Ioflupane I 123

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. Determine whether an image is normal or abnormal by assessing the extent (as indicated by shape) and intensity of the striatal signal. Image interpretation does not involve integration of the striatal image appearance with clinical signs and/or symptoms. Normal: In transaxial images, normal images are characterized by two symmetric comma- or crescent-shaped focal regions of activity mirrored about the median plane. Striatal activity is distinct, relative to surrounding brain tissue (Figure 1). Abnormal: Abnormal Ioflupane I 123 Injection images fall into at least one of the following three categories (all are considered abnormal). Activity is asymmetric, e.g., activity in the region of the putamen of one hemisphere is absent or greatly reduced with respect to the other. Activity is still visible in the caudate nuclei of both hemispheres resulting in a comma or crescent shape in one and a circular or oval focus in the other. There may be reduced activity between at least one striatum and surrounding tissues (Figure 2). Activity is absent in the putamen of both hemispheres and confined to the caudate nuclei. Activity is relatively symmetric and forms two roughly circular or oval foci. Activity of one or both is generally reduced (Figure 3). Activity is absent in the putamen of both hemispheres and greatly reduced in one or both caudate nuclei. Activity of the striata with respect to the background is reduced (Figure 4).

4 CONTRAINDICATIONS Ioflupane I 123 Injection is contraindicated in patients with known serious hypersensitivity to ioflupane I-123 [see Warnings and Precautions ( 5.1 )] . Known serious hypersensitivity to ioflupane I 123 ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions including dyspnea, edema, rash, erythema, and pruritus have been reported. Have treatment measures available prior to Ioflupane I 123 Injection administration. ( 5.1 ) Thyroid Accumulation of Iodine-123: Thyroid uptake of iodine-123 may result in an increased long-term risk for thyroid neoplasia. ( 2.2 , 5.2 ) Radiation Risk: Ensure safe handling to minimize radiation exposure to the patient and healthcare providers. Advise patients to hydrate before and after administration and to void frequently after administration. ( 2.1 , 5.3 ) 5. 1 Hypersensitivity Reactions Hypersensitivity reactions, including dyspnea, edema, rash, erythema, and pruritus, have been reported following Ioflupane I 123 Injection administration [ see Adverse Reactions ( 6.2 ) ]. The reactions have generally occurred within minutes of Ioflupane I 123 Injection administration and have either resolved spontaneously or following the administration of corticosteroids and antihistamines. Ioflupane I 123 Injection is contraindicated in patients with known serious hypersensitivity to ioflupane I-123 [ see Contraindications ( 4 ) ]. Have treatment measures available and monitor patients for symptoms or signs of a hypersensitivity reaction. 5.2 Thyroid Accumulation of Iodine-123 Ioflupane I 123 Injection may contain up to 6% of free iodide (iodine-123). Thyroid uptake of iodine-123 may result in an increased long-term risk for thyroid neoplasia. To decrease thyroid accumulation of iodine-123, block the thyroid gland before administration of Ioflupane I 123 Injection [ see Dosage and Administration ( 2.2 ) ]. 5.3 Radiation Risk Ioflupane I 123 Injection contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Ensure safe handling to minimize radiation exposure to patients and healthcare providers. Advise patients to hydrate before and after administration and to void frequently after administration [see Dosage and Administration ( 2.1 )].

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 )

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

8. 1 Pregnancy Risk Summary Radioactive iodine products cross the placenta and can permanently impair fetal thyroid function. Administration of an appropriate thyroid blocking agent is recommended before use of Ioflupane I 123 Injection in a pregnant woman to protect the woman and fetus from accumulation of iodine-123 [ see Dosage and Administration ( 2.2 ) ]. There are no available data on Ioflupane I 123 Injection use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with ioflupane I-123. All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. Administration of Ioflupane I 123 Injection at a dose of 185 MBq (5 mCi) results in an absorbed radiation dose to the uterus of 0.3 rad (3.0 mGy). Radiation doses greater than 15 rad (150 mGy) have been associated with congenital anomalies but doses under 5 rad (50 mGy) generally have not. Advise pregnant women of the potential risks of fetal exposure to radiation doses with administration of Ioflupane I 123 Injection. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.