Package Insert: Information for the Patient

Clinimix N12G20 Infusion Solution

Read this package insert carefully before starting administration of this medication, as it contains important information for you.

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

Clinimix is a solution for infusion. It is supplied in a bag with 2 chambers. 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 of the bag to open the seals.

Clinimix is administered to feed adults and children through a tube connected to a vein when normal oral feeding is not suitable.

Clinimix should only be administered under medical supervision.

CLINIMIX should not be administered if:

• You are allergic to the active ingredients or any of the other components of this medication (listed in section 6),
• Your body has problems using certain amino acids,
• You have severe high blood sugar (severe hyperglycemia),
• Your blood is excessively acidic (metabolic acidosis due to excessive lactate),

Your doctor will decide whether to administer this medication based on factors such as age, weight, and clinical condition, along with the results of all tests performed.

Warnings and precautions

Consult your doctor or nurse before CLINIMIX is administered to you.

If any abnormal signs or symptoms of an allergic reaction develop, such as fever, chills, skin rash, or difficulty breathing, excessive sweating, nausea, and headache, inform your doctor or nurse: the infusion will be stopped immediately. Your doctor will monitor your condition while you are receiving this medication and may change the dose or add other nutrients, such as lipids, vitamins, electrolytes, and oligoelements if deemed necessary.

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

If you are severely malnourished to the point where you need to receive nutrition through a vein, it is recommended that parenteral nutrition be initiated slowly and carefully.

Your doctor will monitor your condition at the start of the infusion, especially if you currently have problems with the liver, kidneys, adrenal glands, heart, or circulation. Your doctor should also be aware of severe conditions that affect how the body handles sugars, fats, proteins, or salts (metabolic disorders). If any abnormal signs develop, including venous irritation, the infusion should be stopped.

To check the effectiveness and safety of administration, your doctor will perform laboratory and clinical tests while you are receiving this medication. If you are receiving this medication for several weeks, your blood will be analyzed regularly. In particular, in cases of glucose intolerance, blood glucose and urine glucose will be monitored regularly, 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, the solution (in bags and in administration equipment) must be protected from exposure to light until the administration is complete. Exposure of Clinimix to ambient light, especially after mixing with oligoelements and/or vitamins, generates peroxides and other degradation products that can be reduced by protecting the solution from light exposure.

Interaction of CLINIMIX with other medications

Inform your doctor or nurse if you are taking or have taken recently or may need to take any other medication.

Pregnancy, breastfeeding, and fertility

If you are pregnant or breastfeeding, or believe you may be pregnant or intend to become pregnant, consult your doctor before using this medication.

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

CLINIMIX can be administered to adults and children.

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

It is a solution for infusion that is administered through a plastic tube connected to a vein in your arm or a large vein in your chest.

Dose – Adults and Children

Your doctor will decide on the dose you need and the time for which it will be administered, based on age, weight, height, clinical condition, daily fluid volume, and energy and nitrogen needs.

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

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

A bag infusion usually lasts between 8 and 24 hours.

If you are administered more CLINIMIX than you should

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

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

To prevent these cases, your doctor will regularly monitor your condition and analyze your blood parameters.

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

Like all medications, this medication may produce adverse effects, although not everyone will experience them. If you notice any change in how you feel during treatment or after it, inform your doctor or nurse immediately.

The tests your doctor will perform while administering this medication should minimize the risk of adverse effects.

Infusion will be stopped immediately if any abnormal sign or symptoms of an allergic reaction develop, such as abnormally high or low blood pressure, appearance of blue or purple skin discoloration, abnormally high heart rate, difficulty breathing, vomiting, nausea, skin eruptions, increased body temperature, excessive sweating, and chills.

Other adverse effects have been observed, which occur with more or less frequency:

• Anaphylaxis (a severe allergic reaction that starts quickly and can cause death).
• High levels of glucose, ammonia, and nitrogen-containing compounds in the blood.
• Impairment of liver function, abnormal liver function blood tests.
• Inflammation of the gallbladder, presence of gallstones in the gallbladder.
• Inflammation of 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 pulmonary blood vessels.

Reporting 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 prospectus. You can also report them directly through the Spanish System of Pharmacovigilance of Medicines for Human Use: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

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

When used in newborns and children under 2 years, the solution (in the bags and administration equipment) must be protected from exposure to light until the administration is completed (see section 2).

Do not use this medication after the expiration date that appears on the packaging and outer packaging (MM/YYYY). The expiration date is the last day of the month indicated.

Do not freeze.

Store the container in the outer packaging.

Do not dispose of the medication through the drains or trash. If in doubt, ask your pharmacist how to dispose of the containers and medication that you no longer need. In this way, you will help protect the environment.

Composition of Clinimix

The active principles of each bag of the reconstituted solution are:

The other components are:

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

Aspect of CLINIMIX and contents of the package

CLINIMIX is a perfusion solution that is presented in a multi-layered plastic bag with two chambers. The inner layer (contact layer) of the bag is made of polymers (a mixture of polyolefin copolymers) to be compatible with the authorized components and additives. Other layers are made of EVA (polyethylene-vinyl-acetate) and a copolyester.

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

To prevent contact with air oxygen, the bag is packaged in the interior of an overbag that acts as an oxygen barrier, which contains an oxygen absorbent.

Packaging sizes

1000 ml bag: cardboard box with 8 bags

1 bag of 1000 ml

1500 ml bag: cardboard box with 6 bags

1 bag of 1500 ml

2000 ml bag: cardboard box with 4 bags

1 bag of 2000 ml

Only some packaging sizes may be commercially available.

Marketing authorization holder

Baxter S.L.

Pouet de Camilo 2,

46394 Ribarroja del Turia (Valencia) Spain

Responsible for manufacturing

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

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

Clinimix N12G20, perfusion solution

Last review of this leaflet was in September 2021

More detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS)http://www.aemps.gob.es/

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This information is intended solely for healthcare professionals:

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:

2. Dosage and administration form

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

Dose and infusion rate

The dosemust be individualized according to the patient's nutritional needs/liquid, energy expenditure, clinical status, body weight, and ability to metabolize the components of Clinimix, as well as any additional energy or protein administered orally/enterally. In addition, daily liquid, nitrogen, and energy needs decrease continuously with age.

In adults, needs range from 0.16 g of nitrogen/kg/day (approximately 1 g of amino acid/kg/day) to 0.32 g of nitrogen/kg/day (approximately 2 g of amino acid/kg/day).

In newborns, needs range from 0.16 g of nitrogen/kg/day (approximately 1 g of amino acid/kg/day) to 0.40 g of nitrogen/kg/day (approximately 2.5 g of amino acid/kg/day).

In adults and patients 12 to 18 yearsneeds of calories range from 25 kcal/kg/day to 40 kcal/kg/day, depending on the patient's nutritional status and catabolic level.Patients under 12 years may have higher requirements.

There may be clinical situations where patients require amounts of nutrients that differ from the composition of Clinimix. In this situation, any volume adjustment (dose) must take into account the resulting effect on the dosing of all other nutritional components of Clinimix. The infusion rate and volume must be established by a prescribing physician with experience in pediatric intravenous fluid therapy.

This medicinal product does not contain the amino acids cysteine and taurine, considered conditionally essential for newborns and infants.

This medicinal product is not recommended for premature newborns, full-term newborns, and children under 2 years.

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

The infusion time must be greater than 8 hours. Normally, the infusion rate is gradually increased during the first hour without exceeding 2.5 ml/kg body weight/hour, and the maximum dose is 40 ml/kg body weight/day.

Administration form

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

Administration route

It will be administered by intravenous peripheral or central route according to the final osmolarity of the mixture. In general, the accepted limit for peripheral infusion is approximately 800 mOsm/l, but it varies greatly depending on the age, general condition of the patient, and characteristics of the peripheral veins.

3. Warnings and special precautions for use

WARNING

With Clinimix formulations, hypersensitivity reactions/perfusion have been reported, including hypotension, hypertension, peripheral cyanosis, tachycardia, dyspnea, vomiting, nausea, urticaria, skin rash, pruritus, erythema, hyperhidrosis, fever, and chills.

With other parenteral nutrition products, anaphylaxis has been reported.

When initiating any intravenous infusion, special clinical monitoring is required. In case of abnormal signs or symptoms, such as hypersensitivity reaction or infusion reaction, the infusion must be stopped immediately.

Solutions containing glucose must be used with caution, in any case, in patients with known allergy to corn or corn-derived products.

Pulmonary vascular embolism has been reported in patients receiving parenteral nutrition.

In some cases, fatal outcomes have been reported. Excessive addition of calcium and phosphate increases the risk of calcium phosphate precipitation. Precipitates have been reported even in the absence of phosphate salt in the solution. Precipitation has also been reported in the in-line filter and is suspected to occur in vivo.

If signs of respiratory distress are present, the infusion must be stopped and a medical evaluation initiated.

Aside from inspecting the solution, the infusion equipment, and the catheter, they must be checked periodically for precipitates.

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

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

Symptomatic treatment and laboratory control of fever/chills, leukocytosis, technical complications with the access device, and hyperglycemia may help recognize early infections.

The appearance of septic complications can be reduced by emphasizing the use of aseptic technique in catheter placement, maintenance, and preparation of the nutritional formula.

Refeeding syndrome may occur in severely malnourished patients, characterized by changes in intracellular potassium, phosphate, and magnesium. It may also be accompanied by thiamine deficiency and fluid retention. Strict monitoring and gradual intake of nutrients, avoiding overfeeding, can prevent these complications.

Hypertonic solutions may cause venous irritation if infused through a peripheral vein. The choice of 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 it varies greatly with age and general condition of the patient and characteristics of peripheral veins.

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

PRECAUTIONS

Before starting the infusion, severe fluid and electrolyte imbalances, severe fluid overload, and severe metabolic disorders must be corrected.

Complications may occur if nutrient intake is not adapted to the patient's needs, or if the metabolic capacity of any nutritional component is not evaluated accurately. Adverse metabolic effects may occur due to inadequate or excessive administration of nutrients, or due to the composition of a mixture not appropriate for the patient's specific needs.

It is essential to perform frequent clinical evaluations and laboratory tests to ensure proper control during administration. These include ionogram and functional tests of the kidneys and liver.

The patient's electrolyte needs must be carefully determined and controlled, especially in solutions without electrolytes.

Glucose intolerance is a common metabolic complication in severely stressed patients. Infusion of this solution may cause hyperglycemia, glycosuria, and hyperosmolar syndrome. Blood glucose and urine glucose must be monitored regularly, and if necessary, insulin doses must be adjusted for diabetics.

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

Care must be taken when administering Clinimix to patients with adrenal insufficiency.

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

Aside from routine liver function tests, patients with pre-existing liver disease or liver insufficiency must be monitored for possible symptoms of hyperammonemia.

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

In patients receiving amino acid solutions, an increase in blood ammonia levels and hyperammonemia may occur. In some patients, this may indicate the presence of a congenital disorder of amino acid metabolism (see Section 4.3 of the Technical Dossier) or liver insufficiency.

Blood ammonia levels must be regularly measured in newborns and infants to detect hyperammonemia, which may indicate the presence of a congenital disorder of amino acid metabolism.

According to degree and etiology, hyperammonemia may require immediate intervention.

A too rapid infusion of amino acids may cause nausea, vomiting, and chills. In these cases, the infusion must be stopped immediately.

Generally, the dose for elderly patients must be cautious, taking into account the higher frequency of liver, kidney, or heart insufficiency and concomitant diseases or pharmacotherapy.

Pediatric population

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

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

4. Practical information on preparation and handling

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

Use the solution only if it is transparent, colorless, or slightly yellowish, and if the container is not damaged.

CLINIMIXmust be at room temperature before use.

CLINIMIXactivation can be done in the overbag or once it has been removed.

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, it must be protected from exposure to light until the end of administration. Exposure of Clinimix to ambient light, especially after mixing it with oligoelements or vitamins, generates peroxides and other degradation products that can be reduced if the product is protected from exposure to light.

Supplementation

Patients receiving parenteral nutrition for a long period should be provided with lipids, vitamins, and oligoelements.

If additional components are required, their compatibility and the stability of the mixtures must be checked.

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

• lipid emulsions (e.g. ClinOleic) at a rate of 50 to 250 ml per liter of CLINIMIX

• Electrolytes: per liter of CLINIMIX

• Oligoelements: per liter of CLINIMIX

• Vitamins: per liter of CLINIMIX

Stability data for supplementing Clinimix with other commercially available lipid emulsions and other additives or nutrients are available on request.

If a slight cream is observed, the mixture must be thoroughly mixed by gentle agitation to obtain a uniform emulsion before infusion.

Additions must be made in aseptic conditions.

Additions can be made with a syringe or with a transfer device with a needle.

• Adding with syringe or transfer device with needle.

• Prepare the injection point (the single tube, see Figure 1).
• Pierce the tube and inject.
• Mix the solution and additives.

Incompatibilities

Additives may be incompatible, consult the manufacturer for more details.

If additional components are required, their compatibility and the stability of the mixtures must be checked.

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

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

5. Shelf life

2 years if stored in the overbag.

It is recommended to use the product immediately after opening the non-permanent seal between the two compartments. However, once reconstituted (i.e., after opening the internal non-permanent seal), the stability of the reconst