SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

OLICLINOMEL N8-800, emulsion for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

This medicinal product is presented in the form of a 3-compartment bag. Composition of 1000 ml of emulsion:

Active substances	15% lipid emulsion compartment (corresponding to 15g/100ml) (200 ml)	12.5% amino acid solution compartment (corresponding to 12.5g/100ml) (400 ml)	31.25% glucose solution compartment (corresponding to 31.25g/100ml) (400 ml)
Refined olive oil + Refined soya-bean oil*	30.00 g
Alanine		10.35 g
Arginine		5.75 g
Glycine		5.15 g
Histidine		2.40 g
Isoleucine		3.00 g
Leucine		3.65 g
Lysine (As lysine hydrochloride)		2.90 g (3.62 g)
Methionine		2.00 g
Phenylalanine		2.80 g
Pro line		3.40 g
Serine		2.50 g
Threonine		2.10 g
Tryptophan		0.90 g
Tyrosine		0.20 g
Valine		2.90 g
Anhydrous glucose (As glucose monohydrate)			125.00 g (137.50 g)

* Mixture of refined olive oil (approximately 80%) and refined soya-bean oil (approximately 20%) corresponding to a ratio essential fatty acids / total fatty

acids of 20%.

For full list of excipients, see section 6.1

After the contents of the three compartments have been mixed, the ternary mixture provides the following:

Nitrogen (g)	16.5
Amino acids (g)	100
Glucose (g)	250
Lipids (g)	60
Total calories (kcal)	2000
Non-protein calories (kcal)	1600
Glucose calories (kcal)	1000
Lipid calories (kcal)	600
Non-protein calorie/nitrogen ratio	97
Phosphate (mmol)**	4.5
Acetate (mmol)	85
Chloride (mmol)	40

** Phosphates provided by the lipid emulsion

pH:    6.0

Osmolarity: 1230 mOsm/l

3    PHARMACEUTICAL FORM

Emulsion for infusion.

Appearance prior to reconstitution:

•    The lipid emulsion is a homogeneous liquid with a milky appearance.

•    The amino acid and glucose solutions are clear and colourless or slightly yellow.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

OLICLINOMEL N8-800 is indicated for parenteral nutrition for 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

The dosage depends on the patient’s energy expenditure, clinical status, body weight, and the ability to metabolize the constituents of OLICLINOMEL, as well as

additional energy or proteins provided orally/enterally; therefore, the bag size should be chosen accordingly.

The administration may be continued for as long as is required by the patient’s clinical conditions.

The maximum daily dose should not be exceeded in adult and pediatric patients. Due to the static composition of the multi-chamber bag, the ability to simultaneously meet all nutrient needs of the patient may not be possible. Clinical situations may exist where patients require amounts of nutrients varying from the composition of the static bag.

In adults

Requirements

Average nitrogen requirements are 0.16 to 0.35 g/kg/day (approximately 1 to 2 g amino acids/kg/day).

Energy requirements vary depending on the patient's nutritional state and level of catabolism. On average these are 20 to 40 kcal/kg/day.

Maximum daily dose

The maximum daily dose is 40 ml/kg body weight (equivalent to 2.00 g amino acids, 5.00 g glucose and 1.20 g lipids/kg), i.e. 2800 ml of the emulsion for infusion for a patient weighing 70 kg.

In adolescents and children greater than two years of age There have been no studies performed in the pediatric population.

Requirements

Average nitrogen requirements are:

Children 2-11 years of age: 0.16 to 0.35 (up to 0.45) g/kg/day equivalent to 1- 2 (up to 3) g amino acids/kg/day.

Children 12-18 years of age: 0.16 to 0.35 g/kg/day equivalent to 1- 2 g amino acids/kg/day.

Energy requirements vary depending on the patient's age, nutritional state and level of catabolism. On average these range between:

Children 2-11 years of age: 60-90 kcal/kg/day.

Children 12-18 years of age: 30-75 kcal/kg/day

Posology

The dosage is based on fluid intake and daily nitrogen requirements.

These intakes should be adjusted to take account of the child's hydration status.

Maximum daily dose

The maximum daily dose is 60 ml/kg body weight (equivalent to 3 g amino acids, 7.5 g glucose and 1.8 g lipids/kg body weight).

As a general rule do not exceed doses of 3 g/kg/day amino acids and/or 17 g/kg/day glucose and/or 3 g/kg/day lipids and/or 100ml/kg/day fluid, except in particular cases.

Method of administration

FOR INTRAVENOUS USE THROUGH A CENTRAL VEIN ONLY (Due to high osmolarity of OLICLINOMEL).

For single use only.

It is recommended that after opening the bag, the contents should be used immediately and not stored for subsequent infusion.

Appearance after reconstitution: Homogeneous liquid with a milky appearance.

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

The recommended duration of the parenteral nutrition infusion is between 12 and 24 hours.

The administration flow rate should be adjusted to take account of the dose being administered; the characteristics of the final mixture being infused, the daily volume intake and the duration of the infusion (see section 4.4).

Normally, the flow rate should be increased gradually during the first hour.

In general, the infusion for small children should start in the low dose i.e. 12.5 - 25 ml/kg and increased progressively up to a maximum dosage of 60 ml/kg/day.

Maximum infusion rate in Adults

As a general rule, do not exceed 2.0 ml/kg/hour of the emulsion for infusion, i.e. 0.10 g amino acids, 0.25 g glucose and 0.06 g lipids/kg body weight per hour.

Maximum infusion rate in children 2-11 years of age:

In this group of age, the limiting factor for hourly rate is the amino acid concentration. As a general rule, do not exceed 4.0 ml/kg/hour of the emulsion for infusion, i.e. 0.20 g amino acids, 0.50 g glucose and 0.12 g lipids/kg body weight per hour.

Maximum infusion rate in children 12-18 years of age:

In this group of age, the limiting factor for hourly rate is the amino acid concentration. As a general rule, do not exceed 2.4 ml/kg/hour of the emulsion for infusion, i.e. 0.12 g amino acids, 0.30 g glucose and 0.07 g lipids/kg body weight per hour.

4.3 Contraindications

The use of OLICLINOMEL N8-800 is contraindicated in the following cases:

In premature neonates, infants and children less than 2 years old, as the calorie-nitrogen ratio and energy supply are inappropriate.

Hypersensitivity to egg, soybean or peanut proteins, or to any other active substance or excipients (listed in section 6.1).

Congenital abnormalities of amino acid metabolism.

Severe hyperlipidaemia or severe disorders of lipid metabolism characterized by hypertriglyceridemia.

Severe hyperglycaemia

4.4 Special warnings and precautions for use

OLICLINOMEL N8-800 must not be administered through a peripheral vein.

An excessively fast administration of total parenteral nutrition (TPN) solutions, including OLICLINOMEL N8-800, may result in severe or fatal consequences.

The infusion must be stopped immediately if any signs or symptoms of an allergic reaction (such as sweating, fever, chills, headache, skin rashes, dyspnoea or bronchospasm) develop. This medicinal product contains soyabean oil and egg phosphatide. Soybean and egg proteins may cause hypersensitivity reactions. Crossallergic reactions between soybean and peanut proteins have been observed.

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

Specific clinical monitoring is required when an intravenous infusion is started.

Pulmonary vascular precipitates causing pulmonary vascular embolism and respiratory 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 formation of calcium phosphate precipitates (see section 6.2).

Precipitates of various natures have been reported even in the absence of phosphate salt in the solution.

Suspected precipitate formation in the blood stream has also been reported.

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

If signs of respiratory distress occur, the infusion should be stopped and medical evaluation initiated.

Do not add other medicinal products or substances to any components of the bag or to the reconstituted emulsion without first confirming their compatibility and the stability of the resulting preparation (in particular the stability of the lipid emulsion). Formation of precipitates or destabilization of the lipid emulsion could result in vascular occlusion (see section 6.2 and 6.6).

Vascular access infection and sepsis are complications that may occur in patients receiving parenteral nutrition particularly in case of poor maintenance of catheters, immunosuppressive effects of illness or drugs. Careful monitoring of signs, symptoms and laboratory test results for fever/chills, leukocytosis, technical complications with the access device, and hyperglycaemia can help recognize early infections. Patients who require parenteral nutrition are often predisposed to infectious complications due to malnutrition and/or their underlying disease state. The occurrence of septic complications can be decreased with heightened emphasis on aseptic technique in catheter placement, and maintenance, as well as aseptic technique in the preparation of the nutritional formula.

Monitor water and electrolyte balance, serum osmolarity, serum triglycerides, acid/base balance, blood glucose, liver and kidney function tests, coagulation tests, and blood count, including platelets and coagulation parameters throughout treatment

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.

Serum triglyceride concentrations and the ability of the body to remove lipids must be checked regularly.

Serum triglyceride concentrations must not exceed 3 mmol/l during the infusion.

These concentrations should not be determined before a minimum of a 3-hour period of continuous infusion.

If a lipid metabolism abnormality is suspected, it is recommended that tests be performed daily by measuring serum triglycerides after a period of 5 to 6 hours without administering lipids. In adults, the serum must be clear in less than 6 hours after stopping the infusion containing the lipid emulsion. The next infusion should only be administered when the serum triglyceride concentrations have returned to normal values.

Fat overload syndrome has been reported with similar products. The reduced or limited ability to metabolize the lipids contained in OliClinomel may result in a "fat overload syndrome" which may be caused by overdose; however the signs and symptoms of this syndrome may also occur when the product is administered according to instructions (see also section 4.8).

In the event of hyperglycaemia, the infusion rate of OLICLINOMEL must be adjusted and/or insulin administered. (See section 4.9)

When making additions, the final osmolarity of the mixture must be measured before administration. The mixture obtained should be administered through a central or peripheral venous line depending on its final osmolarity. If the final mixture, which is administered, is hypertonic it may cause irritation of the vein when administered into a peripheral vein.

Although there is a natural content of trace elements and vitamins in the product, the levels are insufficient to meet body requirements and these should be added to prevent deficiencies from developing. See instructions for making additions to this product. (See section 6.6)

Caution should be exercised in administering OLICLINOMEL N8-800 to patients with increased osmolarity, adrenal insufficiency, heart failure or pulmonary dysfunction.

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. This syndrome has been reported with similar products

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

Hepatic Insufficiency

Use with caution in patients with hepatic insufficiency because of the risk of developing or worsening neurological disorders associated with hyperammonaemia. Regular clinical and laboratory tests are required particularly liver function parameters, blood glucose, electrolytes and triglycerides.

Renal Insufficiency

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, triglycerides and electrolyte status should be closely monitored in these patients.

Hematologic

Use with caution in patients with coagulation disorders and anaemia. Blood count and coagulation parameters should be closely monitored.

Endocrine and Metabolism Use with caution in patients with:

•    Metabolic acidosis. Administration of carbohydrates is not recommended in the presence of lactic acidosis. Regular clinical and laboratory tests are required.

•    Diabetes mellitus. Monitor glucose concentrations, glucosuria, ketonuria and where applicable adjust insulin dosages.

•    Hyperlipidaemia due to the presence of lipids in the emulsion for infusion. Regular clinical and laboratory tests are required.

•    Amino acid metabolism disorders

Extravasation

Catheter site should be monitored regularly to identify signs of extravasation. If extravasation occurs, the administration should be stopped immediately, keeping the inserted catheter or cannula in place for immediate management of the patient. If possible, aspiration should be performed through the inserted catheter/ cannula in order to reduce the amount of fluid present in the tissues before removing the catheter/ cannula.

Depending on the extravasated product (including the product(s) being mixed with OLICLINOMEL, if applicable) and the stage/extent of any injury, appropriate specific measures should be taken. Options for management may include nonpharmacologic, pharmacologic and/or surgical intervention. If there is any deterioration of the affected area (continued pain, necrosis, ulceration, suspected compartment syndrome), surgery should be consulted immediately.

The extravasation site should be monitored at least every 4 hours during the first 24 hours, then once daily.

The infusion should not be restarted in the same central vein.

Special precautions in paediatrics

When administered to children greater than 2 years old, any unused reconstituted emulsion should be discarded.

Vitamin and trace element supplementation is always required. Paediatric formulations should be used.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

OLICLINOMEL N8-800 contains vitamin K, naturally present in lipid emulsions. The amount of Vitamin K in recommended doses of OLICLINOMEL N8-800 are not expected to influence effects of coumarin derivatives.

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

The lipids contained in this emulsion may interfere with the results of certain laboratory tests (for example, bilirubin, lactate dehydrogenase, oxygen saturation, blood haemoglobin) if the blood sample is taken before the lipids have been eliminated (these are generally eliminated after a period of 5 to 6 hours without receiving lipids).

4.6 Pregnancy and lactation

There are not at present sufficient relevant clinical findings to assess the tolerability of the ingredients in OLICLINOMEL N8-800 in women who are pregnant or breastfeeding.

In the absence of data, the prescriber must assess the risks/benefits before deciding to administer this emulsion either during pregnancy or to women who are breast-feeding.

4.7 Effects on ability to drive and use machines

There are no data on the effects of the ability to operate and automobile or other heavy machinery.

4.8 Undesirable effects

Potential undesirable effects may occur as a result of inappropriate use (for example: overdose, excessively fast infusion rate) (see sections 4.4 and 4.9).

At the beginning of the infusion, any abnormal signs or symptoms of an allergic reaction (e.g. sweating, fever, shivering, headache, skin rashes, dyspnoea, brochospasm) should be cause for immediate discontinuation of the infusion.

OLICLINOMEL N4-550E, N7-1000E, and N8-800 have been used in three (3) clinical trials to evaluate the ease of use, safety and nutritional efficacy of the product.

One trial was a randomized, double-blind, active-controlled, efficacy and safety study conducted with OLICLINOMEL N8-800. Twenty-eight patients with various medical conditions (i.e., postsurgical fasting, severe malnutrition, enteral intake insufficient or forbidden) were included and treated; patients in the OLICLINOMEL group received drug product up to 40 mL/kg/d over 5 days.

The other two trials were open-label, non-comparative studies to evaluate the ease of use, safety and efficacy of OLICLINOMEL in gastrointestinal surgery patients. In these trials, a total of 36 patients received drug product up to 40 mL/kg/d over 5 days in OLICLINOMEL N4-550E study (N = 20), and up to 36 mL/kg/d over 5 days in OLICLINOMEL N7-1000E study (N = 16).

The pooled data (64 patients) from these 3 clinical trials and the postmarketing experience indicate the following adverse drug reactions (ADRs) related to OLICLINOMEL.

System Organ Class (SOC)	Preferred MedDRA Term	Frequencya
IMMUNE SYSTEM DISORDERS	Hypersensitivity	commonb
	Bronchospasm (as part of allergic reaction)	Not knownc
NERVOUS SYSTEM DISORDERS	Headache	commonb
	Tremor	Not knownc
GASTROINTESTINAL DISORDERS	Diarrhoea Abdominal pain Vomiting Nausea	common Not knownc Not knownc Not knownc
RENAL AND URINARY DISORDERS	Azotemia	commonb
HEPATO-BILIARY DISORDERS	Hepatitis cholestatic Cholestasis Jaundice	Not knownc Not knownc Not knownc
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	Erythema* Hyperhydrosis	Not knownc Not knownc
MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS	Musculoskeletal pain Back pain Chest pain Pain in extremity Muscle spasm	Not knownc Not knownc Not knownc Not knownc Not knownc
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	Chills Infusion site extravasation Infusion site pain* Infusion site swelling* Infusion site vesicles* Catheter site phlebitis* Injection site oedema* Localized oedema* Oedema peripheral* Pyrexia Feeling hot* Hyperthermia Malaise Inflammation Necrosis/ulcer*	b common commonb commonb commonb commonb Not knownc Not knownc Not knownc Not knownc Not knownc Not knownc Not knownc Not knownc Not knownc Not knownc
INVESTIGATIONS	Blood bilirubin increased Hepatic enzyme increased Gamma-glutamyltransferase increased Blood triglycerides increased Blood alkaline phosphatase increased Blood glucose increased Hyperglycaemia	Not knownc commonb commonb commonb commonb Not knownc Not knownc

a: Frequency is defined as very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to <    1/100): rare (> 1/10,000 to < 1/1000); very rare (< 1/10,000); and not known (cannot be estimated

from the available data).

b: ADR reported during clinical trials. These studies included only 64 patients who were exposed to OLICLINOMEL.

c: ADR reported during postmarketing experience with OLICLINOMEL.

*: Adverse reactions that can be associated with extravasation

Class reactions

The following has been reported with other similar products:

•    Fat Overload Syndrome (very rare)

Fat overload syndrome has been reported with similar products. This may be caused by inappropriate administration (e.g. overdose and/or infusion rate higher than recommended; however the signs and symptoms of this syndrome may also occur at the start of an infusion when the product is administered according to instructions.

The reduced or limited ability to metabolize the lipids contained in OLICLINOMEL N8-800, accompanied by prolonged plasma clearance may result in a “fat overload syndrome”. This syndrome is associated with a sudden deterioration in the patient's clinical condition and is characterized by findings such as hyperlipidemia, fever, liver fatty infiltration (hepatomegaly), deteriorating liver function, anaemia, leucopoenia, thrombocytopenia, coagulation disorders, and central nervous system manifestations (e.g. coma), requiring hospitalization. The syndrome is usually reversible when the infusion of the lipid emulsion is stopped.

•    Vascular disorders (frequency not known - cannot be estimated from the available data): Pulmonary vascular precipitates (pulmonary vascular embolism and respiratory distress) (see Section 4.4)

Paediatric population

Thrombocytopenia has been reported in children receiving lipid infusions.

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.

Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

In the event of inappropriate administration (overdose, and/or infusion rate higher than recommended), signs of hypervolaemia and acidosis may occur.

An excessively fast administration of Total Parenteral Nutrition (TPN) solutions, including OLICLINOMEL, may result in severe or fatal consequences. (See section

4.4 Special warning and precautions for use).

Hyperglycaemia, glucosuria, and a hyperosmolar syndrome may develop if excessive glucose is administered.

Excessively fast infusion or administration of an inappropriately large volume may cause nausea, vomiting, chills, and electrolyte disturbances. In such situations, the infusion should be stopped immediately.

The reduced or limited ability to metabolize lipids may result in a "fat overload syndrome", the results of which are usually reversible after the infusion of the lipid emulsion is stopped (see also section 4.8).

In some serious cases, haemodialysis, haemofiltration or haemodiafiltration may be necessary.

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Solutions for parenteral nutrition / combinations ATC code: B05BA10

OLICLINOMEL N8-800 is a ternary mixture of macronutrients enabling the nitrogen/energy balance to be maintained from the nitrogen source (L series amino acids) and energy in the form of glucose and essential fatty acids.

This formulation without electrolytes allows individual electrolyte intake to be adapted to meet specific requirements.

The amino acid solution contains 15 L series amino acids (including 8 essential amino acids), which are indispensable for protein synthesis.

The amino acids also represent an energy source, their oxidation resulting in excretion of nitrogen in the form of urea.

The amino acid profile is as follows:

-    Essential amino acids/total amino acids: 40.5%

-    Essential amino acids (g)/total nitrogen (g): 2.5

-    Branched-chain amino acids/total amino acids: 19%

The carbohydrate source is glucose (125 g/l).

The lipid emulsion is an association of refined olive oil and refined soya-bean oil (ratio 80/20), with the following approximate distribution of fatty acids:

-    15% saturated fatty acids (SFA)

-    65% monounsaturated fatty acids (MUFA)

-    20% polyunsaturated essential fatty acids (PUFA)

The phospholipid/triglyceride ratio is 0.06.

The moderate essential fatty acid (EFA) content improves the status of their upper derivatives while correcting EFA deficiency.

Olive oil contains significant amount of alpha tocopherol which, combined with a moderate PUFA intake, contributes to improve vitamin E status and reduce lipid peroxidation.

5.2 Pharmacokinetic properties

The ingredients (amino acids, glucose, lipids) are distributed, metabolised and removed in the same way as if they had been administered individually.

The pharmacokinetic properties of the amino acids administered intravenously are principally the same as those of amino acids supplied by oral feeding. Amino acids from food proteins, however, first pass through the vena porta before reaching the systemic circulation.

The elimination rate of lipid emulsions depends on particle size. Small lipid particles appear to delay clearance whereas they increase lipolysis by lipoprotein lipase.

The size of the lipid particles in the emulsion contained in OLICLINOMEL N8-800 is close to that of chylomicrons and this emulsion therefore has a similar elimination rate.

5.3 Preclinical safety data

No preclinical studies have been performed on the OLICLINOMEL N8-800 finished product.

However, preclinical studies performed using the solutions of amino acids, and glucose contained in OLICLINOMEL N8-800 of different qualitative compositions and concentrations have not revealed any specific toxicity.

Preclinical toxicity studies performed using the lipid emulsion contained in OLICLINOMEL N8-800 have identified the changes, which are conventionally found with a high intake of a lipid emulsion: fatty liver, thrombocytopaenia and elevated cholesterol.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lipid emulsion compartment:

Purified egg phosphatide

Glycerol

Sodium oleate

Sodium hydroxide (for pH adjustment) Water for injections

Amino acid solution compartment: Glacial acetic acid (for pH adjustment) Water for injections

Glucose solution compartment: Hydrochloric acid (for pH adjustment) Water for injections

6.2    Incompatibilities

Do not add other medicinal products or substances to any components of the bag or to the reconstituted emulsion without first confirming their compatibility and the stability of the resulting preparation (in particular the stability of the lipid emulsion or formation of precipitates) (see section 6.6).

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 formation of calcium phosphate precipitates.

Incompatibilities may be produced for example by excessive acidity (low pH) or inappropriate content of divalent cations (Ca²+ and Mg²+), which may de-stabilise the lipid emulsion.

Check compatibility with solutions administered simultaneously through the same administration set, catheter, or cannula.

Do not administer before, simultaneously with, or after blood through the same equipment because of the risk of pseudoagglutination.

6.3    Shelf life 2 years in the overwrap

It is recommended that the product be used immediately after the non-permanent seals between the 3 compartments have been opened.

However the reconstituted emulsion has been shown to be stable for a maximum of 7 days between 2°C and 8°C followed by a maximum of 48 h at temperatures not exceeding 25°C.

When adding supplements to OLICLINOMEL N8-800, already reconstituted (see section 6.6), and when not used immediately, chemical and physical in-use stability has been demonstrated for 7 days at 2°C to 8°C followed by 48 hours below 25°C. However, from a microbiological point of view, any admixture should be used immediately. If not used immediately, in-use storage times and conditions after reconstitution and prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C, unless addition of supplements has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Do not freeze.

Keep container in the outer carton in order to protect from light. For storage of the reconstituted emulsion, see section 6.3

6.5    Nature and contents of container

The 3 compartment bag is a multi-layer plastic bag. The inner (contact) layer of the bag material is made of a blend of polyolefinic copolymers and is compatible with amino acid solutions, glucose solutions and lipid emulsions. Other layers are made of EVA (poly(ethylene vinyl acetate)), and of a copolyester.

The bag is packaged in an oxygen barrier overwrap, which contains an oxygen absorber in a sachet.

The glucose compartment is fitted with an injection site to be used for addition of supplements.

The amino acid compartment is fitted with an administration site for insertion of the spike of the infusion set.

After the seals have been broken, the capacity of the bag is sufficient to enable vitamins, electrolytes and trace elements to be added.

A 3 compartment bag contains 2000 ml: (800 ml 12.5% amino acid solution (corresponding to 12.5g/100ml) + 800 ml 31.25% glucose solution (corresponding to 31.25g/100ml) + 400 ml 15% lipid emulsion (corresponding to 15g/100ml)

Pack sizes:

Carton with 4 bags 1 bag of 2000 ml

Not all pack sizes may be marked

Special precautions for disposal

a.To open

-    Tear the protective overwrap.

-    Discard the oxygen absorber sachet after removing the overwrap.

-    Confirm the integrity of the bag and of the non-permanent seals.

-    Use only if the bag is not damaged, if the non-permanent seals are intact (i.e. no mixture of the contents of the three compartments), if the amino acids solution and the glucose solution are clear, colorless, or slightly yellow, practically free of visible particle, and if the lipid emulsion is a homogeneous liquid with a milky appearance.

b.Mixing the solutions and the emulsion

Ensure that the product is at ambient temperature when breaking the non-permanent seals.

Manually roll the bag onto itself, starting at the top of the bag (hanger end).

The non-permanent seals will disappear from the side near the inlets.

Continue to roll until the seals are open along half of their length.

Mix by inverting the bag at least 3 times.

c. Preparation of the infusion

Aseptic conditions must be observed.

Suspend the bag.

Remove the plastic protector from the administration outlet.

Firmly insert the spike of the infusion set into the administration outlet.

d. Additions

The capacity of the bag is sufficient to enable additions such as, vitamins, electrolytes, and trace elements. Any additions (including vitamins) may be made into the reconstituted mixture (after the non-permanent seals have been opened and the contents of the three compartments have been mixed).

Vitamins may also be added into the glucose compartment before the mixture has been reconstituted (before opening the non-permanent seals and before mixing the solutions and the emulsion).

OLICLINOMEL N8-800 may be supplemented with:

Electrolytes

Stability has been demonstrated per litre of the ternary mixture up to a total quantity of:

Sodium:

Potassium:

Magnesium:

Calcium:

Mineral phosphate:

Organic phosphate: 22 mmol/l

Trace elements and vitamins

Trace elements and vitamins: Stability has been demonstrated with commercially available preparations of vitamins and trace elements (containing up to 1 mg of iron). Compatibility for other additives is available upon request.

Paediatric formulations are required for children.

Additions must be performed under aseptic conditions and by a qualified personnel. These additions are made into the injection site using an injection needle:

-    Prepare the injection site,

-    Puncture the injection site and inject,

-    Mix the contents of the bag and the additives.

e.Administration

For single use only.

Only administer the product after the non-permanent seals between the 3 compartments have been broken and the contents of the 3 compartments have been mixed.

Ensure that the final emulsion for infusion does not show any evidence of phase separation.

After opening the bag, the contents must be used immediately. The opened bag must never be stored for a subsequent infusion.

Do not reconnect any partially used bag.

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

Any unused product or waste material and all necessary devices must be discarded.

Do not store any partially used bags and discard all devices after use

It is recommended to use an administration set known to be compatible with the infusion of lipid containing admixture.

7. MARKETING AUTHORISATION HOLDER

Baxter Healthcare Limited

Caxton Way

Thetford

Norfolk

IP24 3SE United Kingdom

8.    MARKETING AUTHORISATION NUMBER

PL 00116/0378

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

08/06/2006

10    DATE OF REVISION OF THE TEXT

04/02/2016