Smoflipid (Page 3 of 6)

5.3 Hypersensitivity Reactions

SMOFlipid contains soybean oil, fish oil, and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut. SMOFlipid is contraindicated in patients with known hypersensitivity to fish, egg, soybean, peanut protein, or to any of the active or inactive ingredients in SMOFlipid. If a hypersensitivity reaction occurs, stop infusion of SMOFlipid immediately and initiate appropriate treatment and supportive measures.

5.4 Infections

Lipid emulsions, such as SMOFlipid, can support microbial growth and are an independent risk factor for the development of catheter-related bloodstream infections. To decrease the risk of infectious complications, ensure aseptic techniques are used for catheter placement, catheter maintenance, and preparation and administration of SMOFlipid.

Monitor for signs and symptoms of infection including fever and chills, as well as laboratory test results that might indicate infection (including leukocytosis and hyperglycemia). Perform frequent checks of the intravenous catheter insertion site for edema, redness, and discharge.

5.5 Fat Overload Syndrome

Fat overload syndrome is a rare condition that has been reported with intravenous lipid injectable emulsions and is characterized by a sudden deterioration in the patient’s condition (e.g., fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, hepatomegaly, deteriorating liver function, and central nervous system manifestations such as coma). A reduced or limited ability to metabolize lipids, accompanied by prolonged plasma clearance (resulting in higher lipid levels), may result in this syndrome. Although fat overload syndrome has been most frequently observed when the recommended lipid dose or infusion rate was exceeded, cases have also been described when the lipid formulation was administered according to instructions.

If signs or symptoms of fat overload syndrome occur, stop SMOFlipid. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped.

5.6 Refeeding Syndrome

Administering PN to severely malnourished patients may result in refeeding syndrome, which is characterized by the intracellular shift of potassium, phosphorus, and magnesium as patients become anabolic. Thiamine deficiency and fluid retention may also develop. To prevent these complications, closely monitor severely malnourished patients and slowly increase their nutrient intake.

5.7 Hypertriglyceridemia

The use of SMOFlipid is contraindicated in patients with hypertriglyceridemia with serum triglyceride concentrations >1,000 mg/dL.

Patients with conditions such as inherited lipid disorders, obesity, diabetes mellitus, or metabolic syndromes have a higher risk of developing hypertriglyceridemia with the use of SMOFlipid. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of SMOFlipid. Excessive dextrose administration may further increase such risk.

Evaluate patients’ capacity to metabolize and eliminate the infused lipid emulsion by measuring serum triglycerides before the start of infusion (baseline value) and regularly throughout treatment. If triglyceride levels are above 400 mg/dL in adults, stop the SMOFlipid infusion and monitor serum triglyceride levels to avoid clinical consequences of hypertriglyceridemia such as pancreatitis. In pediatric patients with hypertriglyceridemia, lower triglyceride levels (i.e., below 400 mg/dL) may be associated with adverse reactions. Monitor serum triglyceride levels to avoid potential complications with hypertriglyceridemia such as pancreatitis, lipid pneumonitis, and neurologic changes, including kernicterus.

To minimize the risk of new or worsening of hypertriglyceridemia, assess high-risk patients for their overall energy intake including other sources of lipids and dextrose, as well as concomitant drugs that may affect lipid and dextrose metabolism.

5.8 Aluminum Toxicity

SMOFlipid contains no more than 25 mcg/L of aluminum. Prolonged PN administration in patients with renal impairment may result in aluminum reaching toxic levels. Preterm neonates are at greater risk because their kidneys are immature and they require large amounts of calcium and phosphate solutions that contain aluminum.

Patients with impaired kidney function, including preterm neonates, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day can accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading in these patients may occur at even lower rates of administration.

5.9 Essential Fatty Acid Deficiency

Treatment-emergent cases of moderate or severe essential fatty acid deficiency (EFAD) (defined as the triene [Mead acid] to tetraene [arachidonic acid] ratio >0.2 and >0.4, respectively) were not observed in pediatric clinical trials of SMOFlipid up to 28 days [see Adverse Reactions (6.1)].

However, cases of EFAD have been reported in adult and pediatric patients in the postmarketing period with the use of SMOFlipid. The median time to onset was greater than 28 days among cases that reported time to onset.

Monitor patients for laboratory evidence (e.g., abnormal fatty acid levels) and clinical symptoms of EFAD (e.g., skin manifestations, poor growth). Laboratory testing using the triene to tetraene ratio may not be adequate to diagnose EFAD, and assessment of individual fatty acid levels may be needed. Ensure patients are receiving recommended dosages of SMOFlipid to prevent EFAD [see Dosage and Administration (2.3), Description (11)].

5.10 Monitoring/Laboratory Tests

Throughout treatment, monitor serum triglycerides [see Warnings and Precautions (5.7)] , fluid and electrolyte status, blood glucose, liver and kidney function, coagulation parameters, and complete blood count including platelets.

The lipids contained in SMOFlipid may interfere with some laboratory blood tests (e.g., hemoglobin, lactate dehydrogenase, bilirubin, oxygen saturation) if blood is sampled before lipids have cleared from the bloodstream. Conduct these blood tests at least 6 hours after stopping the infusion.

SMOFlipid contains vitamin K that may counteract anticoagulant activity [see Drug Interactions (7)].

6 ADVERSE REACTIONS

Adverse reactions described elsewhere in this Prescribing Information are:

  • Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders [see Warnings and Precautions (5.1)]
  • Death in Preterm Neonates [see Warnings and Precautions (5.2)]
  • Hypersensitivity Reactions [see Warnings and Precautions (5.3)]
  • Infections [see Warnings and Precautions (5.4)]
  • Fat Overload Syndrome [see Warnings and Precautions (5.5)]
  • Refeeding Syndrome [see Warnings and Precautions (5.6)]
  • Hypertriglyceridemia [see Warnings and Precautions (5.7)]
  • Aluminum Toxicity [see Warnings and Precautions (5.8)]
  • Essential Fatty Acid Deficiency [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The safety database for SMOFlipid includes exposure in 399 patients (229 adults; 170 pediatric) in 9 clinical trials. Adult patients were exposed for 5 days to 4 weeks in 5 clinical trials. The pooled population exposed to SMOFlipid was adult patients up to 89 years old (20 to 89 years of age), 43% female and 99% Caucasian. The most frequently reported medical histories in the SMOFlipid group were surgical and medical procedures (84%), neoplasms (57%), gastrointestinal disorders (53%), vascular disorders (37%), and infections and infestations (20%). SMOFlipid was used as a component of PN which also included dextrose, amino acids, vitamins, and trace elements. Two of the 5 studies in adults were performed with SMOFlipid as a component of PN delivered in a 3- chamber bag.

Table 2: Adverse Reactions in >1% of Adult Patients Treated with SMOFlipid
Adverse Reaction Number of Patients in SMOFlipid Group (N=229) Number of Patients in Comparator Group (N=230)
Nausea 20 (9%) 26 (11%)
Vomiting 15 (7%) 12 (5%)
Hyperglycemia 12 (5%) 5 (2%)
Flatulence 10 (4%) 4 (2%)
Pyrexia 9 (4%) 11 (5%)
Abdominal pain 8 (4%) 5 (2%)
Blood triglycerides increased 6 (3%) 4 (2%)
Hypertension 6 (3%) 9 (4%)
Sepsis 5 (2%) 4 (2%)
Dyspepsia 5 (2%) 1 (0%)
Urinary tract infection 4 (2%) 3 (1%)
Anemia 4 (2%) 2 (1%)
Device related infection 4 (2%) 2 (1%)

Less common adverse reactions occurring in ≤1% of adult patients who received SMOFlipid were dyspnea, leukocytosis, diarrhea, pneumonia, cholestasis, dysgeusia, increased blood alkaline phosphatase, increased gamma-glutamyltransferase, increased C-reactive protein, tachycardia, liver function test abnormalities, headache, pruritus, dizziness, rash and thrombophlebitis.

The 170 patients treated with SMOFlipid in four pediatric trials consisted of 149 patients <28 days of age, 13 patients 28 days to <2 years of age, and 8 patients 2 to 7 years of age; the duration of exposure was 7 to 84 days. Forty five percent of the pediatric patients were female, and 89% were Caucasian. Most pediatric patients were preterm neonates with feeding intolerance or other conditions requiring short-term (<29 days) PN.

The hepatic safety of SMOFlipid was evaluated in Pediatric Study 1, a randomized, active- controlled, double-blind, parallel-group, multi-center study that included 152 neonates and

9 patients ranging in age from 29 to 153 days who were expected to require PN for at least 28 days.

PNAC (defined as direct bilirubin >2mg/dl with a second confirmed elevation >2mg/dl at least 7 days later) occurred in 2.4% (2/83) of SMOFlipid-treated patients and 11.5% (9/78) in soybean oil lipid emulsion-treated patients. Most PNAC events occurred in patients who were treated for longer than 28 days.

The estimated cumulative incidence of PNAC is shown in the Kaplan-Meier cumulative incidence curve in Figure 1 [see Clinical Trials (14)].

Figure 1 Cumulative Incidence Curve of Time to Parenteral Nutrition-Associated Cholestasis (PNAC) with Standard Error Bars

Figure 1
(click image for full-size original)

In the same trial, EFAD was determined by calculating the Holman index (the triene [Mead acid] to tetraene [arachidonic acid] ratio; T:T ratio). At the end of the first 28 days of treatment, 2.4% (2/83) SMOFlipid-treated patients and 2.6% (2/78) soybean oil lipid emulsion-treated patients had suspected EFAD (T:T ratio >0.05), and there were no cases of moderate (T:T ratio >0.2) or severe (T:T ratio >0.4) EFAD. There are insufficient data from this trial to determine the incidence of EFAD with duration of SMOFlipid treatment greater than 28 days because of substantial patient discontinuation from PN during the first 28 days.

Table 3: Adverse Reactions in >1% of Pediatric Patients Treated with SMOFlipid
Adverse Reaction Number of Patients in SMOFlipid Group (N=170) Number of Patients in Comparator Group (N=163)
Anemia 30 (18%) 33 (20%)
Vomiting 16 (9%) 16 (10%)
Gamma-glutamyltransferase increased 10 (6%) 12 (7%)
Nosocomial infection 10 (6%) 6 (4%)
Cholestasis 7 (4%) 10 (6%)
Pyrexia 7 (4%) 7 (4%)
C-reactive protein increased 6 (4%) 7 (4%)
Hyperbilirubinemia 5 (3%) 7 (4%)
Abdominal pain 4 (2%) 5 (3%)
Bilirubin conjugated increased 3 (2%) 7 (4%)
Diarrhea 3 (2%) 4 (3%)
Tachycardia 3 (2%) 4 (3%)
Thrombocytopenia 3 (2%) 4 (3%)
Hyperglycemia 3 (2%) 2 (1%)
Sepsis 3 (2%) 2 (1%)

Less common adverse reactions occurring in ≤1% of pediatric patients who received SMOFlipid were decreased hematocrit, metabolic acidosis, increased blood triglycerides, infection, increased blood alkaline phosphatase, increased alanine aminotransferase, fluid overload, hypertension, hypertriglyceridemia, and rash.

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