SPL UNCLASSIFIED SECTION.

2.1 Important Safety Information. AZEDRA is radiopharmaceutical. Handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves and effective radiation shielding when handling AZEDRA. Radiopharmaceuticals, including AZEDRA, should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA [see Use in Specific Populations (8.1), (8.3)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed. (8.2). Lactation: Advise women not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on its mechanism of action, AZEDRA can cause fetal harm [see Clinical Pharmacology 12.1 )]. There are no available data on AZEDRA use in pregnant women. No animal studies using iobenguane 131 have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including AZEDRA, have the potential to cause fetal harm. Advise pregnant women of the risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. 8.2 Lactation. Risk SummaryThere are no data on the presence of iobenguane 131 in human milk or its effects on the breastfed infant or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with AZEDRA and for 80 days after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating AZEDRA [see Use in Specific Populations 8.1 )].ContraceptionAZEDRA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1 )]. FemalesAdvise women of reproductive potential to use effective contraception during treatment with AZEDRA and for months following the final dose of AZEDRA. MalesBased on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with AZEDRA and for months following the final dose of AZEDRA [see Dosage and Administration 2.6 )].InfertilityThe recommended cumulative dose of 37 GBq of AZEDRA results in radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration 2.6 )].. 8.4Pediatric Use. The safety and effectiveness of AZEDRA have been established in patients 12 years and older with unresectable and iobenguane scan positive, locally advanced or metastatic, pheochromocytoma and paraganglioma (PPGL) which require systemic anticancer therapy. Use of AZEDRA for this indication is supported by evidence from an adequate and well-controlled study in adults and pediatric patients 12 years and older [see Adverse Reactions 6.1 ), Clinical Studies 14 )]. The risks of radiation associated with AZEDRA is greater in pediatric patients than that in adult patients due to greater absorbed radiation doses and longer life expectancy. Ensure the therapeutic benefit of AZEDRA outweighs these greater risks prior to administration in pediatric patients. The safety and effectiveness of AZEDRA have not been established in pediatric patients younger than 12 years old with unresectable and iobenguane scan positive, locally advanced or metastatic PPGL which require systemic anticancer therapy. 8.5Geriatric Use. Of the patients enrolled in all clinical studies of AZEDRA, 17% were 65 years or older and 1% were 75 years or older. Clinical studies of AZEDRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 Renal Impairment. The radiation dose to patients with renal impairment may be increased due to the delayed elimination of the drug [see Clinical Pharmacology 12 )]. Adjust the therapeutic dose based on radiation exposure estimates from the dosimetry assessment [see Dosage and Administration 2.2 ), Clinical Pharmacology 12 )]. The safety of AZEDRA in patients with severe renal impairment (CLcr 30 mL/min) or end-stage renal disease has not been studied.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Risk from Radiation Exposure: Minimize radiation exposure consistent with institutional radiation safety practices and patient management procedures. (2.1), (5.1)Myelosuppression: Monitor blood cell counts. Withhold and dose reduce AZEDRA as recommended based on severity of cytopenia. (5.2)Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies: The time to development of MDS or acute leukemia ranged from 12 months to years. (5.3)Hypothyroidism: Initiate thyroid-blocking medication prior to administration and continue after each dose. Monitor for hypothyroidism and thyroid-stimulating hormone levels before starting AZEDRA and annually thereafter. (2.3, 5.4)Elevations in blood pressure: Monitor blood pressure frequently during the first 24 hours after each therapeutic dose. (5.5)Renal Toxicity: Monitor renal function during and after treatment. (5.6)Pneumonitis: Monitor patients for signs and symptoms of pneumonitis and treat appropriately. (5.7)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to fetus and to use effective contraception. (5.8)Risk of Infertility: May cause infertility (5.9). Risk from Radiation Exposure: Minimize radiation exposure consistent with institutional radiation safety practices and patient management procedures. (2.1), (5.1). Myelosuppression: Monitor blood cell counts. Withhold and dose reduce AZEDRA as recommended based on severity of cytopenia. (5.2). Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies: The time to development of MDS or acute leukemia ranged from 12 months to years. (5.3). Hypothyroidism: Initiate thyroid-blocking medication prior to administration and continue after each dose. Monitor for hypothyroidism and thyroid-stimulating hormone levels before starting AZEDRA and annually thereafter. (2.3, 5.4). Elevations in blood pressure: Monitor blood pressure frequently during the first 24 hours after each therapeutic dose. (5.5). Renal Toxicity: Monitor renal function during and after treatment. (5.6). Pneumonitis: Monitor patients for signs and symptoms of pneumonitis and treat appropriately. (5.7). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to fetus and to use effective contraception. (5.8). Risk of Infertility: May cause infertility (5.9). 5.1 Risk from Radiation Exposure. AZEDRA contributes to patients overall long-term radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. These risks of radiation associated with the use of AZEDRA are greater in pediatric patients than in adults [see Use in Specific Populations (8.4)]. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with AZEDRA consistent with institutional good radiation safety practices and patient management procedures [see Dosage and Administration (2.1)]. 5.2 Myelosuppression. Severe and prolonged myelosuppression occurred during treatment with AZEDRA [see Adverse Reactions (6.1)]. Among the 88 patients who received therapeutic dose of AZEDRA, 33% experienced Grade thrombocytopenia, 16% experienced Grade neutropenia, and 7% experienced Grade anemia. Five percent of patients experienced febrile neutropenia. In Study IB12B following the first therapeutic dose, patients who experienced Grade neutropenia reached neutrophil nadir at median of 36 days (27 55 days) and remained at nadir for median of 12 days (8 22 days) until recovery to less than or equal to Grade 3. Following the second dose, patients who experienced Grade neutropenia reached nadir at median of 43 days (38 47 days) and remained at nadir for median of 18.5 days (8 31 days) until recovery to less than or equal to Grade 3.Monitor blood cell counts weekly for up to 12 weeks or until levels return to baseline or the normal range. Withhold and dose reduce AZEDRA as recommended based on severity of the cytopenia [see Dosage and Administration (2.4)].. 5.3 Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies. Myelodysplastic syndrome (MDS) or acute leukemias were reported in 6.8% of the 88 patients who received therapeutic dose of AZEDRA [see Adverse Reactions (6.1)]. The time to development of MDS or acute leukemia ranged from 12 months to years.Two of the 88 patients developed non-hematological malignancy. One patient developed colon cancer at 18 months and one patient developed lung adenocarcinoma at 27 months following the first therapeutic dose.. 5.4 Hypothyroidism. Hypothyroidism was reported in 3.4% of the 88 patients who received therapeutic dose of AZEDRA [see Adverse Reactions (6.1)]. The time to worsening of hypothyroidism was months in one patient, and the time to development of hypothyroidism was less than one month in one patient and 18 months in one patient. Initiate thyroid-blocking medications starting at least day before and continuing for 10 days after each AZEDRA dose to reduce the risk of hypothyroidism or thyroid neoplasia [see Dosage and Administration (2.3)]. Evaluate for clinical evidence of hypothyroidism and measure thyroid-stimulating hormone (TSH) levels prior to initiating AZEDRA and annually thereafter.. 5.5 Elevations in Blood Pressure. Eleven percent of the 88 patients who received therapeutic dose of AZEDRA [see Adverse Reactions (6.1)] experienced worsening of pre-existing hypertension defined as an increase in systolic blood pressure to >=160 mmHg with an increase of 20 mmHg or an increase in diastolic blood pressure to >= 100 mmHg with an increase of 10 mmHg. All changes in blood pressure occurred within the first 24 hours post infusion. Monitor blood pressure frequently during the first 24 hours after each therapeutic dose of AZEDRA.. 5.6 Renal Toxicity. Of the 88 patients who received therapeutic dose of AZEDRA [see Adverse Reactions (6.1)], 7% developed renal failure or acute kidney injury and 22% demonstrated clinically significant decrease in glomerular filtration rate (GFR) measured at or 12 months. Monitor renal function during and after treatment with AZEDRA. Patients with baseline renal impairment may be at greater risk of toxicity; perform more frequent assessments of renal function in patients with mild or moderate impairment. AZEDRA has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min).. 5.7 Pneumonitis. Fatal pneumonitis occurred weeks after single dose in one patient in the expanded access program for Study IB12B (n=11). Pneumonitis was not diagnosed among the 88 patients enrolled in Study IB12 or IB12B [see Adverse Reactions 6.1 )]. Monitor patients for signs and symptoms of pneumonitis and treat appropriately. 5.8 Embryo-Fetal Toxicity Based on its mechanism of action, AZEDRA can cause fetal harm. There are no available data on the use of AZEDRA in pregnant women. No animal studies using iobenguane 131 have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including AZEDRA, have the potential to cause fetal harm.Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA [see Dosage and Administration (2.1)]. Advise females and males of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with AZEDRA and for months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for months after the final dose [see Use in Specific Populations (8.1), (8.3)].. 5.9 Risk of Infertility Radiation exposure associated with AZEDRA may cause infertility in males and females. The recommended cumulative dose of 37 GBq of AZEDRA results in radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration (2.6), Use in Specific Populations (8.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described elsewhere in the labeling:Myelosuppression [see Warnings and Precautions (5.2)] Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies [see Warnings and Precautions (5.3)] Hypothyroidism [see Warnings and Precautions (5.4)] Elevations in Blood Pressure [see Warnings and Precautions (5.5)] Renal Toxicity [see Warnings and Precautions (5.6)] Pneumonitis [see Warnings and Precautions (5.7)] Myelosuppression [see Warnings and Precautions (5.2)] Secondary Myelodysplastic Syndrome, Leukemia and Other Malignancies [see Warnings and Precautions (5.3)] Hypothyroidism [see Warnings and Precautions (5.4)] Elevations in Blood Pressure [see Warnings and Precautions (5.5)] Renal Toxicity [see Warnings and Precautions (5.6)] Pneumonitis [see Warnings and Precautions (5.7)] The most common Grade 3-4 adverse reactions (>= 10%) were lymphopenia, neutropenia, thrombocytopenia, fatigue, anemia, increased international normalized ratio, nausea, dizziness, hypertension, and vomiting. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Progenics Pharmaceuticals, Inc at 1-800-362-2668 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The data in Warnings and Precautions reflect exposure to AZEDRA in 88 patients with iobenguane-scan positive recurrent or unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL) who received therapeutic dose of AZEDRA in one of two clinical studies (IB12 or IB12B). The Warnings and Precautions also include data from 11 patients enrolled in an expanded access program for Study IB12B [see Warnings and Precautions (5)].The safety data below was evaluated in two studies in patients with recurrent or unresectable, locally advanced or metastatic PPGL. Study IB12 was an open-label, multi-center, single-arm dose-finding study in adult patients with malignant or recurrent PPGL. The study consisted of 12-month efficacy phase with 1 year follow-up. Twenty-one patients received dosimetric dose (~5 mCi), followed by one therapeutic dose (~500 mCi) of AZEDRA. Study IB12B was an open-label, multi-center, single-arm study in 68 adult and pediatric patients age 12 years and older with recurrent or unresectable, locally advanced or metastatic PPGL [see Clinical Studies (14)]. Patients with evidence of liver dysfunction (aspartate aminotransferase or alanine aminotransferase >= 2.5 times the upper limit of normal or total bilirubin 1.5 times the upper limit of normal), history of liver disease (including hepatitis and chronic alcohol abuse), or severe renal impairment (creatinine clearance 30 mL/min) were excluded. Patients who had received external beam radiation to 25% of bone marrow, received whole body radiotherapy, or who had received any systemic radiotherapy resulting in myelosuppression within months of study entry, were also excluded. The safety data described below are based on pooled safety data from studies IB12 and IB12B. total of 88 patients received at least one therapeutic dose of AZEDRA and 50 patients received two therapeutic doses (one patient received treatment in both studies). Adverse reactions from studies IB12 and IB12B are presented in Table 5. The most common severe (Grade 3-4) adverse reactions were lymphopenia (78%), neutropenia (59%), thrombocytopenia (50%), fatigue (26%), anemia (24%), increased international normalized ratio (18%), nausea (16%), dizziness (13%), hypertension (11%), and vomiting (10%). Twelve percent of patients discontinued treatment due to adverse reactions (thrombocytopenia, anemia, lymphopenia, nausea and vomiting, multiple hematologic adverse reactions).Table 5: Adverse Reactions Occurring in >=10% of Patients with PPGL Receiving Therapeutic Dose of AZEDRA in Studies IB12B and IB12 aNCI CTCAE version 3.0.bBased on laboratory data.cIncludes vomiting and retching.dIncludes sialoadenitis, salivary gland pain, and salivary gland enlargement.eIncludes abdominal pain, abdominal pain upper, and abdominal pain lower.fIncudes fatigue, asthenia. gIncludes upper respiratory tract infection, sinusitis, rhinorrhea, upper-airway cough syndrome, nasopharyngitis.hOnly assessed in Study IB12B (N=68).iIncludes dizziness and dizziness postural.jIncludes dysgeusia, hypogeusia and ageusia.kIncludes blood pressure increased and hypertension.Adverse ReactionAll Gradesa, (%)Gradesa - 4, (%)Hematologicb Lymphopenia9678 Anemia9324 Thrombocytopenia9150 Neutropenia8459Gastrointestinal Nausea7816 Vomitingc 5810 Dry mouth482 Sialadenitisd 391 Diarrhea253 Abdominal paine 236 Constipation197 Oropharyngeal pain140 Dyspepsia100General Fatiguef 7126 Pyrexia142 Injection site pain100 Hyperhidrosis100 Alopecia100Infections Upper respiratory tract infectiong 162 Urinary tract infection111Investigationsb Increased international normalized ratioh 8518 Increased blood alkaline phosphatase535 Increased aspartate aminotransferase502 Increased alanine aminotransferase432Metabolism and nutrition Decreased appetite305 Dehydration164 Decreased weight 161Musculoskeletal and connective tissue disorders Back pain172 Pain in extremity 150Nervous system Dizzinessi 3413 Headache326 Dysgeusiaj 241Respiratory, thoracic, and mediastinal disorders Cough180 Dyspnea187Vascular Hypotension244 Hypertensionk 2011 Tachycardia103The following clinically significant adverse reactions were observed in 10% of patients treated with AZEDRA:Cardiac: palpitations (9%), syncope and presyncope (8%)Endocrine: decreased TSH (5%), hypothyroidism (3%) Gastrointestinal: dysphagia (7%), abdominal distension (6%), gastroesophageal reflux disease (6%), stomatitis (3%)General: insomnia (9%), chills (8%), chest pain (6%)Infections: candida infection (6%) Investigations: prolonged prothrombin time (9%)Musculoskeletal and connective tissue: arthralgia (8%), neck pain (8%), pain in jaw (7%), muscle spasms (6%)Renal and urinary disorders: proteinuria (9%), renal failure (7%), Respiratory: epistaxis (9%), nasal congestion (7%), pulmonary embolism (3%)Skin and subcutaneous tissue: dry skin (8%), rash (8%), petechiae (7%) Vascular: orthostatic hypotension (9%).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. AZEDRA is an 131 labeled iobenguane. Iobenguane is similar in structure to the neurotransmitter norepinephrine (NE) and is subject to the same uptake and accumulation pathways as NE. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues, such as the heart, lungs, adrenal medulla, salivary glands, liver, and spleen as well as tumors of neural crest origin. Pheochromocytoma and paraganglioma (PPGL) are tumors of neural crest origin that express high levels of the NE transporter on their cell surfaces. Following intravenous administration, AZEDRA is taken up and accumulates within pheochromocytoma and paraganglioma cells, and radiation resulting from radioactive decay of 131 causes cell death and tumor necrosis.. 12.2 Pharmacodynamics. 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.. 12.3 Pharmacokinetics. The pharmacokinetics (PK) of iobenguane 131 following dosimetric dose were characterized in patients with malignant PPGL and other malignancies. The mean blood area under curve (AUC) of iobenguane 131 at the recommended dosimetric dose is uCih/mL (CV 33%). The mean maximum concentration (Cmax) for iobenguane 131 is 0.06 uCi/mL (CV 36%), which generally occurred at the end of the AZEDRA infusion.DistributionThe volume of distribution (mean +- SD) of iobenguane 131 is 2893 +- 592 mL/kg. The blood levels of radioactivity declined with distribution half-life (mean +- SD) of 0.37 +- 0.22 hours. The non-radioactive form of iobenguane 131 is 61% to 63% bound to human plasma proteins. EliminationThe mean clearance is 62 +- 24 mL/hr/kg for iobenguane 131 and the mean terminal blood half-life is 35 +- 14 hours.MetabolismIobenguane 131 does not undergo hepatic metabolism.ExcretionIobenguane 131 is primarily eliminated renally with cumulative excretion of 50 +- 10% within 24 hours and 80 +- 10% within 120 hours following AZEDRA administration. Unchanged 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 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 PopulationsEight 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 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 StudiesIn Vitro StudiesThe 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 substrate or inhibitor of P-glycoprotein.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 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 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 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 additional years. 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 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 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 (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 IB12Ba Calculated using the Agresti-Coull method.b Exact Confidence Interval.At least the first therapeutic dose N=68Reduction of all antihypertensive medications by at least 50% maintained for at least months, (%) Number of patients17 Proportion of patients (95% CIa)25% (16%, 37%)Best confirmed overall tumor response per RECIST Number of patients15 Overall response rate (95%CIb)22% (14%, 33%) Responders with Duration of Response >= months53%.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None.

DESCRIPTION SECTION.

11 DESCRIPTION. AZEDRA (iobenguane 131) injection, for intravenous use, is radioactive therapeutic agent. The drug substance iobenguane 131 is substituted benzylguanidine with 131 in the meta position of the benzene ring.Iobenguane 131 is described as 131 meta-iodobenzylguanidine. The molecular weight is 279.1 Daltons and the structural formula is as follows:AZEDRA (iobenguane 131) 555 MBq/mL (15 mCi/mL) injection is sterile, clear, colorless to pale yellow solution. Each single-dose vial contains iobenguane (0.006 mg/mL), sodium ascorbate (58 mg/mL) and sodium gentisate (23 mg/mL) in Water for Injection, USP. The pH range of the solution is 4.5 to 5.5, with specific activity of ~2,500 mCi/mg (92,500 MBq/mg).. Chemical Structure. 11.1 Physical Characteristics. 131 decays with beta and gamma emissions with physical half-life of 8.021 days. The principal beta emission has mean energy of 191.6 keV, and the principal gamma emission has energy of 364.5 keV.. 11.2 External Radiation. The specific gamma ray constant for 131 is 2.2 R/mCi hour at cm. 2.55 cm thickness of Pb will attenuate the radiation emitted by factor of about 1,000.Table summarizes radioactive decay properties of 131.Table 6: Physical Decay Chart: Iodine 131: Half-Life 8.021 Days.a Calibration day.DaysFraction Remaining0a 110.91720.84130.77240.70850.64960.59570.54680.50190.459100.421110.387120.355130.325140.298.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Verify pregnancy status in females of reproductive potential prior to administering AZEDRA. (2.1)Block thyroid prior to administering AZEDRA. (2.2)Do not administer if platelet count is less than 80,000/mcL or absolute neutrophil count is less than 1,200/mcL. (2.4)Administer AZEDRA intravenously as dosimetric dose followed by two therapeutic doses administered 90 days apart. (2.2)The recommended dosimetric dose is: Patients greater than 50 kg: 185 to 222 MBq (5 to mCi) Patients 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg) The recommended therapeutic dose for each of the doses is: Patients greater than 62.5 kg: 18,500 MBq (500 mCi) Patients 62.5 kg or less: 296 MBq/kg (8 mCi/kg) Adjust AZEDRA therapeutic doses based on radiation dose estimates results from dosimetry, if needed. (2.2). Verify pregnancy status in females of reproductive potential prior to administering AZEDRA. (2.1). Block thyroid prior to administering AZEDRA. (2.2). Do not administer if platelet count is less than 80,000/mcL or absolute neutrophil count is less than 1,200/mcL. (2.4). Administer AZEDRA intravenously as dosimetric dose followed by two therapeutic doses administered 90 days apart. (2.2). The recommended dosimetric dose is: Patients greater than 50 kg: 185 to 222 MBq (5 to mCi) Patients 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg) Patients greater than 50 kg: 185 to 222 MBq (5 to mCi) Patients 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg). The recommended therapeutic dose for each of the doses is: Patients greater than 62.5 kg: 18,500 MBq (500 mCi) Patients 62.5 kg or less: 296 MBq/kg (8 mCi/kg) Patients greater than 62.5 kg: 18,500 MBq (500 mCi) Patients 62.5 kg or less: 296 MBq/kg (8 mCi/kg). Adjust AZEDRA therapeutic doses based on radiation dose estimates results from dosimetry, if needed. (2.2). 2.1 Important Safety Information. AZEDRA is radiopharmaceutical. Handle with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.1)]. Use waterproof gloves and effective radiation shielding when handling AZEDRA. Radiopharmaceuticals, including AZEDRA, should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA [see Use in Specific Populations (8.1), (8.3)].. 2.2Recommended Dosage. Administer thyroid blockade and other pre- and concomitant medications as recommended [see Dosage and Administration (2.3)].Dosimetric DoseThe recommended AZEDRA dosimetric dose administered as an intravenous injection is:Patients weighing greater than 50 kg: 185 to 222 MBq (5 or mCi)Patients weighing 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg)Dosimetry and Biodistribution AssessmentFollowing the AZEDRA dosimetric dose:Acquire anterior/posterior whole body gamma camera images within hour of the AZEDRA dosimetric dose and prior to patient voiding (Day 0; Scan 1).Acquire additional images on Day or following patient voiding (Scan 2).Acquire additional images between Days 2-5 following patient voiding (Scan 3).For each individual patient, calculate the radiation dose estimates to normal organs and tissues per unit activity [D (organ)] of administered dose using data extracted from these images. Calculate in accordance with the Medical Internal Radiation Dose (MIRD) schema or related methodology. Whenever possible, use patient-specific organ masses (e.g., estimated from imaging).Therapeutic DosageThe recommended AZEDRA therapeutic dose is based on body weight and reduced, if necessary, based on the dosimetry data. Administer total of therapeutic doses intravenously minimum of 90 days apart.Weight Based Dose per Therapeutic CyclePatients weighing greater than 62.5 kg: 18,500 MBq (500 mCi)Patients weighing 62.5 kg or less: 296 MBq/kg (8 mCi/kg)Determine if Dose Reduction Needed Based on Critical Organ LimitsCalculate the estimated critical organ absorbed-dose by multiplying the dosimetry-derived radiation absorbed-dose per unit activity [D (organ)] by weight based therapeutic total activity (Aw).If resulting estimated critical organ absorbed-dose is less than threshold absorbed-dose (T) shown in Table 1, no dose adjustment is necessary.If resulting estimated critical organ absorbed-dose exceeds threshold absorbed-dose (T) shown in Table 1, calculate the reduced therapeutic total activity (i.e., the cumulative activity that would be administered in therapeutic cycles) using the following equation: Reduced Therapeutic Total Activity= Aw x[T Aw D (organ)]Example: 75 kg patient qualifies for therapeutic total activity of 1000 mCi (Aw). For the kidneys, the dosimetry yields an estimated critical organ absorbed dose per unit activity of 0.027 Gy/mCi [D (kidney)]. Thus, the estimated critical organ absorbed-dose to the kidney is 27 Gy [Aw D (organ)], which exceeds the threshold absorbed-dose for the kidneys (T) of 18 Gy (Table 1). Using the equation above the reduced therapeutic total activity to be administered to this patient is 666.7 mCi. 1000 mCi [18 Gy 1000 mCi 0.027 Gy/mCi]Table 1: Absorbed-dose Threshold Values for Radiation Toxicity in Critical OrgansThreshold of ~0.5 Gy for both heart and carotid artery, derived from experience with external-beam radiotherapy and associated with fractionated exposure, has also been proposed to support an ~1% mortality rate of cardiovascular and cerebrovascular deaths in >10-15 years; however, uncertainty is associated with the value 0.5 Gy cited for vascular disease (ICRP publication 118, p.300, Table 4.5). Consider benefits/risks to patients.Organ~1%-rate: mortality or organ failure associated with diseaseTime to death or organ failureThreshold absorbed-dose for ~1%-rate mortality or organ failure (Gy)Red marrowH-ARS mortality1-2 months12LungsPneumonitis mortality1-7 months16.5KidneysRenal failure>1 year18LiverHepatomegaly, ascites: possible organ failure0.5-3 months31Small intestineGI-ARS mortality6-9 days40. Patients weighing greater than 50 kg: 185 to 222 MBq (5 or mCi). Patients weighing 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg). Acquire anterior/posterior whole body gamma camera images within hour of the AZEDRA dosimetric dose and prior to patient voiding (Day 0; Scan 1).. Acquire additional images on Day or following patient voiding (Scan 2).. Acquire additional images between Days 2-5 following patient voiding (Scan 3).. Patients weighing greater than 62.5 kg: 18,500 MBq (500 mCi). Patients weighing 62.5 kg or less: 296 MBq/kg (8 mCi/kg). Calculate the estimated critical organ absorbed-dose by multiplying the dosimetry-derived radiation absorbed-dose per unit activity [D (organ)] by weight based therapeutic total activity (Aw).. If resulting estimated critical organ absorbed-dose is less than threshold absorbed-dose (T) shown in Table 1, no dose adjustment is necessary.. If resulting estimated critical organ absorbed-dose exceeds threshold absorbed-dose (T) shown in Table 1, calculate the reduced therapeutic total activity (i.e., the cumulative activity that would be administered in therapeutic cycles) using the following equation: Reduced Therapeutic Total Activity= Aw x[T Aw D (organ)]. Example: 75 kg patient qualifies for therapeutic total activity of 1000 mCi (Aw). For the kidneys, the dosimetry yields an estimated critical organ absorbed dose per unit activity of 0.027 Gy/mCi [D (kidney)]. Thus, the estimated critical organ absorbed-dose to the kidney is 27 Gy [Aw D (organ)], which exceeds the threshold absorbed-dose for the kidneys (T) of 18 Gy (Table 1). Using the equation above the reduced therapeutic total activity to be administered to this patient is 666.7 mCi. 1000 mCi [18 Gy 1000 mCi 0.027 Gy/mCi]. 2.3Thyroid Blockade and Other Pre- and Concomitant Medications. Thyroid BlockadeAdminister inorganic iodine starting at least 24 hours before and continuing for 10 days after each AZEDRA dose [see Warnings and Precautions (5.4)]. HydrationInstruct patients to increase fluid intake to at least two liters day starting at least day before and continuing for week after each AZEDRA dose to minimize irradiation to the bladder [see Warnings and Precautions (5.1)]. Drugs that Reduce Catecholamine Uptake or Deplete StoresDiscontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least half-lives before administration of either the dosimetry dose or therapeutic dose of AZEDRA. Do not administer these drugs until at least days after each AZEDRA dose [see Drug Interactions (7.1)]. AntiemeticAdminister antiemetics 30 minutes prior to administering each AZEDRA dose.. 2.4Dose Modifications for Adverse Reactions. Recommended dose modifications of AZEDRA for adverse reactions are provided in Table and the recommended dose or dose reduction for the second therapeutic dose of AZEDRA for myelosuppression are provided in Table 3.Table 2: Recommended Dose Modifications of AZEDRA for Adverse ReactionsAdverse ReactionDose ModificationMyelosuppression [see Warnings and Precautions (5.2)] Do not administer the first therapeutic dose for platelet counts less than 80,000/mcL or absolute neutrophil counts (ANC) less than 1,200/mcL.Do not administer the second therapeutic dose until platelets and neutrophils return to baseline or to the normal range. Reduce the second therapeutic dose for the following: platelet count less than 25,000/mcL, ANC less than 500/mcL, or life-threatening anemia for more than days febrile neutropenia platelet count less than 50,000/mcL with active bleedingPneumonitis [see Warnings and Precautions (5.7)] Do not administer the second therapeutic dose if pneumonitis is diagnosed after the first therapeutic dose. Table 3: Recommended Dose or Dose Reduction for Second Therapeutic Dose of AZEDRA for MyelosuppressionPatient PopulationIf first therapeutic dose was weight based,If first therapeutic dose was reduced based on critical organ limits,Patients weighing greater than 62.5 kgReduce the second therapeutic dose to 425 mCi Reduce second therapeutic dose to 85% of the first dosePatients weighing 62.5 kg or lessReduce the second therapeutic dose to mCi/kgReduce second therapeutic dose to 85% of the first dose. platelet count less than 25,000/mcL, ANC less than 500/mcL, or life-threatening anemia for more than days febrile neutropenia platelet count less than 50,000/mcL with active bleeding. 2.5Preparation and Administration. Refer to the Package Handling Instructions supplied with the frozen vial. Discard if the temperature recording device displays an alarm icon indicating that the temperature exceeded -70oC during shipment.Use aseptic technique and radiation shielding when administering the AZEDRA solution. Use tongs when handling vial to minimize radiation exposure.Confirm the amount of radioactivity of AZEDRA in the radiopharmaceutical vial with an appropriate dose calibrator prior to and after AZEDRA administration.Inspect visually for particulate matter and discoloration prior to administration whenever solution and container permit. The AZEDRA solution should be clear, colorless to pale yellow solution without any particulate matter. Discard if particulate matter or discoloration is observed.Dosimetric Dose PreparationThaw the vial to room temperature in lead pot. Do not heat or refreeze. Confirm complete thawing and gently swirl to ensure homogeneity.Insert venting unit (consisting of needle, 0.2-micron sterile filter, and charcoal filter) to avoid pressurizing the contents of the vial during dilution. Swirl gently to ensure homogeneity.Add sufficient volume of 0.9% Sodium Chloride Solution, USP to the vial to yield concentration of mCi/mL (37 MBq/mL). Swirl gently to ensure homogeneity.Draw the dosimetric dose into 10 mL shielded syringe and place in the dose calibrator to ensure that the activity is within +- 10% of dose. Discard unused medicinal product or waste material in accordance with local and federal laws. Maintain at room temperature and administer within hours of retrieval from frozen storage.Dosimetric Dose AdministrationAdminister the dosimetric dose over 60 seconds.Therapeutic Dose PreparationThaw the appropriate number of vials (2 or 3) to room temperature in lead pots. Do not heat or refreeze.Swirl each AZEDRA vial to ensure homogeneity.Insert venting unit into each AZEDRA vial to avoid pressurizing the contents of the vial during dilution.Insert venting unit into sterile 50-mL glass vial. Transfer the entire contents of the two therapeutic vials into 50-mL glass vial. Measure the radioactivity. If radioactivity in the 50-mL glass vial exceeds the therapeutic dose, withdraw and discard the appropriate volume using shielded syringe. Add 0.9% Sodium Chloride Solution, USP to total volume of 50 mL. If radioactivity in the 50-mL glass vial is less than the therapeutic dose, use shielded syringe to withdraw the appropriate volume from third AZEDRA vial and add to the 50-mL glass vial. Add 0.9% Sodium Chloride Solution, USP to total volume of 50 mL. Swirl gently to ensure homogeneity.Remove the venting unit and place the 50-mL glass vial into dose calibrator to ensure that the activity is within +- 10% of therapeutic dose. Maintain at room temperature and administer within hours of retrieval from frozen storage. Discard unused medicinal product or waste material in accordance with local and federal laws.Therapeutic Dose AdministrationVerify line patency by infusing 250 mL of 0.9% Sodium Chloride Solution, USP (primary intravenous line) at recommended rate of 200 mL/hour.Insert venting unit into the 50-mL glass vial containing the AZEDRA therapeutic dose.Assemble second intravenous line using 19 Gauge 5-inch aspirating needle, 24-inch M-M arterial pressure tubing and primary set specific connector.Clamp the second intravenous line and connect it to the primary intravenous line using the primary set specific connector. Flush the second intravenous line by releasing the clamp and then re-clamp the second intravenous line. Insert the needle of the second intravenous line into the 50-mL glass vial containing the AZEDRA therapeutic dose. Ensure the needle reaches the bottom of the glass vial without touching the sides of the vial.Clamp the primary intravenous line just above the second intravenous line and remove the clamp from the secondary intravenous line.Administer the AZEDRA therapeutic dose over 30 minutes at recommended rate of 100 mL/hour for adults; for pediatric patients 12 years and older administer over 60 minutes at recommended rate of 50 mL/hr. Clamp the secondary intravenous line when the first air bubbles form. Remove the clamp from the primary intravenous line to flush any residual AZEDRA therapeutic dose within this intravenous line with at least 50 mL of 0.9% Sodium Chloride Solution, USP. Remove the clamp from the secondary intravenous line to flush any residual drug in the secondary intravenous line into the 50-mL glass vial.. Refer to the Package Handling Instructions supplied with the frozen vial. Discard if the temperature recording device displays an alarm icon indicating that the temperature exceeded -70oC during shipment.. Use aseptic technique and radiation shielding when administering the AZEDRA solution. Use tongs when handling vial to minimize radiation exposure.. Confirm the amount of radioactivity of AZEDRA in the radiopharmaceutical vial with an appropriate dose calibrator prior to and after AZEDRA administration.. Inspect visually for particulate matter and discoloration prior to administration whenever solution and container permit. The AZEDRA solution should be clear, colorless to pale yellow solution without any particulate matter. Discard if particulate matter or discoloration is observed.. Thaw the vial to room temperature in lead pot. Do not heat or refreeze. Confirm complete thawing and gently swirl to ensure homogeneity.. Insert venting unit (consisting of needle, 0.2-micron sterile filter, and charcoal filter) to avoid pressurizing the contents of the vial during dilution. Swirl gently to ensure homogeneity.. Add sufficient volume of 0.9% Sodium Chloride Solution, USP to the vial to yield concentration of mCi/mL (37 MBq/mL). Swirl gently to ensure homogeneity.. Draw the dosimetric dose into 10 mL shielded syringe and place in the dose calibrator to ensure that the activity is within +- 10% of dose. Discard unused medicinal product or waste material in accordance with local and federal laws. Maintain at room temperature and administer within hours of retrieval from frozen storage.. Administer the dosimetric dose over 60 seconds.. Thaw the appropriate number of vials (2 or 3) to room temperature in lead pots. Do not heat or refreeze.. Swirl each AZEDRA vial to ensure homogeneity.. Insert venting unit into each AZEDRA vial to avoid pressurizing the contents of the vial during dilution.. Insert venting unit into sterile 50-mL glass vial. Transfer the entire contents of the two therapeutic vials into 50-mL glass vial. Measure the radioactivity. If radioactivity in the 50-mL glass vial exceeds the therapeutic dose, withdraw and discard the appropriate volume using shielded syringe. Add 0.9% Sodium Chloride Solution, USP to total volume of 50 mL. If radioactivity in the 50-mL glass vial is less than the therapeutic dose, use shielded syringe to withdraw the appropriate volume from third AZEDRA vial and add to the 50-mL glass vial. Add 0.9% Sodium Chloride Solution, USP to total volume of 50 mL. If radioactivity in the 50-mL glass vial exceeds the therapeutic dose, withdraw and discard the appropriate volume using shielded syringe. Add 0.9% Sodium Chloride Solution, USP to total volume of 50 mL. If radioactivity in the 50-mL glass vial is less than the therapeutic dose, use shielded syringe to withdraw the appropriate volume from third AZEDRA vial and add to the 50-mL glass vial. Add 0.9% Sodium Chloride Solution, USP to total volume of 50 mL.. Swirl gently to ensure homogeneity.. Remove the venting unit and place the 50-mL glass vial into dose calibrator to ensure that the activity is within +- 10% of therapeutic dose. Maintain at room temperature and administer within hours of retrieval from frozen storage. Discard unused medicinal product or waste material in accordance with local and federal laws.. Verify line patency by infusing 250 mL of 0.9% Sodium Chloride Solution, USP (primary intravenous line) at recommended rate of 200 mL/hour.. Insert venting unit into the 50-mL glass vial containing the AZEDRA therapeutic dose.. Assemble second intravenous line using 19 Gauge 5-inch aspirating needle, 24-inch M-M arterial pressure tubing and primary set specific connector.. Clamp the second intravenous line and connect it to the primary intravenous line using the primary set specific connector. Flush the second intravenous line by releasing the clamp and then re-clamp the second intravenous line. Insert the needle of the second intravenous line into the 50-mL glass vial containing the AZEDRA therapeutic dose. Ensure the needle reaches the bottom of the glass vial without touching the sides of the vial.. Clamp the primary intravenous line just above the second intravenous line and remove the clamp from the secondary intravenous line.. Administer the AZEDRA therapeutic dose over 30 minutes at recommended rate of 100 mL/hour for adults; for pediatric patients 12 years and older administer over 60 minutes at recommended rate of 50 mL/hr. Clamp the secondary intravenous line when the first air bubbles form. Remove the clamp from the primary intravenous line to flush any residual AZEDRA therapeutic dose within this intravenous line with at least 50 mL of 0.9% Sodium Chloride Solution, USP. Remove the clamp from the secondary intravenous line to flush any residual drug in the secondary intravenous line into the 50-mL glass vial.. 2.6 Radiation Dosimetry. The mean of the estimated radiation absorbed doses for AZEDRA are shown in Table 4.Table 4: Radiation Absorbed Dose Estimates by Target Organ Following Intravenous Administration of ~5 mCi AZEDRA Table tends to yield underestimates of absorbed dose for patients weighing less than 65 kg, and tends to yield overestimates for patients weighing more than 65 kg. 1-LLI Wall- Lower Large Intestine Wall.2ULI Wall- Upper Large Intestine Wall.Target OrganMean(mGy/MBq)Minimum(mGy/MBq)Maximum(mGy/MBq)Standard Deviation(mGy/MBq)Salivary Glands1.4990.4867.9571.134LLI Wall1 1.1840.0932.7700.356Thyroid0.7790.07111.0001.409Urinary Bladder Wall0.6140.1410.9300.142ULI Wall2 0.5140.0911.1200.138Liver0.5090.1807.8300.862Kidneys0.3600.0850.7720.163Spleen0.3430.0914.4700.495Lungs0.3230.1233.1700.344Heart Wall0.2720.0731.5500.215Small Intestine0.1940.0850.3470.042Osteogenic Cells0.1510.0850.3690.044Gallbladder Wall0.1460.0830.8520.094Ovaries0.1260.0000.2710.046Pancreas0.1170.0680.4840.054Adrenals0.1160.0670.5350.059Uterus0.1120.0000.2470.041Stomach Wall0.1000.0590.2790.033Thymus0.0830.0490.2120.027Muscle0.0820.0490.1880.024Red Marrow0.0790.0480.1750.022Breasts0.0700.0400.1890.024Skin0.0630.0360.1530.018Testes0.0610.0000.1830.036Brain0.0570.0220.2130.028Total Body0.1070.0640.4140.045.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 555 MBq/mL (15 mCi/mL) as clear, colorless to pale yellow solution in single-dose vial.. Injection: 555 MBq/mL (15 mCi/ml) at TOC as clear solution in single-dose vial. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Drugs that Reduce Catecholamine Uptake or Deplete Stores: Discontinue these drugs prior to and following AZEDRA administration. (2.3), (7.1). Drugs that Reduce Catecholamine Uptake or Deplete Stores: Discontinue these drugs prior to and following AZEDRA administration. (2.3), (7.1). 7.1Drugs that Reduce Catecholamine Uptake or Deplete Stores. Based on the mechanism of action of iobenguane, drugs that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells and therefore interfere with dosimetry calculations or the efficacy of AZEDRA. These drugs were not permitted in clinical trials that assessed the safety and efficacy of AZEDRA. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores, such as those listed below, for at least half-lives before administration of either the dosimetry or therapeutic dose of AZEDRA. Do not administer these drugs until at least days after each AZEDRA dose [see Dosage and Administration (2.3)]. CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine)Norepinephrine and dopamine reuptake inhibitors (e.g. phentermine)Norepinephrine and serotonin reuptake inhibitors (e.g. tramadol)Monoamine oxidase inhibitors (e.g. phenelzine and linezolid)Central monoamine depleting drugs (e.g. reserpine)Non-select beta adrenergic blocking drugs (e.g. labetalol)Alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline)Tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine)Botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St Johns Wort, yohimbine). CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine). Norepinephrine and dopamine reuptake inhibitors (e.g. phentermine). Norepinephrine and serotonin reuptake inhibitors (e.g. tramadol). Monoamine oxidase inhibitors (e.g. phenelzine and linezolid). Central monoamine depleting drugs (e.g. reserpine). Non-select beta adrenergic blocking drugs (e.g. labetalol). Alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline). Tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine). Botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St Johns Wort, yohimbine).

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating AZEDRA [see Use in Specific Populations 8.1 )].ContraceptionAZEDRA can cause fetal harm when administered to pregnant woman [see Use in Specific Populations 8.1 )]. FemalesAdvise women of reproductive potential to use effective contraception during treatment with AZEDRA and for months following the final dose of AZEDRA. MalesBased on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with AZEDRA and for months following the final dose of AZEDRA [see Dosage and Administration 2.6 )].InfertilityThe recommended cumulative dose of 37 GBq of AZEDRA results in radiation absorbed dose to the testes and ovaries within the range where temporary or permanent infertility can be expected following external beam radiotherapy [see Dosage and Administration 2.6 )].

GERIATRIC USE SECTION.

8.5Geriatric Use. Of the patients enrolled in all clinical studies of AZEDRA, 17% were 65 years or older and 1% were 75 years or older. Clinical studies of AZEDRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. AZEDRA injection, containing 555 MBq/mL (15 mCi/mL) of I-131 (as iobenguane 131) and 0.006 mg/mL of iobenguane, is sterile, clear, colorless to pale yellow solution for intravenous use supplied in colorless Type borosilicate glass 30 mL single-dose vial. AZEDRA is supplied in dosimetric (2 mL) and therapeutic (22.5 mL) presentations:Dosimetric: 1,110 MBq (30 mCi) of iobenguane 131 at calibration time (NDC 71258-015-02).Therapeutic: 12,488 MBq (337.5 mCi) of iobenguane 131 at calibration time (NDC 71258-015-22).The product vial is in lead shielded container placed in re-sealable plastic bag. The product is shipped on dry ice in USA DOT Type Radioactive package.Store at -70C (-94F).The shelf life is days post calibration time. Discard appropriately at 144 hours.. Dosimetric: 1,110 MBq (30 mCi) of iobenguane 131 at calibration time (NDC 71258-015-02).. Therapeutic: 12,488 MBq (337.5 mCi) of iobenguane 131 at calibration time (NDC 71258-015-22).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. AZEDRA is indicated for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.. AZEDRA is radioactive therapeutic agent indicated for the treatment of adult and pediatric patients 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. HydrationAdvise patients to drink at least liters of liquid day before and for one week following each dose of AZEDRA to minimize irradiation of the bladder [see Dosage and Administration (2.3)]. Radiation RisksAdvise patients to minimize radiation exposure to household contacts consistent with institutional good radiation safety practices and patient management procedures [see Dosage and Administration (2.3), Warnings and Precautions(5.1)].MyelosuppressionAdvise patients to contact their health care provider for any signs or symptoms of neutropenia, thrombocytopenia, or anemia [see Warnings and Precautions (5.2)].Secondary Myelodysplastic Syndrome, Leukemia and Other MalignanciesAdvise patients of the potential for secondary cancers, including myelodysplastic syndrome, acute leukemia, and other malignancies [see Warnings and Precautions (5.3)].HypothyroidismAdvise patients to take thyroid-blocking agents as prescribed. Advise patients of the need for life-long monitoring for hypothyroidism [see Warnings and Precautions (5.4)].Elevations in Blood PressureAdvise patients to contact their health care provider for signs or symptoms that may occur following tumor-hormone catecholamines release and possible risk of increased blood pressure during or 24 hours following each therapeutic AZEDRA dose [see Warnings and Precautions (5.5)].PneumonitisAdvise patients to contact their health care provider for signs or symptoms of pneumonitis [see Warnings and Precautions (5.7)].Drug InteractionsAdvise patients that some medicines interact with AZEDRA and to contact their health care provider before starting any over the counter medicines or herbal or dietary supplements.Embryo-Fetal ToxicityAdvise pregnant women and males and females of reproductive potential of the potential risk to fetus. Advise females to inform their health care provider of known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1), (8.3)].Advise females of reproductive potential to use effective contraception during treatment with AZEDRA and for months after the final dose [see Use in Specific Populations (8.1), (8.3)]. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AZEDRA and for months after the final dose [see Warnings and Precautions (5.8), Use in Specific Populations (8.3)].Lactation Advise females not to breastfeed during treatment with AZEDRA and for 80 days after the final dose [see Use in Specific Populations (8.2)].InfertilityAdvise females and males patients that AZEDRA may impair fertility [see Warnings and Precautions (5.9), Use in Specific Populations (8.3)].Manufactured for:Progenics Pharmaceuticals, Inc. One World Trade Center, 47th floor, Suite New York, NY 10007AZEDRA(R) is registered trademark of Progenics Pharmaceuticals Inc.516104-0221.

INSTRUCTIONS FOR USE SECTION.

AZEDRA(R) (iobenguane 131) injection, for intravenous use Package Handling InstructionsAlways handle dry ice with care and wear personal protective equipmentIMPORTANT: Make sure to save the following texts for courier to pick up (see directions below):Items that will be collected at time of delivery:Temperature monitorAluminum tubesShipping boxLead pot (this is to be collected during the next scheduled delivery date)Reading the Temperature Monitor Locate the temperature monitor on top of the Styrofoam lid in the shipper (Figure 1) Note: do not disconnect the monitor from the probe Immediately read the display screen for the running icon in the upper left corner of the screen (Figures and 3).If the running icon is not present, do not use the product and call AZEDRA Service Connection immediately at 1-844-AZEDRA1 (1-844-293-3721) for further instructions.If the running icon is present, immediately read the display screen for alarm status: (X) for alarm and () for no alarm at the top of the screen (Figures and 3).Press and hold the stop button for - 10 seconds until the stop icon appears in the upper right corner of the screen (Figures and 5) Note: the running icon will disappear when the monitor is stopped If an alarm icon is displayed after holding the stop button for 5/10 seconds (Figure 4), an (X) will be displayed on the temperature monitor screen, do not use. Store the drug product in the lead pot in -70C freezer, and call AZEDRA Service Connection immediately at 1-844-AZEDRA1 (1-844-293-3721) for further instructions.If no alarm icon is displayed after holding the stop button for 5/10 seconds (Figure 5), check mark () will be displayed on the temperature monitor screen. Store the drug product in the lead pot in -70C freezer, or thaw for use.The courier will remain on site or return the same day as the delivery date to retrieve the stopped temperature monitor with probe attached along with the other packaging texts. Lead pot will be collected during the next scheduled delivery date. Unpacking Procedures Remove the temperature monitor probe by unwrapping the probe from around the handle of the assembly container.Remove the assembly container and holding tube containing the lead pot from the square center aluminum tube (Figure 6).Remove the lead pot by unscrewing the assembly container.Place the lead pot containing AZEDRA into <= -70C storage or thaw for use.Place the assembly container and holding tube back into the square center aluminum tube and save for pick up by the courier. Items that will be collected at time of delivery:Temperature monitorAluminum tubesShipping box. Temperature monitor. Aluminum tubes. Shipping box. Lead pot (this is to be collected during the next scheduled delivery date). Reading the Temperature Monitor Locate the temperature monitor on top of the Styrofoam lid in the shipper (Figure 1) Note: do not disconnect the monitor from the probe Immediately read the display screen for the running icon in the upper left corner of the screen (Figures and 3).If the running icon is not present, do not use the product and call AZEDRA Service Connection immediately at 1-844-AZEDRA1 (1-844-293-3721) for further instructions.If the running icon is present, immediately read the display screen for alarm status: (X) for alarm and () for no alarm at the top of the screen (Figures and 3).Press and hold the stop button for - 10 seconds until the stop icon appears in the upper right corner of the screen (Figures and 5) Note: the running icon will disappear when the monitor is stopped If an alarm icon is displayed after holding the stop button for 5/10 seconds (Figure 4), an (X) will be displayed on the temperature monitor screen, do not use. Store the drug product in the lead pot in -70C freezer, and call AZEDRA Service Connection immediately at 1-844-AZEDRA1 (1-844-293-3721) for further instructions.If no alarm icon is displayed after holding the stop button for 5/10 seconds (Figure 5), check mark () will be displayed on the temperature monitor screen. Store the drug product in the lead pot in -70C freezer, or thaw for use.The courier will remain on site or return the same day as the delivery date to retrieve the stopped temperature monitor with probe attached along with the other packaging texts. Lead pot will be collected during the next scheduled delivery date. Locate the temperature monitor on top of the Styrofoam lid in the shipper (Figure 1) Note: do not disconnect the monitor from the probe Note: do not disconnect the monitor from the probe. Immediately read the display screen for the running icon in the upper left corner of the screen (Figures and 3).. If the running icon is not present, do not use the product and call AZEDRA Service Connection immediately at 1-844-AZEDRA1 (1-844-293-3721) for further instructions.. If the running icon is present, immediately read the display screen for alarm status: (X) for alarm and () for no alarm at the top of the screen (Figures and 3).. Press and hold the stop button for - 10 seconds until the stop icon appears in the upper right corner of the screen (Figures and 5) Note: the running icon will disappear when the monitor is stopped Note: the running icon will disappear when the monitor is stopped. If an alarm icon is displayed after holding the stop button for 5/10 seconds (Figure 4), an (X) will be displayed on the temperature monitor screen, do not use. Store the drug product in the lead pot in -70C freezer, and call AZEDRA Service Connection immediately at 1-844-AZEDRA1 (1-844-293-3721) for further instructions.. If no alarm icon is displayed after holding the stop button for 5/10 seconds (Figure 5), check mark () will be displayed on the temperature monitor screen. Store the drug product in the lead pot in -70C freezer, or thaw for use.. The courier will remain on site or return the same day as the delivery date to retrieve the stopped temperature monitor with probe attached along with the other packaging texts. Lead pot will be collected during the next scheduled delivery date.. Unpacking Procedures Remove the temperature monitor probe by unwrapping the probe from around the handle of the assembly container.Remove the assembly container and holding tube containing the lead pot from the square center aluminum tube (Figure 6).Remove the lead pot by unscrewing the assembly container.Place the lead pot containing AZEDRA into <= -70C storage or thaw for use.Place the assembly container and holding tube back into the square center aluminum tube and save for pick up by the courier. Remove the temperature monitor probe by unwrapping the probe from around the handle of the assembly container.. Remove the assembly container and holding tube containing the lead pot from the square center aluminum tube (Figure 6).. Remove the lead pot by unscrewing the assembly container.. Place the lead pot containing AZEDRA into <= -70C storage or thaw for use.. Place the assembly container and holding tube back into the square center aluminum tube and save for pick up by the courier. Package Handling Instructions Figure 1. Package Handling Instructions Figures and 3. Package Handling Instructions Figures and 5. Package Handling Instructions Figure 6.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no data on the presence of iobenguane 131 in human milk or its effects on the breastfed infant or milk production. No lactation studies in animals were conducted. Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with AZEDRA and for 80 days after the final dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. AZEDRA is an 131 labeled iobenguane. Iobenguane is similar in structure to the neurotransmitter norepinephrine (NE) and is subject to the same uptake and accumulation pathways as NE. Iobenguane is taken up by the NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues, such as the heart, lungs, adrenal medulla, salivary glands, liver, and spleen as well as tumors of neural crest origin. Pheochromocytoma and paraganglioma (PPGL) are tumors of neural crest origin that express high levels of the NE transporter on their cell surfaces. Following intravenous administration, AZEDRA is taken up and accumulates within pheochromocytoma and paraganglioma cells, and radiation resulting from radioactive decay of 131 causes cell death and tumor necrosis.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity studies with iobenguane 131 have not been conducted; however, radiation is carcinogen and mutagen. No animal studies were conducted to determine the effects of iobenguane 131 on fertility.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL NDC: 71258-015-02 Dosimetric Dose Vial Label. Dosimetric Dose Vial Label.

PEDIATRIC USE SECTION.

8.4Pediatric Use. The safety and effectiveness of AZEDRA have been established in patients 12 years and older with unresectable and iobenguane scan positive, locally advanced or metastatic, pheochromocytoma and paraganglioma (PPGL) which require systemic anticancer therapy. Use of AZEDRA for this indication is supported by evidence from an adequate and well-controlled study in adults and pediatric patients 12 years and older [see Adverse Reactions 6.1 ), Clinical Studies 14 )]. The risks of radiation associated with AZEDRA is greater in pediatric patients than that in adult patients due to greater absorbed radiation doses and longer life expectancy. Ensure the therapeutic benefit of AZEDRA outweighs these greater risks prior to administration in pediatric patients. The safety and effectiveness of AZEDRA have not been established in pediatric patients younger than 12 years old with unresectable and iobenguane scan positive, locally advanced or metastatic PPGL which require systemic anticancer therapy.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics (PK) of iobenguane 131 following dosimetric dose were characterized in patients with malignant PPGL and other malignancies. The mean blood area under curve (AUC) of iobenguane 131 at the recommended dosimetric dose is uCih/mL (CV 33%). The mean maximum concentration (Cmax) for iobenguane 131 is 0.06 uCi/mL (CV 36%), which generally occurred at the end of the AZEDRA infusion.DistributionThe volume of distribution (mean +- SD) of iobenguane 131 is 2893 +- 592 mL/kg. The blood levels of radioactivity declined with distribution half-life (mean +- SD) of 0.37 +- 0.22 hours. The non-radioactive form of iobenguane 131 is 61% to 63% bound to human plasma proteins. EliminationThe mean clearance is 62 +- 24 mL/hr/kg for iobenguane 131 and the mean terminal blood half-life is 35 +- 14 hours.MetabolismIobenguane 131 does not undergo hepatic metabolism.ExcretionIobenguane 131 is primarily eliminated renally with cumulative excretion of 50 +- 10% within 24 hours and 80 +- 10% within 120 hours following AZEDRA administration. Unchanged 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 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 PopulationsEight 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 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 StudiesIn Vitro StudiesThe 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 substrate or inhibitor of P-glycoprotein.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on its mechanism of action, AZEDRA can cause fetal harm [see Clinical Pharmacology 12.1 )]. There are no available data on AZEDRA use in pregnant women. No animal studies using iobenguane 131 have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including AZEDRA, have the potential to cause fetal harm. Advise pregnant women of the risk to fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.