Clinolipid Injection

The use of CLINOLIPID is contraindicated in patients with the following:

Death in Preterm Infants

Deaths in preterm infants after infusion of intravenous lipid emulsions have been reported1. Autopsy findings included intravascular lipid accumulation in the lungs.

Preterm and small for gestational age infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion.

The safe and effective use of CLINOLIPID in pediatric patients, including preterm infants, has not been established. CLINOLIPID is not indicated for and not recommended for use in pediatric patients.

Hypersensitivity Reactions

Stop infusion immediately and treat patient accordingly if signs or symptoms of a hypersensitivity or allergic reaction develop. Signs or symptoms may include: tachypnea, dyspnea, hypoxia, bronchospasm, tachycardia, hypotension, cyanosis, vomiting, nausea, headache, sweating, dizziness, altered mentation, flushing, rash, urticaria, erythema, pyrexia and chills.

Infections

Patients who require parenteral nutrition are at high risk of infections due to malnutrition and their underlying disease state.

Infection and sepsis may occur as a result of the use of intravenous catheters to administer parenteral nutrition, poor maintenance of catheters, or immunosuppressive effects of illness, drugs, and parenteral formulations.

Decrease the risk of septic complications with heightened emphasis on aseptic technique in catheter placement and maintenance, as well as aseptic technique in the preparation of the nutritional formula.

Carefully monitor for signs and symptoms (including fever and chills) of early infections, including laboratory test results (including leukocytosis and hyperglycemia) and frequent checks of the parenteral access device.

Fat Overload Syndrome

Fat overload syndrome is a rare condition that has been reported with intravenous lipid formulations. A reduced or limited ability to metabolize the lipids contained in CLINOLIPID accompanied by prolonged plasma clearance may result in a syndrome characterized by a sudden deterioration in the patient's condition accompanied by fever, anemia, leukopenia, thrombocytopenia, coagulation disorders, hyperlipidemia, liver fatty infiltration (hepatomegaly), deteriorating liver function, and central nervous system manifestations (e.g., coma). The cause of the fat overload syndrome is unclear. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped. Although it has been most frequently observed when the recommended lipid dose was exceeded, cases have also been described where the lipid formulation was administered according to instructions.

Refeeding Syndrome

Refeeding severely undernourished patients with parenteral nutrition may result in the refeeding syndrome, characterized by the intracellular shift of potassium, phosphorus, and magnesium as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Carefully monitor severely undernourished patients and slowly increase their nutrient intakes, while avoiding overfeeding, to prevent these complications.

Monitoring/Laboratory Tests

Routine Monitoring

Monitor fluid status closely in patients with pulmonary edema or heart failure.

Monitor serum triglycerides, fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, and blood count, including platelets and coagulation parameters, throughout treatment.

Essential Fatty Acids

Monitoring patients for signs and symptoms of essential fatty acid deficiency (EFAD) is recommended. Laboratory tests are available to determine serum fatty acids levels. Reference values should be consulted to help determine adequacy of essential fatty acid status. Increasing essential fatty acid intake (enterally or parenterally) is effective in treating and preventing EFAD.

In Clinolipid Injection, the mean composition of linoleic acid (an omega-6 essential fatty acid) is 35.8 mg/mL (range 27.6 to 44.0 mg/mL) and α-linolenic acid (an omega-3 essential fatty acid) is 4.7 mg/mL (range 1.0 to 8.4 mg/mL). There are insufficient long-term data to determine whether CLINOLIPID 20% can supply essential fatty acids in adequate amounts in patients who may have increased requirements.

Interference with Laboratory Tests

Content of Vitamin K may counteract anticoagulant activity [see Drug Interactions (7)].

The lipids contained in this emulsion may interfere with the results of certain laboratory tests if the blood sample is taken before the lipids are eliminated from the serum (these are generally eliminated after a period of 5 to 6 hours without receiving lipids).

Aluminum Toxicity

CLINOLIPID contains no more than 25 mcg/L of aluminum.

The aluminum contained in CLINOLIPID may reach toxic levels with prolonged administration in patients with impaired kidney function. Preterm infants 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 infants, who receive parenteral levels of aluminum at greater than 4 to 5 mcg/kg/day, accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration of total parenteral nutrition products.

Risk of Parenteral Nutrition Associated Liver Disease

Parenteral Nutrition Associated Liver Disease (PNALD) has been reported in patients who receive parenteral nutrition for extended periods of time, especially preterm infants, and can present as cholestasis or steatohepatitis. The exact etiology is unknown and is likely multifactorial. Intravenously administered phytosterols (plant sterols) contained in plant-derived lipid formulations have been associated with development of PNALD although a causal relationship has not been clearly established. If CLINOLIPID treated patients develop liver test abnormalities consider discontinuation or dose reduction.

Hypertriglyceridemia

Reduce dose of CLINOLIPID and monitor serum triglyceride levels in patients with serum triglyceride concentrations above 400 mg/dL to avoid the clinical consequences associated with hypertriglyceridemia. Serum triglyceride levels above 1000 mg/dL have been associated with an increased risk of pancreatitis.

In the event of overdose, fat overload syndrome may result [see Warnings and Precautions (5.4)]. Stop the infusion to allow lipids to clear from serum. The effects are usually reversible after the lipid infusion is stopped. If medically appropriate, further intervention may be indicated. The lipid administered and fatty acids produced are not dialyzable.

CLINOLIPID administered intravenously provides biologically utilizable source of calories and essential fatty acids.

Mechanism of Action

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 important for membrane structure and function, precursors for bioactive molecules (such as prostaglandins), and as regulators of gene expression.

Pharmacodynamics

Infused essential fatty acids are synthesized into higher derivative fatty acids. Olive oil contains significant amounts of alpha-tocopherol that contributes to Vitamin E status.

Pharmacokinetics

Metabolism and Excretion

The fatty acids, phospholipids, and glycerol found in lipid emulsions are metabolized by cells to carbon dioxide and water. The metabolism of these substances results in the generation of energy in the form of adenosine triphosphate (ATP). Some fatty acids are stored in the body in fat tissue, cell membranes, or as intracellular triglycerides. There is constant turn-over of these tissues, with the result that the lipid components are eventually metabolized to carbon dioxide and water. Carbon dioxide is expired through the lungs. Water is excreted through the kidneys or lost through evaporation/expiration through the skin, lungs, and other tissue surfaces. Some lipids (i.e., phospholipids, cholesterol, and bile acids) are excreted through the biliary system.

Two clinical trials (Study 1 and Study 2) in adults compared CLINOLIPID to a pure soybean oil based intravenous lipid emulsion. Although Study 1 and Study 2 were not adequately designed to demonstrate noninferiority of CLINOLIPID to the soybean oil comparator, they support Clinolipid Injection as a source of calories and essential fatty acids in adults. The lipid dosage was variable in Studies 1 and 2 and adjusted to the patient’s nutritional requirements.

Study 1 was a randomized, open-label, multicenter study. Forty eight (48) patients, aged 17 to 75 years, requiring ≥15 days (mean 22 days) exclusive parenteral nutrition (TPN) were enrolled and randomized to either CLINOLIPID or a pure soybean oil based intravenous lipid emulsion. Nutritional efficacy was assessed by anthropometric indices (body weight, arm circumference, skin-fold thickness), biomarkers of protein metabolism (total protein, albumin) and lipid metabolism. Anthropometric criteria (body weight, arm circumference, and skin fold thickness) were comparable for both groups. Mean total serum protein and albumin increased similarly in both groups.

Study 2 was a randomized, open label multicenter study that enrolled 22 patients aged 32-81 years who required long-term parenteral nutrition. Twelve patients received CLINOLIPID for a mean of 202 days (range 24 to 408 days) and 10 patients received the comparator lipid for a mean of 145 days (range 29-394 days). The two groups had similar outcomes for weight, weight loss, mid-arm circumference and triceps skinfold thickness.

CLINOLIPID lipid injectable emulsion, USP is supplied in single-dose CLARITY polyolefin bags as follows:

The CLARITY Container is a lipid-compatible plastic container (PL 2401-1). The bag is packaged in an oxygen barrier overpouch, which contains an oxygen absorber / oxygen indicator sachet.

CLINOLIPID should be stored at 20 to 25 °C (68 to 77 °F). Excursion permitted between 15 to 30 °C (59 to 86 °F). See USP Controlled Room Temperature. Protect from freezing. Avoid excessive heat. Store in overpouch until ready to use.