Meta-Iodobenzylguanidine (¹³¹I) for Diagnostic Use 9.25 -18.5 MBq/ml solution for injection

[¹³¹I]iobenguane: 9.25-18.5 MBq/ml (0.05-0.5 mg/ml)

Summary of the physical characteristics of the radioactive isotope in the active substance: Iodine-131. Physical half-life 8.02 days.

The most important radiation emissions are as below:

Excipients with known effect

• Benzyl alcohol: 10 mg/ml

• Sodium: 3.54 mg/ml

For a full list of excipients, see section 6.1

Solution for injection.

Clear, colourless solution.

This medicinal product is for diagnostic use only.

Calculation of a therapeutic [¹³¹ I]iobenguane dose from a prior tracer-dose. The sensitivity to diagnostic visualisation, and therefore also to therapeutic efficacy, is different for the listed pathologic entities. Pheochromocytomas and neuro-blastomas are sensitive in approximately 90% of patients, carcinoids in 70% and medullary carcinomas of the thyroid gland (MCT) in only 35%.

Posology

“Tracer” dose to acquire dosimetric information (20-40 MBq). Distribution measurement prior to administration of a therapeutic dose is recommended in order to establish the retention time of the radiopharmaceutical in organs, tumour tissue and normal structures.

Renal impairment

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

Paediatric population:

The recommended dosages are identical for children and adults. Meta- iodobenzylguanidine (¹³¹I) for Diagnostic Use is contraindicated in premature babies and neonates.

Method of administration

The dose is administered intravenously; the duration of the injection should be 30-300 seconds.

Pregnancy is an absolute contraindication.

Hypersensitivity to the active substance or to any of the excipients.

Must not be given to premature babies or neonates.

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.

Individual benefit/risk justification

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

Paediatric population

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

Renal impairment

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

Patient Preparation

Drugs that may interfere with uptake and retention of [¹³¹I]iobenguane should be stopped before treatment (see section 4.5).

The uptake of iobenguane in the chromaffin granules might, though rarely, cause rapid noradrenalin secretion which can induce a transient hypertensive crisis. This necessitates constant monitoring of the patient during administration. Monitoring of both ECG and blood pressure during administration could be indicated in some patients.

Prior to administration, ensure emergency cardiac antihypertensive treatments are readily available. [¹³¹I]iobenguane must be administered slowly.

When diagnostic administration for pheochromocytoma is planned attention is to be given to the interference with uptake of [¹³¹I]iobenguane by medication for control of hypertension (see section 4.5). Incompatible medication should be stopped at least 2 weeks prior to the planned diagnostic administration. If necessary propranolol can be used instead.

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

As with all iodine-131 containing products, a substantial proportion of the absorbed radiation dose is to the thyroid gland as a consequence of concentration of iodine by thyroid tissue. Blocking of the uptake of iodine-131 by the thyroid is therefore recommended to reduce radiation dose.

Blockade may be undertaken using non-radioactive iodine. A daily dose of approximately 100 mg iodine should be administered. This should commence 24-48 hours before the [¹³¹I]iobenguane is administered and should be continued for at least 5 days after its administration, when the estimated activity of iodine-131 in the body will have fallen to an acceptably low level.

Iodine may be administered either as potassium iodide, potassium iodate or Aqueous Iodine Oral solution (Lugol's iodine). If further information is required, refer to literature provided with the blocking agent.

In patients where the diagnostic evaluation shows diffuse bone marrow uptake of [¹³¹I]iobenguane, bone marrow suppression may occur after administration of a therapeutic dose.

Specific warnings

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum recommended dose, i.e. essentially 'sodium-free'.

Precautions with respect to environmental hazard see section 6.6.

The following drugs are known or may be expected to prolong or to reduce the uptake of iobenguane in neural crest tumours. There are additional drugs that may interfere, but no formal proof exists.

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

Decreased uptake was observed under therapeutic regimens involving the administration of:

• Antihypertensive drugs such as reserpine, labetalol, calcium-channel blockers (diltiazem, nifedipine, verapamil).

• Sympathomimetic agents (present in nasal decongestants, such as phenylephrine, ephedrine or phenylpropanolamine).

• Cocaine.

• Tricyclic antidepressants such as amitryptiline and derivatives, imipramine and derivatives, doxepin, amoxepine and loxapine.

For the following drugs inhibition of the uptake of iobenguane is expected to occur, but no proof is yet available:

• Antihypertensives acting through adrenergic neuron blockade (betanidine, debrisoquine, bretylium and guanethidine).

• Antidepressants such as maprotiline and trazolone.

These drugs should be stopped before treatment (usually for four biological half-lives).

Women of childbearing potential:

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. 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:

The use of [¹³¹I]iobenguane is contraindicated in pregnant women because radionuclide procedures carried out on pregnant women also involve radiation dose to the foetus (see section 4.3).

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.

Breastfeeding

Before administering a radiopharmaceutical to a mother who is breastfeeding, consideration should be given as to the possibility of delaying the administration until the mother has ceased breastfeeding.

Breastfeeding should be discontinued after administration of the product and the expressed feeds discarded.

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

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is about 6 mSv when the maximal recommended activity of 40 MBq is administered these adverse reactions are expected to occur with a low probability. In all cases it is necessary to ensure that the risks of the radiation are less than from the disease itself.

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).

Vascular disorders

Common: Hypertension including acute episodes of hypertensive crisis (observed with the therapeutic use of [¹³¹I] iobenguane).

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 at www.mhra.gov.uk/yellowcard

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 rapid acting alpha-adrenergic blocking agent (phentolamine) followed by a beta-blocker (propranolol). Because of the renal elimination pathway maintaining the highest possible urine flow is essential to reduce the absorbed dose to the patient.

Pharmacotherapeutic group: diagnostic radiopharmaceuticals, tumour detection, iobenguane (¹³¹I), ATC code V09IX02.

Mechanism of action

[¹³¹I]iobenguane is a radioiodinated aralkylguanidine. Its structure contains the guanidine- group from guanethidine linked to a benzyl-group into which iodine is introduced. Like quanethidine, the aralkylguanidines are adrenergic neuron blocking agents. As 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.

Pharmacodynamic effects

Of the various aralklyguanidines iobenguane is the preferred substance because of its low liver uptake and its best in vivo stability, resulting in the lowest achievable uptake of liberated iodide by the thyroid. 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 of inhibitors such as cocaine or desmethylimipramine. When the drug is administered in higher concentrations (as in therapeutic usages) passive diffusion processes also become important. The clinical implications towards dosimetry, if any, are unclear.

Subsequently, an active mechanism transfers at least part of the intracellular iobenguane into the storage granules within the cells.

Distribution and 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) is so low that these cannot be visualised with [¹³¹I]iobenguane. Hyperplastic adrenals show a high uptake.

Elimination

Iobenguane is to large extent excreted unaltered by the kidneys. 70 to 90% of administered doses are recovered in urine within 4 days. The following metabolic breakdown products were recovered in urine: iodide-131, [¹³¹I]- metaiodohippuric acid, [¹³¹I]-hydroxy-iodobenzylguanidine and [¹³¹I]- metaiodobenzoic acid. These substances account for approximately 5 to 15% of the administered dose.

Renal/Hepatic impairment

The pharmacokinetics in patients with renal or hepatic impairment has not been characterised.

In dogs 20mg/kg is a lethal dose. Lower dose levels (14mg/kg) cause transient clinical signs of toxic effect. Repeated intravenous administrations in rats of 20 to 40mg/kg induce signs of serious clinical toxicity. Repeated intravenous administrations of 5 to 20mg/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 10mg/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.

The margin of safety between administered amounts of Iobenguane (notably in therapeutic doses) and the level at which unwanted secondary effects might occur is not very wide, therefore patients should be kept under close surveillance during and for at least some hours after the infusion or injection of the drug.

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

Sodium chloride

Water for injections

Benzyl alcohol

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

The shelf life is 3 days from the activity reference date stated on the label.

Store below 25°C. Do not freeze.

Store in the original lead container or in equivalent shielding.

The product is supplied in a clear neutral glass vial sealed with a PTFE-faced butyl rubber closure.

Pack sizes: single vials containing 18.5 MBq to 185 MBq in 18.5 MBq steps.

Not all pack sizes may be marketed.

General warning

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/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.

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

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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

GE Healthcare Limited

Pollards Wood

Nightingales Lane

Chalfont St Giles

Buckinghamshire HP8 4SP

United Kingdom

PL 00221/0124

Date of first authorisation: 14 February 1997

Date of last renewal: 10 October 2001

15/11/2019

DOSIMETRY

The table below shows the dosimetry as calculated according to the Publication (53) of the ICRP (International Commission on Radiological Protection, Radiation Dose to Patients from Radiopharmaceuticals, Pergamon Press (1987)).

Radiation dose to specific organs, which may not be the target organ of therapy, can be influenced significantly by pathophysiological changes induced by the disease process. This should be taken into consideration when using the following information.

With the exception of "uterus" the list includes only those organs which are used in the calculation for the effective (whole body) dose equivalent. These are the seven standard organs and the additional five organs with the highest absorbed dose (marked with *).

The above data are valid in normal pharmacokinetic behaviour. Especially when renal function is impaired, due to disease or due to previous therapy, the effective dose equivalent and the radiation dose delivered to organs (notably to bone, red marrow and lungs) might be increased considerably.

INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS

Withdrawals should be performed under aseptic conditions. The vials must not be opened before disinfecting the stopper, 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.