Iobenguane I-123

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.

Single use vials containing 5 mL solution for intravenous injection (2 mCi/mL at calibration time). 5 mL of sterile solution for intravenous injection in a single use vial (2 mCi/mL at calibration time) ( 3 )

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

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.

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) ].

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 )

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 AdreView administration. ( 8.2 ) 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 )

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.

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.

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) ] .

8.5 Geriatric Use In clinical studies of AdreView in heart disease, 27% of subjects were 65-74 years of age and 17% of subjects were 75 years of age or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. AdreView is excreted by the kidneys, and the risks of adverse reactions, increased radiation dose, and occurrence of falsely negative imaging results, may be greater in patients with severely impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and image interpretation. Consider assessment of renal function in elderly patients prior to AdreView administration.

Iobenguane is similar in structure to the antihypertensive drug guanethedine and to the neurotransmitter norepinephrine (NE). Iobenguane is, therefore, largely subject to the same uptake and accumulation pathways as NE. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and stored in the presynaptic storage vesicles. Iobenguane accumulates in adrenergically innervated tissues such as the adrenal medulla, salivary glands, heart, liver, spleen and lungs as well as tumors derived from the neural crest. By labeling iobenguane with the isotope iodine 123, it is possible to obtain scintigraphic images of the organs and tissues in which the radiopharmaceutical accumulates.