Clinimix N12G20 solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: information for the patient

Clinimix N12G20 solution for infusion

Read the entire leaflet carefully before starting administration of this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor or nurse.
• If you experience any adverse reactions, consult your doctor or nurse, even if they are adverse reactions not listed in this leaflet. See section 4.

Leaflet contents:

1. What CLINIMIX is and what it is used for
2. What you need to know before administration of CLINIMIX
3. How CLINIMIX is administered
4. Possible side effects
5. How to store CLINIMIX
6. Contents of the pack and other information

1. What Clinimix is and what it is used for

CLINIMIX is an infusion solution. It is supplied in a dual-chamber bag. One chamber contains an amino acid solution and the second chamber contains a glucose solution. The chambers are separated by a non-permanent seal. The contents of the chambers must be mixed immediately before administration by rolling the top portion of the bag to break the seals.

CLINIMIX is administered to provide nutrition to adults and children through a tube connected to a vein when normal oral feeding is not suitable.

CLINIMIX must only be administered under medical supervision.

2. What you need to know before starting Clinimix

CLINIMIX must not be administered if:

• you are allergic to the active substances or to any of the other components of this medicine (listed in section 6),
• your body has problems utilizing certain amino acids,
• you have too much sugar in your blood (severe hyperglycemia),
• your blood is excessively acidic (metabolic acidosis due to excess lactate).

In all cases, your doctor will decide whether you should be given this medicine based on factors such as age, weight, and clinical condition, along with the results of all tests performed.

Warnings and precautions

Talk to your doctor or nurse before receiving CLINIMIX.

If any abnormal signs or symptoms of an allergic reaction develop, such as fever, chills, skin rash, difficulty breathing, excessive sweating, nausea, or headache, inform your doctor or nurse immediately: the infusion will be stopped immediately. Your doctor will monitor your condition during administration of this medicine and may adjust the dose or add other nutrients such as lipids, vitamins, electrolytes, and trace elements if considered appropriate.

Certain medications and diseases may increase the risk of developing an infection or sepsis (bacteria in the blood). There is a particular risk of infection or sepsis when a tube (intravenous catheter) is placed into your vein. Your doctor will carefully monitor you for any signs of infection. The use of aseptic techniques (germ-free) when inserting and maintaining the catheter and when preparing the nutritional formulation can reduce the risk of infection.

If you are severely malnourished and require intravenous feeding, parenteral nutrition should be initiated slowly and carefully.

Your doctor will monitor your condition at the start of the infusion, especially if you currently have liver, kidney, adrenal, heart, or circulatory problems. Your doctor should also be aware of any serious conditions affecting how your body handles sugars, fats, proteins, or salts (metabolic disorders). If any abnormal signs occur, including venous irritation, the infusion should be stopped.

To ensure the effectiveness and safety of treatment, your doctor will perform laboratory and clinical tests while you are receiving this medicine. If you receive this medicine for several weeks, your blood will be tested regularly. In particular, in cases of glucose intolerance, blood and urine glucose levels will be routinely monitored, and, if you are a diabetic patient, your insulin dose may need to be adjusted.

Children and adolescents

When used in newborns and children under 2 years of age, the solution (in bags and administration sets) must be protected from exposure to light until administration is complete. Exposure of Clinimix to ambient light, especially after mixing with trace elements and/or vitamins, generates peroxides and other degradation products, which can be minimized by protecting from light exposure.

Interaction of CLINIMIX with other medicines

Inform your doctor or nurse if you are taking, have recently taken, or might need to take any other medicines.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to become pregnant, consult your doctor before using this medicine.

3. How Clinimix is administered

Before administering the product, the non-permanent seal between the two compartments must be broken and the contents mixed.

CLINIMIX can be administered to adults and children.

When used in children under 2 years of age, the solution (in the bags and administration sets) must be protected from exposure to light until administration is complete (see section 2).

This is an infusion solution administered through a plastic tube connected to a vein in your arm or a large vein in your chest.

Dosage – Adults and children

Your doctor will determine the dose you need and the duration of administration based on your age, weight, height, clinical condition, daily fluid volume, and energy and nitrogen requirements.

Follow exactly the administration instructions for CLINIMIX provided by your doctor. Consult your doctor if you have any doubts.

Administration may continue for as long as necessary, depending on your clinical condition.

The infusion of one bag usually lasts between 8 and 24 hours.

If you are given more CLINIMIX than you should

If the administered dose is too high or the infusion is too rapid, it may increase your blood circulation volume or make your blood excessively acidic. The glucose content may increase glucose levels in your blood and urine. Administration of an excessive volume may cause nausea, vomiting, tremors, and electrolyte disturbances. In such situations, the infusion must be stopped immediately.

In some severe cases, your doctor may need to perform temporary renal dialysis to help your kidneys eliminate the excess product.

To prevent such occurrences, your doctor will regularly monitor your condition and analyze your blood parameters.

If you have any further questions about the use of this product, ask your doctor.

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone experiences them. If you notice any change in how you feel during or after treatment, inform your doctor or nurse immediately.

The tests your doctor performs while you are receiving this medicine should minimize the risk of adverse effects.

The infusion will be stopped immediately if any abnormal signs or symptoms of an allergic reaction occur, such as abnormally high or low blood pressure, development of blue or purple skin discoloration, abnormally high heart rate, difficulty breathing, vomiting, nausea, skin rashes, increased body temperature, excessive sweating, and chills.

Other adverse effects have been observed, occurring with varying frequency:

• Anaphylaxis (a severe allergic reaction that develops rapidly and may be fatal).
• High levels of glucose, ammonia, and nitrogen-containing compounds in the blood.
• Impaired liver function, abnormal blood tests of liver function.
• Inflammation of the gallbladder, presence of gallstones in the gallbladder.
• Inflammation of the veins at the infusion site, venous irritation, pain, irritation, burning, swelling.
• Presence of glucose in the urine.
• Diabetic coma.
• Formation of small particles that block the pulmonary blood vessels.

Reporting of adverse effects:

If you experience any type of adverse effect, consult your doctor or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the Spanish Pharmacovigilance System for Human Medicines: https://www.notificaram.es. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Clinimix

Keep this medicine out of the sight and reach of children.

When used in newborns and children under 2 years of age, the solution (in bags and administration sets) must be protected from light exposure until administration is complete (see section 2).

Do not use this medicine after the expiry date stated on the container and outer packaging (MM/YYYY). The expiry date refers to the last day of the month indicated.

Do not freeze.

Keep the container in the outer packaging.

Do not dispose of medicines via wastewater or household waste. If you have any questions about how to dispose of containers or unused medicines, ask your pharmacist. This will help protect the environment.

6. Contents of the container and other information

Composition of Clinimix

The active substances in each bag of the reconstituted solution are:

Active Ingredients	1 L	1.5 L	2 L
L-alanine	7.25 g	10.87 g	14.49 g
L-arginine	4.03 g	6.04 g	8.05 g
Glycine	3.61 g	5.41 g	7.21 g
L-histidine	1.68 g	2.52 g	3.36 g
L-isoleucine	2.10 g	3.15 g	4.20 g
L-leucine	2.56 g	3.83 g	5.11 g
L-lysine (as lysine hydrochloride)	2.03 g (2.54 g)	3.05 g (3.80 g)	4.06 g (5.07 g)
L-methionine	1.40 g	2.10 g	2.80 g
L-phenylalanine	1.96 g	2.94 g	3.92 g
L-proline	2.38 g	3.57 g	4.76 g
L-serine	1.75 g	2.63 g	3.50 g
L-threonine	1.47 g	2.21 g	2.94 g
L-tryptophan	0.63 g	0.95 g	1.26 g
L-tyrosine	0.14 g	0.21 g	0.28 g
L-valine	2.03 g	3.05 g	4.06 g
Anhydrous glucose (as monohydrated glucose)	100 g (110 g)	150 g (165 g)	200 g (220 g)

The other components are:

• acetic acid, hydrochloric acid (to adjust the pH of the solution),
• water for injections.

Appearance of CLINIMIX and contents of the container

CLINIMIX is an infusion solution supplied in a multilayered plastic two-compartment bag. The material of the inner layer (in contact with the solution) of the bag is made of polymers (a mixture of polyolefinic copolymers) compatible with the components and authorized additives. Other layers are made of EVA (ethylene-vinyl acetate) and a copolyester.

Before reconstitution, the glucose and amino acid solutions are clear, colourless or slightly yellowish. After reconstitution, the solution is also clear, colourless or slightly yellowish.

To avoid contact with atmospheric oxygen, the bag is packaged inside an overpouch acting as an oxygen barrier, which contains an oxygen absorber.

Pack sizes

1000 ml bag: cardboard box containing 8 bags

1 bag of 1000 ml

1500 ml bag: cardboard box containing 6 bags

1 bag of 1500 ml

2000 ml bag: cardboard box containing 4 bags

1 bag of 2000 ml

Only certain pack sizes may be marketed.

Marketing Authorization Holder

Baxter S.L.

Pouet de Camilo 2,

46394 Ribarroja del Turia (Valencia), Spain

Manufacturer

Baxter SA, Boulevard René Branquart, 80, 7860 Lessines, Belgium

This medicinal product is authorized in the European Economic Area member states under the following names:

Clinimix N12G20, infusion solution

The last revision of this leaflet was in September 2021

Detailed information on this medicinal product is available on the website of the Spanish Agency of Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

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This information is intended for healthcare professionals only:

1. Quantitative composition

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

	1 l	1.5 l	2 l
Nitrogen (g) Amino acids (g) Glucose (g)	5.8 35 100	8.7 53 150	11.6 70 200
Total calories (kcal) Calories from glucose (kcal)	540 400	810 600	1080 800
Acetate (mmol) Chloride (mmol)	27 15	41 22	54 29
pH Osmolarity (mOsm/l)	6 920

1. Dosage and administration.

Before administering the product, the temporary seal between the two compartments must be broken and the contents of both compartments mixed.

Dosage and infusion rate

The dose should be individualized according to the patient's nutritional/fluid requirements, energy expenditure, clinical condition, body weight, and capacity to metabolize the components of Clinimix, as well as additional energy or protein administered orally/enterally. Furthermore, daily requirements for fluids, nitrogen, and energy continuously decrease with age.

In adults, requirements range between 0.16 g nitrogen/kg/day (approximately 1 g amino acid/kg/day) and 0.32 g nitrogen/kg/day (approximately 2 g amino acid/kg/day).

In infants, requirements range between 0.16 g nitrogen/kg/day (approximately 1 g amino acid/kg/day) and 0.40 g nitrogen/kg/day (approximately 2.5 g amino acid/kg/day).

In adults and patients aged 12 to 18 years, caloric requirements range between 25 kcal/kg/day and 40 kcal/kg/day, depending on the patient's nutritional status and level of catabolism. Patients under 12 years of age may have higher requirements.

There may be clinical situations where patients require nutrient amounts differing from the composition of Clinimix. In such cases, any volume adjustment (dose) must take into account the resulting effect on the dosing of all other nutritional components in Clinimix. The infusion rate and volume must be determined by a prescribing physician experienced in pediatric intravenous fluid therapy.

This medicine does not contain the amino acids cysteine and taurine, considered conditionally essential for neonates and infants.

This medicine is not recommended for premature and term newborns, or for children under 2 years of age.

The administration rate must be adjusted according to the dose, characteristics of the infused solution, total volume intake over 24 hours, and duration of infusion.

The infusion time should exceed 8 hours. Typically, the administration rate is gradually increased during the first hour without exceeding 2.5 ml per kilogram of body weight per hour, and the maximum dose is 40 ml per kilogram of body weight per day.

Method of administration

When used in newborns and children under 2 years of age, the solution (in bags and administration sets) must be protected from exposure to light until administration is complete.

Route of administration

It will be administered intravenously via peripheral or central route depending on the final osmolarity of the mixture. Generally, the accepted limit for peripheral infusion is approximately 800 mOsm/L, but this varies considerably depending on age, the patient's general condition, and characteristics of the peripheral veins.

1. Warnings and special precautions for use

WARNINGS

Hypersensitivity/infusion reactions have been reported with CLINIMIX formulations, including hypotension, hypertension, peripheral cyanosis, tachycardia, dyspnea, vomiting, nausea, urticaria, rash, pruritus, erythema, hyperhidrosis, fever, and chills.

Anaphylaxis has been reported with other parenteral nutrition products.

Special clinical monitoring is required when initiating any intravenous infusion. If any abnormal sign or symptom occurs, such as a hypersensitivity reaction or infusion reaction, the infusion must be stopped immediately.

Glucose-containing solutions must be used with caution, in any case, in patients with known allergy to corn or corn-derived 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 calcium phosphate precipitate formation. Precipitates have been reported even in the absence of phosphate salts in the solution. Precipitation downstream in the in-line filter has also been reported, and in vivo precipitate formation is suspected.

If signs of pulmonary distress occur, the infusion must be stopped and a medical evaluation initiated.

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

The use of intravenous catheters to administer parenteral formulations, poor catheter maintenance, or contaminated solutions may lead to infection and sepsis.

Immunosuppression and other factors such as hyperglycemia, malnutrition, and/or underlying disease status may predispose patients to infectious complications.

Symptomatic care and laboratory monitoring of fever/chills, leukocytosis, technical complications with the access device, and hyperglycemia may help detect early infections.

The occurrence of septic complications can be reduced by placing greater emphasis on the use of aseptic technique during catheter placement, maintenance, and nutritional formula preparation.

Refeeding severely malnourished patients may lead to refeeding syndrome, characterized by intracellular shifts of potassium, phosphate, and magnesium as the patient enters an anabolic state. Thiamine deficiency and fluid retention may also occur. Strict monitoring and gradual nutrient intake, avoiding overfeeding, can prevent these complications.

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

The generally accepted limit for peripheral infusion is around 800 mOsm/L, but this varies considerably with age, the patient's general condition, and characteristics of the peripheral veins.

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

PRECAUTIONS

Before initiating infusion, severe disturbances in water and electrolyte balance, severe fluid overload states, and severe metabolic disorders should be corrected.

Metabolic complications may occur if nutrient intake is not adapted to the patient's requirements, or if the metabolic capacity for any nutritional component is not accurately assessed. Adverse metabolic effects may result from inadequate or excessive administration of nutrients, or from an inappropriate mixture composition for the patient's specific needs.

Frequent clinical assessments and laboratory tests are essential for proper monitoring during administration. These include determination of ionogram and functional tests of kidney and liver.

Electrolyte requirements of patients receiving these solutions must be carefully determined and monitored, especially in the case of electrolyte-free solutions.

Glucose intolerance is a common metabolic complication in severely stressed patients. Infusion of this solution may cause hyperglycemia, glucosuria, and hyperosmolar syndrome. Blood and urine glucose should be routinely monitored, and insulin dosage adjusted as necessary, especially in diabetic patients.

Use with caution in patients with renal insufficiency, particularly if hyperkalemia is present, due to the risk of developing or worsening metabolic acidosis and hyperazotemia if extrarenal waste elimination is not occurring. Fluid and electrolyte status must be carefully monitored in these patients. In cases of severe renal insufficiency, specially formulated amino acid solutions should be selected.

Caution should be exercised when administering Clinimix to patients with adrenal insufficiency.

Circulatory overload should be avoided, especially in patients with pulmonary edema, heart failure, or cardiac insufficiency. Fluid status must be carefully monitored.

In addition to routine liver function tests, patients with pre-existing liver disease or hepatic insufficiency should be monitored for possible signs of hyperammonemia.

It is known that some patients receiving parenteral nutrition may develop hepatobiliary disorders, including cholestasis, hepatic steatosis, fibrosis, and cirrhosis, which may lead to liver failure, as well as cholecystitis and cholelithiasis. The etiology of these disorders is believed to be multifactorial and may differ among patients. Those who develop abnormal laboratory parameters or other signs of hepatobiliary disorders should be promptly evaluated by a clinical expert in liver diseases to identify potential causal and contributing factors, and possible therapeutic and prophylactic interventions.

In patients receiving amino acid solutions, blood ammonia levels may increase, leading to hyperammonemia. In some patients, this may indicate the presence of a congenital amino acid metabolism disorder (see Section 4.3 of the Summary of Product Characteristics) or hepatic insufficiency.

Blood ammonia levels should be frequently measured in newborns and infants to detect hyperammonemia, which may indicate a congenital abnormality in amino acid metabolism.

Depending on severity and etiology, hyperammonemia may require immediate intervention.

Infusing amino acids too rapidly may cause nausea, vomiting, and chills. In such cases, the infusion must be stopped immediately.

In general, dosage in elderly patients should be cautious, taking into account the higher frequency of hepatic, renal, or cardiac insufficiency, concomitant diseases, or concomitant drug therapy.

Pediatric population

• No studies have been conducted in the pediatric population.
• See above regarding monitoring for hyperammonemia in pediatric patients.

Exposure to light of intravenous parenteral nutrition solutions, especially after mixing with trace elements or vitamins, may have adverse effects on clinical outcomes in newborns due to the generation of peroxides and other degradation products. When used in newborns and children under 2 years of age, Clinimix must be protected from ambient light until administration is complete.

1. Practical information on preparation and handling

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

1.		2.		3.
	Break from the top to open the overpouch.	Remove the front part of the overpouch to access the Clinimix bag. Discard the overpouch and the oxygen-absorbing sachet.	Place the bag on a clean, flat surface with the handle facing toward you.
4.		5.		6.
	Lift the hanger area to remove the solution from the top of the bag. Roll the bag tightly until the seal opens completely (approximately halfway).	Mix the contents by inverting the bag at least three times.	Hang the bag. Rotate the protector to remove it from the administration port. Securely connect the spike connector.

Use the solution only if it is clear, colorless or slightly yellowish, and if the container is undamaged.

CLINIMIX must be at room temperature before use.

Activation of CLINIMIX may be performed either within the overpouch or after its removal.

For single use only.

Do not store partially used containers and discard all equipment after use.

Do not reconnect a partially used bag.

Do not connect in series.

When used in newborns and children under 2 years of age, it must be protected from light exposure until administration is complete. Exposure of Clinimix to ambient light, especially after mixing with trace elements or vitamins, generates peroxides and other degradation products, which can be minimized by protecting the product from light exposure.

Supplementation

Lipids, vitamins, and trace elements should be provided to patients receiving long-term parenteral nutrition.

If administration of additives is required, compatibility must be verified and the stability of the mixtures monitored.

Supplementation can be performed after opening the non-permanent seals for all additives (once the two solutions have been mixed). CLINIMIX may be supplemented with:

• Lipid emulsions (e.g., ClinOleic) at a rate of 50 to 250 mL per liter of CLINIMIX

	CLINIMIX N12G20 1 l + 100 ml of Lipids 20%	CLINIMIX N12G20 1.5 l + 250 ml of Lipids 20%	CLINIMIX N12G20 2 l + 250 ml of Lipids 20%
Nitrogen (g) Amino acids (g) Glucose (g) Lipids (g)	5.8 35 100 20	8.7 53 150 50	11.6 70 200 50
Total calories (kcal) Calories from glucose (kcal) Lipid calories (kcal) Glucose/lipid ratio	740 400 200 67/33	1310 600 500 55/45	1580 800 500 62/38
Acetate (mmol) Chloride (mmol)	27 15	41 22	54 29
pH Osmolality (mOsm/l)	6 860	6 830	6 850

• Electrolytes: per liter of CLINIMIX

Up to a final concentration of	Sodium	Potassium	Magnesium	Calcium
80 mmol	60 mmol	5.6 mmol	3.0 mmol

• Trace elements: per liter of CLINIMIX

Up to a final concentration of	Copper	10 μmol	Zinc	77 μmol
Chromium	0.14 μmol	Manganese	2.5 μmol
Fluoride	38 μmol	Cobalt	0.0125 μmol
Selenium	0.44 μmol	Molybdenum	0.13 μmol
Iodine	0.5 μmol	Iron	10 μmol

• Vitamins: per liter of CLINIMIX

Up to a final concentration of	Vitamin A	1750 IU	Biotin	35 μg
Vitamin B6	2.27 mg	Vitamin B1	1.76 mg
Vitamin D	110 IU	Folic acid	207 μg
Vitamin B12	3.0 μg	Vitamin B2	2.07 mg
Vitamin E	5.1 mg	Vitamin C	63 mg
Vitamin PP	23 mg	Vitamin B5	8.63 mg
Vitamin K	75 μg

Stability data for CLINIMIX supplementation with other commercially available lipid emulsions and other additives or nutrients are available upon request.

If a slight creaming is observed, thoroughly mix the solution by gentle agitation to obtain a uniform emulsion prior to infusion.

Additions must be performed under aseptic conditions.

Additions may be carried out using a syringe or a transfer device.

• Addition using a syringe or transfer device with needle.

• Prepare the injection site (the single tube, see Figure 1).

• Pierce the tube and inject.

• Mix the solution and additives.

Incompatibilities

Additives may be incompatible; please consult the manufacturer for further details.

If additives are required, compatibility must be checked and the stability of the mixtures monitored.

The solution must not be administered simultaneously with, before, or after blood administration through the same equipment due to the risk of pseudoagglutination.

As with any parenteral nutrition mixture, the ratios of calcium and phosphate must be taken into account. The addition of excessive amounts of calcium and phosphate, particularly in the form of mineral salts, may lead to the formation of calcium phosphate precipitates.

1. Shelf life

2 years if stored in the overpouch.

It is recommended to use the product immediately after opening the non-permanent seal between the two chambers. However, once reconstituted (i.e., after opening the internal non-permanent seal), the reconstituted solution has been shown to be stable for up to 7 days at a temperature between 2°C and 8°C, followed by up to 48 hours at a temperature not exceeding 25°C.

From a microbiological standpoint, mixtures should be used immediately after additions are made. If not used immediately, the in-use storage duration and conditions prior to use are the responsibility of the user and should not exceed 24 hours at 2–8°C, unless additions were performed under controlled and validated aseptic conditions. If longer storage periods under exceptional circumstances are required, the company may be contacted, as stability data on physical and chemical in-use stability are available for up to 7 days at 2–8°C followed by 48 hours at temperatures below 25°C for the products indicated in the previous section.