Regulatory Decision Summary for Pms-Iron Sucrose

The product was shown to have the same ingredients in the same quantities and the same physical and chemical properties as the CRP. Detailed information on the characterization of iron sucrose was provided by the manufacturer, which supported that the product was essentially the same as the CRP. The United States Food and Drug Administration (FDA) product-specific guidance for Iron Sucrose was used as the basis of the assessment standards. Control of the manufacturing of the active pharmaceutical ingredient and drug product is acceptable to ensure a reproducible product.

Iron carbohydrate complexes like iron sucrose behave as prodrugs, retaining ionic iron until the iron-carbohydrate complex is metabolized. The evaluation of comparative bioavailability between two iron sucrose injectable products requires adapted assessment criteria.

Injected iron sucrose is dissociated by the reticuloendothelial system into iron and sucrose. Released iron is sequestered by transferrin for transport in the serum to the sites of utilization (e.g., in the bone marrow for hemoglobin synthesis or in the liver for storage in ferritin). In the case of less stable injectable iron preparations, this highly regulated process of iron release from carbohydrate complexes can be disrupted. The release of significant amounts of labile iron from the complex can lead to saturation of transferrin and thus, to significant amounts of non-transferrin bound iron (NTBI), particularly if high doses are administered. This NTBI is potentially harmful due to its ability to form free radicals, thereby inducing oxidative stress and cellular toxicity. Hence, it is very useful to monitor NTBI (or "free iron") in circulating blood to evaluate the possibility of toxicity upon IV administration of iron colloidal products.

Accordingly, assessment of equivalence between two iron sucrose products is performed on free iron (TI-TBI) levels in serum samples.

The Health Canada evaluation standards applicable for the determination of bioequivalence between pms-Iron Sucrose and the CRP are in accordance with the approach described in the most recent United States FDA draft guidance document for iron sucrose injectable products (2013).

As per this document, and in order to demonstrate in vivo equivalence between two iron sucrose injection products, a randomized single-dose bioavailability study comparing the proposed iron sucrose injection product to the appropriate CRP should be conducted in healthy subjects. A parallel-group study design rather than cross-over is recommended due to iron deficiency and increased total transferrin binding capacity potentially induced by dense blood sampling. These changes may alter body response to subsequent treatment with parenteral iron products.

The compared products should be administered undiluted as a slow intravenous injection dose of 100 mg over 5 minutes.

The analytes to be measured and reported are:

• Total iron (TI) in serum
• Transferrin-bound iron (TBI) in serum

Measurements should be completed using pre-validated chemical methods, and the following standards should be met:

1. The 90% confidence interval of the Test to Reference product mean ratio of the difference in AUC_T between total iron and transferrin-bound iron* should be between 80.0% - 125.0% inclusive.
2. The relative mean maximum value of the Test to Reference products of the difference in concentration between total iron and transferrin-bound iron over all time points measured should be between 80.0% - 125.0% inclusive.

*AUC_T of total iron and AUC_T of transferrin-bound iron should be calculated separately to maximize the number of data points used in cases of missing data in the transferrin-bound iron and total iron concentration-time profiles. In addition, there is no need to perform baseline correction of total iron and transferrin-bound iron.

The clinical component of the material provided to support this ANDS included comparative bioavailability data obtained following administration of pms-Iron Sucrose and the CRP Venofer in a double blind, randomized, single-dose, two-treatment, single-period, parallel bioequivalence study (Study #443-15) conducted in healthy adult subjects under fasting conditions.

Data and results from Study #443-15 were reviewed by DBE2. Bioequivalence as per the aforementioned assessment standards was successfully demonstrated between pms-Iron Sucrose and Venofer 20 mg/mL solutions.

After evaluation of the data package submitted, Health Canada authorized the product.