Oliclinomel N4-550e Emulsion For Infusion
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Oliclinomel N4-550E, emulsion for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
This medicinal product is presented in the form of a 3-compartment bag. There are four presentations, which have the following different volumes:
|
Compartment |
1000 ml |
1500 ml |
2000 ml |
2500 ml |
|
Lipid emulsion |
200 ml |
300 ml |
400 ml |
500 ml |
|
Amino acid solution |
400 ml |
600 ml |
800 ml |
1000 ml |
|
Glucose solution |
400 ml |
600 ml |
800 ml |
1000 ml |
Composition of a 1000ml bag:
|
Active substances |
10% lipid emulsion compartment (corresponding to 10g/100ml) (200 ml) |
5.5% amino acid solution compartment (corresponding to 5.5g/100ml) (400 ml) |
20% glucose solution compartment (corresponding to 20g/100ml (400 ml) |
|
Refined olive oil + refined soya oil* |
20.00 g | ||
|
Alanine |
4.56 g | ||
|
Arginine |
2.53 g | ||
|
Glycine |
2.27 g | ||
|
Histidine |
1.06 g | ||
|
Isoleucine |
1.32 g | ||
|
Leucine |
1.61 g | ||
|
Lysine (As lysine hydrochloride) |
1.28 g (160g) | ||
|
Methionine |
0.88 g | ||
|
Phenylalanine |
1.23 g | ||
|
Proline |
1.50 g | ||
|
Serine |
1.10 g | ||
|
Threonine |
0.92 g | ||
|
Tryptophan |
0.40 g | ||
|
Tyrosine |
0.09 g | ||
|
Valine |
1.28 g | ||
|
Sodium Acetate, 3H2O |
0.98 g |
|
Sodium glycerophosphate, 5H2O |
2.14 g | ||
|
Potassium chloride |
1.19 g | ||
|
Magnesium chloride, 6H2O |
0.45 g | ||
|
Anhydrous glucose (As glucose monohydrate) |
80.00g (88.00g) | ||
|
Calcium chloride, 2H2O |
0.30 g |
* Mixture of refined olive oil (approximately 80%) and refined soya oil (approximately 20%)
For full list of the excipients, see section 6.1
After the contents of the three compartments have been mixed, the ternary mixture for each of the bag presentations provides the following:
|
Per bag |
1 litre |
1.5 litre |
2 litres |
2.5 litres |
|
Nitrogen (g) |
3.6 |
5.4 |
7.3 |
9.1 |
|
Amino acids (g) |
22 |
33 |
44 |
55 |
|
Total calories (kcal) |
610 |
910 |
1215 |
1520 |
|
Non-protein calories (kcal) |
520 |
780 |
1040 |
1300 |
|
Glucose calories (kcal) |
320 |
480 |
640 |
800 |
|
Lipid calories (kcal) |
200 |
300 |
400 |
500 |
|
Non-protein calorie/nitrogen ratio (kcal/g N) |
144 |
144 |
144 |
144 |
|
Sodium (mmol) |
21 |
32 |
42 |
53 |
|
Potassium (mmol) |
16 |
24 |
32 |
40 |
|
Magnesium (mmol) |
2.2 |
3.3 |
4.4 |
5.5 |
|
Calcium (mmol) |
2 |
3 |
4 |
5 |
|
Phosphate (mmol)** |
8.5 |
13 |
17 |
21 |
|
Acetate (mmol) |
30 |
46 |
61 |
76 |
|
Chloride (mmol) |
33 |
50 |
66 |
83 |
|
pH |
6 |
6 |
6 |
6 |
|
Osmolarity (mOsm/l) |
750 |
750 |
750 |
750 |
** Including phosphates provided by the lipid emulsion
3 PHARMACEUTICAL FORM
After reconstitution:
Emulsion for infusion.
Appearance prior to reconstitution:
• The lipid emulsion is an 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
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.
Maximum daily dose:
The maximum daily dose should not be exceeded in adult and paediatric 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 0.88 g amino acids, 3.2 g glucose, 0.8 g lipids, 0.84 mmol of sodium and 0.64 mmol potassium / 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:
Children 2-11 years of age: Average nitrogen requirements are 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: Average nitrogen requirements are 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 60 and 110 kcal/kg/day:
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 100 ml/kg body weight (equivalent to 2.2 g amino acids, 8 g glucose, 2 g lipids, 2.1 mmol of sodium and 1.6 mmol potassium / 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 100 ml/kg/day fluid, except in particular cases.
Method and duration of administration
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.
BY INTRAVENOUS ADMINISTRATION THROUGH A CENTRAL OR PERIPHERAL VEIN (Due to low osmolarity of OLICLINOMEL)
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.
Maximum infusion rate in adults:
As a general rule, do not exceed 3.0 ml/kg/hour of the emulsion for infusion, i.e. 0.06 g amino acids, 0.24 g glucose and 0.06 g lipids / kg body weight / hour.
As a general rule, do not exceed infusion rates of 0.10 g/kg/hour amino acids and/or 0.25 g/kg/hour glucose and/or 0.15 g/kg/hour lipids, except in particular cases.
Maximum infusion rate in children 2-11 years of age:
In this group of age, the limiting factor for hourly rate is the lipid concentration. As a general rule, do not exceed 6.5 ml/kg/hour of the emulsion for infusion i.e. 0.14 g amino acids, 0.52 g glucose and 0.13 g lipids / kg body weight / hour.
In this group of age, the limiting factor for hourly rate is the lipid concentration. As a general rule, do not exceed 5.5 ml/kg/hour of the emulsion for infusion, i.e. 0.12 g amino acids, 0.44 g glucose and 0.11 g lipids / kg body weight / hour.
As a general rule, the maximum infusion rates are:
Children 2-11 years of age: 0.20 g/kg/hour amino acids and/or 1.20 g/kg/hour glucose and/or 0.13 g/kg/hour lipids, except in particular cases.
Children 12-18 years of age: 0.12 g/kg/hour amino acids and/or 1.20 g/kg/hour glucose and/or 0.13 g/kg/hour lipids, except in particular cases.
4.3 Contraindications
The use of OLICLINOMEL is contraindicated in the following situations:
- 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
- Pathologically-elevated plasma concentration of sodium, potassium, magnesium, calcium, and/or phosphorus
4.4 Special warnings and precautions for use
An excessively fast administration of total parenteral nutrition (TPN) solutions, including OLICLINOMEL, 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, dyspnoeaor bronchospasm) develop. This medicinal product contains soybean oil and egg phosphatide. Soybean and egg proteins may cause hypersensitivity reactions. Cross-allergic reactions between soybean and peanut proteins have been observed.
Specific clinical monitoring is required when an intravenous infusion is started
Severe water and electrolyte equilibration disorders, severe fluid overload states, and severe metabolic disorders must be corrected before starting the infusion.
Ceftriaxone must not be mixed or administered simultaneously with any calcium-containing IV solutions even via different infusion lines or different infusion sites. Ceftriaxone and calcium-containing solutions may be administered sequentially one after another if infusion lines at different sites are used or if the infusion lines are replaced or thoroughly flushed between infusions with physiological salt solution to avoid precipitation. In patients requiring continuous infusion with calcium-containing TPN solutions, healthcare professionals may wish to consider the use of alternative antibacterial treatments which do not carry a similar risk of precipitation. If use of ceftriaxone is considered necessary in patients requiring continuous nutrition, TPN solutions and ceftriaxone can be administered simultaneously, albeit via different infusion lines at different sites. Alternatively, infusion of TPN solution
could be stopped for the period of ceftriaxone infusion, considering the advice to flush infusion lines between solutions (see sections 4.5 and 6.2).
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).
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 tests results for fever/chills, leukocytosis, technical complications with the access device, and hyperglycemia 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 techniques in catheter placement and maintenance, as well as aseptic techniques 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 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.
While OLICLINOMEL N4-550E may be administered through a peripheral vein, thrombophlebitis may develop. The catheter insertion site must be monitored daily for local signs of thrombophlebitis.
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 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 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 extrarenal 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. When involving an extremity, the concerned limb should be elevated.
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 non-pharmacologic, 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 and restarted in another the same peripheral or central vein.
Special precautions in paediatrics
When administered to children greater than 2 years old, it is essential to use a bag which has a volume corresponding to the daily dosage.
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
Precipitation of ceftriaxone-calcium can occur when ceftriaxone is mixed with calcium-containing solutions in the same intravenous administration line. Ceftriaxone must not be mixed or administered simultaneously with calcium-containing intravenous solutions, including OLICLINOMEL, through the same infusion line (e.g., via Y-site). However, ceftriaxone and calcium containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see sections 4.4 and 6.2). .
OLICLINOMEL contains vitamin K, naturally present in lipid emulsions. The amount of Vitamin K in recommended doses of OLICLINOMEL 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).
Due to the potassium content of OLICLINOMEL, special care should be taken in patients treated with potassium sparing diuretics (e.g, amiloride, spironolactone, triamterene) angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists or the immunosuppressants tacrolimus and cyclosporine in view of the risk of hyperkalemia.
4.6 Fertility, pregnancy and lactation
There are not at present sufficient relevant clinical findings to assess the tolerability of the ingredients in OLICLINOMEL in women who are pregnant or breast-feeding.
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, bronchospasm) 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 |
common6 |
|
Bronchospasm (as part of allergic reaction) |
Not knownc | |
|
NERVOUS SYSTEM DISORDERS |
Headache |
commonb |
|
Tremor |
Not knownc | |
|
GASTROINTESTINAL DISORDERS |
Diarrhoea |
common1 |
|
Abdominal pain |
Not knownc | |
|
Vomiting |
Not knownc | |
|
Nausea |
Not knownc | |
|
RENAL AND URINARY DISORDERS |
Azotemia |
common” |
|
HEPATO-BILIARY DISORDERS |
Hepatitis cholestatic |
Not knownc |
|
Cholestasis |
Not knownc | |
|
Jaundice |
Not knownc | |
|
SKIN AND SUBCUTANEOUS TISSUE |
Erythema1 |
Not knownc |
|
DISORDERS |
Hyperhydrosis |
Not knownc |
|
MUSCULOSKELETAL, CONNECTIVE |
Musculoskeletal pain |
Not knownc |
|
TISSUE AND BONE DISORDERS |
Back pain |
Not knownc |
|
Chest pain |
Not knownc | |
|
Pain in extremity |
Not knownc | |
|
Muscle spasm |
Not knownc | |
|
GENERAL DISORDERS AND |
Chills |
commonb |
|
ADMINISTRATION SITE CONDITIONS |
Infusion site extravasation |
commonb |
|
Infusion site pain1 |
commonb | |
|
Infusion site swelling1 |
commonb | |
|
Infusion site vesicles1 |
commonb | |
|
Catheter site phlebitis1 |
Not knownc | |
|
Injection site oedema1 |
Not knownc | |
|
Localized oedema1 |
Not knownc | |
|
Oedema peripheral1 |
Not knownc | |
|
Pyrexia |
Not knownc | |
|
Feeling hot1 |
Not knownc | |
|
Hyperthermia |
Not knownc | |
|
Malaise |
Not knownc | |
|
Inflammation |
Not knownc | |
|
Necrosis/ ulcer1 |
Not knownc | |
|
INVESTIGATIONS |
Blood bilirubin increased |
Not knownc |
|
Hepatic enzyme increased |
commonb | |
|
Gamma-glutamyltransferase increased |
commonb | |
|
Blood triglycerides increased |
commonb | |
|
Blood alkaline phosphatase increased |
commonb | |
|
Blood glucose increased |
Not knownc | |
|
Hyperglycaemia |
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 undesirable effects have been reported with other similar products: 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, 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 characterised by findings such as hyperlipidaemia, fever, liver fatty infiltration (hepatomegaly), deteriorating liver function, anaemia, leucopaenia, thrombocytopaenia, 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 at:
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/mixtures ATC code: B05 BA 10.
This is a ternary mixture 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. In addition, this formulation contains electrolytes.
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 (80 g/l).
The lipid emulsion is an association of refined olive oil and refined soya 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 of the emulsion for infusion (amino acids, electrolytes, 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 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 finished product.
Preclinical studies performed using the solutions of amino acids and glucose contained in OLICLINOMEL of different qualitative compositions and concentrations have not, however, revealed any specific toxicity.
Preclinical toxicity studies performed using the lipid emulsion contained in OLICLINOMEL 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.
Ceftriaxone must not be mixed or administered simultaneously with intravenous calcium-containing solutions, including OLICLINOMEL, through the same infusion line (e.g., via Y-connector) because of the risk of precipitation of ceftriaxone-calcium salt (see section 4.4 and 4.5).
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.
OLICLINOMEL contains calcium ions which pose additional risk of coagulation precipitates in citrate anticoagulated/preserved blood or components.
6.3 Shelf life
2 years if the overwrap is not damaged.
It is recommended that the product is used immediately after the nonpermanent seals between the 3 compartments have been opened.
The reconstituted emulsion has, however, been shown to be stable for a maximum of 7 days at between +2o and +8oC followed by a maximum of 48 h at temperatures not exceeding + 25oC.
After addition of supplements (electrolytes, organic phosphate, trace elements, vitamins; see section 6.6):
For specific admixtures, chemical and physical in-use stability has been demonstrated for 7 days at 2 to 8°C followed by 48 hours below 25°C. From a microbiological point of view, any 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 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.
PACK SIZES:
1000 mL in a 3 compartment bag (400 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 400 ml 20% glucose solution (corresponding to 20g/100ml) + 200 ml 10% lipid emulsion ( corresponding to 10g/100ml)) Carton with 6 bags
1000 ml in a 3 compartment bag (400 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 400 ml 20% glucose solution (corresponding to 20g/100ml) + 200 ml 10% lipid emulsion ( corresponding to 10g/100ml))
1 bag
1500 ml in a 3 compartment bag (600 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 600 ml 20% glucose solution (corresponding to 20g/100ml) + 300 ml 10% lipid emulsion ( corresponding to 10g/100ml)) Carton with 4 bags
1500 ml in a 3 compartment bag (600 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 600 ml 20% glucose solution (corresponding to 20g/100ml) + 300 ml 10% lipid emulsion ( corresponding to 10g/100ml))
1 bag
2000 ml in a 3 compartment bag (800 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 800 ml 20% glucose solution (corresponding to 20g/100ml) + 400 ml 10% lipid emulsion ( corresponding to 10g/100ml))
Carton with 4 bags
2000 ml in a 3 compartment bag (800 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 800 ml 20% glucose solution (corresponding to 20g/100ml) + 400 ml 10% lipid emulsion (corresponding to 10g/100ml))
1 bag
2500 ml in a 3 compartment bag (1000 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 1000 ml 0% glucose solution (corresponding to 20g/100ml) + 500 ml 10% lipid emulsion ( corresponding to 10g/100ml)) Carton with 2 bags
2500 ml in a 3 compartment bag (1000 ml 5.5% amino acid solution (corresponding to 5.5g/100ml)+ 1000 ml 20% glucose solution (corresponding to 20g/100ml) + 500 ml 10% lipid emulsion (corresponding to 10g/100ml))
1 bag
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
a. To open
- Tear the protective overwrap.
- When present, 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) and if the amino acids solution and the glucose solution are clear, colorless, or slightly yellow, practically free of visible particles, 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 nonpermanent 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).
When making additions to the formulation, the final osmolarity of the mixture should be measured before administration via a peripheral vein
OLICLINOMEL may be supplemented with:
- Electrolytes: electrolytes already present in the bag should be taken into account: stability has been demonstrated up to a total quantity of 150 mmol of sodium, 150 mmol of potassium, 5.6 mmol of magnesium and 5 mmol of calcium per litre of the ternary mixture.
- Organic phosphate: stability has been demonstrated for additions of up to: 15 mmol per bag.
- 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.
Additions must be performed by qualified personnel under aseptic conditions.
These additions are made into the injection site using a 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 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.
7. MARKETING AUTHORISATION HOLDER
Baxter Healthcare Ltd
Caxton Way
Thetford
Norfolk
IP24 3SE
United Kingdom
PL 00116/0356
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
08/06/2006
10 DATE OF REVISION OF THE TEXT
27/01/2016
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;