ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Hypersensitivity and injection site reactions have been reported following DaTscan 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 GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Study Experience. The data from clinical studies reflect exposure to DaTscan 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 DaTscan 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.. 6.2Postmarketing 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 DaTscan administration. The reactions either resolved spontaneously or following the administration of corticosteroids and antihistamines. Injection site pain has also been reported.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal 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 DaTscan; 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.

13.1Carcinogenesis, 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 PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. The active drug substance in DaTscan 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 DaTscan 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 DaTscan 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 DaTscan were evaluated in two multicenter, single-arm studies (Study and Study 2) that evaluated 284 adult patients with tremor. In the studies, DaTscan 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 DaTscan 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 DaTscan 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)].DaTscan 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 DaTscan image results with the reference clinical diagnostic standard. Positive percent agreement represents the percent of patients with abnormal DaTscan images among all the patients with clinical diagnostic reference standard of PS. The negative percent agreement represents the percent of patients with normal DaTscan images among the patients with non-PS clinical diagnostic reference standard. Table 4: Positive and Negative Percent Agreements for Studies and Positive percent agreement (95 CI)(% patients with an abnormal DaTscan image among patients with PS)Negative percent agreement (95 CI)(% patients with normal DaTscan image among patients with 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, = 185 93 (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 DaTscan as screening or confirmatory test and for monitoring disease progression or response to therapy has not been established.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. DaTscan 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. DaTscan [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 ug 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:. Figures 1-4. Chemical Structure. 11.1Physical 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. 11.2External 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 Shielding Calculation based on attenuation and energy-transfer coefficients obtained from National Institute of Standards Technology Internal Report NISTIR 5632. Shield Thickness cm of lead (Pb)Reduction in In-air Collision Kerma0.040.50.1310-1 0.7710-2 2.1610-3 3.6710-4.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. DaTscan 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 DaTscan. (2.2)The recommended DaTscan dose is 111 to 185 MBq (3 to mCi). (2.4)Begin SPECT imaging between and hours post-injection. (2.6). DaTscan 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 DaTscan. (2.2). The recommended DaTscan 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. DaTscan 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. DaTscan 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 DaTscan administration in order to permit frequent voiding. Encourage the patient to void frequently for the first 48 hours following DaTscan administration [see Dosage and Administration (2.5) ].. 2.2 Thyroid Blockade Before DaTscan Injection. Before administration of DaTscan, 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 DaTscan [see Warnings and Precautions (5.2) ]. 2.3 Preparation and Administration. Assess pregnancy status before administering DaTscan to female of reproductive potential.Use aseptic procedures and radiation shielding during preparation and administration. Inspect the DaTscan vial prior to administration and do not use it if the vial contains particulate matter or discoloration [see Description (11) ]. Administer DaTscan as slow intravenous injection (administered over period of not less than 15 to 20 seconds) via an arm vein.. Assess pregnancy status before administering DaTscan to female of reproductive potential.. Use aseptic procedures and radiation shielding during preparation and administration. Inspect the DaTscan vial prior to administration and do not use it if the vial contains particulate matter or discoloration [see Description (11) ]. Administer DaTscan as slow intravenous injection (administered over period of not less than 15 to 20 seconds) via an arm vein.. 2.4Recommended Dose. The recommended dose is 111 to 185 MBq (3 to mCi) administered intravenously [see Clinical Studies (14) ]. 2.5Radiation Dosimetry. The estimated radiation absorbed doses to an average adult from intravenous injection of DaTscan 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 DaTscanORGAN TISSUEABSORBED DOSE PER UNIT ADMINISTERED ACTIVITY (uGy MBq)Adrenals 12.9Brain 17.8Striata 230Breasts 7.8Esophagus 10Gallbladder Wall 26.4GI Tract Stomach Wall 11.2Small Intestine Wall 21.2Colon Wall The absorbed dose to the colon wall is the mass-weighted sum of the absorbed doses to the upper and lower large intestine walls, DColon 0.57DULI 0.43DLLI [Publication 80 of the ICRP (International Commission on Radiological Protection); Annals of the ICRP 28 (3). Oxford: Pergamon Press; 1998] 39.8Upper Large Intestine Wall 38.1Lower Large Intestine Wall 42Heart Wall 12.9Kidneys 10.9Liver 27.9Lungs 41.2Muscle 9.4Osteogenic Cells 28.2Ovaries 16.8Pancreas 13Red Marrow 9.2Skin 6Spleen 10.4Testes 8.5Thymus 10Thyroid 9Urinary Bladder Wall 53.1Uterus 16.1Total Body 11.3EFFECTIVE DOSE PER UNIT ADMINISTERED ACTIVITY (uSv/MBq) 21.3 The Effective Dose resulting from DaTscan administration with an administered activity of 185 MBq (5 mCi) is 3.94 mSv in an adult.. 2.6Imaging Guidelines. Begin SPECT imaging to hours following DaTscan 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. 2.7Image Interpretation. DaTscan 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 DaTscan 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).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Single-use 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-use vial [74 MBq (2 mCi)/mL at calibration time]. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. The ioflupane within DaTscan binds to the dopamine transporter. Drugs that bind to the dopamine transporter with high affinity may interfere with the image obtained following DaTscan 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 DaTscan administration may minimize the interference with DaTscan image is unknown. The impact of dopamine agonists and antagonists upon DaTscan 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 DaTscan imaging. (7) The effects of dopamine agonists and antagonists on DaTscan 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. DaTscan is supplied in 10-mL glass vials containing total volume of 2.5 mL of solution with total radioactivity of 185 MBq (5 mCi) at calibration time. Each vial is enclosed in lead container of appropriate thickness.NDC 17156-210-01. StorageStore DaTscan at 20 to 25C (68 to 77F). This product does not contain preservative. Store DaTscan within the original lead container or equivalent radiation shielding.Do not use DaTscan (Ioflupane 123 Injection) preparations after the expiration date and time stated on the label.. HandlingThis preparation is approved for use by persons licensed by the Illinois Emergency Management Agency pursuant to 32 IL. Adm. Code Section 330.260(a) and 335.4010 or equivalent licenses of the Nuclear Regulatory Commission or an Agreement State.

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%.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. DaTscan 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, DaTscan may be used to help differentiate essential tremor from tremor due to PS (idiopathic Parkinsons disease, multiple system atrophy and progressive supranuclear palsy). DaTscan is an adjunct to other diagnostic evaluations. DaTscan (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, DaTscan may be used to help differentiate essential tremor from tremor due to PS (idiopathic Parkinsons disease, multiple system atrophy and progressive supranuclear palsy). DaTscan 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 DaTscan [see Use in Specific Populations (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 DaTscan administration in order to minimize radiation exposure to breastfed infant [see Use in Specific Populations (8.2)].are sensitive to DaTscan.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 DaTscan and to void frequently for the first 48 hours following DaTscan administration.. are pregnant. Advise pregnant woman of the potential risks of fetal exposure to radiation doses with DaTscan [see Use in Specific Populations (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 DaTscan administration in order to minimize radiation exposure to breastfed infant [see Use in Specific Populations (8.2)].. are sensitive to DaTscan.. 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 DaTscan, 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 DaTscan administration in order to minimize radiation exposure to breastfed infant.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. The active drug substance in DaTscan 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 DaTscan 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. 13.1Carcinogenesis, 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.. 13.2Animal 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 DaTscan; 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 DaTscan 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 2.5 mL Vial Label. GE HealthcareNDC 17156-210-01DaTscan(TM) Ioflupane 123 Injection Ioflupane 123 185 MBq (5 mCi) in 2.5 mLat calibration.Radiopharmaceutical for Intravenous Injection.Single Use VialRx ONLYStore at 20-25C (68-77F).Expires hours after calibrationtime.Each mL contains 74 MBq (2 mCi) of Ioflupane 123 at calibration,0.07 0.13 ug ioflupane, 5.7 mgacetic acid, 7.8 mg sodium acetate,0.05 mL ethanol.See package insert for dosage and administration.CAUTIONRADIOACTIVEMATERIALGE HealthcareMedi-Physics, Inc.Arl. Hgts, IL 60004800-654-0118Product No. 2010Est. Lic. No. 100129-A41-2010AVOLUME: 2.5 mL RADIOACTIVECONCENTRATION: 74 MB q/mL(2 mC i/mL) TOTALACTIVITY: 185 MBq(5 mCi) CALIB.DATE:CALIB.TIME: 1200 LOTNO.: 2010 . PRINCIPAL DISPLAY PANEL 2.5 mL Vial Label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

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

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 DaTscan 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 DaTscan 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 DaTscan at 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 rad (50 mGy) generally have not. Advise pregnant women of the potential risks of fetal exposure to radiation doses with administration of DaTscan.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.

SPL UNCLASSIFIED SECTION.

2.1 Radiation Safety. DaTscan 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. DaTscan 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 DaTscan administration in order to permit frequent voiding. Encourage the patient to void frequently for the first 48 hours following DaTscan administration [see Dosage and Administration (2.5) ].

STORAGE AND HANDLING SECTION.

StorageStore DaTscan at 20 to 25C (68 to 77F). This product does not contain preservative. Store DaTscan within the original lead container or equivalent radiation shielding.Do not use DaTscan (Ioflupane 123 Injection) preparations after the expiration date and time stated on the label.

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 DaTscan 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 DaTscan 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 DaTscan 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 DaTscan 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 DaTscan at 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 rad (50 mGy) generally have not. Advise pregnant women of the potential risks of fetal exposure to radiation doses with administration of DaTscan.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 DaTscan, 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 DaTscan administration in order to minimize radiation exposure to breastfed infant.. 8.4 Pediatric Use. DaTscan is not indicated for use in children. The safety and efficacy of DaTscan 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 DaTscan imaging has not been established. DaTscan is excreted by the kidney and patients with severe renal impairment may have increased radiation exposure and altered DaTscan images.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity reactions have been reported following DaTscan administration. Have anaphylactic and hypersensitivity treatment measures available prior to DaTscan administration. (5.1)Administer thyroid-blocking agent before DaTscan administration. (5.2). Hypersensitivity reactions have been reported following DaTscan administration. Have anaphylactic and hypersensitivity treatment measures available prior to DaTscan administration. (5.1). Administer thyroid-blocking agent before DaTscan administration. (5.2). 5.1Hypersensitivity Reactions. Hypersensitivity reactions have been reported following DaTscan 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 DaTscan. If the patient is known or strongly suspected of having had hypersensitivity reaction to DaTscan, the decision to administer DaTscan 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 DaTscan administration and, following administration, observe patients for symptoms or signs of hypersensitivity reaction.. 5.2Thyroid Accumulation. The DaTscan 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 DaTscan [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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of DATSCAN 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 DATSCAN 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 DATSCAN 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.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of DATSCAN. Because these 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. Immune system disorders: Hypersensitivity, including dyspnea, edema, rash, erythema, and pruritus General disorders and administration site conditions: Injection site pain.

RECENT MAJOR CHANGES SECTION.

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

RENAL IMPAIRMENT SUBSECTION.

8.6Renal Impairment. DATSCAN is excreted by the kidney and patients with severe renal impairment may have increased radiation exposure and altered DATSCAN images.