Ioflupane

12.1 Mechanism of Action The active drug substance in Ioflupane I 123 Injection is N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[ 123 I]iodophenyl)nortropane or ioflupane I-123. In vitro , ioflupane binds reversibly to the human dopamine transporter (DaT) (Ki = 0.62 nM; IC 50 = 0.71 nM). Autoradiography of post-mortem human brain slices exposed to radiolabeled ioflupane shows concentration of the radiolabel in striatum (caudate nucleus and putamen). The specificity of the binding of ioflupane I-125 to dopamine transporter was demonstrated by competition studies with the DaT inhibitor GBR 12909 (a dopamine reuptake inhibitor), the serotonin reuptake inhibitor citalopram, and the norepinephrine reuptake inhibitor desipramine in post-mortem human brain slices exposed to radiolabeled ioflupane. Citalopram reduced binding in the neocortex and thalamus with only minor effects in the striatum. This indicated that the binding in the cortex and thalamus is mainly to the serotonin reuptake sites. Desipramine showed no effect on the level of striatal binding of ioflupane I- 125, but reduced extrastriatal binding by 60 to 85%. The binding of ioflupane I-125 to the striatum was abolished in the presence of high concentrations of GBR 12909, indicating selectivity of ioflupane binding for the pre-synaptic DaT. Following administration of Ioflupane I 123 Injection to humans, radioactive decay of the iodine-123 emits gamma radiation which can be detected externally using gamma detectors, allowing visualization of the brain striata through SPECT imaging [ see Clinical Pharmacology ( 12.3 ) ].

1 INDICATIONS AND USAGE Ioflupane I 123 Injection is indicated as an adjunct to other diagnostic evaluations for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging in adult patients with: ● suspected Parkinsonian syndromes (PS) or ● suspected dementia with Lewy bodies (DLB). Ioflupane I 123 Injection is a radioactive diagnostic agent indicated as an adjunct to other diagnostic evaluations for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging in adult patients with: suspected Parkinsonian syndromes (PS) or suspected dementia with Lewy bodies (DLB). ( 1 )

2 DOSAGE AND ADMINISTRATION Administer a thyroid-blocking agent at least one hour before the dose of Ioflupane I 123 Injection. ( 2.2 ) The recommended dose of Ioflupane I 123 Injection in adult patients is 111 MBq to 185 MBq (3 mCi to 5 mCi) administered intravenously over at least 20 seconds. ( 2.3 ) Measure patient dose using a dose calibrator immediately prior to administration. ( 2.4 ) Begin SPECT imaging between 3 hours and 6 hours post-injection. ( 2.6 ) Figure 1,2,3,4 2.1 Radiation Safety Ioflupane I 123 Injection emits radiation and must be handled with safety measures to minimize radiation exposure to healthcare providers and patients [ see Warnings and Precautions ( 5.3 ) ]. Radiopharmaceuticals should be used by or under the control of healthcare providers who are qualified by specific training and experienced in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. To minimize radiation exposure, encourage hydration prior to and following Ioflupane I 123 Injection administration in order to permit frequent voiding. Encourage the patient to void frequently for the first 48 hours following Ioflupane I 123 Injection administration [ see Dosage and Administration ( 2.5 ) ]. 2.2 Thyroid Blockade Before Ioflupan e I 123 Injection Administration Administer Potassium Iodide Oral Solution or Strong Iodine Solution (e.g., Lugol's Solution) equivalent to 100 mg iodide to block uptake of iodine-123 by the patient's thyroid at least one hour before the dose of Ioflupane I 123 Injection [ see Warnings and Precautions ( 5.2 ) ]. 2.3 Recommended Dos age The recommended dose of Ioflupane I 123 Injection in adult patients is 111 MBq to 185 MBq (3 mCi to 5 mCi) administered intravenously over at least 20 seconds. 2. 4 Preparation and Administration Assess pregnancy status before administering Ioflupane I 123 Injection to a female of reproductive potential [ see Use in Specific Populations ( 8.1 ) ]. Use aseptic procedures and radiation shielding during preparation and administration. Inspect the Ioflupane I 123 Injection vial for particulate matter and discoloration prior to administration and do not use it if the vial contains particulate matter or discoloration. Measure patient dose using a dose calibrator immediately prior to administration. Discard unused portion. 2.5 Radiation Dosimetry The estimated radiation absorbed doses to an adult from intravenous injection of Ioflupane I 123 Injection are shown in Table 1. The values are calculated assuming urinary bladder emptying at 4.8-hour intervals and appropriate thyroid blocking (iodine-123 is a known Auger electron emitter). Table 1 Estimated Radiation Absorbed Doses from Ioflupane I 123 Injection ORGAN / TISSUE ABSORBED DOSE PER UNIT ADMINISTERED ACTIVITY (μGy / MBq) Adrenals 12.9 Brain 17.8 Striata 230 Breasts 7.8 Gallbladder Wall 26.4 GI Tract Esophagus 10 Stomach Wall 11.2 Small Intestine Wall 21.2 Colon Wall a 39.8 Upper Large Intestine Wall 38.1 Lower Large Intestine Wall 42 Heart Wall 12.9 Kidneys 10.9 Liver 27.9 Lungs 41.2 Muscle 9.4 Osteogenic Cells 28.2 Ovaries 16.8 Pancreas 13 Red Marrow 9.2 Skin 6 Spleen 10.4 Testes 8.5 Thymus 10 Thyroid 9 Urinary Bladder Wall 53.1 Uterus 16.1 Total Body 11.3 EFFECTIVE DOSE PER UNIT ADMINISTERED ACTIVITY (µSv/MBq) 21.3 a The absorbed dose to the colon wall is the mass-weighted sum of the absorbed doses to the upper and lower large intestine walls, D c olon = 0.57D ULI + 0.43D LLI [Publication 80 of the ICRP (International Commission on Radiological Protection); Annals of the ICRP 28 (3). Oxford: Pergamon Press; 1998] The Effective Dose resulting from a Ioflupane I 123 Injection administration with an administered activity of 185 MBq (5 mCi) is 3.94 mSv in an adult. 2.6 Imaging Instructions Begin SPECT imaging 3 hours to 6 hours following Ioflupane I 123 Injection administration. Use a gamma camera fitted with high-resolution collimators and set to a photopeak of 159 keV with a ± 10% energy window. Angular sampling should be at least 120 views over 360 degrees. Position the patient supine with the head on an off-the-table headrest, use a flexible head restraint such as a strip of tape across the chin or forehead if necessary to help avoid movement, and set a circular orbit for the detector heads with the radius as small as possible (typically 11 cm to 15 cm). Obtain images with matrix size and zoom factors selected to give a pixel size of 3.5 mm to 4.5 mm. Collect a minimum of 1.5 million counts for optimal images. 2.7 Image Interpretation Interpret Ioflupane I 123 Injection images visually, based upon the appearance of the striata. Reconstructed pixel size should be between 3.5 mm and 4.5 mm with slices 1 pixel thick. Optimum presentation of the reconstructed images for visual interpretation is transaxial slices parallel to the anterior commissure-posterior commissure (AC-PC) line. Determi

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: • Hypersensitivity Reactions [ see Warnings and Precautions ( 5.1 ) ] The following adverse reactions were reported at ≤1%: headache, nausea, vertigo, dry mouth and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact CURIUM US LLC at 1-866-789-2211 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Ioflupane I 123 Injection cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data from clinical trials reflect exposure to Ioflupane I 123 Injection in 942 subjects with a mean age of 66 years (range 25 years to 90 years). Among these subjects, 42% were female and 99% White. Subjects received 88 MBq to 287 MBq (2 mCi to 8 mCi) [median 173 MBq (4.7 mCi)] intravenously as a single dose. The recommended dose of Ioflupane I 123 Injection is 111 MBq to 185 MBq (3 mCi to 5 mCi) [ see Dosage and Administration ( 2.3 ) ]. The following adverse reactions were reported at a rate of 1% or less: headache, nausea, vertigo, dry mouth, and dizziness. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Ioflupane I 123 Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders : Hypersensitivity, including dyspnea, edema, rash, erythema, and pruritus General disorders and administration site conditions : Injection site pain

7 DRUG INTERACTIONS Ioflupane I 123 binds to the dopamine transporter [ see Clinical Pharmacology ( 12.1 ) ]. Drugs that bind to the dopamine transporter with high affinity may interfere with the image obtained following Ioflupane I 123 Injection administration. These potentially interfering drugs consist of: amoxapine, amphetamine, armodafinil, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, modafinil, norephedrine, phentermine, phenylpropanolamine, selegiline, and sertraline. Selective serotonin reuptake inhibitors (paroxetine and citalopram) may increase or decrease ioflupane binding to the dopamine transporter. Whether discontinuation of these drugs prior to Ioflupane I 123 Injection administration may minimize the interference with a Ioflupane I 123 Injection image is unknown. The impact of dopamine agonists and antagonists upon Ioflupane I 123 Injection imaging results has not been established. Amoxapine, amphetamine, armodafinil, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, modafinil norephedrine, phentermine, phenylpropanolamine, selegiline, sertraline, citalopram and paroxetine may interfere with Ioflupane I 123 Injection imaging. The effects of dopamine agonists and antagonists on Ioflupane I 123 Injection imaging have not been established. ( 7 )