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July 30, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209607s000lbl.pdf

On July 30, 2018, the Food and Drug Administration approved iobenguane I 131 (AZEDRA, Progenics Pharmaceuticals, Inc.) for adult and pediatric patients (12 years and older) with iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL) who require systemic anticancer therapy.

Approval was based on Study IB12B (NCT00874614), an open-label, single-arm, multicenter clinical trial in patients 12 years and older with iobenguane scan-positive, unresectable, locally advanced or metastatic PPGL. Of the 68 evaluable patients, 17 (25%; 95% CI: 16%, 37%) experienced a 50% or greater reduction of all antihypertensive medication for at least six months. Overall tumor response (RECIST 1.0) occurred in 15 patients (22%; 95% CI: 14%, 33%), with 53% achieving a response duration of at least 6 months.

The most common grade 3-4 adverse reactions (≥10%) were lymphopenia, neutropenia, thrombocytopenia, fatigue, anemia, increased international normalized ratio, nausea, dizziness, hypertension, and vomiting. In the pooled safety population, 6.8% of patients who received a therapeutic dose of iobenguane I 131 developed myelodysplastic syndrome or acute leukemia.

Iobenguane I 131 is administered in an initial dosimetric dose, followed by two therapeutic doses that are adjusted based on dosimetry. The recommended therapeutic dose is 18,500 MBq (500 mCi) for patients weighing more than 62.5 kg and 296 MBq/kg (8 mCi/kg) for patients 62.5 kg or less.

View full prescribing Information for Azedra.

FDA granted this application priority review, orphan product, fast track status, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist’s Applications to Practice

Iobenguane I 131 for Treatment of Iobenguane Scan–Positive Unresectable Locally Advanced or Metastatic Pheochromocytoma or Paraganglioma

Author: Ashley Sabus, PharmD
PGY-2 Pediatric Pharmacy Resident
Children’s Hospital Colorado
Aurora, CO

What is the potential role for iobenguane I 131 in the treatment of pheochromocytoma or paraganglioma?

  • Iobenguane I 131 is the first medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of unresectable locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL) requiring systemic therapy.1 The structure of iobenguane I 131 is similar to that of norepinephrine (NE), permitting uptake by NE transporters and accumulation in adrenergically innervated tissues. Pheochromocytoma and paraganglioma have a neural crest origin and are therefore sensitive to iobenguane I 131 uptake. Radiation exposure from I 131 decay leads to cell death and tumor necrosis.2
  • Surgical resection is the mainstay of treatment for both benign and malignant PPGL. For patients with metastatic disease, the National Comprehensive Cancer Network (NCCN) recommends continuous alpha blockade with or without alpha-methyltyrosine and with or without beta blockade, in combination with cytoreductive resection as first-line therapy.3 Systemic chemotherapy with cyclophosphamide, vincristine, or dacarbazine, or all three, may be used for unresectable disease; however, many tumors are unresponsive to this treatment.3,4 The NCCN also recognizes iodine-131 metaiodobenzylguanidine (MIBG) as a primary treatment option for patients with PPGL, distant metastases, and prior positive MIBG scan with dosimetry.3 Iobenguane I 131 is a novel version of MIBG made with UltraTrace technology, which improves delivery of radiation to the tumor. It is the first effective systemic therapy option, targeting tumor-related symptoms such as high blood pressure for patients with unresectable, metastatic PPGL.1
  • The safety and efficacy of iobenguane I 131 was demonstrated in an open-label multicenter single-arm study of 68 adult and pediatric patients 12 years of age and older with iobenguane scan–positive unresectable locally advanced or metastatic PPGL. The study included an initial 12-month assessment period and 4 years of long-term follow-up. The primary objective was to determine the proportion of patients who experienced a 50% or greater reduction of all antihypertensive medications lasting for at least 6 months. Seventeen out of 68 patients (25%) achieved this objective (95% confidence interval [CI]: 16%–37%).2 Secondarily, the study assessed overall tumor response measured by Response Evaluation Criteria in Solid Tumors Version 1.0 and found that 15 patients (22%) were considered overall responders (95% CI: 14%–33%).2

What role can pharmacists play in the management of patients on iobenguane I 131?

  • Iobenguane I 131 is administered intravenously as a single dosimetric dose followed by two therapeutic doses given 90 days apart. Dosimetry data are used to measure the dosage of ionizing radiation absorbed by body tissues. Therapeutic dose reductions may be required on the basis of this information.2 In adults, treatment should be infused over 30 minutes at a rate of 100 ml/hr. For pediatric patients, it should be administered over 60 minutes at a rate of 50 ml/hr.2
    • Dosimetric dose
      • Patients >50 kg: 185–222 MBq (5 to 6 mCi)
      • Patients 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg)
    • Therapeutic dose
      • Patients >62.5 kg: 18,500 MBq (500 mCi)
      • Patients 62.5 kg or less: 296 MBq/kg (8 mCi/kg)
  • In order to protect against adverse effects of radiation (e.g., hypothyroidism, thyroid neoplasma, bladder irradiation, and nausea), patients should receive pretreatment with the following: inorganic iodine administered at least 24 hours before and for 10 days after each dose of iobenguane I 131; minimum fluid intake of two liters per day starting at least 1 day prior to administration of iobenguane I 131 and continuing for 1 week after the dose; antiemetics administered 30 minutes prior to each dose.2
  • Drugs that reduce catecholamine uptake or deplete stores may interfere with incorporation of iobenguane I 131 into malignant PPGL cells, thereby decreasing therapeutic efficacy. Medications such as central nervous system stimulants, norepinephrine and serotonin reuptake inhibitors, nonselective beta blockers, tricyclic antidepressants, and supplements such as St. John’s wort should be discontinued at least 5 half-lives prior to treatment with iobenguane I 131. Continue to avoid use for at least 7 days after each dose.2
  • Patients treated with iobenguane I 131 commonly experience lymphocytopenia (96%), anemia (93%), thrombocytopenia (91%), increased international normalized ratio (INR) (85%), neutropenia (84%), nausea (78%), fatigue (71%), vomiting (58%), and dizziness (34%). In clinical trial IB12B, patients with grade-4 neutropenia reached neutrophil nadir at a median of 36 days (27–55 days) and recovered to grade 3 or less after a median of 12 days (8–22 days). Time to nadir was more prolonged following the second therapeutic dose, with a median time to nadir of 43 days (38–47 days), and nadir duration of 18.5 days. Hypertension, beginning within 2–4 hours of treatment, was noted in 20% of patients. The risk for acute elevations in blood pressure is highest during the first 24 hours postinfusion.2
  • Less common but severe adverse effects include pneumonitis and secondary malignancies. One case of fatal pneumonitis was reported in clinical trials. If the patient experiences signs and symptoms of this condition, the second dose of iobenguane I 131 should not be administered. In regard to secondary malignancies, approximately 6.8% of patients who received therapeutic doses of iobenguane I 131 developed myelodysplastic syndrome, acute leukemia, or nonhematologic malignancy. Time to development ranged from 12 months to 7 years.2
  • Based on the adverse-effect profile of iobenguane I 131, important monitoring parameters include blood pressure, which should be assessed frequently during the first 24 hours after each therapeutic dose; complete blood cell count (CBC) with differential weekly for up to 12 weeks or until levels return to baseline; thyroid-stimulating hormone (TSH) level before starting therapy and annually thereafter; renal function tests during and after treatment (more frequently for patients with mild or moderate renal impairment); and signs and symptoms of pneumonitis.2
  • In patients with renal impairment, dosimetry data should be used to adjust therapeutic doses on the basis of radiation exposure estimates.2
  • The mechanism of action of iobenguane I 131 suggests that it is likely to cause fetal harm. Patients should be counseled on the importance of using effective contraception during treatment and for 4 months after the last dose in males and 7 months after the last dose in females.2
  • Patients experiencing neutropenia or thrombocytopenia require dose modifications. The first therapeutic dose of iobenguane I 131 should not be administered if the platelet count is less than 80,000/mcl or absolute neutrophil count (ANC) is less than 1,200/mcl. For the second therapeutic dose, hold administration until platelets and neutrophils return to baseline or normal range. The second therapeutic dose should be reduced according to recommended dose modifications for a platelet count <25,000/mcl, ANC <500/mcl, or life-threatening anemia for >7 days, febrile neutropenia, or platelet count <50,000/mcl with active bleeding. Specific guidelines are provided in the package insert.2
  • Azedra Service Connection is a complimentary program that provides one-on-one assistance with out-of-pocket costs and reimbursement. Eligible patients with commercial insurance can use the commercial out-of-pocket programs and independent third-party co-pay foundations for assistance with co-pay expenses. Patients without insurance have access to the Progenics Uninsured Patient Program, which provides Azedra free of cost to those who qualify.5

Clinical Pearls

  • Iobenguane I 131 is classified as a radiopharmaceutical. In order to minimize radiation exposure, those handling the medication should wear waterproof gloves and radiation shielding and use tongs to manipulate the vial.2
  • Iobenguane I 131 is supplied as a single-dose vial (15 mCi/ml) and should be stored at –70 °C. A recording device on the vial will display an alarm icon if the temperature rises above this limit. The shelf life of iobenguane I 131 is 6 days.2
  • With time, iobenguane I 131 may decrease the need for antihypertensive treatment. Monitor blood pressure and adjust medications accordingly.1
  • The safety and efficacy of iobenguane I 131 in pediatric patients 12 years of age and older was established in the IB12B clinical trial. Of note, pediatric patients are at higher risk for adverse effects associated with radiopharmaceuticals because of greater absorption of radiation doses and prolonged life expectancy. Risks and benefits of treatment with iobenguane I 131 in this population should be carefully assessed. No safety or efficacy data exist for children less than 12 years old.2
  • The safety of iobenguane I 131 has not been studied in patients with renal impairment. Delayed clearance may result in increased radiation exposure and significant adverse effects. Avoid use in patients with creatinine clearance (CrCl) <30 ml/min.2

References

  1. U.S. Food and Drug Administration. FDA approves first treatment for rare adrenal tumors. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm615155.htm. 2018. Accessed September 1, 2018.
  2. Azedra (iobenguane I 131) [package insert]. New York, NY: Progenics Pharmaceuticals, Inc.; July 2018.
  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Neuroendocrine and Adrenal Tumors. Version 3.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf. Accessed September 25, 2018.
  4. Jimenez P, Tatsui C, Jessop A, et al. Treatment for malignant pheochromocytomas and paragangliomas: 5 years of progress. Curr Oncol Rep. 2017;19:83.
  5. Azedra Support Program. Available at: https://azedra.com/support-program/. 2018. Accessed September 1, 2018.
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