CLINIMIX E

Dosage and Administration, Instructions for Use ( 2.3 , 2.7 ) 04/2021 Warnings and Precautions (5.6) 04/2021 Dosage and Administration (2.1 , 2.3 , 2.4 , 2.6 , 2.8) 09/2020

1 INDICATIONS AND USAGE CLINIMIX E is indicated as a source of calories, protein, and electrolytes for patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. CLINIMIX E may be used to treat negative nitrogen balance in patients. CLINIMIX E is indicated as a source of calories, protein, and electrolytes for patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. CLINIMIX E may be used to treat negative nitrogen balance in patients. ( 1 )

2 DOSAGE AND ADMINISTRATION See full prescribing information for information on preparation, administration, instructions for use, dosing considerations, including the recommended dosage in adults and pediatrics, and dosage modifications in patients with kidney disease. ( 2.1 , 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 ) 2.1 Preparation Prior to Administration • CLINIMIX E is available in a three port container configuration and a two port container configuration. • Three Port Container: the ports consist of one medication port, one additive port and one outlet port. Additives can be introduced to the container through the medication port and lipids through the additive port on the three port container. • Two Port Container: the ports consist of one medication port and one outlet port. Additives, including lipids, can be introduced to the container through the medication port on the two port container. • Tear protective overwrap at slit and remove solution container. Small amounts of moisture may be found on the solution container from water permeating from inside the container. The amount of permeated water is insufficient to affect the solution significantly. If larger amounts of water are found, the container should be checked for tears or leaks. • Inspect the container prior to activation. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Evaluate the following: • If the outlet or additive port protectors are damaged, detached, or not present, discard container as solution path sterility may be impaired. • Check to ensure seal between chambers is intact, solutions are contained in separate chambers, and the content of the individual chambers is clear, colorless or slightly yellow. Discard if the seal is broken or if the solution is bright yellow or yellowish brown. • Check for minute leaks by separately squeezing each chamber. If external leaks or leakage between the chambers are found, discard solution as sterility or stability may be impaired. • Lipids and/or additives can be introduced to the container after opening seal between chambers. Because additives may be incompatible, evaluate all additions to the plastic container for compatibility. Activate chambers of container prior to introduction of additives. Mix thoroughly when additives have been introduced. Supplemental medication may be added with a 19 to 22 gauge needle through the medication port. • Calcium and phosphate ratios must be considered. Excess addition of calcium and phosphate, especially in the form of mineral salts, may result in the formation of calcium phosphate precipitates [see Warnings and Precautions (5.1) ]. • Inspect the container to ensure precipitates have not formed during the mixing or addition of additives. A slight yellow color does not alter the quality and efficacy of this product. If lipid has been added, ensure the emulsion has not separated. Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. Discard the admixture if any of the above are observed. 2.2 Important Administration Instructions • Set the vent to the closed position on a vented intravenous administration set to prevent air embolism. • Use a dedicated line without any connections to avoid air embolism. • CLINIMIX E is for intravenous infusion only into a central or peripheral vein. The choice of a central or peripheral venous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 900 mOsm/L or greater must be infused through a central catheter [see Warnings and Precautions (5.7) ]. • For central vein infusion only: CLINIMIX E 4.25/10, 5/15, 5/20, 8/10, 8/14 • For central or peripheral vein infusion: CLINIMIX E 2.75/5 and 4.25/5 • The solution should be inspected for precipitates before admixing, a …

3 DOSAGE FORMS AND STRENGTHS CLINIMIX E injection is available in 1000 mL and 2000 mL dual chamber containers. The individual chambers contain essential and nonessential amino acids with electrolytes and dextrose with calcium. Table 7 describes the individual components of CLINIMIX E. Table 7: INGREDIENTS PER 100mL OF CLINIMIX E Strength of CLINIMIX E CLINIMIX E 2.75/5 sulfite‐free (2.75% Amino Acid in 5% Dextrose) Injection CLINIMIX E 4.25/5 sulfite‐free (4.25% Amino Acid in 5% Dextrose) Injection CLINIMIX E 4.25/10 sulfite‐free (4.25% Amino Acid in 10% Dextrose) Injection CLINIMIX E 5/15 sulfite‐free (5% Amino Acid in 15% Dextrose) Injection CLINIMIX 5/20 sulfite‐free (5% Amino Acid in 20% Dextrose) Injection CLINIMIX E 8/10 sulfite‐free (8% Amino Acid in 10% Dextrose) Injection CLINIMIX E 8/14 sulfite‐free (8% Amino Acid in 14% Dextrose) Injection Dextrose Hydrous, USP (g/100 mL) 5 5 10 15 20 10 14 Amino Acids (g/100 mL) 2.75 4.25 4.25 5 5 8 8 Total Nitrogen (mg/100 mL) 454 702 702 826 826 1320 1320 Essential Amino Acids (mg/100 mL) Leucine 201 311 311 365 365 584 584 Isoleucine 165 255 255 300 300 480 480 Valine 160 247 247 290 290 464 464 Lysine (added as the hydrochloride salt) 159 247 247 290 290 464 464 Phenylalanine 154 238 238 280 280 448 448 Histidine 132 204 204 240 240 384 384 Threonine 116 179 179 210 210 336 336 Methionine 110 170 170 200 200 320 320 Tryptophan 50 77 77 90 90 144 144 Nonessential Amino Acids (mg/100 mL) Alanine 570 880 880 1035 1035 1656 1656 Arginine 316 489 489 575 575 920 920 Glycine 283 438 438 515 515 824 824 Proline 187 289 289 340 340 544 544 Serine 138 213 213 250 250 400 400 Tyrosine 11 17 17 20 20 32 32 Electrolytes (mg/100 mL) Sodium Acetate Trihydrate, USP 217 297 297 340 340 0 0 Dibasic Potassium Phosphate, USP 261 261 261 261 261 261 261 Sodium Chloride, USP 112 77 77 59 59 205 205 Magnesium Chloride, USP 51 51 51 51 51 51 51 Calcium Chloride Dihydrate, USP 33 33 33 33 33 33 33 Electrolyte Profile (mEq/L) Balanced by ions from amino acids. Sodium 35 35 35 35 35 35 35 Potassium 30 30 30 30 30 30 30 Magnesium 5 5 5 5 5 5 5 Calcium 4.5 (2.2 mmol/L) 4.5 (2.2 mmol/L) 4.5 (2.2 mmol/L) 4.5 (2.2 mmol/L) 4.5 (2.2 mmol/L) 4.5 (2.2 mmol/L) 4.5 (2.2 mmol/L) Acetate Derived from glacial acetic acid (for pH adjustment) and sodium acetate. 51 70 70 80 80 83 83 Chloride Contributed by calcium chloride, lysine hydrochloride, magnesium chloride, sodium chloride, and hydrochloric acid. 39 39 39 39 39 76 76 Phosphate (as HPO 4 = ) 30 (15 mmol/L) 30 (15 mmol/L) 30 (15 mmol/L) 30 (15 mmol/L) 30 (15 mmol/L) 30 (15 mmol/L) 30 (15 mmol/L) pH pH of sulfite-free amino acid injection with electrolytes in the outlet port chamber was adjusted with glacial acetic acid and pH of dextrose injection port chamber was adjusted with hydrochloric acid. (Range) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) 6.0 (4.5 to 7.0) Osmolarity (mOsmol/L) (calc) 665 815 1070 1395 1650 1450 1650 Caloric Content (kcal/L) From Dextrose 170 170 340 510 680 343 477 From Amino Acids 110 170 170 200 200 320 320 TOTAL (Dextrose and Amino Acids) 280 340 510 710 880 663 797 CLINIMIX E injection is available in multiple strengths. See full prescribing information for detailed description of each formulation. ( 3 , 11 )

4 CONTRAINDICATIONS The use of CLINIMIX E is contraindicated in: 1. Neonates (28 days of age or younger) receiving concomitant treatment with ceftriaxone, even if separate infusion lines are used, due to the risk of fatal ceftriaxone calcium salt precipitation in the neonate’s bloodstream [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4) ] . 2. Patients with known hypersensitivity to one or more amino acids or dextrose [see Warnings and Precautions (5.3) ] . 3. Patients with inborn errors of amino acid metabolism due to risk of severe metabolic and neurologic complications. 4. Patients with pulmonary edema or acidosis due to low cardiac output. • Concomitant treatment with ceftriaxone in neonates (28 days of age or younger). ( 4 ) • Known hypersensitivity to one or more amino acids or dextrose. ( 4 ) • Inborn errors of amino acid metabolism. ( 4 ) • Patients with pulmonary edema or acidosis due to low cardiac output. ( 4 )

6 ADVERSE REACTIONS 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) ] • Death in neonates due to calcium-ceftriaxone precipitates [see Warnings and Precautions (5.2) ] • Hypersensitivity reactions [see Warnings and Precautions (5.3) ] • Risk of Infections [see Warnings and Precautions (5.4) ] • Refeeding syndrome [see Warnings and Precautions (5.5) ] • Hyperglycemia or hyperosmolar hyperglycemic state [see Warnings and Precautions (5.6) ] • Vein damage and thrombosis [see Warnings and Precautions (5.7) ] • Hepatobiliary disorders [see Warnings and Precautions (5.8) ] • Parenteral Nutrition Associated Liver Disease (PNALD) [see Warnings and Precautions (5.10) ] • Electrolyte imbalance and fluid overload [see Warnings and Precautions (5.11) ] The following adverse reactions from voluntary reports or clinical studies have been reported with CLINIMIX E. 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. • Diuresis • Extravasation • Glycosuria • Hyperglycemia • Hyperosmolar coma Adverse reactions include diuresis, extravasation, glycosuria, hyperglycemia, and hyperosmolar coma. ( 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

7 DRUG INTERACTIONS 7.1 Drugs that Can Cause Hyperkalemia Because of its potassium content, CLINIMIX E should be administered with caution in patients treated with agents or products that can cause hyperkalemia or increase the risk of hyperkalemia, such as potassium sparing diuretics (amiloride, spironolactone, triamterene), with ACE inhibitors, angiotensin II receptor antagonists, or the immunosuppressants tacrolimus and cyclosporine.

8 USE IN SPECIFIC POPULATIONS Pediatric Use: increased risk of hypoglycemia/hyperglycemia: monitor serum glucose concentrations. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no adequate or well-controlled studies in pregnant women with CLINIMIX E. Additionally, animal reproduction studies have not been conducted with amino acids and electrolytes and dextrose. It is not known whether CLINIMIX E can cause fetal harm when administered to a pregnant woman. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. However, the estimated 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 Based on clinical practice guidelines, parenteral nutrition should be considered in cases of severe maternal malnutrition where nutritional requirements cannot be fulfilled by the enteral route because of the risks to the fetus associated with severe malnutrition, such as preterm delivery, low birth weight, intrauterine growth restriction, congenital malformations and perinatal mortality. 8.2 Lactation Risk Summary It is not known whether CLINIMIX E is present in human milk. There are no data on the effects of CLINIMIX E on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CLINIMIX E and any potential adverse effects on the breastfed child from CLINIMIX E or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of CLINIMIX E in pediatric patients have not been established by adequate and well-controlled studies. Use of dextrose, amino acid infusions and electrolytes in pediatric patients is based on clinical practice [see Dosage and Administration (2.8) ] . Deaths have occurred in neonates (28 days of age or younger) who received concomitant intravenous calcium-containing solutions with ceftriaxone resulting from calcium-ceftriaxone precipitates in the lungs and kidneys, even when separate infusion lines were used. CLINIMIX E is contraindicated in neonates receiving ceftriaxone [see Contraindications (4) , Warnings and Precautions (5.2) ]. Newborns, especially those born premature and 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. Hypoglycemia in the newborn can cause prolonged seizures, coma and brain damage. Hyperglycemia has been associated with intraventricular hemorrhage, late onset bacterial and fungal infection, retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, prolonged length of hospital stay, and death. Plasma electrolyte concentrations should be closely monitored in the pediatric population as this population may have impaired ability to regulate fluids and electrolytes. Because of immature renal function, preterm infants receiving prolonged treatment with CLINIMIX E, may be at risk of aluminum toxicity [see Warnings and Precautions (5.9) ] . Patients, including pediatric patients, may be at risk for Parenteral Nutrition Associated Liver Disease (PNALD) [see Warnings and Precautions (5.10) ] . 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 (5.8) ] . 8.5 Geriatric Use Clinical studies of CLINIMIX E did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from other younger subjects. Other reported clinical experience has not identified differences …

11 DESCRIPTION CLINIMIX E sulfite-free (amino acids with electrolytes in dextrose with calcium) injection for intravenous use consists of sterile, nonpyrogenic, hypertonic solutions in a dual chamber container. The outlet port chamber contains essential and nonessential amino acids with electrolytes. The formulas for the individual electrolytes and amino acids are provided in Table 8 . Table 8: Formulas for Electrolytes and Amino Acids Electrolytes Sodium Acetate C 2 H 3 NaO 2 •3H 2 O Potassium Phosphate, dibasic K 2 HPO 4 Magnesium Chloride MgCl 2 •6H 2 O Sodium Chloride NaCl Essential Amino Acids Leucine (CH 3 ) 2 CHCH 2 CH (NH 2 ) COOH Isoleucine CH 3 CH 2 CH (CH 3 ) CH (NH 2 ) COOH Valine (CH 3 ) 2 CHCH (NH 2 ) COOH Lysine (added as the hydrochloride salt) H 2 N (CH 2 ) 4 CH (NH 2 ) COOH Phenylalanine (C 6 H 5 ) CH 2 CH (NH 2 ) COOH Histidine (C 3 H 3 N 2 ) CH 2 CH (NH 2 ) COOH Threonine CH 3 CH (OH) CH (NH 2 ) COO Methionine CH 3 S (CH 2 )2 CH (NH 2 ) COOH Tryptophan (C 8 H 6 N) CH 2 CH (NH 2 ) COOH Nonessential Amino Acids Alanine CH 3 CH (NH 2 ) COOH Arginine H 2 NC (NH) NH (CH 2 )3 CH (NH 2 ) COOH Glycine H 2 NCH 2 COOH Proline [(CH 2 ) 3 NH CH] COOH Serine HOCH 2 CH (NH 2 ) COOH Tyrosine [C 6 H 4 (OH)] CH 2 CH (NH 2 ) COOH The injection port chamber contains dextrose with calcium. The formula for Calcium Chloride is: CaCl 2 •2H 2 O. Dextrose, USP, is chemically designated D-glucose, monohydrate (C 6 H 12 O 6 • H 2 O) and has the following structure: Dextrose is derived from corn. See Table 7 for composition, pH, osmolarity, ionic concentration and caloric content of the admixed product [see Dosage Forms and Strengths (3) ]. The dual chamber container is a lipid-compatible plastic container (PL 2401 Plastic). CLINIMIX E contains no more than 25 mcg/L of aluminum. Dextrose Hydrous Structural Formula

10 OVERDOSAGE An increased infusion rate of CLINIMIX E can cause hyperglycemia, hyperosmolality, and adverse effects on water and electrolyte balance [see Warnings and Precautions (5.6 , 5.11 )]. Severe hyperglycemia and severe dilutional hyponatremia, and their complications, can be fatal. Discontinue infusion and institute appropriate corrective measures in the event of overhydration or solute overload during therapy, with particular attention to respiratory and cardiovascular systems . For current information on the management of poisoning or overdosage, contact the National Poison Control Center at 1-800-222-1222 or www.poison.org .

16 HOW SUPPLIED/STORAGE AND HANDLING CLINIMIX E (amino acids with electrolytes in dextrose with calcium) injection (sulfite-free) is available in 1000 mL and 2000 mL volumes (See Table 9 ). Table 9: CLINIMIX E Formulations (per 07-19-00-4607 and BE-30-03-649) After mixing, the product represents 1000 mL Code and NDC Number 2000 mL Code and NDC Number CLINIMIX E 2.75/5 sulfite-free (2.75% Amino Acid with Electrolytes in 5% Dextrose with Calcium) Injection Code 2B7735 NDC 0338-1142-03 CLINIMIX E 4.25/5 sulfite-free (4.25% Amino Acid with Electrolytes in 5% Dextrose with Calcium) Injection Code 2B7737 NDC 0338-1144-03 Code 2B7716 NDC 0338-1113-04 CLINIMIX E 4.25/10 sulfite-free (4.25% Amino Acid with Electrolytes in 10% Dextrose with Calcium) Injection Code 2B7738 NDC 0338-1145-03 Code 2B7717 NDC 0338-1115-04 CLINIMIX E 5/15 sulfite-free (5% Amino Acid with Electrolytes in 15% Dextrose with Calcium) Injection Code 2B7740 NDC 0338-1147-03 Code 2B7721 NDC 0338-1123-04 CLINIMIX E 5/20 sulfite-free (5% Amino Acid with Electrolytes in 20% Dextrose with Calcium) Injection Code 2B7741 NDC 0338-1148-03 Code 2B7722 NDC 0338-1125-04 CLINIMIX E 8/10 sulfite-free (8% Amino Acid with Electrolytes in 10% Dextrose with Calcium) Injection Code EADB9943 NDC 0338-210-06 Code EADB9945 NDC 0338-0214-04 CLINIMIX E 8/14 sulfite-free (8% Amino Acid with Electrolytes in 14% Dextrose with Calcium) Injection Code EADB9963 NDC 0338-0202-06 Code EADB9965 NDC 0338-0206-04 Table 9: CLINIMIX E Formulations (per BE-30-04-048) After mixing, the product represents 1000 mL Code and NDC Number 2000 mL Code and NDC Number CLINIMIX E 2.75/5 sulfite-free (2.75% Amino Acid with Electrolytes in 5% Dextrose with Calcium) Injection Code 2B7735L NDC 0338-7020-01 / CLINIMIX E 4.25/5 sulfite-free (4.25% Amino Acid with Electrolytes in 5% Dextrose with Calcium) Injection Code 2B7737L NDC 0338-7022-01 Code 2B7716L NDC 0338-7024-01 CLINIMIX E 4.25/10 sulfite-free (4.25% Amino Acid with Electrolytes in 10% Dextrose with Calcium) Injection Code 2B7738L NDC 0338-7026-01 Code 2B7717L NDC 0338-7028-01 CLINIMIX E 5/15 sulfite-free (5% Amino Acid with Electrolytes in 15% Dextrose with Calcium) Injection Code 2B7740L NDC 0338-7030-01 Code 2B7721L NDC 0338-7032-01 CLINIMIX E 5/20 sulfite-free (5% Amino Acid with Electrolytes in 20% Dextrose with Calcium) Injection Code 2B7741L NDC 0338-7034-01 Code 2B7722L NDC 0338-7036-01 CLINIMIX E 8/10 sulfite-free (8% Amino Acid with Electrolytes in 10% Dextrose with Calcium) Injection Code EADB9943 NDC 0338-0210-06 Code EADB9945 NDC 0338-0214-04 CLINIMIX E 8/14 sulfite-free (8% Amino Acid with Electrolytes in 14% Dextrose with Calcium) Injection Code EADB9963 NDC 0338-0202-06 Code EADB9965 NDC 0338-0206-04 Minimize exposure of CLINIMIX E to heat and avoid excessive heat. Protect from freezing. Store CLINIMIX E at room temperature (25°C/77°F) (may briefly store at up to 40°C/104°F). Refrigerated storage is limited to 9 days once the protective overwrap has been opened. Do not use if the protective overwrap has been previously opened or damaged. For storage of admixed solutions see Dosage and Administration (2.3 , 2.4 ) .