Olive Oil And Soybean Oil

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION • Use a 1.2 micron in-line filter when administering to a patient. ( 2.1 ) • For infusion into a central or peripheral vein. ( 2.2 ) • See full prescribing information for administration and admixing instructions. ( 2.2 , 2.3 ) • CLINOLIPID Pharmacy Bulk Package is only indicated for use in pharmacy admixture programs for the preparation of three-in-one or total nutrition admixtures. ( 2.2 ) • Protect the admixed parenteral solution from light. ( 2.3 ) • Recommended dosage depends on age, energy expenditure, clinical status, body weight, tolerance, ability to metabolize and eliminate lipids, and consideration of additional energy given to the patient. ( 2.4 ) • For information on the age-appropriate infusion rate, see the full prescribing information. ( 2.4 , 5.1 ) Age Initial Dose Maximum Dose Birth to 2 years of age (including preterm and term neonates) 0.5 to 1 g/kg/day 3 g/kg/day Pediatric patients 2 to less than 12 years of age 1 to 2 g/kg/day 3 g/kg/day Pediatric patients 12 to 17 years of age 1 g/kg/day 3 g/kg/day Adults 1 to 1.5 g/kg/day 2.5 g/kg/day 2.1 Use of an Inline Filter When Administering CLINOLIPID to a Patient Fragments of the administration port membrane could be dislodged into the bag after spiking. Use a 1.2 micron in-line filter during administration of CLINOLIPID (alone or as part of an admixture) to remove particulate matter or micro-precipitate contamination during administration of a lipid injection (alone or as part of an admixture). Particulate matter greater than 5 microns has the capability of obstructing blood flow through capillaries, which could lead to embolism and vascular occlusion. Do not use filters of less than 1.2 micron pore size with lipid emulsions. 2.2 Important Administration Instructions Before opening the overwrap, check the color of the oxygen indicator. Compare the color of the indicator to the reference color printed next to the OK symbol depicted in the printed area of the indicator label. Do not use the product if the color of the oxygen absorber/indicator does not correspond to the reference color printed next to the OK symbol. After opening the bag, use the contents immediately and discard unused portion. Visually inspect that the emulsion is a homogeneous liquid with a milky appearance. Inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not exceed the recommended maximum infusion rate (0.75 mL/kg/hour for pediatric patients and 0.5 mL/kg/hour for adults) [see Dosage and Administration (2.4 ) and Warnings and Precautions (5.1) ] . When Administering CLINOLIPID to a Patient : Do not connect flexible bags in series to avoid air embolism due to possible residual gas contained in the primary bag. Air embolism can result if residual gas in the bag is not fully evacuated prior to administration if the flexible bag is pressurized to increase flow rates. Do not use vented administration sets with the vent in the open position. This can result in air embolism. If CLINOLIPID is mixed with dextrose and/or amino acid solutions, check the compatibility before administration by inspecting the mixture closely for the presence of precipitates. Formation of precipitates could result in vascular occlusion. CLINOLIPID can be administered via central or peripheral vein. When administered with dextrose and amino acids, the choice of a central or peripheral venous route should depend on the osmolarity of the final infusate. Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP). Use only a 1.2 micron pore size in-line filter to administer CLINOLIPID. DO NOT use any size less than 1.2 micron pore size in-line filter [see Dosage and Administration (2.1) ] . CLINOLIPID 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 for no longer than 24 hours at no more than 25°C (77°F). CLINOLIPID 1,000 mL Pharmacy Bulk Package: • For admixing use only and not for direct intravenous infusion. Prior to administration, transfer to a separate PN container for individual patient use. • Transfer the contents through the infusion port using a suitable sterile transfer device or dispensing set. Discard any unused contents. Discard any unused portion. • 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 no more than 25°C (77°F). • Once the closure is penetrated use Pharmacy Bulk Package contents within 4 hours. 2.3 Admixing Guidelines When Admixing CLINOLIPID in the Pharmacy: Prepare the admixture using strict aseptic techniques to avoid microbial contamination. Do not add additives directly to CLINOLIPID. Do not add CLINOLIPID to the total parenteral nutrition container first; destabilization of the lipid may occur from such an admixture. Do not use the EXACTAMIX Inlet REF 173 (H938173) with an EXACTAMIX compounder to transfer CLINOLIPID. This inlet spike has been associated with dislodgement of the administration port membrane into the CLINOLIPID bag. Use of EXACTAMIX Inlet REF 174 (H938174) is recommended. The following proper mixing sequence must be followed to minimize pH related problems by ensuring that typically acidic Dextrose Injections are not mixed with lipid emulsions alone: 1. Transfer Dextrose Injection to the Total Parenteral Nutrition Admixture Container 2. Transfer Amino Acid Injection 3. Transfer Lipid Emulsion Amino Acid Injection, Dextrose Injection and Lipid Emulsions may be simultaneously transferred to the admixture container. Use gentle agitation during admixing to minimize localized concentration effects; shake bags gently after each addition. The prime destabilizers of emulsions are excessive acidity (such as a pH below 5) and inappropriate electrolyte content. Give careful consideration to additions of divalent cations (Ca ++ and Mg ++ ), which have been shown to cause emulsion instability. Amino acid solutions exert buffering effects that protect the emulsion. Inspect the admixture closely for separation of the emulsion. This can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the admixed emulsion. The admixture should also be examined for particulates. Discard the admixture if any of the above is observed. Protect the admixed parenteral nutrition solution from light. 2.4 Dosing Considerations The recommended nutritional requirements of lipid and recommended dosages of CLINOLIPID to be administered to meet those requirements for pediatric and adult patients are provided in Table 1 , along with recommendations for the initial and maximum infusion rates. For complete parenteral nutrition, concomitant supplementation with amino acids, carbohydrates, electrolytes, vitamins, and trace elements is necessary. Prior to administration of CLINOLIPID, correct severe water and electrolyte disorders, severe fluid overload states, and severe metabolic disorders. Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. In patients with elevated triglyceride levels, initiate CLINOLIPID injection at a lower dose, and advance in smaller increments, checking the triglyceride levels prior to each adjustment. Adjust the infusion rate by taking into account the dose being administered, the daily volume intake, and the duration of the infusion. Do not exceed the maximum infusion rates in Table 1 [see Warnings and Precautions (5.1) and see Overdosage (10) ] . The recommended duration of infusion for a parenteral nutrition bag is between 12 and 24 hours, depending on the clinical situation. For preterm and term neonates, the recommended duration of infusion is 20 to 24 hours. Treatment with parenteral nutrition may be continued for as long as required by the patient’s condition. The maximum daily dosage of CLINOLIPID should be based on individual total nutritional requirements and patient tolerance ( Error! Hyperlink reference not valid. ). Table 1: Recommended Pediatric and Adult Dosage and Infusion Rate Age Nutritional Requirements Direct Infusion Rate CLINOLIPID Pharmacy Bulk Package is not intended for direct intravenous administration. Recommended Initial Dosage and Maximum Dosage Initial Maximum Birth to 2 years of age (including preterm and term neonates The neonatal period is defined as including term, post-term, and preterm newborn infants. The neonatal period for term and post-term infants is the day of birth plus 27 days. For preterm infants, the neonatal period is defined as the day of birth through the expected age of delivery plus 27 days (i.e., 44 weeks post-menstrual age). ) [see Warnings and Precautions (5.1) ] Initial 0.5 to 1g/kg/day not to exceed 3 g/kg/day Daily dosage should also not exceed a maximum of 60% of total energy requirements [see Overdosage (10) ] . 0.1 to 0.2 mL/kg/hour for the first 15 to 30 minutes; gradually increase the required rate after 30 minutes 0.75 mL/kg/hour Pediatric patients 2 to less than 12 years of age Initial 1 to 2 g/kg/day not to exceed 3 g/kg/day 0.2 to 0.4 mL/kg/hour for the first 15 to 30 minutes; gradually increase the required rate after 30 minutes 0.75 mL/kg/hour Pediatric patients 12 to 17 years of age Initial 1 g/kg/day not to exceed 3 g/kg/day 0.2 to 0.4 mL/kg/hour for the first 15 to 30 minutes; gradually increase the required rate after 30 minutes 0.75 mL/kg/hour Adults 1 to 1.5 g/kg/day not to exceed 2.5 g/kg/day 0.2 mL/kg/hour for the first 15 to 30 minutes; if tolerated, gradually increase the required rate after 30 minutes 0.5 mL/kg/hour

6 ADVERSE REACTIONS 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

12.3 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.