Olive Oil and Soybean Oil

CLINOLIPID is indicated in adults and pediatric patients, including term and preterm neonates, as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. CLINOLIPID is indicated in adults and pediatric patients, including term and preterm neonates, as a source of calories and essential fatty acids for parenteral nutrition (PN) when oral or enteral nutrition is not possible, insufficient, or contraindicated. ( 1 )

CLINOLIPID is a sterile, homogenous, white, milky, lipid injectable emulsion supplied as:

• 20% (20 g/100 mL)(0.2g/mL) of lipid in 100 mL single-dose Flexible Container
• 20% (50 g/250 mL)(0.2g/mL) of lipid in 250 mL single-dose Flexible Container
• 20% (100 g/500 mL)(0.2g/mL) of lipid in 500 mL single-dose Flexible Container
• 20% (200 g/1,000 mL)(0.2g/mL) of lipid in 1,000 mL Pharmacy Bulk Package Injectable emulsion:
• 20% (20 g/100 mL) (0.2 g/mL) of lipid in 100 mL single-dose flexible container ( 3 )
• 20% (50 g/250 mL) (0.2 g/mL) of lipid in 250 mL single-dose flexible container ( 3 )
• 20% (100 g/500 mL) (0.2 g/mL) of lipid in 500 mL single-dose flexible container ( 3 )
• 20% (200 g/1,000 mL) (0.2 g/mL) of lipid in 1,000 mL Pharmacy Bulk Package ( 3 )

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

• Known hypersensitivity to egg, soybean, peanut or to any of the active or inactive ingredients in CLINOLIPID [see Warnings and Precautions (5.3) ] .
• Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride >1,000 mg/dL) [see Warnings and Precautions (5.7) ] .
• Known hypersensitivity to egg, soybean, peanut, or any of the active or inactive ingredients. ( 4 )
• Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglycerides >1,000 mg/dL). ( 4 , 5.7 )

• Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants: Acute respiratory distress, metabolic acidosis, and death after rapid infusion of intravenous lipid emulsions have been reported. ( 5.1 , 8.4 )
• Parenteral Nutrition-Associated Liver Disease : Increased risk in patients who receive parenteral nutrition for greater than 2 weeks, especially preterm neonates. Monitor liver tests: if abnormalities occur, consider discontinuation or dosage reduction. ( 5.2 , 8.4 )
• Hypersensitivity Reactions : Monitor for signs or symptoms. Discontinue infusion if reactions occur. ( 5.3 )
• Risk of Infections, Fat Overload Syndrome, Refeeding Syndrome, Hypertriglyceridemia, and Essential Fatty Acid Deficiency : Monitor for signs and symptoms; monitor laboratory parameters. ( 5.4 , 5.5 , 5.6 , 5.7 , 5.9 )
• Aluminum Toxicity : Increased risk in patients with renal impairment, including preterm neonates. ( 5.8 , 8.4 )

5.1 Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants In the postmarketing setting, serious adverse reactions including acute respiratory distress, metabolic acidosis, and death have been reported in neonates and infants after rapid infusion of intravenous lipid emulsions. Hypertriglyceridemia was commonly reported. Strictly adhere to the recommended total daily dosage; the hourly infusion rate should not exceed 0.75 mL/kg/hour [see Dosage and Administration (2.4) ] . 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 risk due to poor lipid clearance should be considered when administering intravenous lipid emulsions. Carefully monitor the infant’s ability to eliminate the infused lipids from the circulation (e.g., measure serum triglycerides and/or plasma free fatty acid levels). If signs of poor clearance of lipids from the circulation occur, stop the infusion and initiate a medical evaluation [see Warnings and Precautions (5.5 , 5.7 ) and Overdosage (10) ] .

5.2 Parenteral Nutrition Associated Liver Disease and Other Hepatobiliary Disorders Risk of Parenteral Nutrition-Associated Liver Disease Parenteral nutrition-associated liver disease (PNALD), also referred to as intestinal failure-associated liver disease (IFALD), can present as cholestasis or hepatic steatosis, and may progress to steatohepatitis with fibrosis and cirrhosis (possibly leading to chronic hepatic failure). The etiology of PNALD is multifactorial; however, intravenously administered phytosterols (plant sterols) contained in plant-derived lipid emulsions, including CLINOLIPID, have been associated with development of PNALD. Monitor liver tests in patients treated with CLINOLIPID and consider discontinuation or dosage reduction if abnormalities occur. Other Hepatobiliary Disorders Hepatobiliary disorders including cholecystitis and cholelithiasis have developed in some PN-treated patients without preexisting liver disease. Monitor liver tests when administering CLINOLIPID. Patients developing signs of hepatobiliary disorders should be assessed early to determine whether these conditions are related to CLINOLIPID use.

5.3 Hypersensitivity Reactions CLINOLIPID contains soybean oil and egg phospholipids, which may cause hypersensitivity reactions. Cross reactions have been observed between soybean and peanut. In postmarketing experience, anaphylaxis has been reported following CLINOLIPID administration [see Adverse Reactions (6.2 )] . CLINOLIPID is contraindicated in patients with known hypersensitivity to egg, soybean, peanut, or any of the active or inactive ingredients in CLINOLIPID [see Contraindications (4)]. If a hypersensitivity reaction occurs, stop infusion of CLINOLIPID immediately and initiate appropriate treatment and supportive measures.

5.4 Infections Lipid emulsions, such as CLINOLIPID, 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 CLINOLIPID. 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 formulations 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 CLINOLIPID. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped.

5.6 Refeeding Syndrome Administering PN to severely undernourished patients may result in the refeeding syndrome, which is characterized by intracellular shift of potassium, phosphorus, and magnesium as the 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 CLINOLIPID 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 CLINOLIPID. In addition, patients with hypertriglyceridemia may have worsening of their hypertriglyceridemia with administration of CLINOLIPID. 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 CLINOLIPID infusion and monitor serum triglyceride levels to avoid clinical consequences of hypertriglyceridemia such as pancreatitis. 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 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.

5.9 Essential Fatty Acid Deficiency In pediatric trials, EFAD was defined by calculating the Holman index (the triene [Mead acid] to tetraene [arachidonic acid] ratio; T:T ratio > 0.4). […]

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Clinical Decompensation with Rapid Infusion of Intravenous Lipid Emulsion in Neonates and Infants [see Warnings and Precautions (5.1) ]
• Parenteral Nutrition-Associated Liver Disease and Other Hepatobiliary Disorders [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) ] Most common (≥5%) adverse drug reactions from clinical trials in adults were nausea and vomiting, hyperlipidemia, hyperglycemia, hypoproteinemia, and abnormal liver function tests. Most common (≥5%) adverse reactions from clinical trials in pediatric patients were hyperbilirubinemia, patent ductus arteriosus, anemia, gastroesophageal reflux disease, bradycardia, feeding intolerance, neonatal intraventricular hemorrhage, increased alkaline phosphatase, atrial septal defect, hyponatremia, sepsis, and infantile apnea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The CLINOLIPID trials had small sample sizes and patients had a variety of underlying medical conditions both between different trials and within the individual trials. Patients had gastrointestinal diseases/dysfunction or were recovering from gastrointestinal or other surgeries, trauma, burns, or were afflicted by other chronic illness. Adult Trials Commonly observed adverse reactions in 261 adult patients who received CLINOLIPID were nausea and vomiting, hyperlipidemia, hyperglycemia, hypoproteinemia, and abnormal liver function tests and occurred in 2 to 10 % of patients. The largest clinical trial in adult patients (Study 1) enrolled 48 subjects with different underlying diagnoses. Study 2 was a randomized, open label multicenter study that enrolled 22 subjects, aged 32-81 years, who required long-term parenteral nutrition. The most common adverse reactions in Study 1 and Study 2 were infectious complications (urinary tract infection, septicemia, and fever of unknown origin), treatment emergent abnormalities on liver/gallbladder ultrasound and abnormalities of serum chemistries, principally, hepatic function tests. Adverse reactions reported with other intravenous lipid emulsions include hyperlipidemia, hypercoagulability, thrombophlebitis, and thrombocytopenia. Adverse reactions reported in long-term use with other intravenous lipid emulsions include hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, abnormalities in liver function tests, brown pigmentation of the liver and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly, and shock). Pediatric Trials The safety of CLINOLIPID in pediatric patients was evaluated in Studies 3, 4, 5, and 6 [see Clinical Studies (14.2) ] . In Study 3, EFAD was defined by calculating the Holman index (the triene [Mead acid] to tetraene [arachidonic acid] ratio; T:T ratio > 0.4). Although no patient developed EFAD, one CLINOLIPID-treated patient who had a T:T ratio that increased from < 0.2 at baseline to > 0.2 at end of study treatment was considered at risk for EFAD. This patient’s arachidonic and linoleic acid levels remained within the normal range. No soybean oil lipid emulsion-treated patients had a T:T ratio ≥ 0.2. In Studies 3, 4, 5, and 6, adverse reactions occurred at similar rates in subjects treated with CLINOLIPID and the 100% soybean oil comparator. Adverse reactions that occurred in ≥5% of patients included hyperbilirubinemia, patent ductus arteriosus, anemia, gastroesophageal reflux disease, bradycardia, feeding intolerance, neonatal intraventricular hemorrhage, increased alkaline phosphatase, atrial septal defect, hyponatremia, sepsis, and infantile apnea.

6.2 Postmarketing Experience The following adverse reactions have been identified during use of CLINOLIPID. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders : Diarrhea Skin and Subcutaneous Tissue Disorders : Pruritus Immune System Disorders : Hypersensitivity reactions, including anaphylaxis [see Contraindications (4 ), Warnings and Precautions (5.3) ] Investigations : International normalized ratio (INR) decreased in anticoagulated patients [see Drug Interactions (7) ] Hepatobiliary disorders: cholestasis

No drug interaction studies have been performed with CLINOLIPID. Olive and soybean oils have a natural content of Vitamin K 1 that may counteract the anticoagulant activity of coumadin derivatives, including warfarin. The anticoagulant activity of coumarin derivatives, including warfarin, may be counteracted. ( 7 )

8.1 Pregnancy Risk Summary Administration of the recommended dose of CLINOLIPID is not expected to cause major defects, miscarriage, or other adverse maternal or fetal outcomes. No animal reproduction studies have been conducted with lipid injectable emulsion. There are clinical considerations if CLINOLIPID is used in pregnant women [see Clinical Considerations ] . The estimated background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk: Severe malnutrition in a pregnant woman is associated with preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. Parenteral nutrition should be considered if a pregnant woman’s nutritional requirements cannot be fulfilled by oral or enteral intake. It is not known whether the administration of CLINOLIPID to pregnant women provides adequate essential fatty acids to the developing fetus.

8.2 Lactation Risk Summary There are no data available to assess the presence of CLINOLIPID and/or its active metabolite(s) in human milk, the effects on the breastfed child or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CLINOLIPID and any potential adverse effects on the breastfed child from CLINOLIPID or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of CLINOLIPID have been established as a source of calories and essential fatty acids for PN in pediatric patients, including term and preterm neonates, when oral or enteral nutrition is not possible, insufficient, or contraindicated. Use of CLINOLIPID in pediatric patients is supported by evidence from four studies that enrolled pediatric patients, including preterm and term neonates, and additional evidence from clinical studies in adults. Use of CLINOLIPID in older pediatric patients is supported by evidence from two studies in pediatric patients up to 9 years of age treated for a median of 15 and 56 days, respectively, with additional evidence from clinical studies in adults [see Clinical Studies (14.2) ] . No clinically significant cases of EFAD were observed in short term pediatric clinical studies. However, one premature neonate in study 3 became at risk for EFAD after 14 days of treatment based on a Holman Index increase above 0.2. This patient’s arachidonic and linoleic acid levels remained within the normal range [see Adverse Reactions (6.1) ] . Monitor pediatric patients for laboratory evidence of EFAD, including fatty acid profile (i.e., arachidonic acid) because they may be particularly vulnerable to neurologic complications if adequate amounts of essential fatty acids are not provided [see Warnings and Precautions (5.9) ] . In the postmarketing setting, clinical decompensation with rapid infusion of intravenous lipid emulsion in neonates and infants, sometimes fatal, has been reported [see Warnings and Precautions (5.1) ] . Because of immature renal function, preterm infants receiving prolonged treatment with CLINOLIPID may be at risk for aluminum toxicity [see Warnings and Precautions (5.8) ] .

8.5 Geriatric Use Of the total number of subjects in clinical studies of CLINOLIPID, 21% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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.