SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Steripet 250 MBq/ml Solution for injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution for injection contains 250 MBq fludeoxyglucose (¹⁸F) at the date and time of calibration.

The activity per vial ranges from 250 MBq to 2.5 GBq at the date and time of calibration.

Fluorine (¹⁸F) decays to stable oxygen (¹⁸O) with a half-life of 110 minutes by emitting a positronic radiation of maximum energy of 634 keV, followed by photonic annihilation radiations of 511 keV.

Excipient with known effect: 5.19 mg/ml sodium.

For the 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

Steripet is indicated for imaging 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): 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

Posology

Adults and elderly population

The recommended activity for an adult weighing 70 kg is 100 to 400 MBq (this activity has to be adapted according to the body weight of the patient, the type of camera used and acquisition mode), administered by direct intravenous injection.

Renal and hepatic impairment

Careful consideration of the activity to be administered is required since an increased radiation exposure is possible in these patients.

Extensive dose-range and adjustment studies with this medicinal product in normal and special populations have not been performed. The pharmacokinetics of fludeoxyglucose (¹⁸F) in renally impaired patients has not been characterised.

Paediatric population

The use in children and adolescents has to be considered carefully, based upon clinical needs and assessing the risk/benefit ratio in this patient group.

This activity can be determined from the recommended activity for adults on the basis of body mass, using the following multiplying coefficient:

3 kg = 0.10	22 kg = 0.50	42 kg = 0.78
4 kg = 0.14	24 kg = 0.53	44 kg = 0.80
6 kg = 0.19	26 kg = 0.56	46 kg = 0.82
8 kg = 0.23	28 kg = 0.58	48 kg = 0.85
10 kg = 0.27	30 kg = 0.60	50 kg = 0.88
12 kg = 0.32	32 kg = 0.62	52-54 kg = 0.90
14 kg = 0.36	34 kg = 0.64	56-58 kg = 0.92
16 kg = 0.40	36 kg = 0.66	60-62 kg = 0.96
18 kg = 0.44	38 kg = 0.68	64-66 kg = 0.98
20 kg = 0.46	40 kg = 0.70	68 kg = 0.99

Method of administration

For intravenous use.

For multidose use.

The activity of fludeoxyglucose (¹⁸F) has to be measured with a calibrator immediately prior to injection.

The injection of fludeoxyglucose (¹⁸F) must be intravenous in order to avoid irradiation as a result of local extravasation, as well as imaging artefacts.

For instructions on dilution of the medicinal product before administration, see section 12. For patient preparation, see section 4.4.

Image acquisition

The emission scans are usually started 45 to 60 minutes after the injection of fludeoxyglucose (¹⁸F). Provided 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 within a short period of time.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

4.4 Special warnings and precautions for use

Potential for hypersensitivity or anaphylactic reactions

If hypersensitivity or anaphylactic reactions occur, the administration of the medicinal product must be discontinued immediately and intravenous treatment initiated, if necessary. To enable immediate action in emergencies, the necessary medicinal products and equipment such as endotracheal tube and ventilator must be immediately available.

For each patient, the radiation exposure must be justified by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required diagnostic information.

Renal and hepatic impairment

Due to the major renal excretion of fludeoxyglucose (¹⁸F), in patients with reduced kidney function, careful consideration of the indication is required since an increased radiation exposure is possible in these patients.

Paediatric population

For information on the use in paediatric population, see sections 4.2 or 5.1. Careful consideration of the indication is required since the effective dose per MBq is higher than in adults (see section 11).

Patient preparation

Steripet should be given to sufficiently hydrated patients fasting for a minimum of 4 hours, in order to obtain a maximum target 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 their bladder prior to and after the PET examination.

Oncology and neurology and infectious diseases

In order to avoid hyperfixation 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 low background noise.

A blood glucose test should be performed prior to administration since hyperglycaemia may result in a reduced sensitivity of Steripet, especially when glycaemia is greater than 8 mmol/L.

Similarly, PET with fludeoxyglucose (¹⁸F) should be avoided in subjects presenting uncontrolled diabetes.

Cardiology

Since glucose uptake in the myocardium is insulin-dependent, for a myocardial examination a glucose loading of 50 g approximately 1 hour prior to the administration of Steripet 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 PET images with fludeoxyglucose (¹⁸F)

In the exploration of inflammatory bowel diseases, diagnostic performance of fludeoxyglucose (18F) has not been directly compared with that of scintigraphy using

labelled white blood cells which may be indicated prior to fludeoxyglucose (¹⁸F) PET or after fludeoxyglucose (¹⁸F) PET when inconclusive.

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, when search for infectious or inflammatory lesions is not the aim of the fludeoxyglucose (¹⁸F) PET. In cases where fludeoxyglucose (¹⁸F) accumulation can be caused by either cancer, infection or inflammation, additional diagnostic techniques for the determination of the causative pathologic alteration may be required to supplement the information obtained by PET with fludeoxyglucose (¹⁸F). In some settings e.g. staging of myeloma, both malignant and infectious foci are searched for and may be distinguished with a good accuracy on topographic criteria e.g. uptake at extramedullary sites and/or bone and joint lesions would be atypical for multiple myeloma lesions and identified cases associated with infection. There are currently no other criteria to distinguish infection and inflammation by means of fludeoxyglucose (¹⁸F) imaging.

Because of the high uptake of fludeoxyglucose (¹⁸F) in the brain, heart and kidneys, PET/CT with fludeoxyglucose (¹⁸F) has not been evaluated for the detection of septic metastatic foci in these organs when the patient has been referred due to bacteraemia or endocarditis.

False positive or false negative PET with fludeoxyglucose (¹⁸F) results cannot be excluded after radiotherapy within the first 2-4 months. If the clinical indication is demanding an earlier diagnosis by PET with fludeoxyglucose (¹⁸F), the reason for earlier PET with fludeoxyglucose (¹⁸F) 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 PET with fludeoxyglucose (¹⁸F), the reason for earlier PET with fludeoxyglucose (¹⁸F) examination must be reasonably documented. In case of chemotherapy regimen with cycles shorter than 4 weeks, the PET with fludeoxyglucose (¹⁸F) examination should be done just before re-starting a new cycle.

In low-grade lymphoma, lower oesophagus cancer and suspicion of recurrent_ovarian cancer, only positive predictive values have to be considered because of a limited sensitivity of PET with fludeoxyglucose (¹⁸F).

Fludeoxyglucose (¹⁸F) is not effective in detecting brain metastases. The accuracy of fludeoxyglucose (¹⁸F) PET imaging is better using PET/CT than PET cameras alone.

When a hybrid PET-CT scanner is used with or without administration CT contrast media, some artefacts may occur on the attenuation corrected PET images.

After the procedure

Close contact with infants and pregnant women should be restricted during the initial 12 hours following the injection.

Specific warnings

Steripet contains a maximum of 51.9 mg sodium per dose. This should be taken into account in patients on a low sodium diet.

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 (¹⁸F) into the cells. In the case of high blood glucose levels as well as low plasma insulin levels, the influx of fludeoxyglucose (¹⁸F) into organs and tumours is reduced.

No formal studies on the interaction between fludeoxyglucose (¹⁸F) and any contrast for computed tomography have been performed

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

When an administration of radiopharmaceuticals to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular, etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient.

Pregnancy

Radionuclide procedures carried out on pregnant women involve radiation doses to the foetus. Only essential investigations should therefore be carried out during pregnancy, when the likely benefit far exceeds the risk incurred by the mother and foetus.

Administration of Steripet 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.

Breastfeeding

Before administering radiopharmaceuticals to a mother who is breastfeeding consideration should be given to the possibility of delaying the administration of radionuclide until the mother has ceased breastfeeding, and to what is the most appropriate choice of radiopharmaceuticals, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breastfeeding should be interrupted for 12 hours and the expressed feeds discarded.

Close contact with infants should be restricted during the initial 12 hours following injection.

Fertility

It is not known whether fludeoxyglucose (¹⁸F) affects reproductive capacity. Based on intended clinical use the risk of sterility is low.

4.7 Effects on ability to drive and use machines

Not relevant.

4.8 Undesirable effects

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 7.6 mSv when the maximal recommended activity of 400 MBq is administered these adverse reactions are expected to occur with a low probability.

4.9 Overdose

In the event of administration of a radiation overdose with fludeoxyglucose (¹⁸F) the absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by forced diuresis and frequent bladder voiding. It might be helpful to estimate the effective dose that was applied.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: diagnostic radiopharmaceuticals, other diagnostic radiopharmaceuticals for tumour detection, ATC code: V09IX04

Pharmacodynamic effects

At the chemical concentrations used for diagnostic examinations, fludeoxyglucose (¹⁸F) does not appear to have any pharmacodynamic activity.

5.2 Pharmacokinetic properties

Distribution

Fludeoxyglucose (¹⁸F) is a glucose analogue, which is accumulated in all cells using glucose as a primary energy source. Fludeoxyglucose (¹⁸F) is accumulated in tumours with a high glucose turnover.

Following intravenous injection, the pharmacokinetic profile of fludeoxyglucose (¹⁸F) in the vascular compartment is biexponential. It has a distribution time of 1 minute and an elimination time of approximately 12 minutes.

In healthy subjects, fludeoxyglucose (¹⁸F) is widely distributed throughout the body, particularly in the brain and heart, and to a lesser degree in the lungs and liver.

Organ uptake

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 diabetes mellitus. In patients with diabetes mellitus a reduced uptake of fludeoxyglucose (¹⁸F) into the cells occurs due to a changed tissue distribution and glucose metabolism.

Fludeoxyglucose (¹⁸F) is transported via the cell membrane in similar fashion to glucose, but only undergoes the first step of glycolysis resulting in formation of fludeoxyglucose (¹⁸F) -6-phosphate, which remains trapped within the tumour cells and is not further metabolised. Since the following dephosphorylation by intracellular phosphatases is slow, fludeoxyglucose (¹⁸F) -6-phosphate is retained in the tissue over several hours (trapping-mechanism).

Fludeoxyglucose (¹⁸F) 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 (¹⁸F) 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 the pancreas and lung respectively.

Fludeoxyglucose (¹⁸F) 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.

Elimination

Elimination of fludeoxyglucose (¹⁸F) 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 fludeoxyglucose (¹⁸F), the entire urinary system, particularly the bladder, exhibits marked activity.

5.3 Preclinical safety data

In preclinical studies of acute toxicity the 50-fold human dose in dogs and the 1000fold 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 carcinogenic potential have not been performed because of the intended clinical use of the substance (usually a single intravenous application of the substance in the range of ng or pg).

6.1    List of excipients

Sodium dihydrogen phosphate dihydrate Sodium hydroxide Water for injections

6.2    Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Not more than 10 hours from the time of production.

6.4 Special precautions for storage

Store below 25^oC, both before and after the vial is opened.

Storage of radiopharmaceuticals should be in accordance with national regulation on radioactive materials.

6.5 Nature and contents of container

Steripet is supplied in Ph.Eur. Type I clear glass vials sealed with a chlorobutyl rubber closure and an aluminium overseal. One vial contains 1 to 10 mL of solution, corresponding to 250 MBq to 2.5 GBq at calibration time.

Multidose vial

6.6 Special precautions for disposal

Radiopharmaceuticals 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 appropriate licences of the competent official organisation.

Radiopharmaceuticals should be prepared by the user in a manner that satisfies both radiation safety and pharmaceutical quality requirements. Appropriate asceptic precautions should be taken,

(Upper large intestine	0.012	0.015	0.024	0.038	0.070)
(Lower large intestine	0.014	0.017	0.027	0.041	0.070)
Heart	0.067	0.087	0.13	0.21	0.38
Kidneys	0.017	0.021	0.029	0.045	0.078
Liver	0.021	0.028	0.042	0.063	0.12
Lungs	0.020	0.029	0.041	0.062	0.12
Muscles	0.010	0.013	0.020	0.033	0.062
Oesophagus	0.012	0.015	0.022	0.035	0.066
Ovaries	0.014	0.018	0.027	0.043	0.076
Pancreas	0.013	0.016	0.026	0.040	0.076
Red marrow	0.011	0.014	0.021	0.032	0.059
Skin	0.0078	0.0096	0.015	0.026	0.050
Spleen	0.011	0.014	0.021	0.035	0.066
Testes	0.011	0.014	0.024	0.037	0.066
Thymus	0.012	0.015	0.022	0.035	0.066
Thyroid	0.010	0.013	0.021	0.034	0.065
Uterus	0.018	0.022	0.036	0.054	0.090
Remaining organs	0.012	0.015	0.024	0.038	0.064
Effective dose (mSv/MBq)	0.019	0.024	0.037	0.056	0.095

The effective dose resulting from the administration of a maximal recommended activity of 400 MBq of fludeoxyglucose (18F) for an adult weighing 70 kg is about

7.6 mSv.

For an administered activity of 400 MBq the typical radiation doses delivered to the critical organs, bladder, heart and brain are 52 mGy, 27 mGy and 15 mGy, respectively.

12 INSTRUCTIONS FOR PREPARATION OF

RADIOPHARMACEUTICALS (IF APPLICABLE)

Method of preparation

The 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 solution for injection. Withdrawals should be performed under aseptic conditions. The vials must not be opened. The stopper should be disinfected and the solution should be withdrawn via the stopper using a single dose syringe fitted with suitable protective shielding and a disposable sterile needle or using an authorised automated application system.

If the integrity of this vial is compromised, the product should not be used.

Quality control

The solution should be inspected visually prior to use. Only clear solutions, free of visible particles should be used.