AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Iobenguane I-131

Chemical Name:

• (m-[131I]Iodobenzyl)guanidine

Molecular Formula:

• (C₈H₁₀ ¹³¹IN₃)₂•H₂SO₄

Iobenguane I 131, an iodine I 131 radiolabeled synthetic norepinephrine analog (iobenguane; also referred to as metaiodobenzylguanidine [MIBG]), is a highly specific radiopharmaceutical.1,  2,  4,  7,  8

Pheochromocytoma and Paraganglioma

Iobenguane I 131 is used for the treatment of iobenguane scan-positive unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma in patients who require systemic cytotoxic chemotherapy.1,  2 Iobenguane I 131 has been designated an orphan drug by FDA for use in these cancers.3 Pheochromocytoma and paraganglioma are rare neuroendocrine tumors originating from the neural crest that are characterized by catecholamine (i.e., epinephrine, norepinephrine, dopamine) excess,1,  4 which leads to hypertension, palpitations, diaphoresis, or GI disease.7,  8 Because hypertension is observed in more than 95% of patients with malignant pheochromocytoma or paraganglioma tumors, blood pressure control is critical in patients with malignant pheochromocytoma and paraganglioma due to the risks of life-threatening acute hypertensive emergency and the clinical consequences of chronic hypertension.4 The current indication for iobenguane I 131 is based on a reduction of antihypertensive therapy by at least 50% for at least 6 months in 25% of patients with iobenguane scan-positive unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma who received at least one therapeutic dose of iobenguane I 131.1,  2

The current indication for iobenguane I 131 in the treatment of iobenguane scan-positive unresectable advanced pheochromocytoma or paraganglioma is based principally on the results of an open-label, noncomparative, multicenter phase 2 study (Study IB12B) in 74 adults and pediatric patients 12 years of age or older with refractory, unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma who were not candidates for curative therapy (i.e., surgery, chemotherapy).1,  2 Patients were eligible for the study if they were receiving a stable antihypertensive regimen for at least 30 days prior to administration of the first therapeutic dose of iobenguane I 131.1,  2 Patients with a baseline Karnofsky performance status of less than 60 and those with active CNS lesions were excluded from this study.1 In this study, 74 patients received the recommended dosimetric dose of iobenguane I 131, and 50 or 68 of these patients received 2 or at least one therapeutic dose, respectively, of iobenguane I 131 at the recommended dose.1 The primary measure of efficacy was the proportion of patients who were able to reduce by at least 50% or discontinue antihypertensive medication(s) for at least 6 months.1,  2 The median age of the 68 patients who received at least one therapeutic dose of iobenguane I 131 was 55 years (range: 16-72 years); 61% had bone metastases and 50% had lung or liver metastases.1 The median number of prior therapies per patient was 2; 88% of patients had received prior surgery, 50% had received prior external beam radiotherapy, 31% had received prior I 131 metaiodobenzylguanidine (MIBG) therapy, 31% had received prior chemotherapy, 15% had received prior kinase inhibitor therapy, and 4% had received prior therapy with other systemic agents.1 The most common primary tumor diagnosis was pheochromocytoma (78%); 21% of patients had paraganglioma, and 1% had both pheochromocytoma and paraganglioma.1

At the time of the analysis, iobenguane I 131 reduced the requirement for antihypertensive therapy by at least 50% for at least 6 months in 25% of patients who received at least one therapeutic dose of iobenguane I 131.1,  2 In the cohort of patients who received at least one therapeutic dose of iobenguane I 131, the objective response rate was 22%; none of the patients achieved a complete response.1 Approximately one-half (53%) of patients had durable responses of 6 months or more.1 The median overall survival in patients who received at least one therapeutic dose of iobenguane I 131 was 36.7 months; overall survival benefit appeared to be consistent regardless of the presence of lung or liver metastases at baseline.2

General

Iobenguane I 131 is a radiopharmaceutical and should be prepared and used only by a qualified clinician (i.e., authorized by an appropriate regulatory agency) experienced in the safe use and handling of radiopharmaceuticals.1 Procedures for proper handling (e.g., use of waterproof gloves, effective radiation shields, tongs) and disposal of radiopharmaceuticals should be followed when preparing and administering iobenguane I 131.1

To minimize the risk of radiation-induced hypothyroidism or thyroid neoplasm, administration of a thyroid protective agent (i.e., potassium iodide) should be initiated at least 24 hours prior to and continued for 10 days following each dosimetric and therapeutic dose of iobenguane I 131.1,  11 (See Hypothyroidism under Cautions: Warnings/Precautions.)

Because of the potential for nausea and vomiting, an antiemetic should be administered 30 minutes prior to each dose of iobenguane I 131.1

To minimize irradiation to the bladder, adequate oral hydration should begin at least 1 day prior to administration of iobenguane I 131 and continued for 1 week following administration of the radiopharmaceutical.1 The manufacturer recommends oral hydration with at least 2 liters of fluids daily.1

Administration

Iobenguane I 131 is administered by IV injection ( dosimetric dose ) or by IV infusion ( therapeutic dose ).1

Precautions for reducing the risk of radiation exposure (i.e., use of water proof gloves, shielding, tongs) should be followed.1

Iobenguane I 131 injection concentrate must be diluted prior to administration.1 Prior to administration, iobenguane I 131 injection should be inspected visually for particulate matter and discoloration.1 The solution should be clear and colorless to pale yellow; the solution should not be used if it is discolored or if particulate matter is present.1 Radioactivity levels of iobenguane I 131 vial(s) should be confirmed with a calibrated radioactivity measurement system prior to and after administration of the radiopharmaceutical.1

The manufacturer's labeling and dosing and administration guide should be consulted for detailed information on infusion system requirements (e.g., components, set-up) and procedures for IV infusion of therapeutic doses of iobenguane I 131.1,  12

Administration sets and any partially used vials should be discarded according to local and federal regulations.1

Dilution

During shipping and storage, iobenguane I 131 should be kept frozen at a temperature at or below -70ºC in the lead shielded container provided by the manufacturer.1 If deviations in temperature control occur during shipment (i.e., manufacturer-provided temperature monitor indicates exposure to temperatures above -70ºC), the radiopharmaceutical must not be used.1 The shelf-life of the injection concentrate is 144 hours.1

Prior to dilution, frozen iobenguane I 131 injection concentrate must be completely thawed at room temperature for approximately 90 minutes in the lead shielded container; heat sources should not be used.1,  5 To ensure homogeneity of the injection concentrate, the solution should be mixed by gentle swirling.1 Once thawed, the injection concentrate should not be refrozen.1

For preparation of the dosimetric dose , a venting needle (or other suitable venting device) with a 0.2-µm filter and charcoal filter should be inserted into the vial labeled for dosimetric use; the vial should be gently swirled to ensure homogeneity of the injection concentrate.1 An appropriate volume of 0.9% sodium chloride injection should be added to the dosimetric dose vial labeled as containing 15 mCi/mL (equivalent to 555 MBq/mL) of iobenguane I 131 to achieve a final radioactive concentration of 1 mCi/mL (equivalent to 37 MBq/mL).1,  5 The final diluted iobenguane I 131 solution should be gently swirled.1 To prepare the dosimetric dose for administration, the appropriate amount of diluted iobenguane I 131 solution should be withdrawn from the vial using a 10-mL shielded syringe.1 To ensure a level of radioactivity within 10% of the dose, radioactivity of the diluted solution should be measured using a calibrated radioactivity measurement system.1 The final diluted iobenguane I 131 solution should be stored at room temperature and administered within 8 hours after removal from frozen storage.1

For preparation of a therapeutic dose , a venting needle (or other suitable venting device) with a 0.2-µm filter and charcoal filter should be inserted into each of the required number of vials labeled as containing iobenguane I 131 for therapeutic use; each vial should be gently swirled to ensure homogeneity of the injection concentrate.1 A venting needle (or other suitable venting device) also should be inserted into an empty sterile 50-mL glass vial.1 The entire contents of 2 vials labeled as containing iobenguane I 131 for therapeutic use should be transferred to the glass vial followed by confirmation of radioactivity using a calibrated radioactivity measurement system.1 If radioactivity of iobenguane I 131 in the glass vial exceeds the therapeutic dose, the appropriate volume of the injection concentrate should be withdrawn from the vial using a shielded syringe and then an appropriate volume of 0.9% sodium chloride injection should be added to the glass vial to achieve a final admixture volume of 50 mL.1 If radioactivity of iobenguane I 131 in the glass vial is less than the therapeutic dose, the appropriate volume of iobenguane I 131 injection concentrate should be withdrawn from a third vial labeled as containing iobenguane I 131 for therapeutic use using a shielded syringe and added to the glass vial; an appropriate volume of 0.9% sodium chloride injection should then be added to the glass vial to achieve a final admixture volume of 50 mL.1 The final diluted iobenguane I 131 solution for IV injection should be gently swirled.1 To ensure a level of radioactivity within 10% of the dose, radioactivity of the diluted solution should be measured using a calibrated radioactivity measurement system following removal of the venting needle or device.1 The final diluted iobenguane I 131 solution should be stored at room temperature and administered within 8 hours after removal from frozen storage.1

Rate of Administration

Dosimetric dose : Iobenguane I 131 is administered by IV injection over 60 seconds.1

Therapeutic dose : In pediatric patients 12 years of age or older, iobenguane I 131 is administered by IV infusion at a rate of 50 mL/hour over 60 minutes.1 In adult patients, iobenguane I 131 is administered by IV infusion at a rate of 100 mL/hour over 30 minutes.1

Dosage

Pheochromocytoma and Paraganglioma

Prior to administration of the initial therapeutic dose of iobenguane I 131, a single dosimetric dose must be administered to confirm tumor avidity and to allow for individualization of the therapeutic dosage (i.e., dosage reduction to avoid radiation overexposure in critical organs).1,  4

Table 1 indicates the recommended dosimetric dose of iobenguane I 131 in adults and pediatric patients 12 years of age or older.1

Following administration of a single dosimetric dose, dosimetry schema (e.g., internal dosimetry schema of the Medical Internal Radiation Dose [MIRD] Committee of the Society of Nuclear Medicine) should be used to calculate the estimated radiation dose to normal organs and tissues per unit activity (D_organ) using combined data from the imaging studies described in Table 2.1 Patient-specific organ masses (estimated from imaging) should be used when possible.1

Table 3 indicates the recommended therapeutic dosage of iobenguane I 131 for the treatment of unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma in adults and pediatric patients 12 years of age or older; however, dosage adjustment based on estimated absorbed dose to critical organs may be necessary.1

Administration of the first therapeutic dose of iobenguane I 131 therapy should be withheld in patients with absolute neutrophil counts (ANC) less than 1200/mm³ or platelet counts less than 80,000/mm³.1

If the estimated absorbed dose to critical organs (calculated by multiplying D_organ by the cumulative activity of 2 therapeutic doses [Aw]) is less than the absorbed dose threshold for radiation toxicity to critical organs (T_organ) (see Table 4), no dosage adjustment is necessary.1 If the estimated absorbed dose to a critical organ exceeds T_organ, Aw must be reduced.1 Reduced Aw should be calculated using the following formula.1

Formula for Reduced Cumulative Therapeutic Activity (Aw):

Reduced cumulative therapeutic activity (in mCi) = Aw × (T_organ ÷ [Aw × D_organ]) (where Aw is in mCi, T_organ is in Gy, and D_organ is in Gy/mCi)

Dosage Modification for Toxicity

If adverse reactions occur, interruption of therapy, therapeutic dosage reduction, and/or discontinuance of iobenguane I 131 may be necessary based on severity of the adverse effect.1

Hematologic Toxicity

If hematologic toxicity occurs following the first therapeutic dose of iobenguane I 131, reduction of the second therapeutic dose should be based on the method used to individualize the first therapeutic dose (i.e., weight-based, adjusted for critical organ limits).1

If platelet count less than 25,000/mm³ or platelet count less than 50,000/mm³ with active bleeding occurs following the first therapeutic dose of iobenguane I 131, therapy with iobenguane I 131 should be interrupted.1 Once platelet counts improve to normal values or baseline, iobenguane I 131 may be resumed at a reduced dosage (see Table 5).1

If absolute neutrophil count (ANC) less than 500/mm³ or febrile neutropenia occurs following the first therapeutic dose of iobenguane I 131, therapy with iobenguane I 131 should be interrupted.1 Once ANC improves to normal values or baseline, iobenguane I 131 may be resumed at a reduced dosage (see Table 5).1

If life-threatening anemia lasting more than 7 days occurs following the first therapeutic dose of iobenguane I 131, therapy with iobenguane I 131 should be interrupted.1 Once anemia improves to normal values or baseline, iobenguane I 131 may be resumed at a reduced dosage (see Table 5).1

Pneumonitis

If pneumonitis occurs after the first therapeutic dose of iobenguane I 131, the second therapeutic dose of the radiopharmaceutical should not be administered.1 (See Pneumonitis under Cautions: Warnings/Precautions.)

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment at this time.1

Renal Impairment

In patients with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute), the first therapeutic dose of iobenguane I 131 should be adjusted based on the estimated absorbed dose to critical organs, and renal function should be monitored more frequently.1 (See Pheochromocytoma and Paraganglioma under Dosage and Administration: Dosage.) The manufacturer makes no specific dosage recommendations for patients with severe renal impairment (creatinine clearance of less than 30 mL/minute) or end-stage renal disease.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Contraindications

The manufacturer states that there are no known contraindications to the use of iobenguane I 131.1

Warnings/Precautions

Radiation Exposure

The radioactive component of iobenguane I 131 (I 131) contributes to a patient's lifetime cumulative radiation exposure, and development of new malignancies is a known risk of long-term radiation exposure.1 The risk of developing new malignancies is increased in pediatric patients.1 (See Myelodysplastic Syndrome, Acute Leukemia, and Other Malignancies under Cautions: Warnings/Precautions and also see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Institutional good radiation safety practices and patient management procedures should be employed during and after administration of iobenguane I 131 to minimize exposure of patients, medical personnel, and household contacts to radiation.1

Hematologic Effects

Severe and prolonged adverse hematologic effects (e.g., anemia, neutropenia, thrombocytopenia) have been reported in patients receiving iobenguane I 131.1 In clinical trials, grade 4 anemia, thrombocytopenia, or neutropenia occurred in 7, 33, or 16%, respectively, of 88 patients who received at least one therapeutic dose of iobenguane I 131.1 Febrile neutropenia also occurred in 5% of patients receiving a therapeutic dose of iobenguane I 131.1,  4 In the principal efficacy study, nadir neutrophil counts occurred in a median of 36 days in patients who experienced grade 4 neutropenia following the first therapeutic dose of iobenguane I 131; the median time to improvement to grade 3 or less was 12 days.1 Following the second therapeutic dose of iobenguane I 131, nadir neutrophil counts occurred in a median of 43 days in patients who experienced grade 4 neutropenia; the median time to improvement to grade 3 or less was 18.5 days.1

Complete blood cell (CBC) counts should be monitored prior to initiation of iobenguane I 131 therapy and then weekly for up to 12 weeks following each therapeutic dose of iobenguane I 131.1,  4 If hematologic toxicity occurs, CBC counts should be monitored until hematologic parameters recover to baseline or normal range.1 Temporary interruption followed by dose reduction of iobenguane I 131 may be necessary if hematologic toxicity occurs during therapy with iobenguane I 131.1 (See Hematologic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)

Myelodysplastic Syndrome, Acute Leukemia, and Other Malignancies

In clinical trials, myelodysplastic syndrome (MDS) or acute leukemia was reported in 6.8% of 88 patients who received at least one therapeutic dose of iobenguane I 131; the time to occurrence ranged from 12 months to 7 years.1 New primary colon cancer and adenocarcinoma of the lung were individually reported in one patient each following the first therapeutic dose of iobenguane I 131 in clinical trials; the time to occurrence of colon cancer or lung adenocarcinoma was 18 or 27 months, respectively.1

Hypothyroidism

In clinical trials, hypothyroidism was reported in 3.4% of 88 patients who received at least one therapeutic dose of iobenguane I 131.1 In one patient with preexisting hypothyroidism, worsening of hypothyroidism occurred in 4 months.1 The time to development of new-onset hypothyroidism ranged from less than 1 month to 18 months.1

To minimize the risk of radiation-induced hypothyroidism or thyroid neoplasm, a thyroid protective agent (i.e., potassium iodide) should be initiated at least 24 hours prior to each dosimetric or therapeutic dose of iobenguane I 131 and continued for 10 days following each dose.1,  11

Patients receiving iobenguane I 131 should be monitored for manifestations of hypothyroidism.1 Thyroid function (i.e., thyroid stimulating hormone [TSH]) should be evaluated prior to initiation of therapy and indefinitely once a year thereafter.1

Hypertension

In clinical trials, worsening hypertension (defined as a systolic blood pressure of 160 mm Hg or higher with a 20-mm Hg increase from baseline or a diastolic blood pressure of 100 mm Hg or higher with a 10-mm Hg increase from baseline) was reported in 11% of 88 patients who received at least one therapeutic dose of iobenguane I 131.1 All changes in blood pressure occurred during the initial 24 hours following completion of an iobenguane I 131 infusion.1

Blood pressure should be monitored frequently during the initial 24 hours after each therapeutic dose of iobenguane I 131.1

Renal Effects

In clinical trials, renal failure or acute kidney injury was reported in 7% of 88 patients who received at least one therapeutic dose of iobenguane I 131.1 Clinically important decreases in glomerular filtration rate (GFR) at 6 or 12 months were reported in 22% of 88 patients who received a therapeutic dose of iobenguane I 131.1 Preexisting renal impairment may increase the potential for developing treatment-related nephrotoxicity.1

Renal function should be monitored more frequently in patients with mild or moderate renal impairment.1

Pneumonitis

Fatal pneumonitis occurred 9 weeks following administration of a single dose of iobenguane I 131 in 1 of 11 patients enrolled in the expanded-access program of the principal efficacy study; however, no cases of pneumonitis were reported in 88 patients who received at least one therapeutic dose of iobenguane I 131 in clinical trials.1

Patients receiving iobenguane I 131 should be monitored for manifestations of pneumonitis (e.g., cough, dyspnea, difficulty breathing) and should be treated as clinically indicated.1,  9 If pneumonitis occurs after the first therapeutic dose of iobenguane I 131, the second therapeutic dose should not be administered.1

Fetal/Neonatal Morbidity and Mortality

Based on its mechanism of action, iobenguane I 131 may cause fetal harm.1 There are no available data regarding the risk of iobenguane I 131 use in pregnant women or animals to date.1

Pregnancy should be avoided during iobenguane I 131 therapy.1 Pregnancy status should be verified prior to initiation of iobenguane I 131, and females of reproductive potential should be advised to use effective contraceptive methods while receiving iobenguane I 131 and for 7 months after the final dose.1 In addition, male patients with female partners of reproductive potential should use effective methods of contraception while receiving the drug and for 4 months after the final dose.1 If iobenguane I 131 is used during pregnancy or if the patient becomes pregnant while receiving the radiopharmaceutical, the patient should be apprised of the potential fetal hazard.1

Impairment of Fertility

Iobenguane I 131 may impair male and female fertility.1 The recommended cumulative radiation exposure of iobenguane I 131 (37 GBq) results in an absorbed radiation dose in the testis and ovaries that is comparable to the dose at which external beam radiotherapy causes reversible or permanent infertility.1

Specific Populations

Pregnancy

Iobenguane I 131 may cause fetal harm if administered to pregnant women based on its mechanism of action.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

It is not known whether iobenguane I 131 distributes into milk in humans or animals or whether the radiopharmaceutical has any effects on nursing infants and on milk production.1 Because of the potential for serious adverse reactions to iobenguane I 131 in nursing infants, women should be advised to discontinue nursing during iobenguane I 131 therapy and for 80 days after the final dose.1

Pediatric Use

Safety and efficacy of iobenguane I 131 have not been established in pediatric patients younger than 12 years of age with unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma.1

Safety and efficacy of iobenguane I 131 in pediatric patients 12 years of age or older with unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma have been established in the principal efficacy study (Study IB12B).1

Because the absorbed dose of radiation is greater in pediatric patients and pediatric patients have a longer life expectancy than adults, the risk of adverse effects associated with radiation therapy is increased in pediatric patients.1 Prior to initiating therapy in pediatric patients, clinicians should assess whether the potential benefits of iobenguane I 131 therapy outweigh the risks of radiation exposure.1 (See Radiation Exposure under Cautions: Warnings/Precautions.)

Geriatric Use

In clinical trials, 17% of patients receiving iobenguane I 131 were 65 years of age or older and 1% were 75 years of age and older.1 There is insufficient experience in patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

A dedicated hepatic impairment trial for iobenguane I 131 has not been conducted to date; however, iobenguane I 131 does not undergo hepatic elimination.1,  5

Renal Impairment

Because iobenguane I 131 is predominately eliminated by the kidneys, clearance of iobenguane I 131 may be delayed in patients with renal impairment and the delayed clearance may result in an increased dose of radiation to the kidney.1 In the principal efficacy study, 8 of 42 patients (19%) with mild or moderate renal impairment (creatinine clearance of 30-89 mL/minute) required reduction of the therapeutic dosage based on the estimated absorbed dose to critical organs.1 Safety and pharmacokinetics of iobenguane I 131 have not been established in patients with severe renal impairment (creatinine clearance of less than 30 mL/minute) or end-stage renal disease.1 Preexisting renal impairment may increase the risk for developing treatment-related nephrotoxicity.1 (See Renal Effects under Cautions: Warnings/Precautions.)

The manufacturer states that the therapeutic dosage of iobenguane I 131 should be adjusted based on the estimated absorbed dose to critical organs in patients with mild or moderate renal impairment (see Pheochromocytoma and Paraganglioma under Dosage and Administration: Dosage), and renal function should be monitored more frequently.1

Common Adverse Effects

Grade 3 or 4 adverse effects reported in at least 10% of patients receiving iobenguane I 131 include lymphopenia,1 neutropenia,1 thrombocytopenia,1 fatigue,1 anemia,1 elevated international normalized ratio (INR),1 nausea,1 dizziness,1 hypertension,1 and vomiting.1

In vitro studies indicate that nonradioactive iobenguane is not an inhibitor of cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A or inducer of CYP isoenzymes 1A, 2B6, 2C9, 2C19, or 3A.1

In vitro, nonradioactive iobenguane is not a substrate or inhibitor of P-glycoprotein (P-gp).1

Drugs that Reduce Catecholamine Uptake or Deplete Catecholamine Stores

Because drugs that reduce catecholamine uptake or deplete catecholamine stores can affect uptake of iobenguane, these drugs may interfere with estimated absorbed dose calculations following dosimetric doses of iobenguane I 131 and may reduce iobenguane I 131 efficacy.1 In clinical trials, concomitant use of catecholamine-reducing or -depleting drugs was not permitted.1

Administration of drugs that reduce catecholamine uptake or deplete catecholamine stores should be withheld for at least 5 half-lives prior to and for at least 7 days following dosimetric and therapeutic doses of iobenguane I 131.1 Drugs that may reduce catecholamine uptake or deplete catecholamine stores include, but are not limited to, CNS stimulants or amphetamines (e.g., cocaine, dextroamphetamine, methylphenidate), norepinephrine- and dopamine-reuptake inhibitors (e.g., phentermine), norepinephrine- and serotonin-reuptake inhibitors (e.g., tramadol), monoamine oxidase inhibitors (e.g., linezolid, phenelzine), central monoamine-depleting drugs (e.g., reserpine), nonselective β-adrenergic blocking agents (e.g., labetalol), α-adrenergic agonists or α- and β-adrenergic agonists (e.g., ephedrine, naphazoline, phenylephrine, pseudoephedrine), tricyclic antidepressants or norepinephrine-reuptake inhibitors (e.g., amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine), and dietary supplements that may inhibit reuptake of norepinephrine, serotonin, or dopamine (e.g., Ephedra spp. [“ma huang”], St. John's wort [ Hypericum perforatum ], yohimbine).1

Description

Iobenguane I 131, an iodine I 131 radiolabeled synthetic norepinephrine analog (iobenguane; also referred to as metaiodobenzylguanidine [MIBG]), is a highly specific radiopharmaceutical.1,  2,  4,  7,  8 Because of structural similarity to norepinephrine, iobenguane I 131 accumulates in highly sympathetically innervated tissues with high levels of norepinephrine transporters (e.g., heart, lung, adrenal medulla, salivary gland, liver, spleen, pheochromocytoma, paraganglioma).1,  4,  7 The radioactive component of iobenguane I 131 (I 131) induces apoptosis and tumor necrosis.1,  4,  7,  8

Iobenguane I 131 does not undergo hepatic metabolism.1 Iobenguane I 131 is eliminated principally by the kidneys; approximately 50 or 80% of the dose is excreted in urine within 24 or 120 hours, respectively.1 Unchanged I 131 accounts for a mean of 94 or 93% of radioactivity recovered in urine at 0-6 or 6-24 hours, respectively.1 Minor metabolites include free I 131, metaiodohippuric acid (MIHA), and metaiodobenzyl bisguanidine (MMIBG).1 In vivo, nonradioactive iobenguane is 61-63% bound to plasma proteins.1 The mean terminal half-life of iobenguane I 131 is approximately 35 hours.1 I 131 decays with β and γ emissions with a physical half-life of 8 days.1

Advice to Patients

Importance of advising patients to follow standard precautions for minimizing radiation exposure to household contacts.1,  9

Importance of advising patients to drink at least 2 liters of fluids daily beginning at least 1 day prior to and continuing for 1 week following administration of each iobenguane I 131 dose.1

Risk of myelosuppression (e.g., neutropenia, thrombocytopenia, anemia).1 Importance of monitoring complete blood cell (CBC) counts prior to and weekly during therapy.1 Importance of informing clinician promptly if any signs or symptoms of myelosuppression or infection (e.g., fever, chills, dizziness, shortness of breath, bleeding, easy bruising) occur.1,  9

Risk of secondary cancers, including myelodysplastic syndrome (MDS) and acute leukemia.1

Risk of hypothyroidism.1 Importance of advising patients to take a thyroid protective agent as directed.1 Advise patients of the necessity of indefinite monitoring of thyroid function.1

Risk of elevations in blood pressure.1 Importance of informing clinician if signs and symptoms of tumor-hormone catecholamine release or elevations in blood pressure occur during or 24 hours after administration of a therapeutic dose of iobenguane I 131.1

Risk of pneumonitis.1 Importance of informing clinician if manifestations of pneumonitis (e.g., shortness of breath, difficulty breathing, cough) occur.1,  9

Risk of fetal harm.1 Necessity of advising females of reproductive potential that they should use an effective method of contraception while receiving iobenguane I 131 and for 7 months after the final dose.1,  9 Necessity of advising male patients with female partners of reproductive potential that they should use an effective method of contraception while receiving the drug and for 4 months after the final dose.1,  9 Importance of women informing clinicians if they are or plan to become pregnant.1 Apprise patient of potential fetal hazard if used during pregnancy.1

Importance of advising women to avoid breast-feeding while receiving iobenguane I 131 and for 80 days after the final dose.1

Risk of impaired male and female fertility.1,  9

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant diseases.1

Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. Progenics Pharmaceuticals. Azedra^® (iobenguane I 131) injection prescribing information. New York, NY; 2018 Jul.

2. Pryma, D, Chin, B, Noto, R et al. Azedra (iobenguane I 131) in patients with malignant, recurrent and/or unresectable pheochromocytoma or paraganglioma (PPGL): Updated efficacy and safety results from a multi-center, open-label, pivotal phase 2 study. J Clin Oncol . 2018; 36(15_suppl):4005.

3. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 Aug 12. [Web]

4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209607Orig1s000: Multi-discipline review. From FDA website. [Web]

5. Progenics Pharmaceuticals. Azedra^®: Dose Preparation Guide. Accessed 2019 Aug 5. [Web]

6. Noto RB, Pryma DA, Jensen J et al. Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma. J Clin Endocrinol Metab . 2018; 103:213-220. [PubMed 31330766]

7. Jimenez C, Erwin W, Chasen B. Targeted Radionuclide Therapy for Patients with Metastatic Pheochromocytoma and Paraganglioma: From Low-Specific-Activity to High-Specific-Activity Iodine-131 Metaiodobenzylguanidine. Cancers (Basel) . 2019; 11:1-20. [PubMed 31330766]

8. Jimenez C. Treatment for Patients With Malignant Pheochromocytomas and Paragangliomas: A Perspective From the Hallmarks of Cancer. Front Endocrinol (Lausanne) . 2018; 9:1-12. [PubMed 29892268]

9. Progenics Pharmaceuticals. Understanding Azedra^® Therapy. Accessed 2019 Aug 12. [Web]

10. Neumann HPH, Young WF, Eng C. Pheochromocytoma and Paraganglioma. NEJM . 2019; 318:522-65. [PubMed 31390501]

11. Progenics Pharmaceuticals. Patient schedule for the Azedra^® (iobenguane I 131) therapeutic regimen. Accessed 2019 Oct 2. [Web]

12. Progenics Pharmaceuticals. Azedra^®: Dosing and administration guide. Accessed 2019 Oct 2. [Web]

13. Progenics Pharmaceuticals. Azedra^®: Dosimetry guide. Accessed 2019 Oct 2. [Web]