Regulatory Decision Summary for Addnutriv

Overall, the benefit-risk profile was favorable for the use of Addnutriv Trace Elements (TE) for Injection as part of intravenous solutions for parenteral nutrition to meet basal to moderately increased requirements of the trace elements in adults. The addition of trace elements to parenteral nutrition prevented potential deficiencies of trace elements that could have occurred due to patients conditions that did not allow normal feeding.

Evidence to support the safety and efficacy was obtained from two pivotal studies (Shenkin 4854 and Shenkin 4204). In the Shenkin 4854 study, the addition of TE maintained adequate serum levels of TE with the exception of higher serum levels of manganese and chromium in the majority of patients. The Shenkin 4204 study used TE supplementation with lowered manganese and chromium amounts, in line with practice guidelines, as their levels were higher than required in the previous study (Shenkin 4854).

Both studies showed that the addition of TE in parenteral nutrition solution could maintain or increase serum levels to physiological levels. Due to a lack of data, the indication was not recommended in pediatrics. There was no data available on the use of Addnutriv in pregnant women but the administration of Addnutriv for the proposed indication and in doses indicated in this submission are not expected to results in major health issues for pregnant women. In addition, the Product Monograph (PM) states that healthcare professionals should carefully consider the potential risks and benefits for each pregnant patient before prescribing Addnutriv.

No adverse reactions occurred during administration of parenteral nutrition with TE and no major safety issues were identified during the post-marketing of Addamel N (predecessor of Addnutriv).

Potential safety issues identified in this review are mitigated through PM labelling and were as follows:

• Hypersensitivity reactions (iodine, in particular): Hypersensitivity reactions have been documented as the most reported adverse reactions in drugs and depends more on a patients sensitivity. Addnutriv is contraindicated in patients who are hypersensitive to this product or to any ingredient in the formulation.
• Potential accumulation of trace elements in patients such as those with Wilsons disease (copper accumulation), hemochromatosis (iron accumulation), and patients with total biliary obstruction (copper, manganese accumulation). Some TE contained in Addaven are excreted via the bile to the faeces, therefore, if a complete block of the biliary duct system prevents the excretion and homeostasis of such a TE, accumulation may result to toxic levels. Addnutriv is contraindicated in patients with total biliary obstruction, patients with Wilsons disease, and hemochromatosis.
• There is a risk of potential injection site reaction if the formulation is administered undiluted. Addnutriv is formulated as a concentrate for infusion. The undiluted solution has a pH of 2.5 and an osmolality of approx. 3,100 mosm/kg water. High osmolality of a drug may irritate the skin at the site of infusion. This potential risk is mitigated through PM labelling with a statement in the administration section that states "Addnutriv must not be given undiluted."

A Risk Management Plan (RMP) for Addnutriv was submitted by the Sponsor to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimise risks associated with the product.

In conclusion, the submitted evidence demonstrated that Addnutriv could meet basal to moderately increased requirements of the trace elements without any significant safety issues during administration with parenteral nutrition. All potential risks are mitigated through labelling in the PM. Therefore, the data supports the proposed indication in adults. A Notice of Compliance is recommended.