Clinimix E

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.

  The use of Clinimix E is contraindicated in: • Neonates (less than 28 days of age) 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)]. • Patients with known hypersensitivity to one or more amino acids or dextrose [see Warnings and Precautions (5.3)]. • Patients with inborn errors of amino acid metabolism due to risk of severe metabolic and neurologic complications. • Patients with pulmonary edema or acidosis due to low cardiac output.

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. In some cases, fatal outcomes due to pulmonary embolism have occurred. 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.

Precipitation with Ceftriaxone

Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing parenteral nutrition solutions, such as CLINIMIX E, in the same intravenous administration line. Do not administer ceftriaxone simultaneously with Clinimix E via a Y-site.

Deaths have occurred in neonates (less than 28 days of age) 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),Use in Specific Populations (8.4)].

In patients older than 28 days (including adults), ceftriaxone and Clinimix E may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid.

Hypersensitivity Reactions

Hypersensitivity/infusion reactions including anaphylaxis have been reported with CLINIMIX E. Stop 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.

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.

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.

Hyperglycemia or Hyperosmolar Hyperglycemic State

When using Clinimix E 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 CLINIMIX E. Insulin may be administered or adjusted to maintain optimal blood glucose levels during Clinimix E administration.

Vein Damage and Thrombosis

Solutions with osmolarity of 900 mOsm/L or greater must be infused through a central catheter. Clinimix E solutions containing more than 5% dextrose have an osmolarity greater than or equal to 900 mOsm/L. Clinimix E 2.75/10, 4.25/10, 4.25/25, 5/15, 5/20, and 5/25 are indicated for administration into a central vein only, such as the superior vena cava [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.

Clinimix E 2.75/5 and 4.25/5 are indicated for peripheral administration, or may be infused into a central vein [see Dosage and Administration (2.2)]. 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.

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. In some patients this may indicate hepatic insufficiency or the presence of an inborn error of amino acid metabolism [see Contraindications (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.

Aluminum Toxicity

Clinimix E contains no more than 25 mcg/L of aluminum. However, with prolonged parenteral administration in patients with renal impairment, the aluminum contained in CLINIMX E 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.

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. If Clinimix E treated patients develop liver test abnormalities consider discontinuation or dosage reduction.

Electrolyte Imbalance and Fluid Overload

Patients with renal impairment, such as pre-renal azotemia, renal obstruction, and protein-losing nephropathy may be at increased risk of electrolyte and fluid volume imbalance. Patients with cardiac insufficiency due to left ventricular systolic dysfunction are susceptible to excess fluid accumulation. Use Clinimix E with caution in patients with cardiac insufficiency or renal impairment. Clinimix E dosage may require adjustment with specific attention to fluid, protein, and electrolyte content in these patients.

Monitor renal function parameters. Patients developing signs of renal impairment should be assessed early by a clinician knowledgeable in renal disease in order to determine the appropriate Clinimix E dosage and other treatment options.

Monitoring/Laboratory Tests

Monitor fluid and electrolyte status, serum osmolarity, blood glucose, liver and kidney function, blood count and coagulation parameters throughout treatment. In situations of severely elevated electrolyte levels, stop Clinimix E until levels have been corrected.

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.

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	C2H3NaO2•3H2O
Potassium Phosphate, dibasic	K2HPO4
Magnesium Chloride	MgCl2•6H2O
Sodium Chloride	NaCl
Essential Amino Acids
Leucine	(CH3)2 CHCH2CH (NH2) COOH
Isoleucine	CH3CH2CH (CH3) CH (NH2) COOH
Valine	(CH3)2 CHCH (NH2) COOH
Lysine (added as the hydrochloride salt)	H2N (CH2)4 CH (NH2) COOH
Phenylalanine	(C6H5) CH2 CH (NH2) COOH
Histadine	(C3H3N2) CH2CH (NH2) COOH
Threonine	CH3CH (OH) CH (NH2) COO
Methionine	CH3S (CH2)2 CH (NH2) COOH
Tryptophan	(C8H6N) CH2 CH (NH2) COOH
Nonessential Amino Acids
Alanine	CH3CH (NH2) COOH
Arginine	H2NC (NH) NH (CH2)3 CH (NH2) COOH
Glycine	H2NCH2COOH
Proline	[(CH2)3 NH CH] COOH
Serine	HOCH2CH (NH2) COOH
Tyrosine	[C6H4 (OH)] CH2CH (NH2) COOH

The injection port chamber contains dextrose with calcium. The formula for Calcium Chloride is: CaCl2•2H2O. Dextrose, USP, is chemically designated D-glucose, monohydrate (C6H12O6 • H2O) 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.

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

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	Code 2B7713 NDC 0338-1107-04
Clinimix E 2.75/10 sulfite-free (2.75% Amino Acid with Electrolytes in 10% Dextrose with Calcium) Injection	Code 2B7736 NDC 0338-1143-03	Code 2B7714 NDC 0338-1109-04
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 4.25/25 sulfite-free (4.25% Amino Acid with Electrolytes in 25% Dextrose with Calcium) Injection	Code 2B7739 NDC 0338-1146-03	Code 2B7719 NDC 0338-1119-04
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 5/25 sulfite-free (5% Amino Acid with Electrolytes in 25% Dextrose with Calcium) Injection	Code 2B7742 NDC 0338-1149-03	Code 2B7723 NDC 0338-1127-04

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 foil overwrap has been opened.

Do not use if the protective foil overwrap has been previously opened or damaged.

For storage of admixed solutions seeDosage and Administration (2.3, 2.4).