Histidine

Nutrineal is recommended as a non-glucose based peritoneal dialysis solution as part of a peritoneal dialysis regimen for the treatment of chronic renal failure patients. In particular, it is recommended for the malnourished peritoneal dialysis patients.

Administration Nutrineal is intended for intraperitoneal administration only. Not for intravenous administration. Peritoneal dialysis solutions may be warmed in the overpouch to 37°C to enhance patient comfort. However, only dry heat (for example, heating pad, warming plate) should be used.

Solutions should not be heated in water or in a microwave oven due to the potential for patient injury or discomfort. Aseptic technique should be employed throughout the peritoneal dialysis procedure.  Do not administer if the solution is discolored, cloudy, contains particulate matter or shows evidence of leakage, or if seals are not intact.

The drained fluid should be inspected for the presence of fibrin or cloudiness, which may indicate the presence of peritonitis. For single use only. Posology The mode of therapy, frequency of treatment, exchange volume, duration of dwell and length of dialysis should be initiated and supervised by the prescribing physician Treatment should be re-evaluated after 3 months if there is no clinical or biochemical improvement in the status of the patient.

5 l bag is the recommended dose for a 70 kg body weight patient. In smaller patients the fill volume may need to be reduced depending on body size. In exceptional cases, a different posology may be indicated but the dose should not exceed two exchanges per day.

2 g/kg body weight for adult dialysis patients. 30 g/kg body weight/24 h (approximately 25% of the daily protein requirements) for an adult dialysis patient of 70 kg body weight. Elderly: as for adults.

Children and adolescents:

Safety and effectiveness in paediatric patients has not been established. If Nutrineal is used, the recommended posology is one peritoneal dialysis exchange per day. The clinical benefits of Nutrineal have to be balanced versus the risk of side effects in this patient category.

For paediatric patients > 2 years old, a fill volume of 800 to 1400 ml/m2 to a maximum amount of 2000 ml, as tolerated, has been recommended. Fill volumes of 200 to 1000 ml/m2 are recommended in children less than 2 years of age.

The adverse reactions within this section represent those that are thought to have an association with Nutrineal or in conjunction with performing the peritoneal dialysis procedure. Undesirables effects which occurred in patients treated with Nutrineal from clinical trials and post marketing are listed below.

0. The term has been retained to reflect the available source data. Other undesirable effects of peritoneal dialysis related to the procedure: catheter site infection, catheter related complication, hypocalcaemia and peritonitis bacterial.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

1, - serum urea level above 38 mmol/L, - uraemic symptoms, - metabolic acidosis, - inborn errors of amino acid metabolism, - liver insufficiency, - severe hypokalaemia, - uncorrectable mechanical defects that prevent effective PD or increase the risk of infection Documented loss of peritoneal function or extensive adhesions that compromise peritoneal function.

AND CLINICAL USE 3 CONTRAINDICATIONS ........................................................................................................ 3 WARNINGS AND PRECAUTIONS ......................................................................................

4 ADVERSE REACTIONS......................................................................................................... 9 DRUG INTERACTIONS .......................................................................................................

11 DOSAGE AND ADMINISTRATION .................................................................................. 11 OVERDOSAGE ......................................................................................................................

15 ACTION AND CLINICAL PHARMACOLOGY ............................................................... 16 STORAGE AND STABILITY .............................................................................................. 16 DOSAGE FORMS, COMPOSITION AND PACKAGING ...............................................

18 PHARMACEUTICAL INFORMATION............................................................................. 18 CLINICAL TRIALS...............................................................................................................

22 TOXICOLOGY ...................................................................................................................... 23 REFERENCES........................................................................................................................

25 PRIMENE 10% (Amino Acid Injection) Page 3 of 26 PRIMENE 10% (Amino Acid Injection) PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Dosage Form / Strength Clinically Relevant Nonmedicinal Ingredients Intravenous 10% Solution for Infusion For a complete listing see Dosage Forms, Composition and Packaging section.

INDICATIONS AND CLINICAL USE PRIMENE 10% (Amino Acid Injection 10% w/v) is indicated for:  The nutritional support of infants (including those of low birth weight) and young children requiring TPN via either central or peripheral infusion routes.

The purpose of the solution is to prevent nitrogen and weight loss or treat negative nitrogen balance in infants and young children where: (1) the alimentary tract cannot or should not be used, (2) gastrointestinal absorption of protein is impaired, or (3) metabolic requirements for protein are substantially increased, as with extensive burns.

CONTRAINDICATIONS The use of PRIMENE 10% (Amino Acid Injection 10% w/v) is contraindicated in the following populations/situations:  Known hypersensitivity to any of the active substances or excipients, or to components of the container.

For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.  Patients with untreated anuria  Hepatic coma  Congenital abnormality of amino acid metabolism , including those involving branched chain amino acid metabolism such as maple syrup urine disease and isovaleric acidemia.

PRIMENE 10% (Amino Acid Injection) Page 4 of 26 WARNINGS AND PRECAUTIONS General This solution is for compounding only, not for direct infusion. Proper administration of this injection requires knowledge of fluid and electrolyte balance and nutrition as well as clinical expertise in recognition and treatment of the complications which may occur.

The IV administration of these solutions can lead to fluid or solute overload resulting in hyper or hypoosmolal states. The risk of hypoosmolal states is especially present in conditions associated with ADH secretion and is proportional to the infusion rate.

Severe water and electrolyte disorders, severe fluid overload states, and severe metabolic disorders should be corrected before starting the infusion. Hyperammonemia is of special significance in infants. This reaction appears to be related to a deficiency of the urea cycle enzymes of genetic or product origin.

It is essential that blood ammonia be measured frequently in infants. Administration of amino acids in the presence of impaired renal function or gastrointestinal bleeding may augment an already elevated blood urea nitrogen. It is essential to provide adequate calories concurrently if parenterally administered amino acids are to be retained by the body and utilized for protein synthesis.

Concentrated dextrose solutions are an effective source of such calories. With the administration of PRIMENE 10% (Amino Acid Injection 10% w/v) in combination with highly concentrated dextrose solutions, hyperglycemia, glycosuria and hyperosmolar syndrome may result.

Blood and urine glucose should be monitored on a routine basis in patients receiving this therapy Special care must be taken when giving hypertonic dextrose to a diabetic or pre-diabetic patient. To prevent severe hyperglycemia in such patients, insulin may be required.

Strongly hypertonic nutrient solutions should be administered through an indwelling intravenous catheter with the tip located in the superior vena cava. Solutions ideally should be prepared in the hospital pharmacy under a laminar flow hood.

The key factor in their preparation is careful aseptic technique to avoid inadvertent touch contamination during mixing of solutions and addition of other nutrients. Infection and sepsis may occur as a result of intravenous catheters used to administer parenteral formulations, poor maintenance of catheters or contaminated solutions.

Immunosuppression and other factors such as hyperglycemia, malnutrition and/or their underlying disease state may predispose patients to infectious complications. PRIMENE 10% (Amino Acid Injection) Page 5 of 26 Careful symptomatic and laboratory monitoring for fever/chills, leukocytosis, […]

Adverse Drug Reaction Overview Adverse reaction information is based on postmarketing experiences. Post-Market Adverse Drug Reactions The adverse reactions listed below have been identified from post-marketing reports of PRIMENE 10% (Amino Acid Injection) administered as a component of parenteral nutrition.

They are listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity, where feasible.

IMMUNE SYSTEM DISORDERS:

Hypersensitivity reaction:  Face edema  Eyelid edema  Rash Other adverse reactions reported with parenteral amino acid products include: RENAL AND URINARY DISORDERS:  Azotemia METABOLISM AND NUTRITION DISORDERS:  Hyperammonemia  Adverse reactions reported with parenteral nutrition to which the amino acid component may play a causal or contributory role include: GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS:  Chills  Infusion site discolouration  Injection site erythema  Infusion site extravasation  Infusion site induration  Infusion site phlebitis  Infusion site swelling  Infusion site thrombosis  Infusion site warmth  Necrosis  Pyrexia  Swelling PRIMENE 10% (Amino Acid Injection) Page 10 of 26 IMMUNE SYSTEM DISORDER:  Anaphylactic / anaphylactoid reactions, including skin, gastrointestinal and respiratory manifestations  Hypersensitivity reaction INJURY, POISONING AND PROCEDURAL COMPLICATIONS:  Infusion related reaction  Scar INVESTIGATIONS:  Blood bilirubin increased  Hepatic enzyme increased HEPATOBILIARY DISORDERS:  Cholecystitis  Cholelithiasis  Cholestasis  Hepatic cirrhosis  Hepatic failure  Hepatic fibrosis  Hepatic steatosis METABOLISM AND NUTRITION DISORDERS:  Metabolic acidosis MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS:  Arthralgia  Myalgia NERVOUS SYSTEM DISORDERS:  Headache PRIMENE 10% (Amino Acid Injection) Page 11 of 26 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS:  Pulmonary Vascular disorder SKIN AND SUBCUTANEOUS TISSUE DISORDERS:  Blister  Erythema  Pruritus  Urticaria VASCULAR DISORDER:  Hypertension  Hypotension  Infusion site pain  Shock  Vein disorder DRUG INTERACTIONS Overview No interaction studies have been performed by Baxter Healthcare Corporation with PRIMENE 10% (Amino Acid Injection 10% w/v).

Drug-Drug Interactions Because of its antianabolic activity, concurrent administration of tetracycline may reduce the protein-sparing effects of infused amino acids. Drug-Food Interactions No drug-food interaction studies have been evaluated.

Drug-Laboratory Interactions No drug-laboratory interaction studies have been evaluated. Drug-Lifestyle Interactions Interactions with lifestyle have not been evaluated. DOSAGE AND ADMINISTRATION PRIMENE 10% (Amino Acid Injection 10% w/v) is intended for intravenous use.

The product PRIMENE 10% (Amino Acid Injection) Page 12 of 26 is in Pharmacy Bulk Package and not for direct infusion. PRIMENE 10% (Amino Acid Injection 10% w/v) is not intended for fluid or volume replacement. Dosing Considerations The total daily dose of PRIMENE10% (Amino Acid Injection 10% w/v) depends on daily protein requirements and on the patient's metabolic and clinical response.

The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, are probably the best means of assessing individual protein requirements. Dosage should also be guided by the patient's fluid intake limits and glucose and nitrogen tolerances, as well as by metabolic and clinical response.

When used in neonates and children below 2 years, the solution (in containers and administration sets) should be protected from light exposure after admixture through administration. Any unused portion of PRIMENE 10% (Amino Acid Injection 10% w/v) should be discarded and should not be used for subsequent admixing.

Recommended Dose and Dosage Adjustment Parenteral nutrition initiation and duration as well as dosage (dose and rate of administration) depends on a patient’s  age, weight, clinical condition,  nitrogen requirements,  ability to metabolize the constituents of PRIMENE 10% (Amino Acid Injection 10% w/v),  additional nutrition that may be provided parenterally and/or enterally.

5 grams of amino acids per kilogram of body weight per day. Typically, PRIMENE10% (Amino Acid Injection 10% w/v) is admixed with 50% dextrose and supplemented with electrolytes and administered continuously over a 24 hour period. 2 g/kg of protein and 120 Kcal/kg/day.

For premature infants, especially those in catabolic state, these requirements could be even higher. Total daily fluid intake should be appropriate for the patient's age and size. A fluid dose of 125 mL per kilogram body weight per day is appropriate for most infants on TPN.

Provision of additional nitrogen may not be possible due to fluid intake limits, nitrogen, or glucose intolerance. In addition, the provision of sufficient intracellular electrolytes, principally potassium, magnesium, and phosphate, is required for optimum utilization of amino acids, and sufficient quantities of the major extracellular electrolytes sodium, calcium, and chloride, must be given.

Therefore, if oral feeding is not possible or advisable and TPN is necessary, the volume restrictions dictate how to administer Primene, dextrose and most electrolytes in the same hypertonic solution through intravenous lines. Even such hypertonic solutions will not provide the required daily calories.

If prolonged TPN is required (5 days or more), intravenous lipid emulsions will also have to be administered. The following scenario can serve as an example. 5 g/kg of amino acid per day and 125 cc/kg/day fluid volume. 5 g 10 20 Dextrose 50% 42 mL 21 g 71 110 Water for Injection […]

and ADVERSE REACTIONS). The infusion must be stopped immediately if any signs or symptoms of a reaction develop. , uremia). Nitrogen tolerance may be altered and dosage may have to be adjusted. Fluid and electrolyte status should be closely monitored in these patients.

Azotemia has been reported with parenteral administration of solutions containing amino acids, and may occur in particular in the presence of renal impairment. Patients with azotemia from any cause should not be infused with amino acids without regard to total nitrogen intake.

Respiratory Pulmonary vascular precipitates have been reported in patients receiving parenteral nutrition. In some cases, fatal outcomes have occurred. 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 distal to the in‐line filter and suspected in vivo precipitate formation has also been reported. If signs of pulmonary distress occur, the infusion should be stopped and medical evaluation initiated.

In addition to inspection of the solution, the infusion set and catheter should also periodically be checked for precipitates.

Special Populations Pregnant Women:

There are no adequate data on the use of PRIMENE 10% (Amino Acid Injection 10% w/v) in pregnant women. Healthcare professionals should carefully consider the potential risks and benefits for each specific patient before prescribing the product.

Nursing Women:

There are no adequate data on the use of PRIMENE 10% (Amino Acid Injection 10% w/v) in nursing women. Healthcare professionals should carefully consider the potential risks and benefits for each specific patient before administering the product.

Pediatrics:

The product is specifically indicated for the pediatric population. Monitoring and Laboratory Tests Monitoring should be appropriate to the patient’s clinical situation and condition, and may include determinations of fluid balance, water and electrolyte balance, serum osmolarity, and acid / base balance, blood glucose, serum proteins, blood ammonia levels, kidney and liver function tests, electrolytes, hemogram, arterial blood gases, and blood cultures.

PRIMENE 10% (Amino Acid Injection) Page 9 of 26 ADVERSE REACTIONS Adverse Drug Reaction Overview Adverse reaction information is based on postmarketing experiences. Post-Market Adverse Drug Reactions The adverse reactions listed below have been identified from post-marketing reports of PRIMENE 10% (Amino Acid Injection) administered as a component of parenteral nutrition.

They are listed by MedDRA System Organ Class (SOC), then by Preferred Term in order of severity, where feasible.

IMMUNE SYSTEM DISORDERS:

Hypersensitivity reaction:  Face edema  Eyelid edema  Rash Other adverse reactions reported with parenteral amino acid products include: RENAL AND URINARY DISORDERS:  Azotemia METABOLISM AND NUTRITION DISORDERS:  Hyperammonemia  Adverse reactions reported with parenteral nutrition to which the amino acid component may play a causal or contributory role include: GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS:  Chills  Infusion site discolouration  Injection site erythema  Infusion site extravasation  Infusion site induration  Infusion site phlebitis  Infusion site swelling  Infusion site thrombosis  Infusion site warmth  Necrosis  Pyrexia  Swelling PRIMENE 10% (Amino Acid Injection) Page 10 of 26 IMMUNE SYSTEM DISORDER:  Anaphylactic / anaphylactoid reactions, including skin, gastrointestinal and respiratory manifestations  Hypersensitivity reaction INJURY, POISONING AND PROCEDURAL COMPLICATIONS:  Infusion related reaction  Scar INVESTIGATIONS:  Blood bilirubin increased  Hepatic enzyme increased HEPATOBILIARY DISORDERS:  Cholecystitis  Cholelithiasis  Cholestasis  Hepatic cirrhosis  Hepatic failure  Hepatic fibrosis  Hepatic steatosis METABOLISM AND NUTRITION DISORDERS:  Metabolic acidosis MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS:  Arthralgia  Myalgia NERVOUS SYSTEM DISORDERS:  Headache PRIMENE 10% (Amino Acid Injection) Page 11 of 26 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS:  Pulmonary Vascular disorder SKIN AND SUBCUTANEOUS TISSUE DISORDERS:  Blister  Erythema  Pruritus  Urticaria VASCULAR DISORDER:  Hypertension  Hypotension  Infusion site pain  Shock  Vein disorder DRUG INTERACTIONS Overview No interaction studies have been performed by Baxter Healthcare Corporation with PRIMENE 10% (Amino Acid Injection 10% w/v).

Drug-Drug Interactions Because of its antianabolic activity, concurrent administration of tetracycline may reduce the protein-sparing effects of infused amino acids. Drug-Food Interactions No drug-food interaction studies have been evaluated.

Drug-Laboratory Interactions No drug-laboratory interaction studies have been evaluated. Drug-Lifestyle Interactions Interactions with lifestyle have not been evaluated. DOSAGE AND ADMINISTRATION PRIMENE 10% (Amino Acid Injection 10% w/v) is intended for intravenous use.

The product PRIMENE 10% (Amino Acid Injection) Page 12 of 26 is in Pharmacy Bulk Package and not for direct infusion. PRIMENE 10% (Amino Acid Injection 10% w/v) is not intended for fluid or volume replacement. Dosing Considerations The total daily dose of PRIMENE10% (Amino Acid Injection 10% w/v) depends on daily protein requirements and on the patient's metabolic and clinical response.

The determination of nitrogen balance and accurate daily body weights, corrected for fluid balance, are probably the best means of assessing individual protein requirements. Dosage should also be guided by the patient's fluid intake limits and glucose and nitrogen tolerances, as well as by metabolic and clinical response.

When used in neonates and children below 2 years, the solution (in containers and administration sets) should be […]