AZEDRA Solution for injection Ref.[10319] Active ingredients: Iobenguane ¹³¹I

The effect of AZEDRA on the QTc interval was evaluated in 74 patients with unresectable pheochromocytoma or paraganglioma. At the recommended therapeutic dosage, no large mean increases from baseline in the QTc interval (i.e., >20 ms) were detected.

The pharmacokinetics (PK) of iobenguane I 131 following a dosimetric dose were characterized in patients with malignant PPGL and other malignancies. The mean blood area under curve (AUC) of iobenguane I 131 at the recommended dosimetric dose is 1 µCi*h/mL (CV 33%). The mean maximum concentration (C_max) for iobenguane I 131 is 0.06 µCi/mL (CV 36%), which generally occurred at the end of the AZEDRA infusion.

Distribution

The volume of distribution (mean ± SD) of iobenguane I 131 is 2893 ± 592 mL/kg. The blood levels of radioactivity declined with a distribution half-life (mean ± SD) of 0.37 ± 0.22 hours. The non-radioactive form of iobenguane I 131 is 61% to 63% bound to human plasma proteins.

Elimination

The mean clearance is 62 ± 24 mL/hr/kg for iobenguane I 131 and the mean terminal blood half-life is 35 ± 14 hours.

Metabolism

Iobenguane I 131 does not undergo hepatic metabolism.

Excretion

Iobenguane I 131 is primarily eliminated renally with cumulative excretion of 50 ± 10% within 24 hours and 80 ± 10% within 120 hours following AZEDRA administration. Unchanged I 131 accounted for an average of 94% and 93% radioactivity excreted in urine collected at 0-6 and 6-24 hours post-dose, respectively. Minor metabolites detected in some patients included free I 131, quantifiable in 55% of 11 patients in Study IB11, as well as meta-iodohippuric acid (MIHA) and meta-iodobenzyl bisguanidine (MMIBG) quantifiable in one patient each.

Specific Populations

Eight of 42 patients (19%) with mild or moderate renal impairment (CLcr ≥30-89 mL/min by Cockcroft-Gault) required therapeutic dose reductions based on radiation dose estimates to critical organs exceeding Emami limits (absorbed renal dose exceeding 23 Gy). The pharmacokinetics of iobenguane I 131 has not been studied in patients with severe renal impairment (CLcr <30 mL/min) or end-stage renal disease [see Use in Specific Populations (8.6)].

Drug Interaction Studies

In Vitro Studies

The non-radioactive form of iobenguane does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A. It does not induce CYP1A, 2B6, 2C9, 2C19, or 3A. It is not a substrate or inhibitor of P-glycoprotein.

Carcinogenicity studies with iobenguane I 131 have not been conducted; however, radiation is a carcinogen and a mutagen. No animal studies were conducted to determine the effects of iobenguane I 131 on fertility.

The efficacy of AZEDRA in patients with iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL) which require systemic anticancer therapy was established in Study IB12B, an open-label, single-arm, multicenter clinical trial (NCT00874614). Patients were at least 12 years of age and were ineligible for curative therapy. Patients also progressed on prior therapy for PPGL or were not candidates for chemotherapy. Other eligibility criteria required patients' tumors to have definitive iobenguane avidity; at least one tumor site identified by computed tomography (CT), magnetic resonance imaging (MRI), or iobenguane I 131 scan; Karnofsky performance status ≥60; absence of active central nervous system lesions, and no changes to their antihypertensive regimen in the 30 days prior to the first therapeutic dose.

The major efficacy outcome measure was the proportion of patients who experienced a 50% or greater reduction of all antihypertensive medication(s) lasting for at least six months (28 days per month). Overall tumor response measured by RECIST (Response Evaluation Criteria in Solid Tumors version 1.0) was also evaluated. After the final 12-month assessment, patients entered into long-term follow-up for up to 4 additional years.

A total of 74 patients received the dosimetric dose of AZEDRA. Following dosimetry, 68 patients received at least one therapeutic dose and 50 patients received two therapeutic doses administered at least 90 days apart. The dosimetric dose was 185 mBq to 222 MBq (5 mCi to 6 mCi) for patients weighing >50 kg and 3.7 MBq/kg (0.1 mCi/kg) for patients weighing ≤50 kg. The therapeutic dose was 18,500 MBq (500 mCi) for patients weighing >62.5 kg and 296 MBq/kg (8 mCi/kg) for patients weighing ≤62.5 kg. Among the 68 patients, the median age was 55 years (16 to 72 years), 57% were male, 75% were White, 21% were Black, and 4% were Asian. For the primary tumor diagnosis, 78% had pheochromocytoma, 21% had paraganglioma, and 1% had both. Fifty percent (50%) of patients with evaluable imaging studies had lung or liver metastases and 61% had bone metastases at baseline. Eighty-eight percent (88%) underwent prior surgery, 50% received prior external radiation, 31% received prior I 131 MIBG, 31% received prior chemotherapy, 15% received prior kinase inhibitors and 4% received other prior systemic therapies. The median (range) of prior therapies per patient is 2 (0, 7).

The efficacy results are summarized in Table 7. All confirmed responses per RECIST were partial responses.

Table 7. Efficacy Results in Patients with Pheochromocytoma or Paraganglioma in Study IB12B:

^a Calculated using the Agresti-Coull method.
^b Exact Confidence Interval.