AdreView 74 MBq/mL Solution for Injection

Iobenguane (¹²³I), 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% [¹²³I]iobenguane 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 while transmitting pure gamma radiation, with the main emission taking place at 159 keV (Energy level Abundance 83.6 %).

This medicinal product contains:

• Benzyl alcohol: 10.4 mg/ml

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

For the 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.

Solution for injection. Clear, colourless solution.

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).

Posology

Iobenguane (¹²³I) 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:

Adults

• The recommended dosage is 80-200 MBq, higher activities may be justifiable.

Elderly

No special dosage scheme is required for the elderly patient.

Method of administration

Iobenguane (¹²³I) 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.

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

Potential for hypersensitivity or anaphylactic reactions.

The possibility of hypersensitivity including anaphylactic/anaphylactoid reactions should always be considered. 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.

Individual benefit/risk justification

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

Renal impairment and hepatic impairment

Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible.

Paediatric population

For information on the use in paediatric population, see section 4.2. Administered activity for children should be determined based on body weight and should be as low as reasonably achievable for diagnostic image quality.

This medicinal product contains benzyl alcohol (10.4 mg/ml). Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

Patient preparation

The patient should be well hydrated before the start of the examination and urged to void as often as possible during the first hour after the examination in order to reduce radiation.

Before administration of AdreView, administer Potassium Iodide Oral Solution or Lugol's Solution (equivalent to 100 mg iodide for adults, body-weight adjusted for children) or potassium perchlorate (400 mg for adults, body-weight adjusted for children) to block uptake of iodine-123 by the patient's thyroid. Administer the blocking agent at least one hour before the dose of AdreView.

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 (¹²³I) in the chromaffin granules might, in theory, cause rapid noradrenalin secretion which can induce a hypertensive crisis, although the likelihood of such an occurrence is believed to be extremely low. This necessitates constant monitoring of the patient during administration. Iobenguane (¹²³I) must be administered slowly (take at least one minute for the administration of a patient dose).

Drugs known or expected to reduce the Iobenguane uptake should be stopped before administration of AdreView (usually 4 biological half-lives). Whether a particular medication is to be stopped may depend on which type of investigation with iobenguane (¹²³I) is intended. Consultation with the responsible physician for treatment of the patient will be useful. For details please refer to section 4.5.

Specific warnings

This medicinal product contains 10.4 mg/ml benzyl alcohol. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

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 iobenguane (¹²³I) (usually for four biological half-lives to allow complete washout).

Women of childbearing potential

When an administration of radiopharmaceuticals to women 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 radiation (if there are any) should be offerend to the patient.

Pregnancy

No data are available on the use of this product in human pregnancy.

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 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, 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.

No studies on the effects on the ability to drive and use machines have been performed.

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).

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: https://yellowcard.mhra.gov.uk/

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.

Pharmacotherapeutic group: Diagnostic radiopharmaceuticals, tumour detection, iobenguane (¹²³I), ATC code: V09IX01

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.

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.

Distribution/Organ uptake

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 [¹²³I]iobenguane.

Hyperplastic adrenals show a high uptake.

Elimination

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 hydroxyiodobenzylguanidine and radioiodinated meta-iodobenzoic acid. These substances account for approximately 5 to 15% of the administered dose.

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.

Benzyl alcohol

3-iodobenzylguanidine

Sodium dihydrogen phosphate dihydrate

Disodium hydrogen phosphate dihydrate

Water for injections

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

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

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

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.

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.

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

Pack size: 37 to 740 MBq.

Not all pack sizes may be marketed.

General warning

Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Its receipt, storage, use, transfer and siposal are subject to the regulations and/or appropriate licenses of the competent official organisation.

Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

If at any time in the preparation of this product the integrity of this vial is compromised it should not be used.

Administration procedures should be carried out in a way to minimise risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory.

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

Disposal

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 local requirements.

GE Healthcare Limited

Pollards Wood

Nightingales Lane

Chalfont St Giles

Buckinghamshire HP8 4SP

United Kingdom

PL 00221/0140

Date of first authorisation: 01 December 1998

Date of last renewal: 18 June 2002

27/05/2021

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).

The effective dose 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

IF APPLICABLE

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.