SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

AdreView 74 MBq/mL Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

[¹²³I]iobenguane, 37 to 740 MBq, 74 MBq/ml at calibration date and hour.

At calibration time, the radionuclidic purity is at least 99.95% iodine-123 and the main radionuclidic impurities being iodine-125 and tellurium-121 occur for less than 0.05%. The radiochemical purity is at least 97% iobenguane ( I) and the main radiochemical impurity is iodine-123 which is present for less than 3% during the shelf-life (see section 6.3).

The specific activity is greater than 0.15 and less than 1.5 TBq/mmol (0.46-4.6 GBq/mg iobenguane sulphate).

Iodine-123 is a cyclotron produced radionuclide with a physical half-life of

13.2 h, which decays to tellurium-123 by electron capture.

Most important gamma radiation emitted:

Energy level    Abundance (%)

159 keV    83.6

This medicinal product contains:

•    Benzyl alcohol: 10.4mg/ml

•    Sodium: 4.23mg/ml. This needs to be taken into consideration for patients on a controlled sodium diet.

For a full list of excipients, see section 6.1.

The contents of the vial may be used for one or more administrations until time of expiry.

3    PHARMACEUTICAL FORM

Solution for injection. Clear, colourless solution.

CLINICAL PARTICULARS

4.1    Therapeutic indications

This medicinal product is for diagnostic use only.

Diagnostic scintigraphic localisation of tumours originating in tissue that embryologically stems from the neural crest. These are pheochromocytomas, paragangliomas, chemodectomas and ganglioneuromas.

Detection, staging and follow-up on therapy of neuroblastomas.

Evaluation of the uptake of iobenguane. The sensitivity to diagnostic visualisation is different for the listed pathological entities.

Pheochromocytomas and neuroblastomas are sensitive in approx. 90% of patients, carcinoids in 70% and medullary carcinoma of the thyroid (MCT) in only 35%.

Functional studies of the adrenal medulla (hyperplasia) and the myocardium (sympathetic innervation).

4.2    Posology and method of administration

Posology

[123I]iobenguane is administered according to the following dosage scheme:

Paediatric population

•    Children under 6 months (must not be given to premature babies or neonates - see section 4.4): 4 MBq per kg body weight (max. 40 MBq)

•    Children between 6 months and 2 years: 4 MBq per kg body weight (min. 40 MBq).

•    Children over 2 years: a fraction of the adult dosage should be chosen, dependent on body weight.

The recommended dosages are as follows:

weight	activity	weight	activity	weight	activity
3 kg	20 MBq	15 kg	76 MBq	35 kg	140 MBq
4 kg	28 MBq	20 kg	92 MBq	40 kg	152 MBq
6 kg	38 MBq	25 kg	110 MBq	45 kg	162 MBq
8 kg 10 kg	46 MBq 54 MBq	30 kg	124 MBq	50 kg	176 MBq

Adults

•    Adults: the recommended dosage is 80-200 MBq, higher activities may be justifiable.

•    No special dosage scheme is required for the elderly patient.

Method of administration

[123I]iobenguane is administered by slow intravenous injection or infusion. If desired the administration volume can be increased by dilution.

The instructions for preparation of radiopharmaceuticals are given in section 12.

4.3    Contraindications

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

Must not be given to premature babies or neonates

4.4    Special warnings and precautions for use

•    Paediatric population: This medicinal product contains benzyl alcohol (approx.10mg/ml). Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

•    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.

•    Drugs known or expected to reduce the [123I]iobenguane uptake should be stopped before treatment (usually 4 biological half-lives).

•    Thyroid blockade is started 24-48 hours before the [123I]iobenguane is administered and continued for at least 3 days. Blockade by potassium perchlorate is achieved by administration of approx. 400 mg/day. Blockade by potassium iodide, potassium iodate or Lugol solution must be performed with an equivalent of 100 mg of iodine/day.

•    The dose is slowly administered intravenously over several minutes.

•    Whole body anterior and posterior scintigraphic images and/or relevant spot images and/or SPECT images are obtained 24 hours after the [123I]iobenguane administration. These views are eventually repeated at 48 hours.

•    The uptake of iobenguane in the chromaffin granules might, in theory, cause rapid noradrenalin secretion which can induce a hypertensive crisis. This necessitates constant monitoring of the patient during administration. [123I]iobenguane must be administered slowly (take at least one minute for the administration of a patient dose).

4.5    Interaction with other medicinal products and other forms of interaction

The following drugs are known or may be expected to prolong or to reduce the uptake of iobenguane in neural crest tumours.

•    Nifedipine (a Ca-channel blocker) is reported to prolong retention of iobenguane.

•    Decreased uptake was observed under therapeutic regimens involving the administration of antihypertensives that deplete norepinephrine stores or reuptake (reserpine, labetalol), calcium-channel blockers (diltiazem, nifedipine, verapamil), tricyclic antidepressives that inhibit norepinephrine transporter function (amitryptiline, imipramine and derivatives), sympathomimetic agents (present in nasal decongestants, such as phenylephrine, ephedrine, pseudoephedrine or phenylpropanolamine), cocaine, and phenothiazine. These drugs should be stopped before administration of [123I]iobenguane (usually for four biological half-lives to allow complete washout).

4.6    Fertility, pregnancy and lactation

Pregnancy

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.

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

Breastfeeding

Before administering a radioactive medicinal product 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 and as to whether the most appropriate choice of radiopharmaceutical has been made, bearing in mind the secretion of activity in breast milk. If the administration is considered necessary, breast-feeding should be interrupted for three days and the expressed feeds discarded. 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 the ability to drive and use machines have been performed.

4.8 Undesirable effects

The frequencies of the 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 determined with the data available).

Cardiac disorders Frequency not known (cannot be estimated from the available data)	Palpitations.
Congenital, familial and genetic disorders Frequency not known (cannot be estimated from the available data)	Hereditary defects.
Respiratory, thoracic and mediastinal disorders Frequency not known (cannot be estimated from the available data)	Dyspnoea.
Gastrointestinal disorders Frequency not known (cannot be estimated from the available data)	Abdominal cramps.
Neoplasms benign, malignant and unspecified (including cysts and polyps) Frequency not known (cannot be estimated from the available data	Cancer induction.
Vascular disorders Frequency not known (cannot be estimated from the available data	Transient hypertension.
General disorders and administration site conditions Frequency not known (cannot be estimated from	Heat sensations.

the available data)
Immune system disorders Frequency not known (cannot be estimated from the available data)	Blushes, urticaria, nausea, cold chills and other symptoms of anaphylactoid reactions, hypersensitivity.

When the drug is administered too fast palpitations, dyspnoea, heat sensations, transient hypertension and abdominal cramps may occur during or immediately after administration. Within one hour these symptoms disappear.

For each patient, exposure to ionizing 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 reasonable achievable bearing in mind the need to obtain the intended diagnostic or therapeutic result.

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 effective dose is less than 20 mSv. Higher doses may be justified in some clinical circumstances.

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 Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

The effect of an overdose of iobenguane is due to the release of adrenaline. This effect is of short duration and requires supportive measures aimed at lowering the blood pressure:

Prompt injection of a rapidly acting alpha-adrenergic blocking agent (phentolamine) followed by a beta-blocker (propanolol). Because of the renal elimination pathway, maintaining the highest possible urine flow is essential to reduce the influence of radiation. The nature of the radioisotope and the amount of iobenguane present make overdosing improbable.

5 PHARMACOLOGICAL PROPERTIES

Iobenguane is a radioiodinated aralkylguanidine. Its structure contains the guanidine-group from guanethidine linked to a benzyl-group into which iodine is introduced. Like guanethidine the aralkylguanidines are adrenergic neuron blocking agents. As a consequence of a functional similarity between adrenergic neurons and the chromaffin cells of the adrenal medulla iobenguane is able to localise preferentially in the medulla of the adrenal glands. In addition localisation in the myocardium occurs.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals, tumour detection, iobenguane (^{1 3}I), ATC code: V09IX01

Of the various aralkylguanidines iobenguane is the preferred substance because of its lowest liver uptake and its best in vivo stability, resulting in the lowest achievable thyroid uptake of liberated iodide.

Transport of iobenguane across the cell membranes of cells originating from the neural crest is an active process when the concentration of the drug is low (as in diagnostic dosages). The uptake mechanism can be inhibited by uptake inhibitors such as cocaine or desmethylimipramine. After uptake an active mechanism transfers at least part of the intracellular iobenguane into the storage granules within the cells.

5.2 Pharmacokinetic properties

Iobenguane is to a large extent excreted unaltered by the kidneys. Of the administered doses 70 to 90% are recovered in urine within 4 days. The following metabolic breakdown products were recovered in urine: radioiodide, radioiodinated meta-iodohippuric acid, radioiodinated hydroxy-iodobenzylguanidine and radioiodinated meta-iodobenzoic acid. These substances account for approximately 5 to 15% of the administered dose.

The distribution pattern of iobenguane includes rapid initial uptake in liver (33% of the administered dose) and much less in lungs (3%), myocardium (0.8%), spleen (0.6%), and salivary glands (0.4%). Uptake in normal adrenals (adrenal medulla) can lead to visualisation with [ I]iobenguane. Hyperplastic adrenals show a high uptake.

5.3 Preclinical safety data

In dogs 20 mg/kg is a lethal dose. Lower dose levels (14 mg/kg) cause transient clinical signs of toxic effect. Repeated intravenous administrations in rats of 20 to 40 mg/kg induce signs of serious clinical toxicity. Repeated intravenous administrations of 5 to 20 mg/kg do induce effects, including respiratory distress, but long term effects are only a slight increase in weight of liver and heart. Repeated administration in dogs of 2.5 to 10 mg/kg do induce clinical effects, including increased blood pressure and abnormalities in heart rate and in cardiac pulse propagation, but all signs were of a transient nature.

In the test systems used no mutagenic effect could be demonstrated. Studies of carcinogenic effects of iobenguane have not been published.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol

3-iodobenzylguanidine Sodium dihydrogen phosphate dihydrate Disodium hydrogen phosphate dihydrate Water for injections

6.2    Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3    Shelf life

Can be used up to 36 hours post calibration time indicated on the label.

Once opened, store in a refrigerator (2^oC-8°C) and use within one working day.

6.4    Special precautions    for storage

Store below 25°C. Do not refrigerate or freeze.

For storage conditions of the opened medicinal product, see section 6.3.

Store either in original lead container or in equivalent shielding.

Storage should take place in accordance with national regulations for radioactive materials.

6.5    Nature and contents of container

10 ml medicinal glass vial, closed with a Teflon coated rubber stopper and sealed with an aluminium cap. Each vial is enclosed in a lead container of appropriate thickness.

Pack size: 37 to 740 MBq.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Normal safety precautions for handling radioactive materials should be observed. After use, all materials associated with the preparation and administration of radiopharmaceuticals, including any unused product and its container, should be decontaminated or treated as radioactive waste and disposed of in accordance with the conditions specified by the local competent authority. Contaminated material must be disposed of as radioactive waste via an authorised route.

MARKETING AUTHORISATION HOLDER

GE Healthcare Limited Amersham Place Little Chalfont

Buckinghamshire HP7 9NA

8    MARKETING AUTHORISATION NUMBER

PL 00221/0140

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 01 December 1998 Date of last renewal: 18 June 2002

10    DATE OF REVISION OF THE TEXT

29/09/2015

11    DOSIMETRY

The table below shows the dosimetry as calculated according to Publication 80 of the ICRP (International Commission on Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals, Pergamon Press 1998).

Organ	Absorbed dose per unit activity administered (mGy/MBq)
	Adult	15 years	10 years	5 years	1 year
Adrenals	1.7E-02	2.2E-02	3.2E-02	4.5E-02	7.1E-02
Bladder	4.8E-02	6.1E-02	7.8E-02	8.4E-02	1.5E-01
Bone surfaces	1.1E-02	1.4E-02	2.2E-02	3.4E-02	6.8E-02
Brain	4.7E-03	6.0E-03	9.9E-03	1.6E-02	2.9E-02
Breast	5.3E-03	6.8E-03	1.1E-02	1.7E-02	3.2E-02
Gall bladder GI-tract	2.1E-02	2.5E-02	3.6E-02	5.4E-02	1.0E-01
Stomach	8.4E-03	1.1E-02	1.9E-02	3.0E-02	5.6E-02
SI	8.4E-03	1.1E-02	1.8E-02	2.8E-02	5.1E-02
Colon	8.6E-03	1.1E-02	1.8E-02	2.9E-02	5.2E-02
(ULI	9.1E-03	1.2E-02	2.0E-02	3.3E-02	5.8E-02)
(LLI	7.9E-03	1.0E-02	1.6E-02	2.3E-02	4.3E-02)
Heart	1.8E-02	2.4E-02	3.6E-02	5.5E-02	9.7E-02
Kidneys	1.4E-02	1.7E-02	2.5E-02	3.6E-02	6.1E-02
Liver	6.7E-02	8.7E-02	1.3E-01	1.8E-01	3.3E-01
Lungs	1.6E-02	2.3E-02	3.3E-02	4.9E-02	9.2E-02
Muscles	6.6E-03	8.4E-03	1.3E-02	2.0E-02	3.7E-02

Oesophagus	6.8E-03	8.8E-03	1.3E-02	2.1E-02	3.7E-02
Ovaries	8.2E-03	1.1E-02	1.6E-02	2.5E-02	4.6E-02
Pancreas	1.3E-02	1.7E-02	2.6E-02	4.2E-02	7.4E-02
Red marrow	6.4E-03	7.9E-03	1.2E-02	1.8E-02	3.2E-02
Skin	4.2E-03	5.1E-03	8.2E-03	1.3E-02	2.5E-02
Spleen	2.0E-02	2.8E-02	4.3E-02	6.6E-02	1.2E-01
Testes	5.7E-03	7.5E-03	1.2E-02	1.8E-02	3.3E-02
Thymus	6.8E-03	8.8E-03	1.3E-02	2.1E-02	3.7E-02
Thyroid	5.6E-03	7.3E-03	1.2E-02	1.9E-02	3.6E-02
Uterus	1.0E-02	1.3E-02	2.0E-02	2.9E-02	5.3E-02
Remaining organs	6.7E-03	8.5E-03	1.3E-02	2.0E-02	3.7E-02
Effective dose (mSv/MBq)	1.3E-02	1.7E-02	2.6E-02	3.7E-02	6.8E-02
The effective d	ose resulting from an administered activity amount of 200 MBq

is 2.6 mSv in the adult.

The above data are valid in normal pharmacokinetic behaviour. When renal function is impaired due to disease or due to previous therapy, the effective dose delivered to organs might be increased.

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

This radiopharmaceutical may 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 local competent official organisations (see section 6.6).

The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spills of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken.

Solution for intravenous injection, ready to use. Aseptic conditions must be observed during withdrawal of a patient dose from the vial, including microbial decontamination of the rubber stopper with a suitable disinfectant before removal of a dose. This product is not preserved. After removal of a dose from the vial, store at 2°C-8°C and use within one working day.