Leucine, Phenylalanine, Lysine Hydrochloride, Methionine, Isoleucine, Valine, Histidine, Threonine, Tryptophan, Alanine, Glycine, Arginine, Proline, Tyrosine, Serine

TRAVASOL is indicated as a source of amino acids for patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. TRAVASOL may be used to treat negative nitrogen balance in patients. TRAVASOL is indicated as a source of amino acids for patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. TRAVASOL may be used to treat negative nitrogen balance in patients. (1)

TRAVASOL 10% is a sterile solution of 10 grams of amino acids per 100 mL (0.1 gram/mL) available in 500 mL, 1000 mL, and 2000 mL flexible containers, which contain essential and nonessential amino acids. Table 3 describes the individual components of TRAVASOL. Table 3. Ingredients per 100 mL of TRAVASOL Amino Acids 10 g Total Nitrogen 1.65 g Essential Amino Acids Leucine 730 mg Isoleucine 600 mg Lysine (added as the hydrochloride salt) 580 mg Valine 580 mg Phenylalanine 560 mg Histidine 480 mg Threonine 420 mg Methionine 400 mg Tryptophan 180 mg Nonessential Amino Acids Alanine 2.07 g Arginine 1.15 g Glycine 1.03 g Proline 680 mg Serine 500 mg Tyrosine 40 mg Anion profiles per liter Balanced by ions from amino acids. Acetate Derived from pH adjustment with glacial acetic acid. 88 mEq Chloride Contributed by the Lysine Hydrochloride. 40 mEq pH (Range); pH adjusted with glacial acetic acid 6.0 (5.0 to 7.0) Osmolarity (calc) 998 mOsm/L Injection: 10% (0.1 grams/mL), 10 grams of amino acid solution per 100 mL in 500 mL, 1000 mL, and 2000 mL flexible containers. (3)

The use of TRAVASOL is contraindicated in:

• Patients with known hypersensitivity to one or more amino acids [see Warnings and Precautions (5.2) ] .
• Patients with inborn errors of amino acid metabolism due to risk of severe metabolic or neurologic complications.
• Patients with pulmonary edema or acidosis due to low cardiac output.
• Known hypersensitivity to one or more amino acids. (4)
• Inborn errors of amino acid metabolism. (4) Patients with pulmonary edema or acidosis due to low cardiac output. (4)

• Pulmonary Embolism due to Pulmonary Vascular Precipitates: if signs of pulmonary distress occur, stop the infusion and initiate a medical evaluation. (5.1)
• Hypersensitivity Reactions : monitor for signs and symptoms and discontinue infusion if reactions occur. (5.2)
• Risk of Infections, Refeeding Complications, and Hyperglycemia or Hyperosmolar Hyperglycemic State : monitor for signs and symptoms; monitor laboratory parameters. (5.3 , 5.4 , 5.5)
• Vein Damage and Thrombosis: solutions with osmolarity of 900 mOsm/L or more must be infused through a central catheter. (2.2 , 5.6)
• Hepatobiliary Disorders: monitor liver function parameters and ammonia levels. (5.7)
• Aluminum Toxicity: increased risk in patients with renal impairment, including preterm infants. (5.8 , 8.4)
• Parenteral Nutrition Associated Liver Disease: increased risk in patients who receive parenteral nutrition for extended periods of time, especially preterm infants; monitor liver function tests, if abnormalities occur consider discontinuation or dosage reduction. (5.9 , 8.4)
• Electrolyte Imbalance and Fluid Overload: patients with cardiac insufficiency or renal impairment may require adjustment of fluid, protein and electrolyte content. (5.10 , 8.4)

5.1 Pulmonary Embolism due to Pulmonary Vascular Precipitates Pulmonary vascular precipitates causing pulmonary vascular emboli and pulmonary distress have been reported in patients receiving parenteral nutrition, including TRAVASOL. In some cases, fatal outcomes due to pulmonary embolism have occurred. TRAVASOL contains no added phosphorus. Patients, especially those with hypophosphatemia, may require the addition of phosphate. To prevent hypocalcemia, calcium supplementation should always accompany phosphate administration. Excessive addition of calcium and phosphate increases the risk of the formation of calcium phosphate precipitates. Precipitates have been reported even in the absence of phosphate salt in the solution. Precipitation following passage through an in-line filter and suspected in vivo precipitate formation has also been reported. If signs of pulmonary distress occur, stop the infusion and initiate a medical evaluation. In addition to inspection of the solution [see Dosage and Administration (2.1 , 2.2 , 2.3 , 2.4 )] , the infusion set and catheter should also periodically be checked for precipitates.

5.2 Hypersensitivity Reactions Hypersensitivity reactions including anaphylaxis have been reported with parenteral nutrition solutions containing TRAVASOL. Stop the infusion immediately and treat patient accordingly if any signs or symptoms of a hypersensitivity reaction develop. Signs or symptoms may include: hypotension, hypertension, peripheral cyanosis, tachycardia, dyspnea, vomiting, nausea, urticaria, rash, pruritus, erythema, hyperhidrosis, pyrexia, and chills.

5.3 Risk of Infections Patients who require parenteral nutrition are at high risk of infections because the nutritional components of these solutions can support microbial growth. Infection and sepsis may also occur as a result of the use of intravenous catheters to administer parenteral nutrition. The risk of infection is increased in patients with malnutrition-associated immunosuppression, hyperglycemia exacerbated by dextrose infusion, long-term use and poor maintenance of intravenous catheters, or immunosuppressive effects of other concomitant conditions, drugs, or other components of the parenteral formulation (e.g., lipid emulsion). To decrease the risk of infection, ensure aseptic technique in catheter placement and maintenance, as well as aseptic technique in the preparation and administration of the nutritional formula. 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 and insertion site for edema, redness and discharge.

5.4 Refeeding Syndrome Refeeding severely undernourished patients may result in 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. To prevent these complications, monitor severely undernourished patients and slowly increase nutrient intakes.

5.5 Hyperglycemia or Hyperosmolar Hyperglycemic State Administration of parenteral nutrition solutions containing dextrose in patients with diabetes mellitus, impaired glucose tolerance may worsen hyperglycemia. Administration of dextrose at a rate exceeding the patient’s utilization rate may lead to hyperglycemia, coma, and death. Patients with underlying confusion and renal impairment who receive dextrose infusions, may be at greater risk of developing hyperosmolar hyperglycemic state. Monitor blood glucose levels and treat hyperglycemia to maintain optimum levels while administering parenteral nutrition solutions containing dextrose. Insulin may be administered or adjusted to maintain optimal blood glucose levels during administration of parenteral nutrition solutions containing dextrose.

5.6 Vein Damage and Thrombosis TRAVASOL must be diluted and used as an admixture with or without dextrose, electrolytes and/or lipid emulsion. It is not for direct intravenous infusion. Solutions containing more than 5% dextrose or with an osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Dosage and Administration (2.2) ] . The infusion of hypertonic nutrient injections into a peripheral vein may result in vein irritation, vein damage, and/or thrombosis. The primary complication of peripheral access is venous thrombophlebitis, which manifests as pain, erythema, tenderness or a palpable cord. Remove the catheter as soon as possible, if thrombophlebitis develops.

5.7 Hepatobiliary Disorders Hepatobiliary disorders are known to develop in some patients without preexisting liver disease who receive parenteral nutrition, including cholecystitis, cholelithiasis, cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure. The etiology of these disorders is thought to be multifactorial and may differ between patients. Increase in blood ammonia levels and hyperammonemia may occur in patients receiving amino acid solutions, including TRAVASOL. In some patients this may indicate hepatic insufficiency or the presence of an inborn error of amino acid metabolism [see Contraindications (4) and Use in Specific Populations (8.4) ] . Monitor liver function parameters and ammonia levels. Patients developing signs of hepatobiliary disorders should be assessed early by a clinician knowledgeable in liver diseases in order to identify possible causative and contributory factors, and possible therapeutic and prophylactic interventions.

5.8 Aluminum Toxicity TRAVASOL contains no more than 25 mcg/L of aluminum. However, with prolonged parenteral administration in patients with renal impairment, the aluminum contained in TRAVASOL may reach toxic levels. Preterm infants are at a greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with renal impairment, 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.

5.9 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. […]

The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.

• Pulmonary embolism due to pulmonary vascular precipitates [see Warnings and Precautions (5.1) ]
• Hypersensitivity reactions [see Warnings and Precautions (5.2) ]
• Risk of Infections [see Warnings and Precautions (5.3) ]
• Refeeding syndrome [see Warnings and Precautions (5.4) ]
• Hyperglycemia or hyperosmolar hyperglycemic state [see Warnings and Precautions (5.5) ]
• Vein damage and thrombosis [see Warnings and Precautions (5.6) ]
• Hepatobiliary disorders [see Warnings and Precautions (5.7) ]
• Aluminum toxicity [see Warnings and Precautions (5.8) ]
• Parenteral Nutrition Associated Liver Disease [see Warnings and Precautions (5.9) ]
• Electrolyte imbalance and fluid overload [see Warnings and Precautions (5.10) ] The following adverse reactions from voluntary reports or clinical studies have been reported with TRAVASOL. Because many of these reactions were 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.
• Metabolic acidosis
• Alkalosis
• Osmotic diuresis and dehydration,
• Rebound hypoglycemia
• Hypo- and hyper-vitaminosis Adverse reactions include pulmonary vascular emboli, hypersensitivity reactions infection, refeeding syndrome, hyperglycemia and hyperosmolar hyperglycemic state, vein thrombosis, elevated liver function tests, hyperammonemia, electrolyte imbalances, and hypervolemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Pediatric Use : increased risk of hypoglycemia/hyperglycemia: monitor serum glucose concentrations. (8.4)

8.1 Pregnancy Risk Summary Limited published data with injectable amino acids solutions, including TRAVASOL in pregnant women are not sufficient to inform a drug associated risk for adverse developmental outcomes. However, malnutrition in pregnant women is associated with adverse maternal and fetal outcomes [see Clinical Considerations ]. Animal reproduction studies have not been conducted with injectable amino acids solutions, including TRAVASOL. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. Clinical Considerations Disease-Associated Maternal and/or Embryo-Fetal Risk Severe malnutrition in pregnant women 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.

8.2 Lactation Risk Summary There are no data available to assess the presence of injectable amino acids, including TRAVASOL in human milk, the effects of TRAVASOL on the breastfed infant or the effects on milk production. The lack of clinical data during lactation precludes a clear determination of the risk of TRAVASOL to a child during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRAVASOL and any potential adverse effects on the breastfed child from TRAVASOL or from the underlying maternal condition.

8.4 Pediatric Use Neonates, especially premature infants with low birth weight, are at increased risk of developing hypo- or hyperglycemia and therefore need close monitoring during treatment with intravenous glucose solutions to ensure adequate glycemic control in order to avoid potential long term adverse effects [see Dosage and Administration (2.7) ] . Plasma electrolyte concentrations should be closely monitored in the pediatric patients who may have impaired ability to regulate fluids and electrolytes. Hyperammonemia is of special significance in infants (birth to two years). This reaction appears to be related to a deficiency of the urea cycle amino acids of genetic or product origin. It is essential that blood ammonia be measured frequently in infants [see Warnings and Precautions (5.7) ]. Because of immature renal function, preterm infants receiving prolonged parenteral nutrition treatment with TRAVASOL may be at risk of aluminum toxicity [see Warnings and Precautions (5.8) ] . Patients, including pediatric patients, may be at risk for PNALD [see Warnings and Precautions (5.9) ] .

8.5 Geriatric Use Clinical studies with TRAVASOL have not been performed to determine whether subjects aged 65 and over respond differently from other younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

8.6 Renal Impairment In patients with impaired renal function, parenteral nutrition solutions containing TRAVASOL should be administered with caution. Frequent clinical evaluation and laboratory tests to monitor renal function such as serum electrolytes (especially phosphate and potassium) and fluid balance should be conducted [see Dosage and Administration (2.6), Warnings and Precautions (5.10) ].

8.7 Hepatic Impairment In patients with impaired liver function, parenteral nutrition solutions containing TRAVASOL should be administered starting at the low end of the dosing range [see Dosage and Administration (2.5) ] . Frequent clinical evaluation and laboratory tests to monitor liver function such as bilirubin and liver function parameters should be conducted [see Warnings and Precautions (5.7) ].

TRAVASOL is used as a supplement of nutrition in patients, providing amino acids parenterally. The amino acids provide the structural units that make up proteins and are used to synthesize proteins and other biomolecules or are oxidized to urea and carbon dioxide as a source of energy.