Possible side effects

not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

Pack sizes

IRELAND HPRA Pharmacovigilance, Earlsfort Terrace, IRE – Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie; E-mail: [email protected]

1000 ml bag: carton with 8 bags 1000 ml: 1 bag 1500 ml bag: carton with 6 bags 1500 ml: 1 bag 2000 ml bag: carton with 4 bags 2000 ml: 1 bag

UK Via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

Marketing Authorisation Holder

Not all pack sizes may be marketed.

For any information about CLINIMIX, please contact the Marketing Authorisation Holder:

How to store it

CLINIMIX

In the United Kingdom: Baxter Healthcare Ltd Caxton Way Thetford Norfolk IP24 3SE The United Kingdom

Keep this medicine out of the sight and reach of children. When used in neonates and children below 2 years, the solution (in bags and administration sets) should be protected from light exposure until administration is completed (see section 2). This medicine should not be administered after the expiry date, which is stated on the container and the outer packaging (MM/YYYY). The expiry date refers to the last day of that month.

In Republic of Ireland: Baxter Holding B.V. Kobaltweg 49, 3542CE Utrecht, Netherlands

Do not freeze. Keep the container in the outer carton. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Manufacturers Baxter S.A., Boulevard René Branquart, 80, 7860 Lessines, Belgium

Contents of the pack and other information

This medicinal product is authorised in the Member States of the EEA under the following names:

What CLINIMIX contains

Clinimix N14G30E, Solution for Infusion

The active substances for each bag of the reconstituted solution are: Active substances L-alanine L-arginine Glycine L-histidine L-isoleucine L-leucine

1l 8.80 g 4.89 g 4.38 g 2.04 g 2.55 g 3.11 g

1.5 l 13.20 g 7.34 g 6.57 g 3.06 g 3.83 g 4.66 g

In some countries it is registered under a different trade name, as described below: Germany: Clinimix 4,5 % G-E

2l 17.60 g 9.78 g 8.76 g 4.08 g 5.10 g 6.21 g

This leaflet was last revised in 09/2021 Baxter and Clinimix are trademarks of Baxter International Inc.

BE-30-03-500

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CLINIMIX N14G30E, SOLUTION FOR INFUSION The following information is intended for healthcare professionals only:

3. SPECIAL WARNINGS AND PRECAUTIONS FOR USE

1. QUANTITATIVE COMPOSITION

WARNINGS

After the contents of the two compartments have been mixed, the composition of the binary mixture, for all available bag sizes, provides the following:

Hypersensitivity/infusion reactions including hypotension, hypertension, peripheral cyanosis, tachycardia, dyspnoea, vomiting, nausea, urticaria, rash, pruritus, erythema, hyperhidrosis, pyrexia, and chills have been reported with CLINIMIX formulations. Anaphylaxis has been reported with other parenteral nutrition products.

Nitrogen (g) Amino acids (g) Glucose (g) Total calories (kcal) Glucose calories (kcal) Sodium (mmol) Potassium (mmol) Magnesium (mmol) Calcium (mmol) Acetate (mmol) Chloride (mmol) Phosphate as HPO42- (mmol) pH Osmolarity (mOsm/l)

1l 7.0 43 150 770 600 35 30 2.5 2.3 70 40 15

1.5 l 10.5 64 225 1155 900 53 45 3.8 3.4 105 60 23

2l 14.0 85 300 1540 1200 70 60 5.0 4.5 140 80 30

Special clinical monitoring is required at the beginning of any intravenous infusion. Should any abnormal sign or symptom occur, e.g. for hypersensitivity or infusion reaction, the infusion must be stopped immediately. Solutions containing glucose should be used with caution, if at all, in patients with known allergy to corn or corn products. 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 have 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.

6 1415

In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including CLINIMIX N14G30E, through the same infusion line (e.g., via a Y-connector). If the same infusion line is used for sequential administration, the line must be thoroughly flushed with a compatible fluid between infusions.

2. POSOLOGY AND METHOD OF ADMINISTRATION Only administer the product after the non-permanent seal between the two compartments have been broken and the contents of the two compartments have been mixed.

Dosage and infusion rate The dosage should be individualised based on the patient's nutritional/fluid requirements, energy expenditure, clinical status, body weight, and the ability to metabolise constituents of CLINIMIX, as well as additional energy or proteins given orally/enterally. In addition, daily fluid, nitrogen and energy requirements continuously decrease with age.

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 hyperglycaemia, malnutrition and/or their underlying disease state may predispose patients to infectious complications.

In adults, the requirements range from 0.16 g of nitrogen/kg/d (approximately 1 g of amino acid/kg/d) to 0.32 g of nitrogen/kg/d (approximately 2 g of amino acid/kg/d). In infants, the requirements range from 0.16 g of nitrogen/kg/d (approximately 1.0 g of amino acid/kg/d) to 0.40 g of nitrogen/kg/d (approximately 2.5 g of amino acid/kg/d).

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.

In adults and patients 12 to 18 year of age, calorie requirements range from 25 kcal/kg/d to 40 kcal/kg/d, depending on the nutritional status of the patient and the degree of catabolism. Patients less than 12 years of age may have higher requirements.

Refeeding severely undernourished patients may result in the refeeding syndrome that 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.

Clinical situations may exist where patients require amounts of nutrients varying from the composition of CLINIMIX. In this situation any volume (dose) adjustments must take into consideration the resultant effect this will have on the dosing of all other nutrient components of CLINIMIX. The infusion rate and volume should be determined by the consulting physician experienced in pediatric intravenous fluid therapy.

Hypertonic solutions may cause venous irritation if infused into a peripheral vein. The choice of a peripheral or central vein depends on the final osmolarity of the mixture.

This product does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants This medicinal product is not recommended for preterm, and term neonates and for children below 2 years of age.

The general accepted limit for peripheral infusion is about 800 mOsm/l but it varies considerably with the age and the general condition of the patient and the characteristics of the peripheral veins.

The rate of administration should be adjusted according to the dosage, the characteristics of the infused solution, the total volume intake per 24 hours and the duration of the infusion.

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

The infusion time should be higher than 8 hours. Normally, the flow rate is increased gradually during the first hour without exceeding 1.7 ml per kilogram of bodyweight per hour, and the maximal dose is 40 per kilogram of bodyweight per day.

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

Method of administration When used in neonates and children below 2 years, the solution (in bags and administration sets) should be protected from light exposure until administration is completed.

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.

Route of administration The choice of the peripheral or central vein depends on the final osmolarity of the mixture. The general accepted limit for peripheral infusion is about 800 mOsm/l but it varies considerably with the age and the general condition of the patient and the characteristics of the peripheral veins.

Frequent clinical evaluation and laboratory determinations are necessary for correct monitoring during administration. These should include ionogram and kidney and liver function tests. The electrolyte requirements of patients receiving the solutions should be carefully determined and monitored especially for the electrolyte-free solutions. BE-30-03-500

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Glucose intolerance is a common metabolic complication in severely stressed patients. With the infusion of the products, hyperglycaemia, glycosuria, and hyperosmolar syndrome may occur. Blood and urine glucose should be monitored on a routine basis and for diabetics insulin dosage should be adapted, if necessary.

3.

4.

Place the bag flat on a horizontal and clean surface with the handle in front of you.

Lift the hanger area to remove the solution from the top of the bag. Firmly roll the bag until the peal seal is fully open (approximately half way).

5.

6.

Mix by turning the bag upside-down at least 3 times.

Hang the bag. Twist off the protector from the administration outlet. Firmly plug the spike connector.

Use with caution in patients with renal insufficiency, particularly if hyperkalaemia is present, because of the risk of developing or worsening metabolic acidosis and hyperazotemia if extra-renal waste removal is not being performed. Fluid and electrolyte status should be closely monitored in these patients. In case of severe kidney failure, specially formulated amino acid solutions should be preferred. Caution should be exercised in administering CLINIMIX to patients with adrenal insufficiency. Care should be taken to avoid circulatory overload particularly in patients with pulmonary oedema, cardiac insufficiency and/or failure. Fluid status should be closely monitored. In patients with pre-existing liver disease or hepatic insufficiency, apart from routine liver function tests, possible symptoms of hyperammonaemia should be controlled. Hepatobiliary disorders including cholestasis, hepatic steatosis, fibrosis and cirrhosis, possibly leading to hepatic failure, as well as cholecystitis and cholelithiasis are known to develop in some patients on parenteral nutrition. 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 early 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 hyperammonemia 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 newborns and infants to detect hyperammonemia, which may indicate the presence of a congenital abnormality of amino acid metabolism. Depending on extent and aetiology, hyperammonemia may require immediate intervention.

Use only if the solution is clear, colourless or slightly yellow and if the container is undamaged.

A too rapid infusion of amino acid may result in nausea, vomiting and chills. In such cases, discontinue the infusion immediately.

CLINIMIX should be at room temperature before use.

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 drug therapy.

CLINIMIX activation can be performed in the overpouch or after its removal. For single use only. Do not store partly used containers and discard all equipment after use. Do not reconnect partially used bag. Do not connect in series.

Paediatric population

• There have been no studies performed in the paediatric population.
• See above regarding monitoring for hyperammonemia in paediatric patients below 2 years.

When used in neonates and children below 2 years, protect from light exposure, until administration is completed. Exposure of CLINIMIX to ambient light, especially if admixtures include trace elements and/or vitamins, generates peroxides and other degradation products that can be reduced by light exposure.

Light exposure of solutions for intravenous parenteral nutrition, especially after admixture with trace elements and/or vitamins, may lead to generation of peroxides and other degradation products. When used in neonates and children below 2 years, CLINIMIX should be protected from light until administration is completed.

Supplementation

4. PRACTICAL INFORMATION ON PREPARATION AND HANDLING

Lipids, vitamins and trace elements should be provided to patients receiving parenteral nutrition for a long period.

Warning: Administer the product only after breaking the seal and mixing the contents of both compartments.

1.

2.

Tear from the top to open the overpouch.

Peel the front of the overpouch to reveal the CLINIMIX bag. Discard the overpouch and oxygen absorber sachet.

If additives are necessary, compatibilities should be checked and the stability of mixtures should be controlled.

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CLINIMIX N14G30E contains calcium ions which pose additional risk of coagulation precipitated in citrate anticoagulated/preserved blood or components.

The supplementation can be made after opening the peel seal (once the two solutions have been mixed) for all additives. CLINIMIX may be supplemented with: –

CLINIMIX N14G30E 1 l + 250 ml lipids 20% 7.0 43 150 50

CLINIMIX N14G30E 1.5 l + 250 ml lipids 20% 10.5 64 225 50

CLINIMIX N14G30E 2 l + 500 ml lipids 20% 14.0 85 300 100

Total calories (kcal) Glucose calories (kcal) Lipid calories (kcal) Glucose/lipids Ratio

1270 600 500 55/45

1655 900 500 64/36

2540 1200 1000 55/45

Sodium (mmol) Potassium (mmol) Magnesium (mmol) Calcium (mmol) Acetate (mmol) Chloride (mmol) Phosphate as HPO42- (mmol)

35 30 2.5 2.3 70 40 15

53 45 3.8 3.4 105 60 23

70 60 5.0 4.5 140 80 30

pH Osmolarity (mOsm/l)

6 1190

6 1255

6 1190

–

In patients older than 28 days (including adults), ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions, including CLINIMIX N14G30E, through the same infusion line (see section Warnings). If the same infusion line is used for sequential administration, the line must be thoroughly flushed with a compatible fluid between infusions.

5. SHELF LIFE 2 years when stored in the overpouch. It is recommended that the product be used immediately after the non-permanent seal between the 2 chambers have been opened. However, once reconstituted (i.e. internal non-permanent seal opened), stability of the reconstituted emulsion has been demonstrated for a maximum of 7 days between 2°C and 8°C followed by a maximum of 48 h at temperature not exceeding 25°C. When additions have been made, from a microbiological point of view, the admixture 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 be longer than 24 hours at 2 to 8°C, unless additions have been made under controlled and validated aseptic conditions. If longer storage periods are required in exceptional circumstances, the company can be contacted as chemical and physical in-use stability data for 7 days at 2 – 8°C followed by 48 hours below 25°C are available for the products listed in the previous section.

Sodium

Potassium

Magnesium

Calcium

80 mmol

60 mmol

5.6 mmol

3.0 mmol

Zinc Manganese Cobalt Molybdenum Iron

77 μmol 2.5 μmol 0.0125 μmol 0.13 μmol 10 μmol

Biotin vitamin B1 Folic acid vitamin B2 vitamin C vitamin B5

35 μg 1.76 mg 207 μg 2.07 mg 63 mg 8.63 mg

Trace elements: per litre of CLINIMIX

Up to a final concentration of

–

As for other calcium-containing infusion solutions, concomitant treatment with ceftriaxone and CLINIMIX N14G30E is contraindicated in newborns (≤28 days of age), even if separate infusion lines are used (risk of fatal ceftriaxone calcium salt precipitation in the neonate's bloodstream).

Electrolytes: per litre of CLINIMIX

Up to a final concentration of –

As with any parenteral nutrition admixture, calcium and phosphate ratios must be considered. Excess addition of calcium and phosphate, especially in the form of mineral salts, may result in the formation of calcium phosphate precipitates.

Lipid emulsions (for example CLINOLEIC) at a rate of 50 to 250 ml per litre of CLINIMIX

Nitrogen (g) Amino acids (g) Glucose (g) Lipid (g)

Proofread No.: 04

Copper Chromium Fluorine Selenium Iodine

10 μmol 0.14 μmol 38 μmol 0.44 μmol 0.5 μmol

Vitamins: per litre of CLINIMIX

Up to a final concentration of

vitamin A vitamin B6 vitamin D vitamin B12 vitamin E vitamin PP vitamin K

1750 IU 2.27 mg 110 IU 3.0 μg 5.1 mg 23 mg 75 μg

Stability data for supplementation of CLINIMIX with other marketed lipid emulsions and other additives or nutrients are available upon request. If some light creaming is observed, mix thoroughly the admixture by gentle agitation to get a uniform emulsion before the infusion. Additions should be performed under aseptic conditions. Additions can be made with a syringe or a transfer set. •

Addition with a syringe or a transfer set fitted with a needle

• Prepare the injection port site (the single port, see Figure 1 in the SmPC).
• Puncture the port site and inject.
• Mix the solutions and the additives.

Incompatibilities Additives may be incompatible, refer to the manufacturer for further details. If additives are necessary, compatibilities should be checked and the stability of mixtures should be controlled. The solution should not be administered with, before, or after an administration of blood through the same equipment because of the possibility of pseudoagglutination. BE-30-03-500

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