Ioflupane I-123

DATSCAN 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). DATSCAN 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 )

Injection: clear, colorless solution containing 185 MBq (5 mCi) in 2.5 mL at a concentration of 74 MBq/mL (2 mCi/mL) of ioflupane I 123 at calibration date and time supplied in single-dose vials. Injection: 185 MBq (5 mCi) in 2.5 mL at a concentration of 74 MBq/mL (2 mCi/mL) of ioflupane I 123 at calibration date and time supplied in single-dose vials. ( 3 )

DATSCAN 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 )

Hypersensitivity Reactions: Hypersensitivity reactions including dyspnea, edema, rash, erythema, and pruritus have been reported. Have treatment measures available prior to DATSCAN administration. ( 5.1 ) Thyroid Accumulation of Iodine-123: Thyroid uptake of iodine-123 may result in an increased long-term risk for thyroid neoplasia. ( 2.3 , 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 , 2.3 , 5.3 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions, including dyspnea, edema, rash, erythema, and pruritus, have been reported following DATSCAN administration [see Adverse Reactions (6.2) ] . The reactions have generally occurred within minutes of DATSCAN administration and have either resolved spontaneously or following the administration of corticosteroids and antihistamines. DATSCAN 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 DATSCAN 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 DATSCAN [see Dosage and Administration (2.3) ] .

5.3 Radiation Risk DATSCAN 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 , 2.3) ] .

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 GE HealthCare at 1-800-654-0118 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 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 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 DATSCAN is 111 MBq to 185 MBq (3 mCi to 5 mCi) [see Dosage and Administration (2.2) ]. 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 DATSCAN. 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

Ioflupane I 123 binds to the dopamine transporter [see Clinical Pharmacology (12.1) ] . Drugs that bind to the dopamine transporter with high affinity have the potential to impact DATSCAN image interpretation. These potentially interfering drugs include: amoxapine, amphetamine, armodafinil, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, modafinil, norephedrine, phentermine, selegiline, and sertraline. Selective serotonin reuptake inhibitors (paroxetine and citalopram) may increase or decrease ioflupane binding to the dopamine transporter. In patients taking venlafaxine or desvenlafaxine prior to DATSCAN administration, there have been cases of altered DATSCAN uptake that impacted image interpretation. The mechanism of interference of these drugs with DATSCAN imaging is not known. Whether discontinuation of any of the above drugs prior to DATSCAN administration may minimize the impact on image interpretation is unknown; however, if use of these drugs can be safely suspended, consider discontinuing for at least 5 biological half-lives before administration of DATSCAN [see Dosage and Administration (2.3) ]. The impact of dopamine agonists and antagonists upon DATSCAN imaging results has not been established. Amoxapine, amphetamine, armodafinil, benztropine, bupropion, buspirone, cocaine, mazindol, methamphetamine, methylphenidate, modafinil norephedrine, phentermine, selegiline, sertraline, citalopram, paroxetine, venlafaxine, and desvenlafaxine may impact DATSCAN image interpretation. Consider discontinuing drugs that may interfere with DATSCAN images for at least 5 biological half-lives before administration of DATSCAN if use of these drugs can be safely suspended. ( 2.3 , 7 )

Pregnancy: May cause fetal harm. ( 8.1 ) Lactation: Advise a lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least 6 days after DATSCAN administration. ( 8.2 )

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 DATSCAN in a pregnant woman to protect the woman and fetus from accumulation of iodine-123 [see Dosage and Administration (2.3) ] . There are no available data on DATSCAN 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 DATSCAN 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 DATSCAN. 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.

8.2 Lactation Risk Summary Iodine-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 a lactating woman to interrupt breastfeeding and pump and discard breastmilk for at least 6 days (>10 physical half-lives) after DATSCAN administration in order to minimize radiation exposure to a breastfed infant.

8.4 Pediatric Use The safety and efficacy of DATSCAN have not been established in pediatric patients.

8.5 Geriatric Use In the two principal clinical studies of DATSCAN for suspected Parkinsonian syndromes, 45% of the subjects were aged 65 and over, while 10% were 75 and over [see Clinical Studies (14.1) ] . No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

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

The active drug substance in DATSCAN is N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-[ 123 I]iodophenyl)nortropane or ioflupane I 123. In vitro , ioflupane binds reversibly to the human dopamine transporter (DaT) (Ki = 0.62 nM; IC 50 = 0.71 nM). Autoradiography of post-mortem human brain slices exposed to radiolabeled ioflupane shows concentration of the radiolabel in striatum (caudate nucleus and putamen). The specificity of the binding of ioflupane I 125 to dopamine transporter was demonstrated by competition studies with the DaT inhibitor GBR 12909 (a dopamine reuptake inhibitor), the serotonin reuptake inhibitor citalopram, and the norepinephrine reuptake inhibitor desipramine in post-mortem human brain slices exposed to radiolabeled ioflupane. Citalopram reduced binding in the neocortex and thalamus with only minor effects in the striatum. This indicated that the binding in the cortex and thalamus is mainly to the serotonin reuptake sites. Desipramine showed no effect on the level of striatal binding of ioflupane I 125, but reduced extrastriatal binding by 60 to 85%. The binding of ioflupane I 125 to the striatum was abolished in the presence of high concentrations of GBR 12909, indicating selectivity of ioflupane binding for the pre-synaptic DaT. Following administration of 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) ].