AdreView

1 INDICATIONS AND USAGE AdreView is a radiopharmaceutical agent for gamma-scintigraphy indicated for: use in the detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests ( 1.1 ) scintigraphic assessment of sympathetic innervation of the myocardium by measurement of the heart to mediastinum (H/M) ratio of radioactivity uptake in patients with New York Heart Association (NYHA) class II or class III heart failure and left ventricular ejection fraction (LVEF) ≤ 35%. Among these patients, AdreView may be used to help identify patients with lower one and two year mortality risks, as indicated by an H/M ratio ≥ 1.6. ( 1.2 ) Limitations of Use: In patients with congestive heart failure, AdreView utility has not been established for: selecting a therapeutic intervention or for monitoring the response to therapy; using the H/M ratio to identify a patient with a high risk for death. 1.1 Pheochromocytoma and Neuroblastoma AdreView is a radiopharmaceutical indicated for use in the detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests. 1.2 Congestive Heart Failure AdreView is indicated for scintigraphic assessment of sympathetic innervation of the myocardium by measurement of the heart to mediastinum (H/M) ratio of radioactivity uptake in patients with New York Heart Association (NYHA) class II or class III heart failure and left ventricular ejection fraction (LVEF) ≤ 35%. Among these patients, AdreView may be used to help identify patients with lower one and two year mortality risks, as indicated by an H/M ratio ≥ 1.6. Limitations of Use: In patients with congestive heart failure, AdreView utility has not been established for: selecting a therapeutic intervention or for monitoring the response to therapy; using the H/M ratio to identify a patient with a high risk for death.

2 DOSAGE AND ADMINISTRATION AdreView emits radiation and must be handled with appropriate safety measures. ( 2.1 , 2.6 ) Administer thyroid blockade medications to patients at risk for thyroid accumulation of AdreView. ( 2.2 , 5.6 ) Measure patient dose by a suitable radioactivity calibration system immediately prior to administration. ( 2.4 ) For patients ≥ 16 years of age or < 16 years of age and ≥ 70 kg: administer 10 mCi (370 MBq). ( 2.4 , 2.5 ) For patients < 16 years of age and < 70 kg: amount scaled to the adult reference activity based on weight. ( 2.5 ) 2.1 Radiation Safety AdreView emits radiation and must be handled with appropriate 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 experience 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. AdreView dosing is based upon the radioactivity determined using a suitable calibration system immediately prior to administration. To minimize radiation dose to the bladder, prior to and following AdreView administration, encourage hydration to permit frequent voiding. Encourage the patient to void frequently for the first 48 hours following AdreView administration [ see Clinical Pharmacology (12.2) ]. 2.2 Thyroid Blockade Before administration of AdreView to patients at risk for thyroid accumulation of the drug, administer Potassium Iodide Oral Solution or Lugol's Solution (equivalent to 100 mg iodide for adults, body-weight adjusted for children) or potassium perchlorate (400 mg for adults, body-weight adjusted for children) to block uptake of iodine 123 by the patient's thyroid. Administer the blocking agent at least one hour before the dose of AdreView [ see Warnings and Precautions (5.6) ]. Individualize thyroid blockade; for example, the blockade may not be necessary for patients who have undergone thyroidectomy or those with a very limited life expectancy. 2.3 Preparation and Administration Assess pregnancy status before administering AdreView to a female of reproductive potential. Inspect the AdreView vial for particulate matter and discoloration prior to administration. Use aseptic procedures and a radiation shielding syringe during administration. Administer the dose as an intravenous injection over 1 to 2 minutes. A subsequent injection of 0.9% sodium chloride may be used to ensure full delivery of the dose. 2.4 Recommended Dose for Adults For adults (≥ 16 years of age), the recommended dose is 10 mCi (370 MBq) [ see Clinical Studies (14.1 , 14.2) ]. 2.5 Recommended Dose for Pediatric Patients For pediatric patients < 16 years of age weighing ≥ 70 kg, the recommended dose is 10 mCi (370 MBq) [ see Clinical Studies (14.1) ]. For pediatric patients < 16 years of age weighing < 70 kg, the recommended dose should be calculated according to patient body weight as shown in Table 1 [see Clinical Studies (14.1) ] . The benzyl alcohol in AdreView may cause serious adverse reactions in premature or low birth-weight infants [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ] . Table 1. AdreView Dose Preparation for Pediatric Patients Based on a reference activity for an adult scaled to body weight according to the schedule proposed by the European Association of Nuclear Medicine Paediatric Task Group. Weight (kg) Fraction of adult activity AdreView (mCi) pediatric dose AdreView (MBq) pediatric dose 3 0.1 1 37 4 0.14 1.4 52 6 0.19 1.9 70 8 0.23 2.3 85.1 10 0.27 2.7 99.9 12 0.32 3.2 118.4 14 0.36 3.6 133.2 16 0.4 4 148 18 0.44 4.4 162.8 20 0.46 4.6 170.2 22 0.5 5 185 24 0.53 5.3 196.1 26 0.56 5.6 207.2 28 0.58 5.8 214.6 30 0.62 6.2 229.4 32 0.65 6.5 240.5 34 0.68 6.8 251.6 36 0.71 7.1 262.7 38 0.73 7.3 270.1 40 0.76 7.6 281.2 42 0.78 7.8 288.6 44 0.8 8 296 46 0.82 8.2 303.4 48 0.85 8.5 314.5 50 0.88 8.8 325.6 52 0.9 9 333 54 0.9 9 333 56 0.92 9.2 340.4 58 0.92 9.2 340.4 60 0.96 9.6 355.2 62 0.96 9.6 355.2 64 0.98 9.8 362.6 66 0.98 9.8 362.6 68 0.99 9.9 366.3 2.6 Radiation Dosimetry The estimated absorbed radiation doses to adults and children from intravenous administration of AdreView are as shown in Table 2: Table 2. Estimated Absorbed Radiation Dose from AdreView ORGAN / TISSUE ABSORBED DOSE PER UNIT ADMINISTERED ACTIVITY ADULT 15-YEAR OLD 10-YEAR OLD 5-YEAR OLD 1-YEAR OLD NEONATES μGy/ MBq rad/mCi μGy/ MBq rad/mCi μGy/ MBq rad/mCi μGy/ MBq rad/mCi μGy/ MBq rad/mCi μGy/ MBq rad/mCi *OLINDA/EXM calculation based on biodistribution data from Swanson et al. and Publication 53 of the ICRP (International Commission on Radiological Protection) [Annals of the ICRP 1987; 18 (1-4): 329-331] Adrenals 16 0.059 21 0.078 31 0.115 42 0.155 67 0.248 111 0.411 Brain 3.9 0.014 4.9 0.018 8.1 0.030 13 0.048 24 0.089 55.9 0.207 Breast 4.7 0.017 5.9 0.022 9.4 0.035 15 0.056 28 0.104 65.3 0.242 Gallbladder 20 0.074 24 0.089 34 0.126 51 0.189 95 0.352 200 0.740 GI Tract Stomach Wall 7.6 0.028 10 0.037 17 0.063 27 0.100 51 0.189 114 0.422 Small Intestine Wall 7.7 0.028 9.8 0.036 16 0.059 25 0.093 46 0.170 104 0.385 Colon Wall 8.1 0.030 10 0.037 16 0.059 26 0.096 46 0.170 104.3 0.386 Upper Large Intestine Wall 8.4 0.031 11 0.041 18 0.067 30 0.111 53 0.196 119 0.440 Lower Large Intestine Wall 7.7 0.028 9.6 0.036 15 0.056 21 0.078 38 0.141 84.9 0.314 Heart Wall 18 0.067 23 0.085 35 0.130 53 0.196 94 0.348 182 0.673 Kidneys 13 0.048 16 0.059 24 0.089 35 0.130 59 0.218 132 0.488 Liver 67 0.248 87 0.322 130 0.481 180 0.666 330 1.221 720 2.664 Lungs 16 0.059 23 0.085 32 0.118 48 0.178 89 0.329 215 0.796 Muscles 6 0.022 7.6 0.028 12 0.044 17 0.063 33 0.122 75.1 0.278 Esophagus 6 0.022 7.6 0.028 11 0.041 18 0.067 32 0.118 72.2 0.267 Osteogenic Cells 16 0.059 21 0.078 31 0.115 47 0.174 100 0.370 254 0.940 Ovaries 7.9 0.029 10 0.037 15 0.056 22 0.081 41 0.152 92.3 0.342 Pancreas 12 0.044 15 0.056 25 0.093 39 0.144 68 0.252 143 0.529 Red marrow 5.6 0.021 6.8 0.025 10 0.037 15 0.056 30 0.111 89.5 0.331 Skin 3.7 0.014 4.4 0.016 7.1 0.026 11 0.041 21 0.078 53.1 0.196 Spleen 20 0.074 27 0.100 42 0.155 64 0.237 110 0.407 282 1.043 Testes 5.4 0.020 7.1 0.026 11 0.041 16 0.059 30 0.111 69.9 0.259 Thymus 6 0.022 7.6 0.028 11 0.041 18 0.067 32 0.118 72.2 0.267 Thyroid 4.7 0.017 6.1 0.023 9.9 0.037 16 0.059 30 0.111 69.4 0.257 Urinary Bladder Wall 66 0.244 84 0.311 110 0.407 110 0.407 200 0.740 478.0 1.769 Uterus 11 0.041 14 0.052 21 0.078 28 0.104 51 0.189 110.0 0.407 Whole Body 8.1 0.030 10 0.037 16 0.059 24 0.089 44 0.163 104.0 0.385 EFFECTIVE DOSE µSv/MBq 13.7 18.1 26.7 37.6 68 162 mSv/mCi 0.507 0.670 0.988 1.39 2.52 6 The effective dose resulting from an administered activity amount of 10 mCi is 5.07 mSv in an adult. 2.7 Imaging Guidelines Pheochromocytoma and Neuroblastoma Begin whole body planar scintigraphy imaging 24 ± 6 hours following administration of AdreView. Single photon emission computed tomography (SPECT) may be performed following planar scintigraphy, as appropriate [ see Clinical Studies (14.1) ]. Congestive Heart Failure Begin anterior planar imaging of the chest at 4 hours (± 10 minutes) following administration of AdreView. Single photon emission computed tomography (SPECT) can then be performed. The recommended collimator for all imaging is a low-energy high-resolution. The recommended matrix for planar images is 128×128. The camera should be positioned to include the entire heart and as much of the upper chest as possible within the field of view [ see Clinical Studies (14.2) ]. 2.8 Estimation of the H/M Ratio among Patients with Congestive Heart Failure Initial evaluation of cardiac AdreView images involves visual examination of the location, pattern and intensity of cardiac radioactivity uptake to guide quantitative assessment (see Step 1 below). Perform quantitative assessment of radioactivity uptake in terms of the heart/mediastinum ratio (H/M) on anterior planar images of the chest (see Step 2 below). Step 1. Visual Guidelines for AdreView Cardiac Uptake on Anterior Planar Chest Images a. Normal: Distinct visualization of the left ventricular myocardium in the left lower chest, with greater uptake in the heart than in the adjacent lungs and mediastinum (Figure 1). Figure 1. Normal anterior planar AdreView image of the chest b. Abnormal: Homogeneously or heterogeneously decreased cardiac uptake, with indistinct or absent visualization of the left ventricular myocardium. Cardiac activity is usually less than or equal to that of the adjacent left lung (Figure 2a). In extreme cases, little or no AdreView uptake is seen in the left lower chest (Figure 2b). Figure 2. Abnormal anterior planar AdreView images of the chest: a) Heterogeneously reduced cardiac uptake; b) Absent cardiac uptake Figure 2a Figure 2b Figure 1 Figure 2a Figure 2b Step 2. Quantitate AdreView Cardiac Uptake The AdreView H/M ratio is determined from the activity in heart (H) and mediastinum (M) regions of interest (ROIs) drawn on the anterior planar chest image (Figure 3) using the following procedure: Draw an irregular ROI defining the epicardial border of the heart. If the epicardial border cannot be defined because all or the majority of the myocardium is not visualized, draw the ROI based upon the presumed location of the heart, using the medial aspects of the left and right lower lung for anatomical guidance. Draw a horizontal line to mark the estimated location of the lung apices. If the most superior aspect of the image does not include the lung apices (because of limited field of view for a small gamma camera), draw this line at the top of the image display. Draw a vertical line approximately equidistant from the medial aspects of the right and left lung. Examine the counts for the 12 pixels along the vertical line starting 4 pixels below the intersection point with the horizontal line determined in step 2, and identify the pixel with the lowest counts. If more than one pixel has this same number of counts, choose the most superiorly located pixel. Using the pixel defined in step 4 as the center, draw a square ROI of 7×7 dimensions. Calculate the H/M ratio by dividing the counts/pixel in the total myocardium ROI determined in step 1 by the counts/pixel in the 7×7 pixel mediastinal ROI determined in step 5. Figure 3. Illustration of creation of regions of interest for determination of the H/M ratio Figure 3 Step 3. Interpretation of AdreView H/M Ratio The expected range for AdreView H/M ratio is 1.0 to 2.4 [ see Clinical Studies (14.2) ]. Figure 4. Examples of AdreView Images in Subjects with Lower One and Two Year Mortality Risk Figure 4

4 CONTRAINDICATIONS AdreView is contraindicated in patients with known hypersensitivity to iobenguane or iobenguane sulfate. Known hypersensitivity to iobenguane or iobenguane sulfate. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity reactions have followed AdreView administration. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration. ( 5.1 ) Drugs which block norepinephrine uptake or deplete norepinephrine stores may decrease AdreView uptake. When medically feasible, stop these drugs before AdreView administration and monitor patients for withdrawal signs and symptoms. ( 5.2 ) AdreView contains benzyl alcohol (10.3 mg/mL) which may cause serious reactions in premature or low birth-weight infants. ( 5.3 ) Patients with severe renal impairment may have increased radiation exposure and decreased quality of AdreView images. ( 5.4 ) Failure to block thyroid iodine uptake may result in iodine 123 accumulation in the thyroid. ( 5.6 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions have been reported following AdreView administration. Prior to administration, question the patient for a history of prior reactions to iodine, an iodine-containing contrast agent or other products containing iodine. If the patient is known or strongly suspected to have hypersensitivity to iodine, an iodine-containing contrast agent or other products containing iodine, the decision to administer AdreView 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 AdreView administration [ see Adverse Reactions (6.2) ]. 5.2 Imaging Errors due to Concomitant Medications and Risks Associated with Withdrawal of Medications Many medications have the potential to interfere with AdreView imaging and review of the patient's medications is required prior to AdreView dosing due to the risk for unreliable imaging results. If the AdreView imaging information is essential for clinical care, consider the withdrawal of the following categories of medications if the withdrawal can be accomplished safely: antihypertensives that deplete norepinephrine stores or inhibit reuptake (e.g., reserpine, labetalol), antidepressants that inhibit norepinephrine transporter function (e.g., amitriptyline and derivatives, imipramine and derivatives, selective serotonin reuptake inhibitors), and sympathomimetic amines (e.g., phenylephrine, phenylpropanolamine, pseudoephedrine and ephedrine). The period of time necessary to discontinue any specific medication prior to AdreView dosing has not been established [ see Drug Interactions (7) ]. Pheochromocytoma and Neuroblastoma Drugs which interfere with norepinephrine uptake in neuroendocrine tumors may lead to false negative imaging results. When medically feasible, stop these drugs before AdreView administration and monitor patients for the occurrence of clinically significant withdrawal symptoms, especially patients with elevated levels of circulating catecholamines and their metabolites. Congestive Heart Failure Many commonly used cardiovascular, pulmonary, and neuropsychiatric medications interfere with AdreView imaging (see above). AdreView imaging should not be performed if discontinuation of these medications would involve risks which outweigh the value of AdreView imaging. In clinical trials, patients were not eligible for AdreView imaging if they were receiving medications in the above categories and the risks for medication withdrawal were unacceptable or if they were not clinically stable (e.g., experiencing continuing chest pain, hemodynamic instability, or clinically significant arrhythmia). 5.3 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including AdreView. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When administering AdreView in infants consider the combined daily metabolic load of benzyl alcohol from all sources including AdreView (contains 10.3 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4) ] . 5.4 Increased Radiation Exposure in Patients with Severe Renal Impairment AdreView is cleared by glomerular filtration and is not dialyzable. The radiation dose to patients with severe renal impairment may be increased due to the delayed elimination of the drug. Delayed AdreView clearance may also reduce the target to background ratios and decrease the quality of scintigraphic images. These risks importantly may limit the role of AdreView in the diagnostic evaluation of patients with severe renal impairment. AdreView safety and efficacy have not been established in these patients [ see Clinical Pharmacology (12.2) ]. 5.5 Imaging Errors due to Conditions that Affect the Sympathetic Nervous System Individuals with conditions that affect the sympathetic nervous system, e.g., Parkinsonian syndromes such as Parkinson's disease or multiple system atrophy, may show decreased cardiac uptake of AdreView independent of heart disease. 5.6 Thyroid Accumulation Failure to block thyroid uptake of iodine 123 may result in an increased long term risk for thyroid neoplasia [ see Dosage and Administration (2.2) ]. 5.7 Hypertension Assess the patient's pulse and blood pressure before and intermittently for 30 minutes after AdreView administration. AdreView may increase release of norepinephrine from chromaffin granules and produce a transient episode of hypertension, although this was not observed in the clinical studies. Prior to AdreView administration, ensure emergency cardiac and anti-hypertensive treatments are readily available.

7 DRUG INTERACTIONS The following drugs have the potential to decrease the uptake of norepinephrine and cause false negative imaging results: antihypertensives that deplete norepinephrine stores or inhibit reuptake (e.g., reserpine, labetalol), antidepressants that inhibit norepinephrine transporter function (e.g., amitriptyline and derivatives, imipramine and derivatives, selective serotonin reuptake inhibitors), sympathomimetic amines (e.g., phenylephrine, phenylpropanolamine, pseudoephedrine and ephedrine), and cocaine. Clinical studies have not determined which specific drugs may cause false negative imaging results nor whether all drugs in any specific pharmacologic class have the same potential to produce the negative imaging results. Increasing the dose of AdreView will not overcome any potential uptake limiting effect of these drugs. Before AdreView administration, discontinue (for at least 5 biological half-lives) drugs known or expected to reduce norepinephrine uptake, as clinically tolerated. Amitryptiline and derivatives, imipramine and derivatives, other antidepressants that inhibit norepinephrine transporter, antihypertensives that deplete norepinephrine stores or inhibit reuptake, sympathomimetic amines and cocaine: Discontinue for 5 biological half-lives prior to AdreView administration ( 7 )

6 ADVERSE REACTIONS Serious hypersensitivity reactions have been reported following AdreView administration. The most common adverse reactions, dizziness, rash, pruritis, flushing, headache, and injection site hemorrhage occurred in < 1.3% of patients. ( 6.1 , 6.2 ) 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 Study Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical development 1346 patients were exposed to AdreView, 251 patients with known or suspected pheochromocytoma or neuroblastoma, 985 patients with heart failure, and 110 control patients. All patients were monitored for adverse reactions over a 24 hour period following AdreView administration. Pheochromocytoma and Neuroblastoma Serious adverse reactions were not observed in the AdreView clinical study. Adverse reactions were all mild to moderate in severity and were predominantly isolated occurrences (≤ 2 patients) of one of the following reactions: dizziness, rash, pruritus, flushing or injection site hemorrhage. Congestive Heart Failure No serious adverse reactions to AdreView were observed in clinical studies. Adverse reactions that occurred with a frequency > 1% were associated with the injection site (1.3%), problems such as hematoma and bruising. The other most common reactions were flushing (0.3%) and headache (0.4%). The adverse reactions were predominantly of mild to moderate intensity. 6.2 Postmarketing Experience Because postmarketing 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. Hypersensitivity reactions have uncommonly been reported during the postmarketing use of AdreView [ see Warnings and Precautions (5.1) ].

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 AdreView in a pregnant woman to protect the woman and fetus from accumulation of I 123 [see Dosage and Administration (2.2) ]. There are no available data on AdreView 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 iobenguane 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. Advise pregnant women of the potential risks of fetal exposure to radiation doses with administration of AdreView. AdreView contains 10.3 mg/mL of benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see Warnings and Precautions (5.3) and Use in Specific Populations (8.4) ]. 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.