Technescan Lyomaa
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Trade name : TechneScan® LyoMAA.
(Mallinckrodt Medical catalogue number : DRN 4378).
Kit for preparation of (99mTc) human albumin macroaggregates injection (Technetium (99mTc) macrosalb injection, Ph.Eur.No.296).
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Composition of the contents of one vial:
Macroaggregates of human serum albumin 2.0mg.
The product is prepared from batches of human albumin but has been screened for hepatitis B surface antigen (HBsAg), antibodies for human immunodeficiency virus (anti-HIV) and antibodies for hepatitis C virus (anti-HCV).
For a full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Powder for injection.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
This product is for diagnostic use only.
• Pulmonary perfusion scintigraphy.
• As secondary indication 99mTc-albumin macroaggregates may be used for venoscintigraphy
4.2 Posology and method of administration
Adults
Recommended activities to be administered intravenously to an adult weighing 70 kg varies between 37 - 185 MBq (1 - 5mCi). The number of particles per
administered dose must be in a range of 60 x 103 - 700 x103. The lung test may start immediately after injection.
Children
The activity to be administered in children should be a fraction of the adult activity and should be calculated according to the following equation :
Paediatric dosage (MBq) = Adult dosage (MBq) x Child weight (kg)
70
Although body weight is the more used factor on which to base the adjustment of the activity administered, in a limited number of cases the body surface area may be considered to be more appropriate.
Paediatric dosage (MBq) = Adult dosage (MBq) x Child body surface (m2)
1.73
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and precautions for use
The possibility of hypersensitivity including serious, life-threatening, fatal anaphylactic/anaphylactoid reactions should always be considered. Advanced life support facilities should be readily available.
Special care should be exercised when administering 99mTc-MAA to patients with significant right to left cardiac shunt. In order to minimise the possibility of microembolism to the cerebral and renal circulations 99mTc-MAA should be given by slow intravenous injection and the number of particles reduced by up 50 %. Such precautions are also advised in patients with respiratory failure complicating pulmonary hypertension.
Standard measures for preventing transmission of infections from pharmaceuticals made of human blood or plasma, include selection of donators, test of individual donators and plasma pools for finding specific infective agents, and effective manufacturing steps for inactivation/elimination of virus as a part of manufacturing process as well. In spite of that, the risk of transmission of infectious agents cannot be eliminated completely, as long as pharmaceuticals made of human blood or plasma are used. This also applies to new virus of unknown nature and other pathogens as well.
There are no reports of virus transmission in connection with albumin, made in accordance with specifications in Ph. Eur. and in accordance with routine processes.
It is strongly recommended that the product name and batch number are stated every time Maasol is given to a patient, in order to maintain a connection between the patient and the product’s batch number.
For each patient, exposure to ionising radiation must be justifiable on the basis of likely benefit. The activity administered must be such that the resulting radiation dose is as low as reasonably achievable bearing in mind the need to obtain the intended diagnostic or therapeutic result.
Radiopharmaceutical should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licences of the competent official organisation.
Radiopharmaceuticals should be prepared by the user in a manner which satisfies both radiation safety and pharmaceutical requirements. Appropriate aseptic precautions should be taken.
Contents of the vial are intended only for use in the preparation of 99mTc-human albumin macroaggregates (MACROSALB) Injection and are not to be administered directly to the patient without first undergoing the preparative procedure.
The syringe should be gently swirled immediately prior to the injection to homogenise the injectate. Blood should never be drawn into the syringe because that induces the formation of small clots.
Excipients:
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.
4.5 Interaction with other medicinal products and other forms of interaction
Changes in the biological distribution of 99mTc-MAA may be induced by different drugs.
Pharmacologic interactions may be caused by chemotherapeutic agents, heparin, bronchodilators.
Toxicological interactions may be caused by heroin, nitrofurantoin, busulfan, cyclophosphamide, bleomycin, methotrexate, methysergide.
Pharmaceutic interactions may be caused by magnesium sulphate.
4.6 Fertility, Pregnancy and lactation
Only imperative investigations should be carried out during pregnancy, when likely benefit exceeds the risks incurred by mother and fetus.
Radionuclide procedures carried out on pregnant women also involve radiation doses to the fetus.
When it is necessary to administer radioactive medicinal products to women of childbearing potential, information should always be sought about pregnancy. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. Where uncertainty exists it is important that radiation exposure should be the minimum consistent with achieving the desired clinical information.
Alternative techniques which do not involve ionising radiation should be considered.
Breast feeding:
If the administration is considered necessary, breast feeding should be interrupted for 12 hours and the expressed feeds discarded.
Before administering a radioactive medicinal product to a mother who is breastfeeding consideration should be given as to whether the investigation could be reasonably delayed until the mother has ceased breast feeding and as to whether the most appropriate choice of radiopharmaceutical has been made, bearing in mind the secretion of activity in breast milk.
Breast-feeding can be restarted when the level in the milk will not result in a radiation dose to a child greater than 1 mSv.
4.7 Effects on ability to drive and use machines
No studies on the effects on ability to drive and use machines have been performed.
4.8 Undesirable effects
For safety with respect to transmissible agents see section 4.4.
The frequencies of undesirable effects are defined as follows:
Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data)
Immune system disorders
Frequency not known: Hypersensitivity-type reactions, with chest pain, rigor and collapse and including life-threatening anaphylaxis. Application site hypersensitivity.
Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. For diagnostic nuclear medicine investigations the
current evidence suggests that these adverse effects will occur with low frequency because of the low radiation doses incurred.
For most diagnostic investigations using a nuclear medicine procedure the radiation dose delivered (EDE) is less than 20 mSv.
Higher doses may be justified under some clinical circumstances.
4.9 Overdose
Overdose, as commonly intended (i.e., excessive quantity in weight) is not expected, but overdose may be understood as the administration of a very high number of particles. The number of MAA particles per adult patient must not exceed 1.5 x 106.
The dangers to be expected relating to the inadvertent administration of excess radioactivity may be reduced by promoting a diuresis and frequent voiding of urine.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Phamacotherapeutic group: Diagnostic radiopharmaceuticals for the respiratory system. ATC code: V09E B01
99mTc-MAA, when administered in usual doses, shows no pharmacodynamic effects detectable clinically or/and analytically.
5.2 Pharmacokinetic properties
Following injection into a superficial vein of the systemic venous circulation, the macroaggregates are carried at the speed of this circulation to the first capillary filter, i.e. the capillary tree of the pulmonary artery system. The albumin macroaggregate particles do not penetrate the lung parenchyma (interstitial)or of the capillary. When pulmonary flow distribution is normal, the compound distributes over the entire pulmonary area following physiologic gradients : when district flow is altered the areas of reduced flow are reached by a proportionally smaller amount of particles. The technetium labelled macroaggregates remain in the lungs for variable periods of time, depending of the structure, size and number of particles.
The disappearance of activity from the particles in the lungs is governed by an exponential law; the larger aggregates have a longer biological half-life, whereas particles between 5 and 90 pm in diameter have a half-life ranging from 2 - 8 hours.
The decrease in pulmonary concentration is caused by the mechanical breakdown of the particles occluding the capillaries, stemming from the systo-diastolic pressure pulsations within the capillary itself.
The products of macroaggregate break-down, once recirculated as albumin microcolloid, are quickly removed by the macrophages of the reticuloendothelial system, i.e. essentially the liver and the spleen.
The microcolloid is metabolized with introduction of the radioactive label
(99mTc) into the systemic circulation from which it is removed and excreted in urine.
5.3 Preclinical safety data
Correlation exists between the size of the MAA and their toxic effects.
The pathophysiologic mechanism responsible for toxicity is shown to be the increase of the pulmonary blood pressure. With particulars from 10 - 50 pm in diameter the first pulmonary signs of toxicity in dogs (e.g. tachypnea) appear after injection of 20 to 25 mg per kg of body weight.
A sharp increase of the pulmonary blood pressure is noticed when 20 mg of less than 80 pm sized MAA are injected, where no significant pressure changes are recorded with 40 mg of less than 35 pm MAA particles.
With suspension of MAA up to 150 pm diameter, no blood pressure changes appear below 10 mg/kg, while larger diameter suspensions (up to 300 pm) typical blood pressure changes in pulmonary artery appear when the doses exceeds 5 mg/kg.
Doses of 20 - 50 mg/kg cause sudden death for respiratory failure. A safety factor of 100 is found after injection in dogs of 14,000 99mTc-MAA (size : 30 -50 pm).
The repeated-dose toxicity studies performed in dogs show no detectable variations in the general behaviour of the animals.
No evidence of pathological changes in the main organs has been detected.
There is no evidence in the literature of teratogenic, mutagenic or carcinogenic effect of the unlabelled product.
Dosimetry
Technetium (99mTc) decays with the emission of gamma radiation with energy of 140 KeV and a half-life of 6 hours to technetium (99mTc) which can be regarded as quasi stable.
For this product the effective equivalent resulting from an administered activity of 185 MBq is typically 2.2 mSv (per 70 kg individual).
According to ICRP 53 (1988) the radiation doses absorbed by the patient are the following :
Absorbed dose per unit activity administered (mGy/MBq)
|
Organ |
Adult |
15 years |
10 years |
5 years |
1 year |
|
Adrenals |
5.8E-03 |
8.7E-03 |
1.3E-02 |
1.9E-02 |
3.1E-02 |
|
Bladders wall |
1.0E-02 |
1.3E-02 |
1.9E-02 |
2.8E-02 |
5.1E-02 |
|
Bone Surfaces |
3.5E-03 |
4.4E-03 |
6.4E-03 |
9.7E-03 |
1 .9E-02 |
|
Breast |
5.6E-03 |
5.5E-03 |
1.0E-02 |
1 .4E-02 |
2.2E-02 |
|
G I-tract Stomach wall |
4.0E-03 |
5.2E-03 |
7.8E-03 |
1.2E-02 |
2.0E-02 |
|
Small intestine |
2.1 E-03 |
2.6E-03 |
4.3E-03 |
7.0E-03 |
1 .3E-02 |
|
Upper large intest |
2.2E-03 |
2.9E-03 |
5.0E-03 |
8.4E-03 |
1 .5E-02 |
|
Lower large intest |
4.6E-03 |
2.1 E-03 |
3.5E-03 |
5.4E-03 |
1.0E-02 |
|
Kidneys |
3.7E-03 |
4.8E-03 |
7.2E-03 |
1.1E-02 |
1.8E-02 |
|
Liver |
1.6E-02 |
2.1E-02 |
3.0E-02 |
4.3E-02 |
7.5E-02 |
|
Lungs |
6.7E-02 |
9.9E-02 |
1.4E-01 |
2.1E-01 |
4.0E-01 |
|
Ovaries |
1.8E-03 |
2.3E-03 |
3.7E-03 |
5.9E-03 |
1.1E-02 |
|
Pancreas |
5.8E-03 |
7.5E-03 |
1.1E-02 |
1.7E-02 |
2.9E-02 |
|
Red marrow |
4.4E-03 |
6.2E-03 |
8.3E-03 |
1.1E-02 |
1 .7E-02 |
|
Spleen |
4.4E-03 |
5.6E-03 |
8.3E-03 |
1.3E-02 |
2.2E-02 |
|
Testes |
1.1E-03 |
1.4E-03 |
2.3E-03 |
3.7E-03 |
7.1 E-03 |
|
Thyroid |
2.0E-03 |
3.3E-03 |
5.5E-03 |
9.0E-03 |
1 .6E-02 |
|
Uterus |
2.4E-03 |
2.9E-03 |
4.6E-03 |
7.1 E-03 |
1.3E-02 |
|
Other tissue |
2.9E-03 |
3.6E-03 |
5.2E-03 |
7.8E-03 |
1.4E-02 |
|
Effective Dose equivalent (mSv/MBq) |
1.2E-02 |
1.8E-02 |
2.5E-02 |
3.8E-03 |
6.9E-02 |
For an administered activity of 185 MBq the typical radiation dose to the target organ, lungs, is 12.3 mGy and the typical radiation dose to the critical organs, adrenals, bladder wall, liver, pancreas, spleen, are 1.07, 1.85, 2.96, 1.07 and 0.81 mGy respectively.
6.1 List of excipients
After reconstitution of the vial contents and after labelling with the eluate of a 99mTc-generator (usually 0.9% sodium chloride) the solution will in addition to sodium chloride also contain acetate, tin(II) chloride and human serum albumin.
Properties of the medicinal product after reconstitution and labelling: Technetium (99mTc) Macrosalb Injection is a white liquid suspension of particles which may separate on standing.
Labelling yield : > 95%
Free pertechnetate : < 5%
pH : 5.0 to 7.0
In the labelled product the distribution of particle size (largest dimension) is as follows;
95% of the particles is between 10 and 100 pm, of which the large majority is between 10 and 90 pm.
No particles are larger than 150 pm. The number of particles per vial is 4.5 x 106.
6.2 Incompatibilities
None known.
6.3 Shelf life
The expiry date for this product is 36 months from the day of manufacture. The expiry date is stated on the label of each vial and on the carton. The labelled product may be used for 12 hours after preparation.
6.4 Special precautions for storage
The lyophilisate should be stored at 2 - 8°C.
The labelled product should be stored at 15 - 25°C.
Storage should be in accordance with national regulations for radioactive material.
6.5 Nature and contents of container
10 ml Type 1 Ph.Eur glass vial closed with a bromobutyl rubber stopper. Type I Ph.Eur.
TechneScan® LyoMAA is supplied as five vials in a carton.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
Add aseptically the required amount of Sodium Pertechnetate (99mTc) Injection (Fission or Non-fission) minimum 370 MBq, maximum 3.7 GBq, in a volume
of 1 - 10 ml to a vial TechneScan® LyoMAA. Do not use a venting needle, relieve the excess of pressure in the vial by withdrawing a volume of gas equal to the introduced volume of eluate. Carefully swirl the vial a few times to suspend the free-dried albumin macroaggregates. Incubate for 5 minutes at room temperature. Swirl vial before withdrawing a dose. Under no circumstances the preparation should be left in contact with air.
Instructions for Quality Control.
Labelling yield 5 minutes after labelling. Determination of free 99mTc by membrane filtration. Use a polycarbonate membrane filter with circular 3 pm pores in a suitable holder. Place 0.2 ml of the injection on the membrane and filter with 20 ml saline solution.
The radioactivity passing the membrane must be not more than 5% of the total radioactivity in the 0.2 ml of the injection.
For particulars consult the Ph.Eur. monograph 296.
The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting, etc. Therefore, radiation protection precautions in accordance with national regulations must be taken.
The residues may be put in an ordinary waste bin sofar as the activity of vials and syringes does not exceed that of background when measured with a low level radiation detector.
Waste must be disposed of according to national regulations
7 MARKETING AUTHORISATION HOLDER
Mallinckrodt Medical B.V.
Westerduinweg 3 1755 LE Petten Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PL 12288/0013
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
21 November 2002
10 DATE OF REVISION OF THE TEXT
27/02/2015