Iobenguane I 123 Injection for Intravenous Use

AdreView (iobenguane i 123 injection for intravenous use) is a radiopharmaceutical indicated for use in the detection of primary or metastatic pheochromocytoma or neuroblastoma as an adjunct to other diagnostic tests.

Clinical Study Experience

Serious adverse reactions were not observed in the AdreView (iobenguane i 123 injection for intravenous use) clinical study. The data described below reflect AdreView (iobenguane i 123 injection for intravenous use) exposure to 251 patients with known or suspected pheochromocytoma or neuroblastoma. The average ages were 49 years (range 17 – 88 years) for adults and, for pediatric patients, 4 years (range 1 month - 16 years). Slightly less than half the patients were male. All patients were monitored for adverse reactions over a 24 hour period following AdreView (iobenguane i 123 injection for intravenous use) administration.

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.

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.

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].

Mechanism of Action

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.

Pharmacodynamics

AdreView (iobenguane i 123 injection for intravenous use) is a diagnostic radiopharmaceutical which contains a small quantity of iobenguane that is not expected to produce a pharmacodynamic effect [see DESCRIPTION]. To minimize radiation dose to the thyroid gland, this organ should be blocked before dosing [see DOSAGE AND ADMINISTRATION]. Since iobenguane is excreted mainly via the kidneys, patients with severe renal insufficiency may experience increased radiation exposure and impaired imaging results. Frequent voiding should be encouraged after administration to minimize the radiation dose to the bladder [see WARNINGS AND PRECAUTIONS]. The calculation of the estimated radiation dose is shown in Table 2 [see DOSAGE AND ADMINISTRATION].

Pharmacokinetics

Iobenguane is rapidly cleared from the blood and accumulates in adrenergically innervated tissues [see CLINICAL PHARMACOLOGY]. Retention is especially prolonged in highly adrenergically innervated tissues (e.g., the adrenal medulla, heart, and salivary glands).

The majority of the iobenguane dose is excreted unaltered by the kidneys via glomerular filtration. A rapid initial clearance of circulating iobenguane is observed, followed by a slow clearance as iobenguane is released from other compartments. In patients with normal renal function, 70 to 90% of the administered dose is recovered unaltered in urine within 4 days. Iobenguane is not cleared by dialysis [see WARNINGS AND PRECAUTIONS]. Most of the remaining radioactivity recovered in the urine is in the form of the radioiodinated metabolite m-iodohippuric acid (MIHA) (typically ≤ 10%) and free radioiodide (typically ≤ 6%). The enzymatic process responsible for metabolism has not been well characterized and the pharmacologic activity of these metabolites has not been studied. Only a small amount ( < 1%) of the injected dose is eliminated via the feces.

Animal Toxicology and/or Pharmacology

Iobenguane sulfate testing in dogs revealed electrocardiographic (ECG) changes after administration of 202 times the mg/m2 conversion of the maximum human dose for a 60 kg adult; the no observable effect level (NOEL) was not determined. When iobenguane was tested in a cell system stably expressing hERG-1 potassium channels, inhibition of potassium channels was not observed at an 80 µM iobenguane concentration and the IC50 was 487 µM.

Clinical Studies

The safety and efficacy of AdreView (iobenguane i 123 injection for intravenous use) were assessed in an open-label, multicenter, multinational trial of 251 subjects with known or suspected neuroblastoma or pheochromocytoma. Diagnostic efficacy for the detection of metabolically active neuroblastoma or pheochromocytoma was determined by comparison of focal increased radionuclide uptake on planar scintigraphy at 24 ± 6 hours post-administration of AdreView (iobenguane i 123 injection for intravenous use) against the definitive diagnosis (standard of truth). Anterior and posterior planar whole-body images, or alternatively whole-body overlapping spot images, were acquired from the head to below the knees. Additional spot images were performed as deemed appropriate at the discretion of the clinical image reviewer. SPECT imaging of the thorax and abdomen was then obtained when possible.

Of the 251 subjects dosed with AdreView (iobenguane i 123 injection for intravenous use) , 100 had known or suspected neuroblastoma and 151 had known or suspected pheochromocytoma. The population included 154 adults and 97 pediatric patients; the majority of adults were female (59%), the majority of pediatric subjects were male (58%). The adult subjects had a mean age of 49 years (range 17 to 88 years). The pediatric patients (56 males and 41 females) consisted of 32 infants (1 month up to 2 years of age), 62 children (2 years up to 12 years) and three adolescents (12 years up to 16 years).

The definitive diagnosis (standard of truth) for the presence or absence of metabolically active pheochromocytoma or neuroblastoma was determined by histopathology or, when histopathology was unavailable, a composite of imaging (i.e., CT, MRI, [131I]-mIBG scintigraphy), plasma/urine catecholamine and/or catecholamine metabolite measurements, and clinical follow-up. A standard of truth was available for 211 subjects (127 with pheochromocytoma, 84 with neuroblastoma) and this group comprised the diagnostic efficacy population. For 93 of these subjects, the standard of truth was based solely upon histopathology. Of 211 subjects in the efficacy population, all had planar scintigraphy and 167 subjects had SPECT in addition to planar imaging. All images were assessed independently by three readers blinded to all clinical data. Table 5 summarizes the AdreView (iobenguane i 123 injection for intravenous use) performance characteristics, by reader.

Table 5. AdreView (iobenguane i 123 injection for intravenous use) Planar Imaging: Sensitivity and Specificity

Performance characteristics (sensitivity and specificity) of AdreView (iobenguane i 123 injection for intravenous use) planar imaging in patients with known or suspected neuroblastoma were similar to those in patients with known or suspected pheochromocytoma. Among the selected patients who also underwent SPECT imaging, similar performance characteristics of AdreView (iobenguane i 123 injection for intravenous use) scintigraphy were observed when SPECT plus planar imaging was compared to planar imaging alone.

Iobenguane I-123 is in a group of drugs called diagnostic radiopharmaceuticals (RAY dee oh far ma SOO tik als). Iobenguane I-123 is a radioactive agent that allows images of specific organs in the body to be detected by a gamma camera.

Iobenguane I-123 is used to detect certain kinds of cancer of the adrenal glands

Iobenguane I-123 may also be used for purposes not listed in this medication guide.

You should not receive this medication if you are allergic to iobenguane. Tell your doctor if you have ever had any type of reaction to another contrast agent, or to potassium.

Before you are treated with iobenguane I-123, tell your doctor if you have kidney disease, a thyroid disorder, if you are dehydrated or unable to urinate, or if you are allergic to iodine.

Tell your doctor about all other medications you are using, especially antidepressants, cold medicines, blood pressure medications, or ADHD medications. You may need to stop using certain drugs for a short time before you receive iobenguane I-123

Drink extra fluids before you receive iobenguane I-123, and for at least 48 hours afterward. Follow your doctor's instructions about the types and amount of liquids you should drink before and after your test. Iobenguane I-123 is radioactive and it can cause dangerous effects on your bladder if it is not properly eliminated from your body through urination.

Do not allow yourself to become dehydrated during the first few days after receiving iobenguane I-123. Call your doctor if you have any vomiting or diarrhea during this time. Follow your doctor's instructions about the types and amount of fluids you should drink.

You should not receive this medication if you are allergic to iobenguane. Tell your doctor if you have ever had any type of reaction to another contrast agent, or to potassium.

To make sure you can safely receive iobenguane I-123, tell your doctor if you have any of these other conditions:

• kidney disease;
• a thyroid disorder;
• if you are dehydrated or unable to urinate; or
• if you are allergic to iodine.

FDA pregnancy category C. It is not known whether iobenguane I-123 will harm an unborn baby. Tell your doctor if you are pregnant before you are treated with iobenguane I-123.

It is not known whether iobenguane I-123 passes into breast milk or if it could harm a nursing baby. Do not breast-feed within 6 days after receiving iobenguane I-123. If you use a breast pump during this time, throw out any milk you collect. Do not feed it to your baby.

Older adults may need kidney function tests before receiving iobenguane I-123. Your kidney function may also need to be watched closely after you have received this medication.