Source: FDA, National Drug Code (US) Revision Year: 2021
The use of CLINIMIX E is contraindicated in:
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 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/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.
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 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.
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 dehydration, resulting in a transient reduction in glomerular filtration rate and pre-renal azotemia, 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.
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 4.25/10, 5/15, 5/20, 8/10 and 8/14 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 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.
CLINIMIX E contains no more than 25 mcg/L of aluminum. The aluminum contained in CLINIMIX E may reach toxic levels with prolonged administration in patients with impaired kidney function.
Preterm infants are at greater risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum. Patients with impaired kidney function, 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.
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.
Patients with abnormal renal function due to pre-renal azotemia, renal obstruction, or intrinsic kidney disease 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 kidney disease. 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 kidney disease should be assessed early by a clinician knowledgeable in kidney disease in order to determine the appropriate CLINIMIX E dosage and other treatment options.
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.
The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information.
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.
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.
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.
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.
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.
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)].
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 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.
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