CRESNI 11.1% SOLUTION FOR INFUSION - summary of medicine characteristics

Cresni 11.1% solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

3   PHARMACEUTICAL FORM

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Cresni is indicated for parenteral nutrition in adults and children greater than 2 years of age when oral or enteral nutrition is impossible, insufficient or contraindicated.

4.2 Posology and method of administration

Posology

Cresni is not recommended for use in children less than 2 years of age due to inadequate composition (see sections 4.4; 5.1 and 5.2 of the SmPC).

The maximum daily dose mentioned below should not be exceeded.

The flow rate must be increased gradually during the first hour and then be adjusted to take into account the dose being administered, the daily volume intake, and the duration of the infusion.

In adults

The dosage depends on the patient’s energy expenditure, clinical status, body weight, and the ability to metabolize the constituents of Cresni, as well as additional energy or proteins provided orally/enterally.

The average daily nitrogen/amino acid requirements are:

0.16 to 0.32 g nitrogen /kg body weight (1 to 2 g of amino acids/kg), depending on the patient's nutri­tional status and degree of catabolic stress. Special populations may require up to 0.4 g nitrogen/kg body weight (2.5 g of amino acids/kg).

– 20 to 40 kcal/kg,

– 20 to 40 mL fluid /kg, or 1 to 1.5 mL per expended kcal.

In children, greater than 2 years of age

There have been no studies performed in the paediatric population.

The dosage depends on the patient’s energy expenditure, clinical status, body weight, and the ability to metabolize constituents of Cresni, as well as additional energy or proteins given orally/enterally.

In addition, daily fluid, nitrogen, and energy requirements continuously decrease with age. Two groups, ages 2 to 11 years and 12 to 18 years, are considered.

Recommended values from 2018 ESPGHAN/ES­PEN/ESPR Guidelines

In general, it is recommended to start the infusion for small children with a low daily dose and gradually increase it up to the maximal dosage (see above).

Method of administration

For single use only.

The choice of a central or peripheral venous route should depend on the osmolarity of the final infusate. Solutions with osmolarity of 850 mOsm/L or greater must be infused through a central catheter.

It is recommended that, after opening the bag, the content is used immediately. Any unused portion of Cresni should be discarded and should not be used for subsequent admixing.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

The recommended duration of infusion for a parenteral nutrition bag is between 12 and 24 hours.

Treatment with parenteral nutrition may be continued for as long as required by the patient’s clinical conditions.

As indicated on an individual basis, vitamins and trace elements and other components (including glucose and lipids) can be added to the parenteral nutrition regimen to meet nutrient needs and prevent deficiencies and complications from developing (see Section 6.2).

Fat emulsion coadministration should be considered when prolonged parenteral nutrition is required in order to prevent essential fatty acid deficiency (EFAD).

For instructions for preparation and handling of the solution for infusion, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

Congenital abnormality of amino acid metabolism

4.4 Special warnings and precautions for use

Warnings

Anaphylactic/a­naphylactoid reactions and other hypersensitivi­ty/infusion reactions have been reported with amino acid solutions administered as a component of parenteral nutrition (see Section 4.8). The infusion must be stopped immediately if any signs or symptoms of a reaction develop.

Pulmonary vascular precipitates causing pulmonary vascular emboli and pulmonary distress 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 incline 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.

Infection and sepsis may occur as a result of the use of intravenous catheters 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.

Careful symptomatic and laboratory monitoring for fever/chills, leukocytosis, technical complications with the access device, and hyperglycemia can help recognize early infections.

The occurrence of septic complications can be decreased with heightened emphasis on aseptic technique in catheter placement, maintenance, as well as aseptic technique in nutritional formula preparation.

Refeeding severely undernourished patients may result in the refeeding syndrome, which is characterized by the shift of potassium, phosphorus, and magnesium intracellularly as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. Careful monitoring and slowly increasing nutrient intakes while avoiding overfeeding can prevent these complications.

Hypertonic infusion solutions may cause irritation of the vein when administered into a peripheral vein (see Section 4.8).

Do not connect containers in series in order to avoid air embolism due to possible residual air contained in the primary container.

Precautions

Monitoring should be appropriate to the patient’s clinical situation and condition, and should include determinations of water and electrolyte balance, serum osmolarity, acid/base balance, blood glucose, liver and kidney function.

Metabolic complications may occur if the nutrient intake is not adapted to the patient's requ­irements, or the metabolic capacity of any given dietary component is not accurately assessed. Adverse metabolic effects may arise from administration of inadequate or excessive nutrients or from inappropriate composition of an admixture for a particular patient's needs.

Amino acid solutions should be used with caution in patients with pre-existing liver disease or liver insufficiency. Liver function parameters should be closely monitored in these patients, and they should be monitored for possible symptoms of hyperammonaemia (see below).

Patients on parenteral nutrition may experience hepatic complications (including cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure, as well as cholecystitis and cholelithiasis) and should be monitored accordingly. The aetiology of these disorders is thought to be multifactorial and may differ between patients. Patients developing abnormal laboratory parameters or other signs of hepatobiliary disorders should be assessed by a clinician knowledgeable in liver diseases in order to identify possible causative and contributory factors, and possible therapeutic and prophylactic interventions.

Increase in blood ammonia levels and hyperammonaemia may occur in patients receiving amino acid solutions. In some patients, this may indicate the presence of a congenital disorder of amino acid metabolism (see Section 4.3) or hepatic insufficiency.

Blood ammonia should be measured frequently in children to detect hyperammonaemia, which may indicate the presence of a congenital abnormality of amino acid metabolism.

Depending on extent and aetiology, hyperammonaemia may require immediate intervention. Should symptoms of hyperammonaemia develop, administration should be discontinued and the patient’s clinical status re-evaluated.

Azotaemia has been reported with parenteral administration of solutions containing amino acids, and may occur in particular in the presence of renal impairment.

Use with caution in patients with pulmonary oedema or heart failure. Fluid status should be closely monitored.

Use with caution in patients with renal insufficiency. Fluid and electrolyte status should be closely monitored in these patients

Severe water and electrolyte disorders, severe fluid overload states, and severe metabolic disorders should be corrected before starting the infusion.

Cresni must not be administered simultaneously with blood through the same infusion tubing because of the possibility of pseudoaggluti­nation.

Paediatric population

When administered to children greater than 2 years of age, it is essential to use a final container that has a volume corresponding to the daily dosage.

Vitamin and trace elements supplementation is always required. Paediatric formulations must be used for supplementation when available.

See Precautions above regarding monitoring for hyperammonaemia in paediatric patients.

Geriatric popultaion

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of Cresni in pregnant women. No animal reproductive studies have been performed with Cresni (see section 5.3). Physicians should carefully consider the potential risks and benefits for each specific patient before administering.

Breast-feeding

Amino acids/metabolites are excreted in human milk, but at therapeutic doses of Cresni no effects on the breastfed newborns/infants are anticipated. Physicians should carefully consider the potential risks and benefits for each specific patient before administering.

Fertility

No data available.

4.7 Effects on ability to drive and use machines

There is no information of the effects of Cresni on the ability to operate an automobile or other heavy machinery.

4.8 Undesirable effects

The following adverse reactions have been reported in the post-marketing experience.

The frequency of these events cannot be estimated from available data:

Anaphylactic/a­naphylactoid reactions include skin, gastrointestinal and severe circulatory (shock) and respiratory manifestations as well as other hypersensitivi­ty/infusion reactions, including pyrexia, chills, hypotension, hypertension, arthralgia, myalgia, urticaria/rash, pruritus, erythema, and headache.

Adverse reactions reported with parenteral nutrition to which the amino acid component may play a causal or contributory role include:

Metabolism and nutrition disorders: Hyperammonaemia

Hepatobiliary disorders: Parenteral nutrition-associated liver disease (including hepatic failure, hepatic cirrhosis, hepatic fibrosis, cholestasis, hepatic steatosis, blood bilirubin increased, hepatic enzyme increased; cholecystitis, cholelithiasis)

Renal and urinary disorders: Azotaemia

General disorders and administration site conditions: Infusion site thrombosis; infusion site phlebitis, infusion site pain, infusion site erythema, infusion site warmth, infusion site swelling, infusion site induration

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 Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Solutions for parenteral nutrition / amino acids.

ATC code: B05BA01

Mechanism of action

The therapeutic aim of parenteral nutrition is to provide the body with essential nutrients to maintain structural components, and to promote physical development when oral or enteral nutrition is impossible, insufficient or contraindicated. As a component of a balanced parenteral nutrition regimen, infusion of an amino acid solution will result in the maintenance of a normal pattern and concentration of amino acids in the blood plasma, thus providing substrates for the synthesis of proteins and peptides to support cell, organ and skeletal, cardiac and respiratory muscle functions, and wound healing. Amino acids also represent an energy source, their oxidation resulting in the excretion of nitrogen in the form of urea. Amino acids supply the substrate for synthesis of structural and functional proteins that are required to maintain body homeostasis. Importantly, they are required for growth, tissue repair and organ function (i.e., enzymatic activity). Parenteral nutrition maintains a positive protein intake and supports lean body mass and function. In order for parenterally administered amino acids to be retained by the body and utilized for protein synthesis adequate calories must be administered concurrently.

5.2 Pharmacokinetic properties

Absorption

Intravenous amino acids are directly bioavailable to cells and transported into tissues by active membrane-based transporters where they are used for synthesis of proteins.

Distribution

Protein synthesis stimulation requires adequate availability of all essential amino acids. The amino

acids are transported into tissues by active transporters. The amino acids can be utilized by all tissues in the body where they supply substrate for protein or peptide synthesis, act as regulators of various enzymes and genes, or are converted to other bioactive compounds (such as nitric oxide, glutathione, gamma amino butyric acid). Thus, amino acids have both structural and regulatory roles within the body.

Biotransformation

Amino acid biotransformation takes place in many tissues where the amino acids supply the substrate for protein or peptide synthesis, act as regulators of various enzymes and genes, or are converted to other bioactive compounds such as nitric oxide, glutathione and gamma aminobutyric acid. Metabolism takes place in many tissues; however, the liver and the muscles are the major organs for amino acid metabolism.

Elimination

Small quantities of amino acids may be excreted unchanged through the kidneys. Amino acids may be oxidized to CO2 and nitrogen, which is then converted to urea and excreted in the urine via the kidneys.

5.3 Preclinical safety data

Non-clinical studies have not been performed with Cresni. The amino acids contained in Cresni are substances which occur naturally in the organism.

6.1 List of excipients

Glacial acetic acid (for pH adjustment)

Water for injections

6.2 Incompatibilities

Do not add other medicinal products or substances without first confirming their compatibility and the stability of the resulting preparation.

As with any parenteral nutrition admixture, calcium and phosphate ratios must be considered, especially in the form of mineral salts, as excessive addition of calcium and phosphate increases the risk of the formation of calcium phosphate precipitates (see Section 4.4).

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

2 years when stored in the overpouch.

After first opening, use immediately.

Shelf life after supplementation (electrolytes, trace elements, vitamins, glucose, lipids):

For specific admixtures, in-use stability of the Cresni formulation has been demonstrated for 7 days between 2°C and 8°C followed by 48 hours at 25°C (see also section 6.6).

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not to be longer than 24 hours at 2 to 8°C, unless addition has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not freeze.

Store in the overpouch to protect Cresni from oxidation.

For storage conditions of the admixed medicinal product, see section 6.3.

6.5 Nature and contents of container

Cresni is supplied in a multilayer plastic bag. The inner (contact) layer of the bag material is made of a blend of polyolefinic copolymers. Other layers are made of polyethylene vinyl acetate (EVA), and of copolyester.

Two multilayer port tubes are present on the 500 mL and 1000 mL container sizes, one for administration and one for injection.

The inner (contact) layer of the tubes is made of polyethylene vinyl acetate (EVA). The other layers are made of polyolefinic copolymers.

The administration site is made of a blend of polyolefinic copolymers and EVA.

The injection site is an assembly of a molded part made of a blend of polyolefinic copolymers and EVA and a synthetic rubber.

The bag is packaged in an oxygen barrier overpouch.

Pack sizes:

500 mL: 1 carton with 12 bags

1000 mL: 1 carton with 6 bags

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Confirm the integrity of the container. Use only if the container is not damaged and if the solution is clear and colourless or slightly yellow.

To open:

Do not remove from overpouch until ready to use.

Remove the protective overpouch. Discard the overpouch.

Check container for leaks.

Cresni should only be mixed with other intravenous solutions for administration, if compatibility has been proven in advance.

Cresni can be mixed with the following additives:

Multivitamin preparations

Multi-trace element preparations

Sodium salt

Potassium salt

Magnesium salt

Calcium salt

Phosphate salt

The compatibility indicative table below shows possible additions of multi-trace element product such as Nutryelt and multivitamin product such as Cernevit and generics of electrolytes and trace elements in defined quantities. The addition of clinically needed electrolytes and trace elements should take into account the amounts already included in the initial bag formulation.

Compatibility may vary between products from different sources and healthcare professionals are advised to carry out appropriate checks when mixing Cresni with other parenteral solutions.

If additions to the container are made (500 and 1000 mL presentations on­ly):

Observe strict aseptic conditions.

Ensure stability and compatibility of additives.

Prepare the injection site of the container.

Puncture the injection site and inject the additives using an injection needle or a reconstitution device.

Mix contents of the container and the additives thoroughly.

Inspect final solution for particulate matter.

After completion of admixture, check container for leaks.

Ensure proper storage requirements of additives are followed.

Preparation of the infusion:

Observe strict aseptic conditions.

Suspend the bag.

Remove the plastic protector from the administration outlet.

Firmly insert the infusion set spike into the administration outlet.

Administration of the infusion:

For single use only.

Do not reconnect any partially used container.

Use immediately after opening the bag; do not store the opened bag for a subsequent infusion.

Do not connect containers in series in order to avoid air embolism due to possible residual air contained in the primary container.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Baxter Healthcare Ltd

Caxton Way, Thetford,

Norfolk, IP24 3SE

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL00116/0700