the real-world setting, including the potential risk of delayed wound healing and potential medication errors. In addition, the sponsor will be requested to provide the interim/final results stemming from all ongoing/planned/post-market safety studies.

Benefit-Harm-Uncertainty (BHU) Profile

Based on the total available evidence, it is concluded that Xfusor has clinically meaningful effects on post-surgical pain. The BHU profile of Xfusor for the two proposed indications was deemed favorable provided it is used under the conditions recommended in the approved PM. Therefore, a Notice of Compliance was recommended.

For further details about Xfusor, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.