Celsunax - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Celsunax 74 MBq/mL solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of solution contains 74 MBq ofioflupane (123I) at reference time (0.07 to 0.13 |.ig/mL of ioflupane).

Each 2.5 mL single dose vial contains 185 MBq ioflupane (123I) (specific activity range 2.5 to

• 4.5 × 10          ­Bq/mmol) at reference time.

Each 5 mL single dose vial contains 370 MBq ioflupane (123I) (specific activity range 2.5 to

• 4.5 × 10 Bq/mmol) at reference time.

Iodine-123 has a physical half-life of 13.2 hours. It decays emitting gamma radiation with a predominant energy of 159 keV and X-rays of 27 keV.

Excipient with known effect

This medicinal product contains 39.5 g/L ethanol, resulting in a maximum of 197 mg of ethanol in 5 mL solution.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution.

clinical setting.

Posology

Clinical efficacy has been demonstrated across the range 110 to 185 MBq. Do not exceed 185 MBq and do not use when the activity is below 110 MBq.

Patients must undergo appropriate thyroid blocking treatment prior to injection to minimise thyroid uptake of radioactive iodine, for example by oral administration of approximately 120 mg potassium iodide 1 to 4 hours prior to injection of Celsunax.

Special populations

Renal and hepatic impairment

Formal studies have not been carried out in patients with significant renal or hepatic impairment. No data are available (see section 4.4).

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

Paediatric population

The safety and efficacy of Celsunax in children aged 0 to 18 years has not been established. No data are available.

Method of administration

For intravenous use.

Vial for single use.

For patient preparation, see section 4.4.

Precautions to be taken before handling or administering the medicinal product

Celsunax should be used without dilution. To minimise the potential for pain at the injection site during administration, a slow intravenous injection (not less than 15 to 20 seconds) via an arm vein is recommended.

Image acquisition

SPECT imaging should take place between three and six hours post-injection. Images should be acquired using a gamma camera fitted with a high-resolution collimator and calibrated using the 159 keV photopeak and a ± 10% energy window. Angular sampling should preferably be not less than 120 views over 360 degrees. For high resolution collimators the radius of rotation should be consistent and set as small as possible (typically 11–15 cm). Experimental studies with a striatal phantom, suggest that optimal images are obtained with matrix size and zoom factors selected to give a pixel size of 3.5–4.5 mm for those systems currently in use. A minimum of 500k counts should be collected for optimal images. Normal images are characterised by two symmetrical crescent-shaped areas of equal intensity. Abnormal images are either asymmetric or symmetric with unequal intensity and/or loss of crescent.

4.3 Contraindications

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

• – Pregnancy (see section 4.6).

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, if necessary, intravenous treatment initiated. The necessary resuscitative medicinal products and equipment (e.g. endotracheal tube and ventilator) have to be readily available, to enable immediate action in emergencies.

This radiopharmaceutical may be received, used and administered only by authorised persons in designated clinical settings. Its receipt, storage, use, transfer and disposal are subject to the regulations and the appropriate licences of the local competent official organisations.

Individual benefit/risk justification

For each patient, exposure to ionising radiation must be justifiable on the basis of likely benefit. The activity administered must be such that the resulting dose is as low as reasonably achievable bearing in mind the need to obtain the intended diagnostic result.

Renal impairment/hepatic impairment

Formal studies have not been carried out in patients with significant renal or hepatic impairment. In the absence of data, Celsunax is not recommended in cases of moderate to severe renal or hepatic impairment.

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

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 hours after the examination in order to reduce radiation.

Specific warnings

This medicinal product contains up to 197 mg of alcohol (ethanol) in each dose which is equivalent to 39.5 mg/mL (5% by volume). The amount in 5 mL of this medicinal product is equivalent to 5 mL beer or 2 mL wine. The small amount of alcohol in this medicinal product will not have any noticeable effects.

Precautions with respect to environmental hazard see section 6.6.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed in humans.

Ioflupane binds to the dopamine transporter. Active substances that bind to the dopamine transporter with high affinity may therefore interfere with Celsunax diagnosis. These include: –      amfetamine,

• – benzatropine,

• – buproprion,

• – cocaine,

• – mazindol,

• – methylphenidate, –       phentermine,

• – sertraline.

Active substances shown during clinical studies not to interfere with Celsunax imaging include:

• – amantadine,

• – trihexyphenidyl,

• – budipine,

• – levodopa,

• – metoprolol,

• – primidone,

• – propranolol,

• – selegiline.

Dopamine agonists and antagonists acting on the postsynaptic dopamine receptors are not expected to interfere with Celsunax imaging and can therefore be continued if desired. Medicinal products shown in animal studies not to interfere with Celsunax imaging include pergolide.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Where 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 satisfactory imaging. Alternative techniques which do not involve ionising radiation should be considered.

Pregnancy

Animal reproductive toxicity studies have not been performed with this product. Radionuclide procedures carried out on pregnant women also involve radiation doses to the foetus. Administration of 185 MBq of ioflupane (123I) results in an absorbed dose to the uterus of 3.0 mGy. Celsunax is contraindicated in pregnancy (see section 4.3).

Breast-feeding

It is not known whether ioflupane (123I) is excreted in human milk. Before administering a radioactive medicinal product to a breast-feeding mother, 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 radioactivity in breast milk. If administration is considered necessary, breast-feeding should be interrupted for 3 days and substituted by formula feeding. During this time, breast milk should be expressed at regular intervals and the expressed feeds should be discarded.

Fertility

No fertility studies have been performed. No data are available.

4.7 Effects on ability to drive and use machines

Celsunax has no known influence on the ability to drive and use machines.

4.8 Undesirable effects

The following undesirable effects are recognised for ioflupane (123I):

Tabulated summary of adverse reactions

The frequencies of adverse reactions 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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

MedDRA system organ classification (SOC)	Adverse reaction	Frequency
Immune system disorders	Hypersensitivity	Not known
Metabolism and nutrition disorders	Appetite increased	Uncommon
Nervous system disorders	Headache	Common
	Dizziness, formication (paraesthesia), dysgeusia	Uncommon
Ear and labyrinth disorders	Vertigo	Uncommon
Vascular disorders	Blood pressure decreased	Not known
Respiratory, thoracic and mediastinal disorders	Dyspnea	Not known
Gastrointestinal disorders	Nausea, dry mouth	Uncommon
	Vomiting	Not known
Skin and subcutaneous tissue disorders	Erythema, pruritus, rash, urticaria, hyperhidrosis	Not known
General disorders and administration site conditions	Injection site pain (intense pain or burning sensation following administration into small veins)	Uncommon
	Feeling hot	Not known

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. As the effective dose is 4.63 mSv when the maximal recommended activity of 185 MBq is administered these adverse events are expected to occur with a low probability.

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 national reporting system listed in

4.9 Overdose

In cases of administration of a radiation overdose, frequent micturition and defaecation should be encouraged in order to minimise radiation dose to the patient. Care should be taken to avoid contamination from the radioactivity eliminated by the patient using such methods.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmace­uticals, central nervous system, ATC code: V09AB03

At the chemical concentrations used for diagnostic examinations, Celsunax does not appear to have any pharmacodynamic activity.

Mechanism of action

Ioflupane is a cocaine analogue. Studies in animals have shown that ioflupane binds with high affinity to the presynaptic dopamine transporter and so radiolabelled ioflupane (123I) can be used as a surrogate marker to examine the integrity of the dopaminergic nigrostriatal neurons. Ioflupane also binds to the serotonin transporter on 5-HT neurons but with lower (approximately 10-fold) binding affinity.

There is no experience in types of tremor other than essential tremor.

Clinical efficacy

Clinical studies in patients with dementia with Lewy bodies

In a pivotal clinical study including evaluation of 288 subjects with dementia with Lewy bodies (DLB) (144 subjects), Alzheimer’s disease (124 subjects), vascular dementia (9 subjects) or other (11 subjects), the results of an independent, blinded visual assessment of the ioflupane (123I) images were compared to the clinical diagnosis as determined by physicians experienced in the management and diagnosis of dementias. Clinical categorisation into the respective dementia group was based on a standardised and comprehensive clinical and neuropsychiatric evaluation. The values for the sensitivity of ioflupane (123I) in determining probable DLB from non-DLB ranged from 75.0% to 80.2% and specificity from 88.6% to 91.4%. The positive predictive value ranged from 78.9% to 84.4% and the negative predictive value from 86.1% to 88.7%. Analyses in which both possible and probable DLB patients were compared with non-DLB dementia patients demonstrated values for the sensitivity of ioflupane (123I) ranging from 75.0% to 80.2% and specificity from 81.3% to 83.9% when the possible DLB patients were included as non-DLB patients. The sensitivity ranged from 60.6% to 63.4% and specificity from 88.6% to 91.4% when the possible DLB patients were included as DLB patients.

5.2 Pharmacokinetic properties

Distribution

Ioflupane (123I) is cleared rapidly from the blood after intravenous injection; only 5% of the administered activity remains in whole blood at 5 minutes post-injection.

Organ uptake

Uptake in the brain is rapid, reaching about 7% of injected activity at 10 minutes post-injection and decreasing to 3% after 5 hours. About 30% of the whole brain activity is attributed to striatal uptake.

Elimination

At 48 hours post-injection, approximately 60% of the injected radioactivity is excreted in the urine, with faecal excretion calculated at approximately 14%.

5.3 Preclinical safety data

Non-clinical data for ioflupane reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity.

Studies on reproductive toxicity and to assess the carcinogenic potential of ioflupane have not been performed.

Environmental Risk Assessment (ERA)

After use, all materials associated with the preparation and administration of radiopharmace­uticals, including any unused medicinal 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.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Acetic acid, glacial (E260)

Sodium acetate trihydrate (E262)

Ethanol (96%) (E1510)

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

24 hours from the end of the synthesis (EOS) time stated on the label.

6.4 Special precautions for storage

Do not store above 25°C. Do not freeze.

Store in the original lead shielding.

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

6.5 Nature and contents of container

Sterile 10 mL glass vial (Type I) with a rubber stopper and a flip cap.

The vial is placed into a lead container for protective shielding.

Pack size of 1 vial containing 2.5 mL or 5 mL of solution.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

General warning

Normal safety precautions for handling radioactive materials should be observed.

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 licences 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.

7. MARKETING AUTHORISATION HOLDER

Pinax Pharma GmbH

Lausitz Mühlenweg 5

04924 Bad Liebenwerda

Germany

8. MARKETING AUTHORISATION NUMBERS

EU/1/21/1560/001 (2.5 mL)

EU/1/21/1560/002 (5 mL)

9. DATE OF FIRST AUTHORISATION

Date of first authorisation: