SubstansellerProdukt/ Substance or Product / Ärende/Case / Datum/Date
Alphalipid / UpdateofSmPC / 10 June 2015
Update of SmPC section 6.3, 6.4 and 6.6 in in accordance to Guidelines.
Suggested changes are marked in strikethrough text and bold italic.
SUMMARY OF PRODUCT CHARACTERISTICS
1.NAME OF THE MEDICINAL PRODUCT
Alphalipid
200 mg/ml emulsion for infusion
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
1000mlof the emulsion contain:
Soya-bean oil, refined200g
Energy content:2000kcal/l (8.4MJ/l)
Excipient with known effect:
Sodium 0.03mg/ml (see section 4.4)
For the full list of excipients, see section6.1.
3.PHARMACEUTICAL FORM
Alphalipidis a milky white emulsion for infusion.
Osmolality:about 350mOsm/kg water
pH:6.0-8.5
4.CLINICAL PARTICULARS
4.1Therapeutic indications
Medical conditions that require parenteral nutrition for supply of energy and essential fatty acids.
4.2Posology and method of administration
Posology
Adults
The patient’s ability to eliminate the infused fat should determine the dosage (see Treatment monitoring below).
The quantity of fat administered intravenously should normally not exceed 3 g/kg bodyweight/day. The highest permitted infusion rate is 1.6 ml/min, equivalent to an infusion time of at least 5 hours for 500 ml.
Paediatric population
The child’s ability to eliminate fat should determine the dosage (see Treatment monitoring below).
The recommended daily dose is 0.54g fat/kg bodyweight. The infusion rate should not exceed 0.17g fat/kg bodyweight/hour (4g fat/kg per 24hours). In premature and very low birth weight infants Alphalipid should preferably be administered continuously over 24hours. The initial dosage should be 0.51g fat/kg bodyweight/day. The dose should then be increased gradually by 0.51gfat/kg bodyweight/day up to 2g fat/kg bodyweight/day. The dosage may be increased to 4g/kg/day only under close monitoring of serum triglyceride concentrations, liver function and oxygen saturation.
Method of administration
Alphalipid should be administered as an intravenous infusion.
Treatment monitoring
Adults: where intravenous fat emulsion is indicated for more than a week, the patient’s ability to eliminate fat should be checked. A sample of blood should be taken before the start of the infusion and centrifuged. If the plasma is milky or opalescent, the planned infusion should be postponed. Be aware that hypertriglyceridaemia may pass undetected with this method. In patients in whom impaired fat tolerance may be expected, measurement of the serum triglyceride concentration is therefore recommended. The elimination of fat should be checked daily in the medical conditions mentioned in section 4.4.
Paediatric population: in infants treated with Alphalipid the ability to eliminate fat should be tested regularly. In infants receiving long-term parenteral nutrition, particularly premature infants, platelet count, liver function and serum triglycerides should be monitored daily. Specific measurement of the serum triglyceride concentration is recommended for this group.
4.3Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section6.1.
Hypersensitivity to egg protein.
Hypersensitivity to soya-bean protein or peanut protein. Alphalipid contains soya-bean oil. Cross-allergy occurs between peanuts and soya-beans.
Acute shock.
Conditions involving severe hyperlipidaemia.
Severe hepatic failure.
Haemophagocytic syndrome.
4.4Special warnings and precautions for use
Caution should be observed in conditions with impaired fat metabolism, such as renal impairment, uncontrolled diabetes, pancreatitis, hepatic impairment, hypothyroidism (if hypertriglyceridaemia is present) and sepsis. If Alphalipid is given in these conditions, the serum triglyceride concentration should be monitored closely.
Paediatric population
Alphalipid should be given with caution to neonates and premature infants with hyperbilirubinaemia and in cases of suspected pulmonary hypertension.
Interference with serological testing
Alphalipid may interfere with certain laboratory tests (bilirubin, lactate dehydrogenase, oxygen saturation, Hb, etc.) if blood is sampled before the administered fat has been cleared from the blood. In most patients fat is cleared from the blood 56 hours after the end of the infusion.
This medicinal product contains 0,65mmol sodium (15 mg) per 500 ml, i.e. essentially ‘sodium- free’.
4.5Interaction with other medicinal products and other forms of interaction
Certain medicinal products such as insulin can affect the body’s lipase system. This type of interaction, however, is considered to be of limited clinical significance.
Heparin in clinical doses causes a transient increase in lipolysis in plasma, resulting in a transient decrease in triglyceride clearance due to depletion of lipoprotein lipase.
Soya-bean oil has a natural content of vitamin K1. This is considered important only in patients treated with coumarin derivatives, which interact with vitamin K1.
4.6Fertility, pregnancy and lactation
Data on a limited number of exposed pregnancies indicate no adverse effects of Alphalipid on pregnancy or on the health of the fetus/newborn child. To date, no other relevant epidemiological data are available. Caution should be exercised when prescribing to pregnant women.
Breastfeeding
There is insufficient information on the excretion of soya-bean oil in human milk.
Fertility
There is insufficient information on the effect on fertility.
4.7Effects on ability to drive and use machines
Alphalipid has no known or negligible influence on the ability to drive and use machines.
4.8Undesirable effects
The following frequencies are taken as a basis when evaluating undesirable effects:
Very common:1/10
Common:1/100 to <1/10
Uncommon:1/1000 to <1/100
Rare:1/10,000 to <1/1,000
Very rare:<1/10,000
Not known:cannot be estimated from the available data
Following undesirable effects were reported for the reference soya-bean emulsion for infusion:
System organ class / Frequency / EventBlood and lymphatic system disorders / Rare / Haemolysis, reticulocytosis, thrombocytopenia (in association with long-term treatment in infants)
Vascular disorders / Rare / Hypertension, hypotension
Respiratory, thoracic and mediastinal disorders / Rare / Tachypnoea
Hepatobiliary disorders / Rare / Hepatic impairment
Skin and subcutaneous tissue disorders / Uncommon / Flushing
Rare / Skin rash, urticaria
Reproductive system and breast disorders / Rare / Priapism
General disorders and administration site conditions / Uncommon / Fever, chills, nausea
Rare / Anaphylactic reaction, headache, abdominal pain, tiredness
The rare side effects can occur during or following infusion (early effects) or after extended treatment. Early effects that occur at the recommended dose include allergic reactions, abdominal pain, haemolysis, headache, hypertension, hypotension, priapism, reticulocytosis, tachypnoea and tiredness.
Effects reported in long-term treatment include thrombocytopenia in infants.
Fat overload syndrome
An impaired ability of the patient to eliminate Alphalipid can lead to fat overload syndrome, which may be caused by overdose. This syndrome may appear during severe hypertriglyceridaemia, even at the recommended infusion rate, and in association with a sudden change in the patient’s clinical condition, such as renal function impairment or infection.
Fat overload syndrome is characterised by hyperlipidaemia, fever, fat infiltration, hepatomegaly, splenomegaly, anaemia, leukopenia, thrombocytopenia, coagulation disorder and coma. The symptoms are usually reversible if the treatment is discontinued.
Transient changes in liver function have been noted in association with intravenous nutrition, but the cause is unknown.
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 reaction via the national reporting system listed in Appendix V*.
4.9Overdose
See section4.8 under “Fat overload syndrome”.
A marked overdose of fat emulsions containing triglycerides can result in metabolic acidosis, particularly if carbohydrates are not given concomitantly.
5.PHARMACOLOGICAL PROPERTIES
5.1Pharmacodynamic properties
Pharmacotherapeutic group: Solutions for parenteral nutrition, fat emulsions, ATC code: B05BA02.
Alphalipid is a fat emulsion for intravenous use containing soya-bean oil emulsified with egg phospholipids. Particle size and biological properties are similar to those of natural chylomicrons. Unlike chylomicrons, Alphalipid does not contain cholesterol esters or apolipoproteins, while its phospholipid content is significantly higher.
5.2Pharmacokinetic properties
The fat particles in Alphalipid are in principle distributed and eliminated in the same way as natural chylomicrons.
5.3Preclinical safety data
Refined soya-bean oil emulsion for infusion has been used clinically for many years. Its safety is based on clinical experience.
6.PHARMACEUTICAL PARTICULARS
6.1List of excipients
purified egg yolk phospholipids
glycerol
sodium oleate
sodium hydroxide
water for injections
6.2Incompatibilities
This medicinal product should not be mixed with other substances except those mentioned in section 6.6.
6.3Shelf life
Shelf life in the unopened bottle:
2 years
Shelf life in the opened container:
Because of the risk of microbial contamination the infusionproductshould be used immediately.
Any unused infusion should be discarded.
Shelf life after compounding:
Chemical and physical in-use stability has been demonstrated for 4 weeks at 25°C under light protection.
From a microbiological point of view, the product 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 compounding has taken place in controlled and validated aseptic conditions.
With the substances and concentration according to section 6.6 in Ethyl-Vinyl-Acetate (EVA) infusion bags under aseptic conditions, the requirements of GMP Annex I should be considered: 4 weeks if the admixure is stored below 25 °C under light protection. Storage under cooling conditions is preferable. Do not freeze the compounded emulsion.
6.4Special precautions for storage
This medicinal product does not require any special storage conditions.
Do not freeze.
For storage conditions after compounding, see section 6.3.
From a microbiological point of view, the product should be used immediately. See sections 6.3 and 6.6 for further information.
6.5Nature and contents of container
Type II glass bottle with 100 ml, 250 ml or 500ml infusion, closed with a chlorobutyl rubber stopper sealed with an aluminium capsule.
Pack sizes:
Glass bottle:20 x 100 ml
20 x 250 ml
10 x 500 ml
Not all pack sizes may be marketed.
6.6Special precautions for disposal and other handling
Do not use the product if the package is damaged.
Do not use if you notice phase separation of the emulsion.
Compounding
Alphalipid may be compounded with medicinal products containing amino acids, glucose and electrolyte solutions under aseptic conditions to produce Intradialytic Parenteral Nutrition (IDPN) and Total Parenteral Nutrition (TPN) admixtures.
Medicinal products with the volume of 5 ml and more should be mixed with Alphalipid at once, using an automatic filling system. Volumes below 5 ml may be added separately to the pre-mixture. These processes should be executed under aseptic conditions (see section 6.3).
The table below shows the highest concentration of components for which the chemical and physicalstability has been demonstratedover 4 weeks was confirmed under storage conditions below 25°C (see section 6.3):
Components / Composition forIntradialytic Parenteral Nutrition per 100 ml / Composition for
Total Parenteral Nutrition per 100 ml
Alphalipid [g] / 4.7 / 4.0
Amino acids [g] / 5.4 / 4.3
Glucose [g] / 15.9 / 13.4
Omega 3-fatty acids [g]
(source: Omegaven) / 0.102 / 0.086
Electrolytes / 0
Sodium [mmol] / 5.460
Calcium [mmol] / 0.606
Magnesium [mmol] / 0.550
Zinc [µmol] / 1.006
Potassium [mmol] / 3.371
Chloride [mmol] / 6.965
Phosphate [mmol] / 1.195
Acetate [mmol] / 0.000
Citrate [mmol] / 0.129
Malate [mmol] / 0.302
Saccharate[mmol] / 0.049
Gluconate [mmol] / 0.701
Water for injections can be used to adjust the target concentrations of the corresponding components.
7.MARKETING AUTHORISATION HOLDER
FORMULA GmbH
Goerzallee 305 b
14167 Berlin
Germany
8.MARKETING AUTHORISATION NUMBER
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10.DATE OF REVISION OF THE TEXT
2014-04-16