Smoflipid (Page 5 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

SMOFlipid provides a biologically utilizable source of calories and essential fatty acids.

Fatty acids serve as an important substrate for energy production. The most common mechanism of action for energy production derived from fatty acid metabolism is beta oxidation. Fatty acids are also important for membrane structure and function, as precursors for bioactive molecules (such as prostaglandins), and as regulators of gene expression.

12.2 Pharmacodynamics

The pharmacodynamic effects of SMOFlipid have not been fully characterized.

12.3 Pharmacokinetics

SMOFlipid provides fatty acids in the form of triglycerides which are hydrolyzed by lipoprotein lipase to release free fatty acids. Alpha-linolenic acid and linoleic acid are metabolized within a common biochemical pathway through a series of desaturation and elongation steps. Downstream products of alpha-linolenic acid are EPA and DHA, and linoleic acid is converted to arachidonic acid.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with SMOFlipid have not been performed to evaluate the carcinogenic potential or effects on fertility.

No mutagenic effects were observed in the following in vitro studies with SMOFlipid: bacterial gene mutation assay in Salmonella typhimurium , chromosomal aberration assay in human lymphocytes, and hypoxanthine phosphoribosyl transferase (HPRT) gene mutation assay in V79 cells.

In an in vivo bone marrow cytogenic study in rats, no mutagenic effect was observed.

14 CLINICAL STUDIES

14.1 Adult Clinical Studies

The efficacy of SMOFlipid compared to soybean oil lipid emulsions was evaluated in 3 clinical studies in adult patients. Nutritional efficacy in adult studies was assessed by changes in anthropometric indices (body weight, height, and body mass index [BMI]), changes in lipid and protein metabolism (albumin), and fatty acid parameters. Of the 354 adult patients (176 SMOFlipid; 178 comparator), 62% were male, 99% were Caucasian, and ages ranged from 19 to 96 years. All patients received SMOFlipid or the comparator as part of a PN regimen. Although Adult Study 1, Adult Study 2, and Adult Study 3 were not adequately designed to demonstrate the noninferiority of SMOFlipid to the soybean oil comparator, they support SMOFlipid as a source of calories and essential fatty acids in adults. The lipid dosage was variable in these studies and adjusted to the patient’s nutritional requirements.

Adult Study 1 was a double-blind, randomized, active-controlled, parallel-group, multicenter study in patients who required PN for at least 28 days. Seventy-five patients were enrolled, and 73 patients were treated with either SMOFlipid or a soybean oil lipid emulsion. Changes in mean triglyceride levels from baseline values to Week 4 were similar in both the SMOFlipid and comparator groups. Mean albumin levels demonstrated a comparable decrease in both groups. Mean changes in body weight (kg) and BMI (kg/m2) were similar in both the SMOFlipid and comparator group.

Adult Study 2 was a phase 3, randomized, double-blind, active-controlled, multicenter study. A total of 249 postoperative adult patients were randomized to receive either SMOFlipid or a soybean oil intravenous lipid emulsion for at least 5 days as part of their total parenteral nutrition (TPN) regimen. From baseline to Day 6, mean triglyceride levels increased similarly in both the SMOFlipid and comparator groups.

Adult Study 3 was a double-blind randomized, active-controlled, parallel-group, single-center study in 32 adult patients who required TPN for 10 to 14 days. Patients were treated with either SMOFlipid or a soybean oil lipid emulsion. The increase in mean triglyceride levels from baseline to the final assessment was similar in both the SMOFlipid and comparator groups.

14.2 Pediatric Clinical Studies

The efficacy of SMOFlipid compared to soybean oil lipid emulsions in pediatric patients of all age groups, including term and preterm neonates, was evaluated in 333 pediatric patients in 4 randomized active-controlled, double-blind, parallel-group controlled clinical studies. Although Pediatric Studies 1, 2, 3, and 4 were not adequately designed to demonstrate the noninferiority of SMOFlipid to the soybean oil comparator, they support SMOFlipid as a source of calories and essential fatty acids in pediatric patients. The 333 pediatric patients (170 SMOFlipid; 163 comparator) consisted of 296 patients who were <28 days old, 22 patients 29 days to <2 years old, and 15 patients 2 to <12 years old. Fifty percent of the pediatric patients were male and 87% were Caucasian. All patients received SMOFlipid or the comparator as part of a PN regimen. Nutritional efficacy in neonates was assessed by changes in anthropometric indices (body weight, height, head circumference). Nutritional efficacy in pediatric patients, 28 days to 12 years of age, was assessed by changes in triglyceride concentrations and fatty acid parameters.

Pediatric Study 1 enrolled 152 preterm and term neonates (birth up to 28 days) and 9 patients ranging in age from 29 to 153 days. Patients were treated with either SMOFlipid (n=83) or a soybean oil lipid emulsion (n=78). A total of 119 patients (61 SMOFlipid; 58 comparator) received study treatment for ≥14 days. A total of 25 patients received SMOFlipid for ≥29 days; 5 patients received SMOFlipid for the maximum study duration of 78-84 days.

Pediatric Studies 2 and 3 enrolled 60 and 84 preterm neonates, respectively, who were treated with either SMOFlipid or a soybean oil lipid emulsion (72 neonates in each group). The median treatment duration for SMOFlipid group was 12 days in Pediatric Study 2 and 7 days in Pediatric Study 3.

Pediatric Study 4 enrolled 13 patients 5 months to <2 years of age and 15 patients 2 to 11.5 years of age. Patients were treated with either SMOFlipid (n=15) or a soybean oil lipid emulsion (n=13) with a median treatment duration of 27 days.

In Pediatric Studies 1, 2 and 3, which enrolled neonates, SMOFlipid-treated patients showed increases in the median body weight, height/length, and head circumference (which was measured in Studies 1 and 3) comparable to the soybean oil lipid emulsion-treated patients. Mean triglyceride levels from baseline to the final assessment in Pediatric Studies 1, 2, and 3 were variable in these neonates, but overall differences between groups were not considered clinically relevant. Mean triglyceride levels in Pediatric Study 4 were variable, but remained within the normal range.

16 HOW SUPPLIED/STORAGE AND HANDLING

SMOFlipid is a sterile lipid injectable emulsion with a lipid content of 0.2 gram/mL available in Flexible Containers in the following sizes:

Product Code Unit of Sale Strength Each
830307310 NDC 63323-820-00Unit of 10 20 grams/100 mL(0.2 grams/mL) NDC 63323-820-01100 mL single-dose Bag
830307312 NDC 63323-820-12Unit of 20 20 grams/100 mL(0.2 grams/mL) NDC 63323-820-02100 mL single-dose Bag
830570310 NDC 63323-820-74Unit of 10 50 grams/250 mL(0.2 grams/mL) NDC 63323-820-04250 mL single-dose Bag
830820310 NDC 63323-820-50Unit of 12 100 grams/500 mL(0.2 grams/mL) NDC 63323-820-03500 mL single-dose Bag
830920310 NDC 63323-820-10Unit of 6 200 grams/1000 mL(0.2 grams/mL) NDC 63323-820-051000 mL Pharmacy Bulk Package Bag

Store below 25°C (77°F). Avoid excessive heat. Do not freeze. If accidentally frozen, discard container. Store in overpouch until ready for use.

SMOFlipid 100 mL, 250 mL and 500 mL single-dose Flexible Containers.

After removing the overpouch, infuse immediately. If not used immediately, the product should be stored at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours. After removal from storage, infuse within 12 hours when using a Y-connector or within 24 hours if used as part of an admixture [see Dosage and Administration (2.2)].

SMOFlipid 1000 mL Pharmacy Bulk Package

Use the Pharmacy Bulk Package immediately for admixing after removal from overpouch. If not used immediately, the product should be stored for no longer than 24 hours at 2°C to 8°C (36°F to 46°F). After removal from storage, and once the closure is penetrated, use Pharmacy Bulk Package contents within 4 hours [see Dosage and Administration (2.2)].

Admixtures

Infuse admixtures containing SMOFlipid immediately. If not used immediately, admixtures should be stored at 2°C to 8°C (36°F to 46°F) for no longer than 24 hours. After removal from storage, infuse within 24 hours [see Dosage and Administration (2.2)].

Protect the admixed PN solution from light [see Dosage and Administration (2.2)].

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