Adreview

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 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.
  )
• 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 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.
  )

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.

• AdreView emits radiation and must be handled with appropriate safety measures. (
  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)

  ].
  ,
  2.6 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.
  )
• Administer thyroid blockade medications to patients at risk for thyroid accumulation of AdreView. (
  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.
  ,
  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)

  ].
  )
• Measure patient dose by a suitable radioactivity calibration system immediately prior to administration. (
  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)

  ].
  )
• For patients ≥ 16 years of age or < 16 years of age and ≥ 70 kg: administer 10 mCi (370 MBq). (
  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 PatientsBased 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
  )
• For patients < 16 years of age and < 70 kg: amount scaled to the adult reference activity based on weight. (
  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 PatientsBased 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
  )

Single use vials containing 5 mL solution for intravenous injection (2 mCi/mL at calibration time).

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

  Risk Summary

  Iodine 123 (I 123), the radionuclide in AdreView, 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 AdreView administration in order to minimize radiation exposure to a breastfed infant.
  )
• Pediatrics: safety and effectiveness have not been established in pediatric patients < 1 month of age or in any pediatric patient with heart failure. (
  8.4 Pediatric Use

  The safety and effectiveness of AdreView have been established in the age groups 1 month to 16 years in patients with known or suspected neuroblastoma

  [see Clinical Studies (14.1)]

  . Safety and effectiveness in pediatric patients below the age of 1 month or in any pediatric patient with congestive heart failure have not been established.

  Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. 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 Warnings and Precautions (5.3)]

  .
  )

• Hypersensitivity reactions have followed AdreView administration. Have anaphylactic and hypersensitivity treatment measures available prior to AdreView administration. (
  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)

  ].
  )
• 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 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).
  )
• AdreView contains benzyl alcohol (10.3 mg/mL) which may cause serious reactions in premature or low birth-weight infants. (
  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)]

  .
  )
• Patients with severe renal impairment may have increased radiation exposure and decreased quality of AdreView images. (
  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)

  ].
  )
• Failure to block thyroid iodine uptake may result in iodine 123 accumulation in the thyroid. (
  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)

  ].
  )