Contents of the package leaflet for the medicine DATSCAN 74 MBQ/ml solution for injection

1. NAME OF THE MEDICINAL PRODUCT

DaTSCAN 74 MBq/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains ioflupane (123I) 74 MBq at reference time (0.07 to 0.13 μg/ml of ioflupane).

Each 2.5 ml single dose vial contains 185 MBq ioflupane (123I) (specific activity range 2.5 to4.5 x 1014 Bq/mmol) at reference time.

Each 5 ml single dose vial contains 370 MBq ioflupane (123I) (specific activity range 2.5 to4.5 x 1014 Bq/mmol) at reference time.

Excipient(s) with known effect

This medicinal product contains 39.5 g/l ethanol.

For the full list of excipients see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

DaTSCAN is indicated for detecting loss of functional dopaminergic neuron terminals in the striatum:

* In adult patients with clinically uncertain Parkinsonian Syndromes, for example those with earlysymptoms, in order to help differentiate Essential Tremor from Parkinsonian Syndromes relatedto idiopathic Parkinson’s Disease, Multiple System Atrophy and Progressive Supranuclear Palsy.

DaTSCAN is unable to discriminate between Parkinson's Disease, Multiple System Atrophy and

Progressive Supranuclear Palsy.

* In adult patients, to help differentiate probable dementia with Lewy bodies from Alzheimer’sdisease.

DaTSCAN is unable to discriminate between dementia with Lewy bodies and Parkinson’s diseasedementia.

4.2 Posology and method of administration

Prior to administration appropriate resuscitation equipment should be available.

DaTSCAN should only be used in adult patients referred by physicians experienced in the managementof movement disorders and/or dementia. DaTSCAN should only be used by qualified personnel with theappropriate government authorisation for the use and manipulation of radionuclides within a designatedclinical setting.

Posology

Clinical efficacy has been demonstrated across the range 111 to 185 MBq. Do not exceed 185 MBq anddo not use when the activity is below 110 MBq.

Patients must undergo appropriate thyroid blocking treatment prior to injection to minimise thyroiduptake of radioactive iodine, for example by oral administration of approximately 120 mg potassiumiodide 1 to 4 hours prior to injection of DaTSCAN.

Special populations
Renal and hepatic impairment

Formal studies have not been carried out in patients with significant renal or hepatic impairment. Nodata are available (see section 4.4).

Paediatric population

The safety and efficacy of DaTSCAN in children aged 0 to 18 years has not been established. No dataare available.

Method of Administration

For intravenous use.

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

Image acquisition

SPECT imaging should take place between three and six hours post-injection. Images should beacquired using a gamma camera fitted with a high-resolution collimator and calibrated using the159 keV photopeak and a ± 10% energy window. Angular sampling should preferably be not less than120 views over 360 degrees. For high resolution collimators the radius of rotation should be consistentand set as small as possible (typically 11-15cm). Experimental studies with a striatal phantom, suggestthat optimal images are obtained with matrix size and zoom factors selected to give a pixel size of3.5-4.5 mm for those systems currently in use. A minimum of 500k counts should be collected foroptimal images.

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

If hypersensitivity reactions occur, the administration of the medicinal product must be discontinuedimmediately and, if necessary, intravenous treatment initiated. Resuscitative medicinal products andequipment (e.g. endotracheal tube and ventilator) have to be readily available.

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

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

The patient should be well hydrated before and after the examination and urged to void as often aspossible during the first 48 hours after the procedure in order to minimise radiation exposure.

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

This medicinal product contains 39.5 g/l (5% volume) ethanol (alcohol), up to 197 mg per dose,equivalent to 5 ml beer or 2 ml wine. Harmful for those suffering from alcoholism. To be taken intoaccount in high-risk groups such as patients with liver disease or epilepsy.

Interpretation of DaTSCAN Images

DaTSCAN images are interpreted visually, based upon the appearance of the striata.

Optimum presentation of the reconstructed images for visual interpretation is transaxial slices parallel tothe anterior commissure-posterior commissure (AC-PC) line. Determination of whether an image isnormal or abnormal is made by assessing the extent (as indicated by shape) and intensity (in relation tothe background) of the striatal signal.

Normal images are characterised by two symmetrical crescent-shaped areas of equal intensity.

Abnormal images are either asymmetric or symmetric with unequal or reduced intensity and/or loss ofcrescent.

As an adjunct, visual interpretation may be assisted by semi-quantitative assessment using CE-markedsoftware, where DaTSCAN uptake in the striatum is compared with uptake in a reference region andratios are compared against an age adjusted healthy subjects’ database. The evaluation of ratios, such asthe left/right striatum DaTSCAN uptake (symmetry) or caudate/putamen uptake, may further help withthe image assessment.

The following precautions should be taken when using semi-quantitative methods:

* Semi-quantification should only be used an adjunct to visual assessment

* Only CE marked software should be used

* Users should be trained in the use of CE marked software by the manufacturer and follow EANMpractice guidelines for image acquisition, reconstruction and assessment

* Readers should interpret the scan visually and then perform the semi-quantitative analysisaccording to manufacturer’s instructions including quality checks for the quantitation processo ROI /VOI techniques should be used to compare uptake in the striatum with uptake in areference regiono Comparison against an age adjusted healthy subjects database is recommended toaccount for age-expected decrease in striatal bindingo The reconstruction and filter settings (including attenuation correction) used can affectthe semi-quantitative values. The reconstruction and filter settings recommended bythe manufacturer of the CE marked software should be followed and should matchthose used for semi-quantification of the healthy subjects database.

o The intensity of the striatal signal as measured by SBR (striatal binding ratio)and asymmetry and caudate to putamen ratio provide objective numerical valuescorresponding to the visual assessment parameters and can be helpful in difficult to readcaseso If the semi-quantitative values are inconsistent with the visual interpretation, the scanshould be evaluated for appropriate placement of the ROIs /VOIs, correct imageorientation and appropriate parameters for image acquisition and attenuation correctionshould be verified. Some software packages can support these processes to reduceoperator-dependent variabilityo Final assessment should always consider both visual appearance and semi-quantitativeresults

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. Medicines that bind to the dopamine transporter with highaffinity may therefore interfere with DaTSCAN diagnosis. These include amfetamine, bupropion,cocaine, codeine, dexamfetamine, methylphenidate, modafinil, and phentermine. Selective serotoninreuptake inhibitors (SSRIs), such as sertraline, may increase or decrease ioflupane binding to thedopamine transporter. Serotonin-norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, maydecrease ioflupane binding to the dopamine transporter especially in patients on higher doses.

Medicines shown during clinical trials not to interfere with DaTSCAN imaging include amantadine,trihexyphenidyl, budipine, levodopa, metoprolol, primidone, propranolol and selegiline. Dopamineagonists and antagonists acting on the postsynaptic dopamine receptors are not expected to interferewith DaTSCAN imaging and can therefore be continued if desired. Medicinal products shown in animalstudies not to interfere with DaTSCAN 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 beassumed pregnant until proven otherwise. Where uncertainty exists, it is important that radiationexposure should be the minimum consistent with achieving satisfactory imaging. Alternative techniqueswhich do not involve ionising radiation should be considered.

Pregnancy

Animal reproductive toxicity studies have not been performed with this product. Radionuclideprocedures carried out on pregnant women also involve radiation doses to the foetus. Administration of185 MBq of ioflupane (123I) results in an absorbed dose to the uterus of 3.0 mGy. DaTSCAN iscontraindicated in pregnancy (see section 4.3).

Breastfeeding

It is not known whether ioflupane (123I) is excreted in human milk. Before administering a radioactivemedicinal product to a breast-feeding mother, consideration should be given as to whether theinvestigation could be reasonably delayed until the mother has ceased breast-feeding and as to whetherthe most appropriate choice of radiopharmaceutical has been made, bearing in mind the secretion ofradioactivity in breast milk. If administration is considered necessary, breast-feeding should beinterrupted for 3 days and substituted by formula feeding. During this time, breast milk should beexpressed 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

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

4.8 Undesirable effects

The following undesirable effects are recognised for DaTSCAN:

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 availabledata). Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.

Immune system disorders

Not known: Hypersensitivity

Metabolism and nutrition disorders

Uncommon: Appetite increased

Nervous system disorders

Common: Headache

Uncommon: Dizziness, formication (paraesthesia), dysgeusia

Ear and labyrinth disorders

Uncommon: Vertigo

Skin and subcutaneous tissue disorders

Not known: Erythema, pruritus, rash, urticaria, hyperhidrosis

Respiratory, thoracic and mediastinal disorders

Not known: Dyspnea

Gastrointestinal disorders

Uncommon: Nausea, dry mouth

Not known: Vomiting

Vascular disorders

Not known: Blood pressure decreased

General disorders and administration site conditions

Uncommon: Injection site pain (intense pain or burning sensation following administration into smallveins)

Not known: Feeling hot

Exposure to ionising radiation is linked with cancer induction and a potential for development ofhereditary defects. As the effective dose is 4.63 mSv when the maximal recommended activity of185 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. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diagnostic radiopharmaceutical central nervous system,

ATC code: V09AB03.

Due to the low quantities of ioflupane injected, pharmacological effects are not expected followingintravenous administration of DaTSCAN at the recommended dosage.

Mechanism of action

Ioflupane is a cocaine analogue. Studies in animals have shown that ioflupane binds with high affinity tothe presynaptic dopamine transporter and so radiolabelled ioflupane (123I) can be used as a surrogatemarker to examine the integrity of the dopaminergic nigrostriatal neurons. Ioflupane also binds to theserotonin 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 trial 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 DaTSCAN images were compared to theclinical diagnosis as determined by physicians experienced in the management and diagnosis ofdementias. Clinical categorisation into the respective dementia group was based on a standardised andcomprehensive clinical and neuropsychiatric evaluation. The values for the sensitivity of DaTSCAN indetermining probable DLB from non-DLB ranged from 75.0% to 80.2% and specificity from 88.6% to91.4%. The positive predictive value ranged from 78.9% to 84.4% and the negative predictive valuefrom 86.1% to 88.7%. Analyses in which both possible and probable DLB patients were compared withnon-DLB dementia patients demonstrated values for the sensitivity of DaTSCAN ranging from 75.0%to 80.2% and specificity from 81.3% to 83.9% when the possible DLB patients were included asnon-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.

Clinical studies demonstrating adjunctive use of semi-quantitative information for image interpretation

The reliability of using semi-quantitative information as an adjunct to visual inspection was analysed infour clinical studies where sensitivity, specificity or overall accuracy between the two methods of imageinterpretation were compared. In the four studies (total n=578), CE-marked DaTSCANsemi-quantitation software was used. The differences (i.e., improvements when addingsemi-quantitative information to visual inspection) in sensitivity ranged between 0.1% and 5.5%, inspecificity between 0.0% and 2.0%, and in overall accuracy between 0.0% and 12.0%.

The biggest of these four studies retrospectively assessed a total of 304 DaTSCAN exams frompreviously conducted Phase 3 or 4 studies, which included subjects with a clinical diagnosis of PS,non-PS (mainly ET), probable DLB, and non-DLB (mainly AD). Five nuclear medicine physicians whohad limited prior experience with DaTSCAN interpretation assessed the images in 2 readings (alone andcombined with semi-quantitative data provided by DaTQUANT 4.0 software) at least 1 month apart.

These results were compared with the subject’s 1-to 3-year follow-up diagnosis to determine diagnosticaccuracy. The improvements in sensitivity and specificity [with 95% confidence intervals] were 0.1%[-6.2%,6.4%] and 2.0% [-3.0%,7.0%]. Also, the results of the combined reading were associated with anincrease in reader confidence.

5.2 Pharmacokinetic properties

Distribution

Ioflupane (123I) is cleared rapidly from the blood after intravenous injection; only 5% of the administeredactivity 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 anddecreasing 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, withfaecal 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 ofsafety pharmacology, single and repeated dose toxicity and genotoxicity.

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

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Acetic acid

Sodium acetate

Ethanol

Water for injections

6.2 Incompatibilities

Not applicable

6.3 Shelf life

2.5 ml vial: 7 hours from the activity reference time stated on the label.

5 ml vial: 20 hours from the activity reference time stated on the label.

6.4 Special precautions for storage

Do not store above 25oC. Do not freeze.

6.5 Nature and contents of container

2.5 or 5 ml solution in a single colourless 10 ml glass vial sealed with a rubber closure and metaloverseal.

Pack size of 1.

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.

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 radioactivewaste 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.

7. MARKETING AUTHORISATION HOLDER

GE Healthcare B.V.

De Rondom 85612 AP, Eindhoven

The Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/00/135/001 (2.5 ml)

EU/1/00/135/002 (5 ml)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 27 July 2000

Date of latest renewal: 28 July 2010

11. DOSIMETRY

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

The estimated absorbed radiation doses to an average adult patient (70 kg) from intravenous injection ofioflupane (123I) are listed in the Table below. The values are calculated assuming urinary bladderemptying at 4.8-hour intervals and appropriate thyroid blocking (Iodine-123 is a known Auger electronemitter). Frequent bladder emptying should be encouraged after dosing to minimise radiation exposure.

Target Organ Absorbed radiation doseµGy/MBq

Adrenals 17.0

Bone surface 15.0

Brain 16.0

Breast 7.3

Gallbladder wall 44.0

Gastrointestinal tract

Stomach wall 12.0

Small intestine wall 26.0

Colon wall 59.0(Upper large intestine wall 57.0)(Lower large intestine wall 62.0)

Heart wall 32.0

Kidneys 13.0

Liver 85.0

Lungs 42.0

Muscles 8.9

Oesophagus 9.4

Ovaries 18.0

Pancreas 17.0

Red marrow 9.3

Salivary glands 41.0

Skin 5.2

Spleen 26.0

Testes 6.3

Thymus 9.4

Thyroid 6.7

Urinary bladder wall 35.0

Uterus 14.0

Remaining organs 10.0

Effective Dose (µSv/MBq) 25.0

Ref.: Publication 128 of the Annals of ICRP (Radiation dose to Patients from Radiopharmaceuticals: A Compendiumof Current Information Related to Frequently Used Substances, 2015

The effective dose (E) resulting from administration of 185 MBq of DaTSCAN injection is 4.63 mSv(per 70 kg individual). The above data are valid in normal pharmacokinetic behaviour. When renal orhepatic function is impaired, the effective dose and the radiation dose delivered to organs might beincreased.

12. INSTRUCTIONS FOR THE PREPARATION OF RADIO PHARMACEUTICAL MEDICINAL PRODUCTS

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. See also section 6.6.

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu

Leaflet DATSCAN 74 MBQ/ml solution for injection

General data about DATSCAN 74 MBQ/ml

Marketing authorisation

Concentrations available for ioflupan iodine 123