Regulatory Decision Summary for Clinimix / Clinimix E
Review decision
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
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What was the purpose of this submission?
The purpose of this Supplement to a New Drug Submission (SNDS) was to introduce five additional strengths of Clinimix / Clinimix E: three strengths of Clinimix (6% amino acid in 5% Dextrose, 8% amino acid in 10% Dextrose, and 8% amino acid in 14% Dextrose), and two strengths of Clinimix E (8% amino acid in 10% Dextrose, and 8% amino acid in 14% Dextrose), which includes the addition of calcium.
Why was the decision issued?
Overall, the benefit-risk balance is favorable for the approval of five additional strengths of Clinimix / Clinimix E: three strengths of Clinimix (6% amino acid in 5% Dextrose, 8% amino acid in 10% Dextrose, and 8% amino acid in 14% Dextrose) and two strengths of Clinimix E (8% amino acid in 10% Dextrose, and 8% amino acid in 14% Dextrose), which include the addition of calcium.
The Sponsor provided an acceptable scientific justification for the proposed new strengths. The new strengths of Clinimix / Clinimix E will enable the achievement of higher protein targets with less risk of fluid overload and hyperglycemia in already predisposed critically ill patients. Higher protein intake in critically ill patients is associated with decreased mortality risk, fewer infections, shorter duration of ventilator support, reduced intensive care unit length of stay (ICU LOS), and shorter time to discharge.
The proposed Clinimix / Clinimix E products have a volume ratio between the amino acid and dextrose chambers of 1.8/1 and 1.5/1 (rounded values). This ratio has changed from 1/1 for current Clinimix / Clinimix E products, resulting in a quantitative change for the amino acid and dextrose chambers. Despite changing volume ratios between the two chambers of the bag, the macronutrients provided in the newer volume ratios provide dosing within parenteral nutrition guideline recommendations. These volume ratios were changed by the sponsor to allow an increase in the amino acid concentration and ultimately meet the need for PN formulations that allow appropriate protein dosing with less risk of fluid overload or overfeeding. These modifications are supported by the latest PN guidelines.
Baxters current Clinimix / Clinimix E Product Monograph (PM) states that protein requirements in traumatized or malnourished patients may be increased substantially. Daily amino acid doses of approximately 1.0 to 1.5 g/kg of body weight for adults are generally sufficient to satisfy protein needs and promote positive nitrogen balance. However, in traumatized and/or malnourished patients, protein intake may be increased substantially, up to 2.5 g/kg of body weight. The American Society for Parenteral and Enteral Nutrition (ASPEN) Clinical Guidelines on Nutrition Support of Hospitalized Adult Patients with Obesity recommend a hypocaloric, high-protein feeding regimen with a protein (amino acid) intake of 2-2.5 g/kg ideal body weight (IBW)/day. The recommendation for morbid obesity is 2.5 g/kg IBW/day.
Many guidelines and studies have evaluated fluid requirements for hospitalized patients acknowledging that many patients require fluid restriction. While increasing protein intake, it should be kept in mind that some patients might need less fluid and calories from carbohydrates depending on their status (e.g., obese patients and patients at risk of hyperglycemia may need less calories). Being able to achieve protein goals with less fluid administration and fewer calories is important in fluid restricted patients and patients at risk of hyperglycemia. In critically ill patients, there might be a need for fluid restriction to avoid fluid overload. Both the ASPEN and the European Society for Parenteral and Enteral Nutrition (ESPN) practice guidelines recommend using parenteral nutrition formulations that provide a balance of macronutrients with fewer calories from carbohydrates in order to reduce the risk of hyperglycemia while still providing adequate protein.
The proposed increases of amino acid were within acceptable limits and consistent with ASPEN and ESPEN guidelines. Clinimix (6% amino acid in 5% Dextrose) would achieve the same protein goal with approximately 16% less fluid administration compared to Clinimix (5% amino acid in 5% Dextrose). Clinimix (8% amino acid in 10% Dextrose) or Clinimix (8% amino acid in 14% Dextrose) would achieve the same protein goal with approximately 37% less fluid administration compared to Clinimix (5% amino acid in 10% Dextrose).
Clinimix (8% amino acid in 10% Dextrose) and Clinimix (8% amino acid in 14% Dextrose) will contain calcium chloride dihydrate to supply calcium at 4.5 mEq (2.2 mmol) per liter of final mixed product. This differs from current Clinimix E formulations which do not contain any calcium. Calcium is a common electrolyte used in parenteral nutrition and a typical daily requirement is in the range of 10-15 mEq. Canadian Clinical Practice Guidelines recommend standard adult doses for calcium that range from 5 to 15 mEq per day (2.5 to 7.5 mmol per day) and both the ASPEN and ESPEN recommend addition of calcium when necessary. The proposed amount of 4.5 mEq (2.2 mmol) calcium per bag would provide recommended daily intake of calcium.
There are no new safety issues that have been identified in this submission. Adverse reactions included in the PM are from post-marketing experience. It is expected that safety issues that have been identified with approved Clinimix / Clinimix E submission would apply to the proposed new strengths of Clinimix / Clinimix E. All of these adverse reactions are addressed through labelling in the Contraindications, Warnings and Precautions sections of the PM.
It is recommended that a Notice of Compliance be issued.
Decision issued
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| CLINIMIX E | 02498413 | BAXTER CORPORATION | ALANINE 1656 MG / 100 ML CALCIUM CHLORIDE 33 MG / 100 ML DEXTROSE 10 G / 100 ML GLYCINE 824 MG / 100 ML HISTIDINE 384 MG / 100 ML L-ARGININE 920 MG / 100 ML L-ISOLEUCINE 480 MG / 100 ML L-LEUCINE 584 MG / 100 ML L-LYSINE HYDROCHLORIDE 464 MG / 100 ML L-PHENYLALANINE 448 MG / 100 ML L-PROLINE 544 MG / 100 ML L-THREONINE 336 MG / 100 ML L-TYROSINE 32 MG / 100 ML L-VALINE 464 MG / 100 ML MAGNESIUM CHLORIDE 24 MG / 100 ML METHIONINE 320 MG / 100 ML POTASSIUM PHOSPHATE DIBASIC 261 MG / 100 ML SERINE 400 MG / 100 ML SODIUM CHLORIDE 205 MG / 100 ML TRYPTOPHAN 144 MG / 100 ML |
| CLINIMIX | 02498448 | BAXTER CORPORATION | ALANINE 1242 MG / 100 ML DEXTROSE 5 G / 100 ML GLYCINE 618 MG / 100 ML HISTIDINE 288 MG / 100 ML L-ARGININE 690 MG / 100 ML L-ISOLEUCINE 360 MG / 100 ML L-LEUCINE 438 MG / 100 ML L-LYSINE HYDROCHLORIDE 348 MG / 100 ML L-PHENYLALANINE 336 MG / 100 ML L-PROLINE 408 MG / 100 ML L-THREONINE 252 MG / 100 ML L-TYROSINE 24 MG / 100 ML L-VALINE 348 MG / 100 ML METHIONINE 240 MG / 100 ML SERINE 300 MG / 100 ML TRYPTOPHAN 108 MG / 100 ML |
| CLINIMIX E | 02498421 | BAXTER CORPORATION | ALANINE 1656 MG / 100 ML CALCIUM CHLORIDE 33 MG / 100 ML DEXTROSE 14 G / 100 ML GLYCINE 824 MG / 100 ML HISTIDINE 384 MG / 100 ML L-ARGININE 920 MG / 100 ML L-ISOLEUCINE 480 MG / 100 ML L-LEUCINE 584 MG / 100 ML L-LYSINE HYDROCHLORIDE 464 MG / 100 ML L-PHENYLALANINE 448 MG / 100 ML L-PROLINE 544 MG / 100 ML L-THREONINE 336 MG / 100 ML L-TYROSINE 32 MG / 100 ML L-VALINE 464 MG / 100 ML MAGNESIUM CHLORIDE 24 MG / 100 ML METHIONINE 320 MG / 100 ML POTASSIUM PHOSPHATE DIBASIC 261 MG / 100 ML SERINE 400 MG / 100 ML SODIUM CHLORIDE 205 MG / 100 ML TRYPTOPHAN 144 MG / 100 ML |
| CLINIMIX | 02498456 | BAXTER CORPORATION | ALANINE 1656 MG / 100 ML DEXTROSE 10 G / 100 ML GLYCINE 824 MG / 100 ML HISTIDINE 384 MG / 100 ML L-ARGININE 920 MG / 100 ML L-ISOLEUCINE 480 MG / 100 ML L-LEUCINE 584 MG / 100 ML L-LYSINE HYDROCHLORIDE 464 MG / 100 ML L-PHENYLALANINE 448 MG / 100 ML L-PROLINE 544 MG / 100 ML L-THREONINE 336 MG / 100 ML L-TYROSINE 32 MG / 100 ML L-VALINE 464 MG / 100 ML METHIONINE 320 MG / 100 ML SERINE 400 MG / 100 ML TRYPTOPHAN 144 MG / 100 ML |
| CLINIMIX | 02498464 | BAXTER CORPORATION | ALANINE 1656 MG / 100 ML DEXTROSE 14 G / 100 ML GLYCINE 824 MG / 100 ML HISTIDINE 384 MG / 100 ML L-ARGININE 920 MG / 100 ML L-ISOLEUCINE 480 MG / 100 ML L-LEUCINE 584 MG / 100 ML L-LYSINE HYDROCHLORIDE 464 MG / 100 ML L-PHENYLALANINE 448 MG / 100 ML L-PROLINE 544 MG / 100 ML L-THREONINE 336 MG / 100 ML L-TYROSINE 32 MG / 100 ML L-VALINE 464 MG / 100 ML METHIONINE 320 MG / 100 ML SERINE 400 MG / 100 ML TRYPTOPHAN 144 MG / 100 ML |