Metatrace Fdg Solution For Injection 3000mbq/Ml
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
MetaTrace FDG Solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
18
1ml solution for injection contains 3000 MBq Fludeoxyglucose ( F) at the date and calibration time (t0 + 2 hour).
The activity per vial is lower or equal to 30GBq at the date and time of calibration.
Fluorine-18 has a half-life of 109.8 minutes by emitting a positronic radiation of maximum energy of 0.633 MeV, followed by photonic annihilation radiations of 0.511MeV.
Fludeoxyglucose F (2-[ F]Fluoro-2-deoxy-D-glucose) is prepared by the phase transfer catalysed nucleophilic substitution on mannose triflate (1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulphonyl-a-D-mannopyranose) with [18F]fluoride.
Hydrolysis under alkaline conditions yields 2-[ F]fluoro-2-deoxy-D-glucose (Fludeoxyglucose 18F).
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Solution for injection
Clear, colourless or slightly yellow solution
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
This medicinal product is for diagnostic use only.
Fludeoxyglucose (18F) is indicated for use with positron emission tomography (PET) in adults and paediatric population.
Oncology
In patients undergoing oncologic diagnostic procedures describing function or diseases where enhanced glucose influx of specific organs or tissues is the diagnostic target. The following indications are sufficiently documented (see also section 4.4):
Diagnosis
• Characterisation of solitary pulmonary nodule
• Detection of cancer of unknown origin, revealed for example by cervical adenopathy, liver or bones metastases
• Characterisation of a pancreatic mass Staging
• Head and neck cancers including assistance in guiding biopsy
• Primary lung cancer
• Locally advanced breast cancer
• Oesophageal cancer
• Carcinoma of the pancreas
• Colorectal cancer particularly in restaging recurrences
• Malignant lymphoma
• Malignant melanoma, Breslow >1.5 mm or lymph node metastasis at first diagnosis Monitoring of therapeutic response
• Malignant lymphoma
• Head and neck cancers
Detection in case of reasonable suspicion of recurrences
• Glioma with high grade of malignancy (III or IV)
• Head and neck cancers
• Thyroid cancer (non-medullary): in patients with increased thyroglobulin serum levels and negative radioactive iodine whole body scintigraphy
• Primary lung cancer
• Breast cancer
• Carcinoma of the pancreas
• Colorectal cancer
• Ovarian cancer
• Malignant lymphoma
• Malignant melanoma
Cardiology
In the cardiologic indication, the diagnostic target is viable myocardial tissue that takes-up glucose but is hypo-perfused, as it must be assessed beforehand using appropriate blood-flow imaging techniques.
• Evaluation of myocardial viability in patients with severe impaired left ventricular function who are candidates for revascularisation when conventional imaging modalities are not contributive
Neurology
In the neurologic indication the interictal glucose hypometabolism is the diagnostic target.
• Localisation of epileptogenic foci in the presurgical evaluation of partial temporal epilepsy
Infectious or inflammatory diseases
In infectious or inflammatory diseases, the diagnostic target is tissue or structures with an abnormal content of activated white blood cells.
In infectious or inflammatory diseases, the following indications are sufficiently documented:
Localisation of abnormal foci guiding the aetiologic diagnosis in case of fever of unknown origin
Diagnosis of infection in case of:
• Suspected chronic infection of bone and /or adjacent structures: osteomyelitis, spondilitis, diskitis or osteitis including when metallic implants are present
• Diabetic patient with a foot suspicious of Charcot’s neuroarthropathy,
osteomyelitis and/or soft tissue infection
• Painful hip prosthesis
• Vascular prosthesis
• Fever in an AIDS patient
• Detection of septic metastatic foci in case of bacteraemia or endocarditis (see also section 4.4).
Detection of the extension of inflammation in case of:
• Sarcoidosis
• Inflammatory bowel disease
• Vasculitis involving the great vessels Therapy follow-up:
Unresectable alveolar echinococcosis, in search for active localisations of the parasite during medical treatment and after treatment discontinuation.
4.2 Posology and method of administration
The recommended activity for adults is 100 to 400 MBq (depending on the body weight of the patient and the type of camera used), administered by direct intravenous injection.
Only few clinical data are available for patients aged under 18 years concerning safety and diagnostic efficacy of the product. Therefore, the use in oncologic paediatrics has to be carefully weighted.
The activity administered to children and to adolescents is a fraction of the activity recommended for adults must be determined from the recommended activity for adults on the basis of body mass, using the following multiplying coefficient as indicated here below (Paediatric European Task Group EANM):
|
3 kg = 0.10 |
12 kg = 0.32 |
22kg = 0.50 |
32 kg = 0.62 |
42 kg = 0.78 |
52-54 kg = 0.90 |
|
4 kg = 0.14 |
14 kg = 0.36 |
24 kg = 0.53 |
34 kg = 0.64 |
44 kg = 0.80 |
56-58 kg = 0.92 |
|
6 kg = 0.19 |
16 kg = 0.40 |
26 kg = 0.56 |
36 kg = 0.66 |
46 kg = 0.82 |
60-62 kg = 0.96 |
|
8 kg = 0.23 |
18 kg = 0.44 |
28 kg = 0.58 |
38 kg = 0.68 |
48 kg = 0.85 |
64-66 kg = 0.98 |
|
10 kg = 0.27 |
20 kg = 0.46 |
30 kg = 0.60 |
40 kg = 0.70 |
50 kg = 0.88 |
68 kg = 0.99 |
Administration of MetaTrace FDG and PET examination
The activity of Fludeoxyglucose (18F) has to be measured with calibrator immediately prior to injection.
The injection must be strictly intravenous in order to avoid irradiation as a result of local extravasations, as well as imaging artefacts.
The emission scans are usually started 40 to 60 minutes after the injection of Fludeoxyglucose ( F). Provided a sufficient activity remains for adequate counting statistics, Fludeoxyglucose (18F) PET can also be performed up to two or three hours after administration, thus reducing background activity.
If required, repeated Fludeoxyglucose (18F) PET examinations can be carried out at short notice.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special warnings and precautions for use
Indication of the PET examination
For all patients, the radiation exposure must be justifiable by the expected diagnostic achieved with the lowest possible radiation dose.
In patients with reduced kidney function, a very careful indication is required since an increased radiation exposure is possible in these patients.
It should be taken into consideration that the effective dose per MBq is higher in children than in adults (see 5.4 dosimetry).
Patient preparation
MetaTrace FDG should be given to sufficiently hydrated patients fasting for a minimum of 4 hours, in order to obtain a maximum enrichment of glucose activity, since glucose uptake in the cells is limited (“saturation kinetics”). The amount of liquid should not be limited (beverages containing glucose must be avoided).
In order to obtain images of best quality and to reduce the radiation exposure of the bladder. Patients should be encouraged to drink sufficient amounts and to empty prior to and after the PET examination.
Oncology and neurology
In order to avoid hyper fixation of the tracer in muscle, it is advisable for patients to avoid all strenuous physical activity prior to the examination and to remain at rest between the injection and examination and during acquisition of images (patients should be comfortably lying down without reading or speaking).
The cerebral glucose metabolism depends on the brain activity. Thus, neurological examinations should be performed after a relaxation period in a darkened room and with less background noise.
A blood glucose test should be performed prior to administration since hyperglycaemia may result in a reduced sensitivity of PET examination with MetaTrace FDG, especially when glycaemia is greater than 8mmol/L. Similarly administration of this product should be avoided in subjects presenting uncontrolled diabetes.
Cardiology
Glucose uptake in the myocardium is insulin-dependent. For a myocardial examination a glucose loading of 50g approximately 1 hour prior to the administration of MetaTrace FDG is recommended. Alternatively, especially for patients with diabetes mellitus, the blood sugar level can be adjusted by a combined infusion of insulin and glucose (Insulin-Glucose-Clamp) if needed.
Interpretation of the FDG PET images
Infectious and/or inflammatory diseases as well as regenerative processes after surgery can result in a significant uptake of Fludeoxyglucose (18F) and therefore lead to false positive results. False positive or false negative FDG-PET results cannot be excluded after radiotherapy within the first 2-4 months. If the clinical indication is demanding an earlier diagnosis by FDG-PET, the reason for earlier examination must be reasonably documented.
A delay of at least 4-6 weeks after the last administration of chemotherapy is optimal, in particular to avoid false negative results. If the clinical indication is demanding an earlier diagnosis by Fludeoxyglucose (18F) PET, the reason for earlier FDG-PET examination must be reasonably documented. In case of chemotherapy regimen with cycles shorter than 4 weeks, the PET examination should be done just before restarting a new cycle.
In low-grade lymphoma, only positive predictive values have to be considered because of a limited sensitivity.
Fludeoxyglucose( F) is not effective in detecting brain metastases.
When applying a coincidence PET (positron emission tomography) scanner system, sensitivity is reduced in comparison to dedicated PET, resulting in reduced detection of lesions smaller than 1 cm.
It is recommended that Fludeoxyglucose ( F)-PET images shall be interpreted in relation with tomographic anatomical imaging modalities (e.g. CT, ultrasonography, MRI). Fusion of the functional Fludeoxyglucose( F)-PET images with morphologic images e.g. PET-CT can lead to an increased sensitivity and specificity, and is recommended in pancreas, head and neck tumours, lymphoma, melanoma, lung cancers and recurrent colorectal cancers.
General warnings
It is recommended to avoid any close contact between the patient and young children during the initial 12 hours following the injection.
Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings and receipt, storage, use, transfer and disposal are subject to the regulations and appropriate licences of the competent authorities.
Radiopharmaceuticals should be prepared by the user in a manner that satisfies both radiation safety and pharmaceutical quality requirements.
MetaTrace FDG should be stored and handled in adequate shielding, so as to protect patients and hospital staff as much as possible. In particular, it is recommended to protect oneself from the effects of B+ radiation and annihilation photons by using an appropriate shielding when performing withdrawals from the vial and injections.
4.5 Interaction with other medicinal products and other forms of interaction
All medicinal products that modify blood glucose levels can affect the sensitivity of the examination (e.g. corticosteroids, valproate, carbamazepine, phenytoin, phenobarbital and catecholamines).
Under administration of colony-stimulating factors (CSFs), there is an increased uptake of Fludeoxyglucose (18F) in the bone marrow and the spleen for several days. This must be taken into account for the interpretation of PET imaging. Separating CSF therapy from PET imaging by an interval of at least 5 days may diminish this interference.
The administration of glucose and insulin influences the influx of Fludeoxyglucose( F) into the cells. In the case of high blood glucose levels as well as low plasma insulin levels, the influx of Fludeoxyglucose ( F) into organs and tumours is reduced.
4.6 Pregnancy and lactation
Pregnancy
There is no clinical experience with the use of Fludeoxyglucose (18F) in pregnant women.
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 that do not involve ionising radiation have to be considered.
Radionucleide procedures carried out on pregnant women involve radiation doses to the foetus. Administration of MetaTrace FDG at activity of 400 MBq results in an absorbed dose to the uterus of 8.4 mGy. In this dose range, lethal effects and the induction of malformations, growth retardations and functional disorders are not to be expected; however, the risk of the induction of cancer and hereditary defects may be increased.
MetaTrace FDG should not be administered during pregnancy unless clearly necessary or when the benefit of the mother overweights the risk of the foetus.
Lactation
Fludeoxyglucose (18F) is excreted into breast milk. Before administering Fludeoxyglucose (18F) to a mother who is breast feeding, consideration should be given as to whether the investigation could be reasonably delayed until the mother has ceased breast feeding. If administration during lactation is unavoidable, breast feeding has to be interrupted for at least 12 hours and the expressed milk has to be discarded. When appropriate, milk may be drawn off prior to administration of MetaTrace FDG. Moreover, for radioprotection reasons, it is recommended to avoid close contact between the mother and the infant during the initial 12 hours following injection.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable effects
Undesirable effects after the administration Fludeoxyglucose (18F) have not been observed to date.
Since the administered substance quantity is very low, the major risk is caused by the radiation. Exposure to ionising radiation can lead to cancer or development of hereditary defects. Most examinations involving nuclear medicine involve levels of radiation (effective dose) less than 20 mSv. These effects can be expected with a low probability. After administration of the maximum recommended activity of this FDG Fludeoxyglucose( F) product, the effective dose is about 7.6 mSv.
4.9 Overdose
An overdose in the pharmacological sense is unlikely given with the doses used for diagnostic purposes.
If an overdose of Fludeoxyglucose ( F) has been administered, the radiation dose delivered to the patient must be reduced by increasing as much as possible the elimination of the radionucleide, by forced diuresis and frequent mictions.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Diagnostic Radiopharmaceuticals ATC code: V09IX04
At the chemical concentrations used for diagnostic examinations, Fludeoxyglucose ( F) does not appear to have any pharmacodynamic activity.
5.2 Pharmacokinetic properties
18
Fludeoxyglucose ( F) is a glucose analogue which is accumulated in all cells using glucose as primary energy source Fludeoxyglucose ( F) is accumulated in tumours with a high glucose turnover.
Following intravenous injection, the pharmacokinetic profile of Fludeoxyglucose ( F) in the vascular compartment is biexponential. It has a distribution time of 1 minute and an elimination time of approximately 12 minutes.
The cellular uptake of Fludeoxyglucose (18F) is performed by tissue-specific carrier systems which are partly insulin-dependent and, thus, can be influenced by eating, nutritional condition and the existence of a diabetes mellitus. In patients with a diabetes mellitus a reduced uptake of Fludeoxyglucose ( F) into the cells occurs due to a changed tissue distribution and glucose metabolism.
18
Fludeoxyglucose ( F) is transported via the cell membrane in similar fashion to glucose, but only undergoes the first step of glycolysis resulting in formation of Fludeoxyglucose ( F) -6-phosphate which remains trapped within the tumour cells and is not further metabolised. Since the following dephosphorylation by intracellular phosphatases is slow, Fludeoxyglucose ( F) -6-phosphate is retained in the tissue over several hours (trapping-mechanism).
In healthy subjects, Fludeoxyglucose ( F) is widely distributed throughout the body, particularly in the brain and heart, and to a lesser degree in the lungs and liver.
18
Elimination of Fludeoxyglucose ( F) is chiefly renal, with 20 % of activity being excreted in urine in the 2 hours following injection.
Binding to renal parenchyma is weak, but because of renal elimination of
18
Fludeoxyglucose ( F), the entire urinary system, particularly the bladder, exhibits marked activity.
Fludeoxyglucose ( F) passes the blood-brain barrier. Approximately 7 % of the injected dose is accumulated in the brain within 80-100 minutes after injection.
Epileptogenic foci exhibit a reduced glucose metabolism in the seizure free phases.
Approximately 3 % of the injected activity is taken-up by the myocardium within 40 minutes. The distribution of Fludeoxyglucose ( F) in normal heart is mainly homogenous; however, regional differences of up to 15 % are described for the interventricular septum. During and after a reversible myocardial ischemia, an increased glucose uptake occurs into the myocardial cell.
0.3 % and 0.9 - 2.4 % of the injected activity are accumulated in pancreas and lung.
18
Fludeoxyglucose ( F) is also bound to a lesser extent to ocular muscle, pharynx and intestine. Binding to muscle may be seen following recent exertion and in the event of muscular effort during the examination.
5.3 Preclinical safety data
In preclinical studies of acute toxicity the 50-fold human dose in dogs and the 1000-fold human dose in mice did not reveal any signs of toxicity.
Studies of chronic toxicity, of mutagenic potential as well as studies of reproduction toxicity and cancerogenic potential have not been performed because of the intended clinical use of the substance (usually a single intravenous application of Fludeoxyglucose ( F) in the range of ng or pg).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ethanol
Water for injection
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in 6.6.
6.3 Shelf life
12 hrs after production time and following the first use.
The date and time of the expiration are indicated on the external side of the original packaging as well as on the each vial.
6.4 Special precautions for storage
The product should be stored at room temperature in its original packaging.
This product should be stored in accordance with national regulations concerning radioactive products.
6.5 Nature and contents of container
Multidose, maximum 10ml glass vial, colourless Type I of the European Pharmacopoeia, closed by a rubber stopper covered by Teflon and sealed by an aluminium capsule.
One vial contains maximum 10ml of solution, corresponding to an active concentration of 3000 MBq per ml at calibration time.
6.6 Special precautions for disposal
MetaTrace FDG is delivered in multidose vial.
MetaTrace FDG package must be checked before use and the activity measured using a calibrator.
The medicinal product may be diluted with sodium chloride 9 mg/ml (0.9%) solution for injection.
Withdrawals should be performed under aseptic conditions. The vials must not be opened after disinfecting the stopper; the solution should be withdrawn via the stopper using a single dose syringe feted with suitable protective shielding and a disposable sterile needle.
The solution should be inspected visually prior to use. Only clear solutions, free of visible particles should be used.
The administration of radiopharmaceuticals creates risks for other people from external radiation or contamination from spills of urine, vomit, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.
Radioactive waste must be disposed of in conformity with the relevant national and international regulations.
7 MARKETING AUTHORISATION HOLDER
PETNET Solutions, a division of Siemens Plc
Faraday House
Sir William Siemens Square
Frimley
Camberley
Surrey
GU16 8QD
8 MARKETING AUTHORISATION NUMBER
PL 21750/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/03/2012
10 DATE OF REVISION OF THE TEXT
20/05/2015
11 DOSIMETRY
The table below shows the dosimetry as calculated according to ICRP 80 Publication
(Radiation Dose to Patients from Radiopharmaceutical Pergamon Press 1999)
Dose absorbed per unit of activity administered (mGy/MBq)
Organ Adult 15 yrs old 10 yrs old 5 yrs old 1 yr old
|
Adrenal glands |
0.012 |
0.015 |
0.024 |
0.038 |
0.072 |
|
Bladder wall |
0.16 |
0.21 |
0.28 |
0.32 |
0.59 |
|
Bone surfaces |
0.011 |
0.014 |
0.022 |
0.035 |
0.066 |
|
Brain |
0.028 |
0.028 |
0.030 |
0.034 |
0.048 |
|
Breasts |
0.0086 |
0.011 |
0.018 |
0.029 |
0.056 |
|
Bile duct |
0.012 |
0.015 |
0.023 |
0.035 |
0.066 |
|
Intestinal wall |
0.011 |
0.014 |
0.022 |
0.036 |
0.068 |
|
Small intestine |
0.013 |
0.017 |
0.027 |
0.041 |
0.077 |
|
Colon |
0.013 |
0.017 |
0.027 |
0.040 |
0.074 |
|
ULI wall |
0.012 |
0.016 |
0.025 |
0.039 |
0.072 |
|
LLI wall |
0.015 |
0.019 |
0.029 |
0.042 |
0.076 |
|
Heart |
0.062 |
0.081 |
0.12 |
0.20 |
0.35 |
|
Kidneys |
0.021 |
0.025 |
0.036 |
0.054 |
0.096 |
|
Liver |
0.011 |
0.014 |
0.022 |
0.037 |
0.070 |
|
Lungs |
0.010 |
0.014 |
0.021 |
0.034 |
0.065 |
|
Muscles |
0.011 |
0.014 |
0.021 |
0.034 |
0.065 |
|
Oesophagus |
0.011 |
0.015 |
0.022 |
0.035 |
0.068 |
|
Ovaries |
0.015 |
0.020 |
0.030 |
0.044 |
0.082 |
|
Pancreas |
0.012 |
0.016 |
0.025 |
0.040 |
0.076 |
|
Bone marrow |
0.011 |
0.014 |
0.022 |
0.032 |
0.061 |
|
Skin |
0.0080 |
0.010 |
0.016 |
0.027 |
0.052 |
|
Spleen |
0.011 |
0.014 |
0.022 |
0.036 |
0.069 |
|
Testes |
0.012 |
0.016 |
0.026 |
0.038 |
0.073 |
|
Thymus |
0.011 |
0.015 |
0.022 |
0.035 |
0.068 |
|
Thyroid |
0.010 |
0.013 |
0.021 |
0.035 |
0.068 |
|
Uterus |
0.021 |
0.026 |
0.039 |
0.055 |
0.10 |
|
Other organs Effective dose |
0.011 |
0.014 |
0.022 |
0.034 |
0.063 |
|
(mSv/MBq) |
0.019 |
0.025 |
0.036 |
0.050 |
0.095 |
18
For Fludeoxyglucose ( F), the effective dose resulting from the administration of an activity of 400 MBq is about 7.6mSv (for an individual weighing 70kg).
For this activity of 400 MBq, the radiation doses delivered to the critical organs, bladder, heart and brain are respectively: 64mGy, 25mGy and 11mGy.
12 INSTRUCTIONS FOR PREPARATION OF
RADIOPHARMACEUTICALS (IF APPLICABLE)
No further preparation of the Fludeoxyglucose F 18 Injection is necessary. It is provided ready to use.