ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS . Hypersensitivity and injection site reactions have been reported following Ioflupane 123 Injection administration. (6.2) In clinical trials, the most common adverse reactions, headache, nausea, vertigo, dry mouth or dizziness occurred in 1% of subjects. (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 Study Experience The data from clinical studies reflect exposure to Ioflupane 123 Injection in 942 subjects with mean age of 66 years (range 25 to 90 years). Among these subjects, 42% were women and 99% Caucasian. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Ioflupane 123 Injection cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, no serious adverse reactions were reported. Other adverse reactions occurred at rate of 1% or less and the reported events consisted of headache, nausea, vertigo, dry mouth or dizziness. These reactions were of mild to moderate severity. 6.2 Postmarketing Experience Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. In the postmarketing experience, hypersensitivity reactions have been reported. The reactions generally related to rash and pruritis within minutes of Ioflupane 123 Injection administration. The reactions either resolved spontaneously or following the administration of corticosteroids and antihistamines. Injection site pain has also been reported.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY . 12.1 Mechanism of Action The active drug substance in Ioflupane 123 Injection is N--fluoropropyl-2-carbomethoxy-3-(4-[123I]iodophenyl)nortropane or ioflupane 123. In vitro, ioflupane binds reversibly to the human recombinant dopamine transporter (DaT) (Ki 0.62 nM; IC50 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 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 125, but reduced extrastriatal binding by 60 to 85%. The binding of ioflupane 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 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 )]. 12.2 Pharmacodynamics As Ioflupane 123 Injection contains very small quantity of ioflupane, no ioflupane pharmacologic effects are expected [see Description 11 )]. 12.3 Pharmacokinetics The pharmacokinetics of ioflupane 123 were studied by monitoring radioactivity following intravenous injection; only 5% of the administered radioactivity remained in whole blood at minutes post-injection. Uptake in the brain reached approximately 7% of injected radioactivity at 10 minutes post-injection and decreased to 3% after hours; striata to background ratios were relatively constant between and hours post-injection. About 30% of the whole brain radioactivity was attributed to striatal uptake. By 48 hours post-injection, approximately 60% of the injected radioactivity has been excreted in the urine, with fecal excretion estimated to be approximately 14%.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The safety and efficacy of Ioflupane 123 Injection were evaluated in two multicenter, single-arm studies (Study and Study 2) that evaluated 284 adult patients with tremor. In the studies, Ioflupane 123 Injection image outcomes were compared to reference clinical diagnostic standard of PS or non-PS. The reference clinical diagnostic standard for PS consisted of the following diagnoses: Parkinsons disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). These three conditions have been associated with dopaminergic neurodegeneration and Ioflupane 123 Injection imaging was not designed to distinguish among the conditions. The reference clinical diagnostic standard for non-PS consisted of an essential tremor (ET) diagnosis or other non-PS diagnosis. Three to hours after Ioflupane 123 Injection administration, subjects underwent SPECT imaging with variety of multi-headed cameras or multi-detector single- slice systems. The median administered activity evaluated in clinical studies was 173 MBq (4.7 mCi) [range, 88 to 287 MBq (2.4 to 7.8 mCi)].Ioflupane 123 Injection images were evaluated by readers blinded to clinical information. Study readers had no other role in patient assessment; Study readers included site investigators. The reference clinical diagnostic standards were the clinical diagnoses established by consensus panel of movement disorder specialists that evaluated data inclusive through 36 months of follow-up (Study 1) or the investigator- determined baseline clinical diagnosis (Study 2). Study consisted of patients with early features of Parkinsonism; patients with features suggestive of MSA or PSP were excluded. Study consisted of patients with clinically established diagnosis of PS (PD, MSA, PSP) or ET.Among the 99 patients in Study 1, 44% were female, 42% were aged 65 or over and all were Caucasian; among the 185 patients in Study 2, 35% were female, 48% were aged 65 or over and 99% were Caucasian. Among the patients in Study 1, the baseline clinical diagnoses consisted of: probable PD (44%), possible PD (31%), benign PD (6%), possible ET (11%), and other diagnoses (7%).Among the patients in Study 2, the baseline clinical diagnoses consisted of: PD (70%), ET (15%), MSA (10%), and PSP (5%).Table shows the positive percent agreement and negative percent agreement of the Ioflupane 123 Injection image results with the reference clinical diagnostic standard. Positive percent agreement represents the percent of patients with abnormal Ioflupane 123 Injection images among all the patients with clinical diagnostic reference standard of PS. The negative percent agreement represents the percent of patients with normal Ioflupane 123 Injection images among the patients with non-PS clinical diagnostic reference standard.Table 4: Positive and Negative Percent Agreements for Studies and 2Positive percent agreement (95 CI)(% patients with an abnormal Ioflupane 123 Injection image among patients with PS)Negative percent agreement (95 CI)(% patients with normal Ioflupane 123 Injection image among patientswith non-PS)Study (patients with early signs and/or symptoms of PS)Reader A, = 9977 (66, 87)96 (82, 100)Reader B, = 9678 (66, 87)96 (82, 100)Reader C, = 9879 (67, 87)96 (82, 100)Study (patients with established diagnoses of PS or ET)Reader A, = 18593 (88, 97)96 (81, 100)Reader B, = 18597 (93, 99)74 (54, 89)Reader C, = 18596 (92, 99)85 (66, 96)Reader D, = 18592 (87, 96)93 (76, 99)Reader E, = 18594 (90, 97)93 (76, 99)The effectiveness of Ioflupane 123 Injection as screening or confirmatory test and for monitoring disease progression or response to therapy has not been established.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Ioflupane 123 Injection is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients, or to iodine. Known hypersensitivity to the active substance or to any of the excipients, or to iodine. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Ioflupane 123 Injection is sterile, pyrogen-free radiopharmaceutical for intravenous injection. The clear and colorless solution is supplied in single-dose vials in which each milliliter contains 0.07 to 0.13 mcg ioflupane, 74 MBq (2 mCi) of iodine 123 (as ioflupane 123) at calibration time, 5.7 mg acetic acid, 7.8 mg sodium acetate and 0.05 mL (5%) ethanol. The pH of the solution is between 4.2 and 5.2. Ioflupane 123 has the following structural formula:. The following structural formula for Ioflupane 123 Injection is sterile, pyrogen-free radiopharmaceutical for intravenous injection. The clear and colorless solution is supplied in single-use vials in which each milliliter contains 0.07 to 0.13 mcg ioflupane, 74 MBq (2 mCi) of iodine 123 (as ioflupane 123) at calibration time, 5.7 mg acetic acid, 7.8 mg sodium acetate and 0.05 mL (5%) ethanol.. 11.1 Physical Characteristics Iodine 123 is cyclotron-produced radionuclide that decays to 123Te by electron capture and has physical half-life of 13.2 hours. The photon that is useful for detection and imaging studies is listed in Table 2.Table Principal Radiation Emission Data Iodine 123RadiationEnergy Level (keV)Abundance (%)Gamma15983. 11.2 External Radiation The specific gamma-ray constant for iodine 123 is 1.6 R/mCi-hr at cm. The first half-value thickness of lead (Pb) for iodine 123 is 0.04 cm. The relative transmission of radiation emitted by the radionuclide that results from interposition of various thicknesses of Pb is shown in Table (e.g., the use of 2.16 cm Pb will decrease the external radiation exposure by factor of about 1,000).Table Reduction in In-air Collision Kerma Caused by Lead ShieldingShield Thickness cm of lead (Pb)Reduction in In-air CollisionKerma0.040.50.1310-10.7710-22.1610-33.6710-4 Calculation based on attenuation and energy-transfer coefficients obtained from National Institute of Standards Technology Internal Report NISTIR 5632.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Ioflupane 123 Injection emits gamma radiation and must be handled with safety measures. (2.1) Measure patient dose by suitable radioactivity calibration system immediately prior to administration. (2.1) Administer thyroid-blocking agent at least one hour before the dose of Ioflupane 123 Injection. (2.2) The recommended Ioflupane 123 Injection dose is 111 to 185 MBq (3 to mCi). (2.4) Begin SPECT imaging between and hours post-injection. (2.6). Ioflupane 123 Injection emits gamma radiation and must be handled with safety measures. (2.1) Measure patient dose by suitable radioactivity calibration system immediately prior to administration. (2.1) Administer thyroid-blocking agent at least one hour before the dose of Ioflupane 123 Injection. (2.2) The recommended Ioflupane 123 Injection dose is 111 to 185 MBq (3 to mCi). (2.4) Begin SPECT imaging between and hours post-injection. (2.6). 2.1 Radiation Safety Ioflupane 123 Injection emits radiation and must be handled with safety measures to minimize radiation exposure to clinical personnel and patients. Radiopharmaceuticals should be used by or under the control of physicians 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. Ioflupane 123 Injection dosing is based upon the radioactivity determined using suitably calibrated instrument immediately prior to administration. To minimize radiation dose to the bladder, encourage hydration prior to and following Ioflupane 123 Injection administration in order to permit frequent voiding. Encourage the patient to void frequently for the first 48 hours following Ioflupane 123 Injection administration [see Dosage and Administration 2.5 )]. 2.2 Thyroid Blockade Before Ioflupane 123 Injection Before administration of Ioflupane 123 Injection, administer Potassium Iodide Oral Solution or Lugols Solution (equivalent to 100 mg iodide) or potassium perchlorate (400 mg) to block uptake of iodine 123 by the patients thyroid. Administer the blocking agent at least one hour before the dose of Ioflupane 123 Injection [see Warnings and Precautions 5.2 )]. 2.3 Preparation and Administration Assess pregnancy status before administering Ioflupane 123 Injection to female of reproductive potential. Use aseptic procedures and radiation shielding during preparation and administration. Inspect the Ioflupane 123 Injection vial prior to administration and do not use it if the vial contains particulate matter or discoloration [see Description 11 )]. Administer Ioflupane 123 Injection as slow intravenous injection (administered over period of not less than 15 to 20 seconds) via an arm vein. Assess pregnancy status before administering Ioflupane 123 Injection to female of reproductive potential. Use aseptic procedures and radiation shielding during preparation and administration. Inspect the Ioflupane 123 Injection vial prior to administration and do not use it if the vial contains particulate matter or discoloration [see Description 11 )]. Administer Ioflupane 123 Injection as slow intravenous injection (administered over period of not less than 15 to 20 seconds) via an arm vein. 2.4 Recommended Dose The recommended dose is 111 to 185 MBq (3 to mCi) administered intravenously [see Clinical Studies 14 )].. 2.5 Radiation Dosimetry The estimated radiation absorbed doses to an average adult from intravenous injection of Ioflupane 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 known Auger electron emitter). Table Estimated Radiation Absorbed Doses from Ioflupane 123 InjectionTable The absorbed dose to the colon wall is the mass- weighted sum of the absorbed doses to the upper and lower large intestine walls, Colon 0.57 ULI 0.43DLLI [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 Ioflupane 123 Injection administration with an administered activity of 185 MBq (5 mCi) is 3.94 mSv in an adult.. Table 1. 2.6 Imaging Guidelines Begin SPECT imaging to hours following Ioflupane 123 Injection administration. Acquire images using gamma camera fitted with high-resolution collimators and set to photopeak of 159 keV with +- 10% energy window. Angular sampling should be not less than 120 views over 360 degrees. Position the subject supine with the head on an off-the-table headrest, flexible head restraint such as strip of tape across the chin or forehead may be used to help avoid movement, and set circular orbit for the detector heads with the radius as small as possible (typically 11 to 15 cm).Experimental studies with striatal phantom suggest that optimal images are obtained with matrix size and zoom factors selected to give pixel size of 3.5 to 4.5 mm. Collect minimum of 1.5 million counts for optimal images. 2.7 Image Interpretation Ioflupane 123 Injection images are interpreted visually, based upon the appearance of the striata. Reconstructed pixel size should be between 3.5 and 4.5 mm with slices pixel thick. Optimum presentation of the reconstructed images for visual interpretation is transaxial slices parallel to the anterior commissure-posterior commissure (AC-PC) line. Determination of whether an image is normal or abnormal is made 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 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 comma or crescent shape in one and 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).. 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 comma or crescent shape in one and 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).. Figure 1,2,3,4.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Single-dose vials containing 185 MBq (5 mCi) in 2.5 mL sterile solution for intravenous injection [74 MBq (2 mCi) per mL at calibration time].. 2.5 mL of sterile solution for intravenous injection in single-dose vial [74 MBq (2 mCi)/mL at calibration time]. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS The ioflupane within Ioflupane 123 Injection binds to the dopamine transporter. Drugs that bind to the dopamine transporter with high affinity may interfere with the image obtained following Ioflupane 123 Injection administration. These potentially interfering drugs consist of: amoxapine, amphetamine, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, 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 123 Injection administration may minimize the interference with Ioflupane 123 Injection image is unknown. The impact of dopamine agonists and antagonists upon Ioflupane 123 Injection imaging results has not been established.. Amoxapine, amphetamine, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, norephedrine, phentermine, phenylpropanolamine, selegiline, sertraline, citalopram and paroxetine may interfere with Ioflupane 123 Injection imaging. (7) The effects of dopamine agonists and antagonists on Ioflupane 123 Injection imaging have not been established.

GERIATRIC USE SECTION.

8.5 Geriatric Use In the two principal clinical studies, 45% of the subjects were aged 65 and over. There were no differences in response compared to younger subjects that would require dose adjustment. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Ioflupane 123 Injection is sterile, clear, colorless solution supplied in 10 mL single-dose vial containing total volume of 2.5 mL with total radioactivity of 185 MBq (5 mCi) of Ioflupane 123 at calibration time and date. Each mL contains 74 MBq (2 mCi) of Ioflupane 123 at calibration time and date. Each vial is enclosed in lead container of appropriate thickness for radiation protection.Catalog No.166 185 megabecquerels (5 mCi) NDC 69945-166-05StorageStore Ioflupane 123 Injection upright at 20 to 25C (68 to 77F). This product does not contain preservative. Store Ioflupane 123 Injection within the original lead container or equivalent radiation shielding. Do not use Ioflupane 123 Injection preparations after the expiration date and time stated on the label. Discard unused portion. HandlingThis preparation is approved for use by persons licensed by the Nuclear Regulatory Commission or an Agreement State.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Ioflupane 123 Injection is radiopharmaceutical indicated for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging to assist in the evaluation of adult patients with suspected Parkinsonian syndromes (PS). In these patients, Ioflupane 123 Injection may be used to help differentiate essential tremor from tremor due to PS (idiopathic Parkinsons disease, multiple system atrophy and progressive supranuclear palsy). Ioflupane 123 Injection is an adjunct to other diagnostic evaluations.. Ioflupane 123 Injection is radiopharmaceutical indicated for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging to assist in the evaluation of adult patients with suspected Parkinsonian syndromes (PS). In these patients, Ioflupane 123 Injection may be used to help differentiate essential tremor from tremor due to PS (idiopathic Parkinsons disease, multiple system atrophy and progressive supranuclear palsy). Ioflupane 123 Injection is an adjunct to other diagnostic evaluations. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Instruct patients to inform their physician or healthcare provider if they:are pregnant. Advise pregnant woman of the potential risks of fetal exposure to radiation doses with Ioflupane 123 Injection [see Use in Specific Population ( 8.1 )]. are breast feeding. Advise lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least days (>10 physical half-lives) after Ioflupane 123 Injection administration in order to minimize radiation exposure to breastfed infant [see Use in Specific Population ( 8.2 )]. are sensitive to Ioflupane 123 Injection. are sensitive to Potassium Iodide Oral Solution or Lugols Solution. have reduced renal or hepatic function.Instruct patients to increase their level of hydration prior to and after receiving Ioflupane 123 Injection and to void frequently for the first 48 hours following Ioflupane 123 Injection administration. Manufactured and Distributed by Curium US LLC, 2703 Wagner Pl, Maryland Heights, MO 63043 U.S.A.CuriumTM and the Curium logo are trademarks of Curium Company.(C) 2021 Curium US LLC All rights reserved.. are pregnant. Advise pregnant woman of the potential risks of fetal exposure to radiation doses with Ioflupane 123 Injection [see Use in Specific Population ( 8.1 )]. are breast feeding. Advise lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least days (>10 physical half-lives) after Ioflupane 123 Injection administration in order to minimize radiation exposure to breastfed infant [see Use in Specific Population ( 8.2 )]. are sensitive to Ioflupane 123 Injection. are sensitive to Potassium Iodide Oral Solution or Lugols Solution. have reduced renal or hepatic function.

LACTATION SECTION.

8.2 Lactation Risk SummaryIodide 123 (I 123), the radionuclide in Ioflupane 123 Injection, is present in human milk. There is no information on the effects on the breastfed infant or on milk production. Advise lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least days (>10 physical half-lives) after Ioflupane 123 Injection administration in order to minimize radiation exposure to breastfed infant.

SPL UNCLASSIFIED SECTION.

2.1 Radiation Safety Ioflupane 123 Injection emits radiation and must be handled with safety measures to minimize radiation exposure to clinical personnel and patients. Radiopharmaceuticals should be used by or under the control of physicians 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. Ioflupane 123 Injection dosing is based upon the radioactivity determined using suitably calibrated instrument immediately prior to administration. To minimize radiation dose to the bladder, encourage hydration prior to and following Ioflupane 123 Injection administration in order to permit frequent voiding. Encourage the patient to void frequently for the first 48 hours following Ioflupane 123 Injection administration [see Dosage and Administration 2.5 )].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action The active drug substance in Ioflupane 123 Injection is N--fluoropropyl-2-carbomethoxy-3-(4-[123I]iodophenyl)nortropane or ioflupane 123. In vitro, ioflupane binds reversibly to the human recombinant dopamine transporter (DaT) (Ki 0.62 nM; IC50 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 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 125, but reduced extrastriatal binding by 60 to 85%. The binding of ioflupane 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 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 )].

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY . 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies on reproductive toxicity have not been conducted. Ioflupane showed no evidence of mutagenic potential in in vitro or in vivo mutagenicity studies. Studies to assess the carcinogenic potential of ioflupane have not been performed.. 13.2 Animal Toxicology and/or Pharmacology Single- and repeated-dose intravenous toxicity studies have been performed using ioflupane in rats, rabbits, and dogs. Additionally, single-dose acute toxicity studies have been performed in cynomolgus monkeys. No mortality or other toxicity was observed at doses up to 5,500 times the maximum clinical dose of Ioflupane 123 Injection; at doses greater than 1,500 times the maximum clinical dose, pharmacological responses such as mydriasis and hyperactivity were seen in some species.

OVERDOSAGE SECTION.

10 OVERDOSAGE The clinical consequence of overdose with Ioflupane 123 Injection has not been reported. It is unknown whether or not ioflupane is dialyzable. Due to the small quantity of ioflupane in each vial, overdosage with ioflupane is not expected to result in pharmacologic effects. The major risks of overdose relates predominantly to increased radiation exposure, with the long-term risks for neoplasia. In case of overdosage of radioactivity, frequent urination and defecation should be encouraged to minimize radiation exposure to the patient; care should be taken to avoid contamination from the radioactivity eliminated by the patient.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 69945-166-05Ioflupane 123 Injection185 MBq (5 mCi) per 2.5 mL at calibration74 MBq (2 mCi) per mLRadiopharmaceutical For Intravenous Use OnlySingle-Dose Vial Discard Unused Portion.Recommended dosage: See Prescribing Information.Each mL contains: 74 MBq (2 mCi) of Ioflupane 123 at calibration date and time, 0.07 0.13 mcg ioflupane, 5.7 mg acetic acid, 7.8 mg sodium acetate, 0.05 ml of dehydrated alcohol (ethanol).Store upright at controlled room temperature 20C to 25C (68F to 77F) in shielded container.Rx onlyTotal Activity: 185 MBq (5 mCi) at calibrationRadioactivity Concentration: 74 MBq/mL (2 mCi/mL)Total Volume: 2.5 mLCal. time: 1200 ET (1100 CT)Expires hours after calibration time.Cal. date:Lot CAUTIONRADIOACTIVE MATERIAL CURIUM(TM) LogoManufactured by: Curium US LLC, 2703 Wagner Place, Maryland Heights, MO 63043R10/2021 A166C0R102021 Can label. R102021 Can label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Ioflupane 123 Injection is not indicated for use in children. The safety and efficacy of Ioflupane 123 Injection have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics As Ioflupane 123 Injection contains very small quantity of ioflupane, no ioflupane pharmacologic effects are expected [see Description 11 )].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics The pharmacokinetics of ioflupane 123 were studied by monitoring radioactivity following intravenous injection; only 5% of the administered radioactivity remained in whole blood at minutes post-injection. Uptake in the brain reached approximately 7% of injected radioactivity at 10 minutes post-injection and decreased to 3% after hours; striata to background ratios were relatively constant between and hours post-injection. About 30% of the whole brain radioactivity was attributed to striatal uptake. By 48 hours post-injection, approximately 60% of the injected radioactivity has been excreted in the urine, with fecal excretion estimated to be approximately 14%.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. In the postmarketing experience, hypersensitivity reactions have been reported. The reactions generally related to rash and pruritis within minutes of Ioflupane 123 Injection administration. The reactions either resolved spontaneously or following the administration of corticosteroids and antihistamines. Injection site pain has also been reported.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryRadioactive 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 123 Injection in pregnant woman to protect the woman and fetus from accumulation of 123 [see Dosage and Administration 2.2 )].There are no available data on Ioflupane 123 Injection use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with ioflupane 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 123 Injection at dose of 185 MBq (5 mCi) results in an absorbed radiation dose to the uterus of 0.3 rad (3 mGy). Radiation doses greater than 15 rad (150 mGy) have been associated with congenital anomalies but doses under rad (50 mGy) generally have not. Advise pregnant women of the potential risks of fetal exposure to radiation doses with administration of Ioflupane 123 Injection. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have 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 to 4% and 15 to 20% respectively.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS . Pregnancy: May cause fetal harm. (8.1) Lactation: Advise lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least days after Ioflupane 123 Injection administration. (8.2) Pediatric: Safety and effectiveness have not been established. (8.4) Pregnancy: May cause fetal harm. (8.1) Lactation: Advise lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least days after Ioflupane 123 Injection administration. (8.2) Pediatric: Safety and effectiveness have not been established. (8.4) 8.1 Pregnancy Risk SummaryRadioactive 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 123 Injection in pregnant woman to protect the woman and fetus from accumulation of 123 [see Dosage and Administration 2.2 )].There are no available data on Ioflupane 123 Injection use in pregnant women to evaluate for drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with ioflupane 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 123 Injection at dose of 185 MBq (5 mCi) results in an absorbed radiation dose to the uterus of 0.3 rad (3 mGy). Radiation doses greater than 15 rad (150 mGy) have been associated with congenital anomalies but doses under rad (50 mGy) generally have not. Advise pregnant women of the potential risks of fetal exposure to radiation doses with administration of Ioflupane 123 Injection. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have 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 to 4% and 15 to 20% respectively.. 8.2 Lactation Risk SummaryIodide 123 (I 123), the radionuclide in Ioflupane 123 Injection, is present in human milk. There is no information on the effects on the breastfed infant or on milk production. Advise lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least days (>10 physical half-lives) after Ioflupane 123 Injection administration in order to minimize radiation exposure to breastfed infant. 8.4 Pediatric Use Ioflupane 123 Injection is not indicated for use in children. The safety and efficacy of Ioflupane 123 Injection have not been established in pediatric patients. 8.5 Geriatric Use In the two principal clinical studies, 45% of the subjects were aged 65 and over. There were no differences in response compared to younger subjects that would require dose adjustment. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.. 8.6 Renal and Hepatic Impairment The effect of renal or hepatic impairment upon Ioflupane 123 Injection imaging has not been established. Ioflupane 123 Injection is excreted by the kidney and patients with severe renal impairment may have increased radiation exposure and altered Ioflupane 123 Injection images.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS . Hypersensitivity reactions have been reported following Ioflupane 123 Injection administration. Have anaphylactic and hypersensitivity treatment measures available prior to Ioflupane 123 Injection administration. (5.1) Administer thyroid-blocking agent before Ioflupane 123 Injection administration. (5.2) Hypersensitivity reactions have been reported following Ioflupane 123 Injection administration. Have anaphylactic and hypersensitivity treatment measures available prior to Ioflupane 123 Injection administration. (5.1) Administer thyroid-blocking agent before Ioflupane 123 Injection administration. (5.2) 5.1 Hypersensitivity Reactions Hypersensitivity reactions have been reported following Ioflupane 123 Injection administration [see Adverse Reactions 6.2 )]. The reactions have generally consisted of skin erythema and pruritis and have either resolved spontaneously or following the administration of corticosteroids and anti-histamines. Prior to administration, question the patient for history of prior reactions to Ioflupane 123 Injection. If the patient is known or strongly suspected of having had hypersensitivity reaction to Ioflupane 123 Injection, the decision to administer Ioflupane 123 Injection should be based upon an assessment of the expected benefits compared to the potential hypersensitivity risks. Have anaphylactic and hypersensitivity treatment measures available prior to Ioflupane 123 Injection administration and, following administration, observe patients for symptoms or signs of hypersensitivity reaction. 5.2 Thyroid Accumulation The Ioflupane 123 Injection may contain up to 6% of free iodide (iodine 123). To decrease thyroid accumulation of iodine 123, block the thyroid gland before administration of Ioflupane 123 Injection [see Dosage and Administration 2.2 )]. Avoid the use of Potassium Iodide Oral Solution or Lugols Solution in patients who are sensitive to such products. Failure to block thyroid uptake of iodine 123 may result in an increased long term risk for thyroid neoplasia.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology Single- and repeated-dose intravenous toxicity studies have been performed using ioflupane in rats, rabbits, and dogs. Additionally, single-dose acute toxicity studies have been performed in cynomolgus monkeys. No mortality or other toxicity was observed at doses up to 5,500 times the maximum clinical dose of Ioflupane 123 Injection; at doses greater than 1,500 times the maximum clinical dose, pharmacological responses such as mydriasis and hyperactivity were seen in some species.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies on reproductive toxicity have not been conducted. Ioflupane showed no evidence of mutagenic potential in in vitro or in vivo mutagenicity studies. Studies to assess the carcinogenic potential of ioflupane have not been performed.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Ioflupane 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 123 Injection in 942 subjects with 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 mCi) [median 173 MBq (4.7 mCi)] intravenously as single dose. The recommended dose of Ioflupane 123 Injection is 111 MBq to 185 MBq (3 mCi to mCi) [see Dosage and Administration 2.3 )].The following adverse reactions were reported at rate of 1% or less: headache, nausea, vertigo, dry mouth, and dizziness.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)11/2022Contraindications (4) 11/2022Warnings and Precautions, Radiation Risk (5.3)11/2022.