Clinolipid Drug Information

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.

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.

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). 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.

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.

• 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.

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. 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 ( Table 1 ). Table 1: Recommended Pediatric and Adult Dosage and Infusion Rate 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.

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). 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.

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. In Study 3, EFAD was defined by calculating the Holman index (the triene to tetraene 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 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.

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 Investigations: International normalized ratio (INR) decreased in anticoagulated patients 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.

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.

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 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.

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.

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.

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. In the postmarketing setting, clinical decompensation with rapid infusion of intravenous lipid emulsion in neonates and infants, sometimes fatal, has been reported. Because of immature renal function, preterm infants receiving prolonged treatment with CLINOLIPID may be at risk for aluminum toxicity.

• 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.
• Severe disorders of lipid metabolism characterized by hypertriglyceridemia (serum triglyceride >1,000 mg/dL).

In the event of overdose, serious adverse reactions may result. 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.