CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Aminosyn-PF 7% Sulfite-Free, (an amino acid injection -- pediatric formula) contains mixture of essential and nonessential amino acids as well as taurine. The amino acid composition has been specifically formulated to provide well-tolerated nitrogen source for nutritional support and therapy for infants and young children. When administered in conjunction with cysteine hydrochloride additive, Aminosyn-PF 7% results in plasma amino acid concentrations approximating profile consistent with that of breast-fed infant. The rationale for Aminosyn-PF 7% is based on the observation of inadequate levels of essential amino acids in the plasma of infants receiving total parenteral nutrition (TPN) using conventional amino acid solutions. Clinical studies in infants who required TPN therapy showed that infusion of Aminosyn-PF 7% resulted in plasma amino acid concentrations approximating those of normal breast or formula fed infants. In addition, weight gains, nitrogen balance, and serum protein concentrations were consistent with an improving nutritional status.When infused with hypertonic dextrose as calorie source, supplemented with cysteine hydrochloride, electrolytes, vitamins, and minerals, Aminosyn-PF 7% provides TPN for infants and young children, with the exception of essential fatty acids. It is thought that the acetate from lysine acetate under the conditions of parenteral nutrition, does not impact net acid-base balance when renal and respiratory functions are normal. Clinical evidence seems to support this thinking; however, confirmatory experimental evidence is not available. The amounts of sodium and acetate in Aminosyn-PF 7% are not of clinical significance. The addition of cysteine hydrochloride additive will contribute to the chloride load. The electrolyte content of any additives that are introduced should be carefully considered and included in input computations. The human newborn conjugates bile with taurine which becomes the primary method of biliary excretion. Taurine deficiency because of its effect on bile salt conjugation and, therefore, on bile salt flow may be of major importance in the genesis of cholestasis. Taurine has also been shown to play role in central nervous system development.

DESCRIPTION SECTION.

DESCRIPTION. Aminosyn(R)-PF 7%, Sulfite-Free, (an amino acid injection -- pediatric formula) is sterile, nonpyrogenic solution for intravenous infusion. Aminosyn(R)-PF 7% is oxygen sensitive. The formulation is described below:Aminosyn-PF 7%An Amino Acid Injection -- Pediatric FormulaEssential Amino Acids (mg/100 mL)Isoleucine534Leucine831Lysine (acetate)475Methionine125Phenylalanine300Threonine360Tryptophan125Valine452 Amount cited is for lysine alone and does not include the acetate salt.Nonessential Amino Acids (mg/100 mL)Alanine490Arginine861L-Aspartic Acid370L-Glutamic Acid576Glycine270Histidine220Proline570Serine347Taurine50Tyrosine44Electrolytes (mEq/L)Sodium (Na+) (mEq/L)NonePotassium (K+) (mEq/L)NoneChloride (Cl) (mEq/L)NoneAcetate (C2H3O2)a (mEq/L)32.5a From lysine acetate.Product CharacteristicsProtein Equivalent (Approx. grams/L)70Total Nitrogen (grams/L)10.69Osmolarity (mOsmol/L)561pH (range)5.5 (5.0 to 6.5)The formulas for the individual amino acids present in Aminosyn-PF 7% are as follows:Essential Amino AcidsIsoleucine, USPC6H13NO2 Leucine, USPC6H13NO2 Lysine Acetate, USPC6H14N2O2 CH3COOHMethionine, USPC5H11NO2SPhenylalanine, USPC9H11NO2 Threonine, USPC4H9NO3 Tryptophan, USPC11H12N2O2 Valine, USPC5H11NO2 Nonessential Amino AcidsAlanine, USPC3H7NO2 Glycine, USPC2H5NO2 Arginine, USPC6H14N4O2 L-Aspartic AcidC4H7NO4 HO2CCH2CH(NH2)CO2HL-Glutamic AcidC5H9NO4 HO2CCH2CHCH(NH2)CO2HHistidine, USPC6H9N3O2 Proline, USPC5H9NO2 Serine, USPC3H7NO3 TaurineC2H7NO3STyrosine, USPC9H11NO3 The flexible plastic container is fabricated from specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly.Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.Exposure to temperatures above 25C/77F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The total daily dose of the solution depends on the daily protein requirements and on the patients metabolic and clinical response.Pediatric requirements for parenteral nutrition are constrained by the greater relative fluid requirements of the infant and greater caloric requirements per kilogram than in the adult.The recommended intravenous dose of Aminosyn-PF 7%, Sulfite-Free, (an amino acid injection -- pediatric formula) is up to 2.5 amino acid/kg/day for infants up to 10 kg. For infants and children larger than 10 kg, the total daily dose of amino acids should be up to 25 amino acids/day for the first 10 kg of body weight plus to 1.25 amino acid for each kg of body weight over 10 kg. Initial amino acid dosage levels of g/kg/day may be increased gradually in increments of 0.5 g/kg/day to approximate desired intake levels.Aminosyn-PF 7% should be diluted with dextrose prior to use. Nonprotein calories should constitute approximately 100 to 130 kcal/kg/day. Part of the nonprotein caloric requirement may be provided as lipid emulsion administered concurrently to provide up to 60% of daily calories at dose not to exceed g fat/kg/day. Fluid intake for the infant receiving central venous TPN should be approximately 125 mL/kg/day (range: 100 to 175 mL/kg/day), depending on the clinical condition of the patient. Premature infants with respiratory distress syndrome suspected of having patent ductus arteriosus should be given fluids more cautiously.Cysteine is considered to be an essential amino acid for infants, especially preterm infants with potentially immature enzyme pathways. Therefore, addition of cysteine supplement to the TPN admixture is recommended. The intake of cysteine by the preterm infant ingesting maternal milk is approximately 78 mg/kg/day. The suggested intravenous dosage level for Cysteine Hydrochloride Injection, USP is 500 mg (10 mL) for every 12.5 (179 mL) of Aminosyn-PF 7% administered (see package insert for Cysteine Hydrochloride Injection, USP). In order to avoid potential insolubility of cysteine hydrochloride in admixtures, the foregoing concentration should not be exceeded.In many patients, provision of adequate calories in the form of hypertonic dextrose may require the administration of exogenous insulin to prevent hyperglycemia and glycosuria. To prevent rebound hypoglycemia, solution containing 5% dextrose should be administered when hypertonic dextrose solutions are abruptly discontinued.SERUM ELECTROLYTES SHOULD BE MONITORED FREQUENTLY. Electrolytes may be added to the nutrient solution as indicated by the patients clinical condition and laboratory determinations of plasma values. Major electrolytes are sodium, chloride, potassium, phosphate, magnesium and calcium. Daily administration of intravenous vitamin supplements including complete complement of fat and water-soluble vitamins is required. Trace metal additives including zinc, copper, manganese, and chromium should also be provided, especially when long-term parenteral therapy is anticipated.Calcium and phosphorus are added to the solution as indicated.Potentially incompatible ions such as calcium and phosphate may be added to alternate infusate bottles to avoid precipitation. In patients with hyperchloremic or other metabolic acidosis, sodium and potassium may be added as the acetate or lactate salts to provide bicarbonate alternates. Bicarbonate should not be administered during infusion of the nutritional solution unless deemed absolutely necessary.Additives may be incompatible. Consult with pharmacist, if available. When introducing additives, use aseptic technique, mix thoroughly and do not store.To ensure the precise delivery of the small volumes of fluid necessary for total parenteral nutrition in infants, accurately calibrated and reliable infusion systems should be used.Central Venous NutritionHypertonic mixtures of amino acids and dextrose may be safely administered by continuous infusion through central venous catheter with the tip located in the superior vena cava. Initial infusion rates should be slow, and gradually increased to the recommended 60-125 mL per kilogram body weight per day. If administration rate should fall behind schedule, no attempt to catch up to planned intake should be made. In addition to meeting protein needs, the rate of administration, particularly during the first few days of therapy, is governed by the patients glucose tolerance. Daily intake of amino acids and dextrose should be increased gradually to the maximum required dose as indicated by frequent determinations of glucose levels in blood and urine.Peripheral Parenteral NutritionFor patients in whom the central venous route is not indicated and who can consume adequate calories enterally, Aminosyn-PF 7% may be administered by peripheral vein with parenteral nonprotein calories. The concentration of dextrose in the final admixture is to 10%, and simultaneous administration of lipid emulsion is recommended both as calorie source and to attenuate the potentially irritating effects of the hypertonic nutritional admixture. Fat emulsion may comprise up to 60% of the daily caloric intake at dosage level not to exceed g fat/kg/day. It is essential that peripheral infusion be accompanied by adequate caloric intake.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. COLOR VARIATION FROM PALE YELLOW TO YELLOW IS NORMAL AND DOES NOT ALTER EFFICACY.WARNING: Do not use flexible container in series connections.

PRECAUTIONS SECTION.

PRECAUTIONS. Clinical evaluation and periodic laboratory determinations are necessary to monitor changes in fluid balance, electrolyte concentrations, and acid-base balance during prolonged parenteral therapy or whenever the condition of the patient warrants such evaluation. Significant deviations from normal concentrations may require the use of additional electrolyte supplements.Strongly hypertonic nutrient solutions should be administered via an intravenous catheter placed in central vein, preferably the superior vena cava.Care should be taken to avoid circulatory overload, particularly in patients with cardiac insufficiency.Special care must be taken when giving hypertonic dextrose to diabetic or pre-diabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required.Administration of glucose at rate exceeding the patients utilization rate may lead to hyperglycemia, coma, and death.The effect of infusion of amino acids, without dextrose, upon carbohydrate metabolism of children is not known at this time. It is essential to provide adequate exogenous dextrose calories concurrently with amino acids. Administration of amino acids without carbohydrates may result in the accumulation of ketone bodies in the blood. Correction of this ketonemia may be achieved by the administration of carbohydrate.Essential fatty acid deficiency (EFAD) is becoming increasingly recognized in patients on long term TPN (more than days). The use of fat emulsion to provide -- 10% of total caloric intake as linoleic acid may prevent EFAD.Peripheral administration of Aminosyn-PF 7%, Sulfite-Free, (an amino acid injection -- pediatric formula) requires appropriate dilution and provision of adequate calories. Care should be taken to assure proper placement of the needle within the lumen of the vein. The venipuncture site should be inspected frequently for signs of infiltration. If venous thrombosis or phlebitis occurs, discontinue infusions or change infusion site and initiate appropriate treatment.Extraordinary electrolyte losses such as may occur during protracted nasogastric suction, vomiting, diarrhea, or gastrointestinal fistula drainage may necessitate additional electrolyte supplementation.Metabolic acidosis can be prevented or readily controlled by adding portion of the cations in the electrolyte mixture as acetate salts and in the case of hyperchloremic acidosis, by keeping the total chloride content of the infusate to minimum.Aminosyn-PF 7% contains no chloride.Aminosyn-PF 7% 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. To assure adequate intake, serum levels should be monitored frequently.Aminosyn-PF 7% contains no more than 25 mcg/L of aluminum. To minimize the risk of possible incompatabilities arising from mixing this solution with other additives that may be prescribed, the final infusate should be inspected for cloudiness or precipitation immediately after mixing, prior to administration, and periodically during administration.SPECIAL PRECAUTIONS FORCENTRAL INFUSIONSADMINISTRATION BY CENTRAL VENOUS CATHETER SHOULD BE USED ONLY BY THOSE FAMILIAR WITH THIS TECHNIQUE AND ITS COMPLICATIONS.. Central vein infusion (with added concentrated carbohydrate solutions) of amino acid solutions requires knowledge of nutrition as well as clinical expertise in recognition and treatment of complications. Attention must be given to solution preparation, administration and patient monitoring. IT IS ESSENTIAL THAT CAREFULLY PREPARED PROTOCOL, BASED ON CURRENT MEDICAL PRACTICES, BE FOLLOWED, PREFERABLY BY AN EXPERIENCED TEAM.SUMMARY HIGHLIGHTS OF COMPLICATIONS (See also Current Medical Literature).1.TechnicalThe placement of central venous catheter should be regarded as surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.2.SepticThe constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.Solutions should ideally be prepared in the hospital pharmacy under laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to brief period of time, preferably less than 24 hours.Administration time for single container and set should never exceed 24 hours.3.MetabolicThe following metabolic complications have been reported with TPN administration: Metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, hyperglycemia and glycosuria, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.Administration of glucose at rate exceeding the patients utilization rate may lead to hyperglycemia, coma and death. CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen-containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.. 1.TechnicalThe placement of central venous catheter should be regarded as surgical procedure. One should be fully acquainted with various techniques of catheter insertion. For details of technique and placement sites, consult the medical literature. X-ray is the best means of verifying catheter placement. Complications known to occur from the placement of central venous catheters are pneumothorax, hemothorax, hydrothorax, artery puncture and transection, injury to the brachial plexus, malposition of the catheter, formation of arteriovenous fistula, phlebitis, thrombosis and air and catheter emboli.. 2.SepticThe constant risk of sepsis is present during administration of total parenteral nutrition. It is imperative that the preparation of the solution and the placement and care of catheters be accomplished under strict aseptic conditions.Solutions should ideally be prepared in the hospital pharmacy under laminar flow hood using careful aseptic technique to avoid inadvertent touch contamination. Solutions should be used promptly after mixing. Storage should be under refrigeration and limited to brief period of time, preferably less than 24 hours.Administration time for single container and set should never exceed 24 hours.. 3.MetabolicThe following metabolic complications have been reported with TPN administration: Metabolic acidosis and alkalosis, hypophosphatemia, hypocalcemia, osteoporosis, hyperglycemia and glycosuria, rebound hypoglycemia, osmotic diuresis and dehydration, elevated liver enzymes, hypo- and hypervitaminosis, electrolyte imbalances and hyperammonemia in children. Frequent evaluations are necessary especially during the first few days of therapy to prevent or minimize these complications.Administration of glucose at rate exceeding the patients utilization rate may lead to hyperglycemia, coma and death. CLINICAL EVALUATION AND LABORATORY DETERMINATIONS, AT THE DISCRETION OF THE ATTENDING PHYSICIAN ARE NECESSARY FOR PROPER MONITORING DURING ADMINISTRATION. Do not withdraw venous blood for blood chemistries through the peripheral infusion site, as interference with estimations of nitrogen-containing substances may occur. Blood studies should include glucose, urea nitrogen, serum electrolytes, ammonia, cholesterol, acid-base balance, serum proteins, kidney and liver function tests, osmolarity and hemogram. White blood count and blood cultures are to be determined if indicated. Urinary osmolality and glucose should be determined as necessary.. Pregnancy Category C. Animal reproduction studies have not been conducted with Aminosyn-PF 7%. It is also not known whether Aminosyn-PF 7% can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Aminosyn-PF 7% should be given to pregnant woman only if clearly needed.

WARNINGS SECTION.

WARNINGS. Safe, effective use of parenteral nutrition requires knowledge of nutrition as well as clinical expertise in recognition and treatment of the complications which can occur. FREQUENT EVALUATION AND LABORATORY DETERMINATIONS ARE NECESSARY FOR PROPER MONITORING OF PARENTERAL NUTRITION. Studies should include blood sugar, serum proteins, kidney and liver function tests, electrolytes, hemogram, carbon dioxide content, serum osmolalities, blood cultures, and blood ammonia levels.Administration of amino acids in the presence of impaired renal function or gastrointestinal bleeding may augment an already elevated blood urea nitrogen. Patients with azotemia from any cause should not be infused with amino acids without regard to total nitrogen intake.Administration of intravenous solutions can cause fluid and/or solute overload resulting in dilution of serum electrolyte concentrations, overhydration, congested states, or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the solutions.Administration of amino acid solutions to patient with hepatic insufficiency may result in plasma amino acid imbalances, hyperammonemia, prerenal azotemia, stupor and coma.Hyperammonemia is of special significance in infants, as its occurrence in the syndrome caused by genetic metabolic defects is sometimes associated, although not necessarily in causal relationship, with mental retardation. This reaction appears to be dose-related and is more likely to develop during prolonged therapy. It is essential that blood ammonia be measured frequently in infants.Conservative doses of amino acids should be given, dictated by the nutritional status of the patient. Should symptoms of hyperammonemia develop, amino acid dosage levels should be reduced and titrated against serum ammonia levels.WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than to 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.