FDA label 444f1ca1-cfd8-44f7-a0cc-be20ad2e73fb

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 7 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 a 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 a patient's 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 a therapeutic dose of AZEDRA, 33% experienced Grade 4 thrombocytopenia, 16% experienced Grade 4 neutropenia, and 7% experienced Grade 4 anemia. Five percent of patients experienced febrile neutropenia. In Study IB12B following the first therapeutic dose, patients who experienced Grade 4 neutropenia reached neutrophil nadir at a median of 36 days (27 – 55 days) and remained at nadir for a 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 4 neutropenia reached nadir at a median of 43 days (38 – 47 days) and remained at nadir for a 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 a therapeutic dose of AZEDRA [see Adverse Reactions ( 6.1 )] . The time to development of MDS or acute leukemia ranged from 12 months to 7 years. Two of the 88 patients developed a 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 a therapeutic dose of AZEDRA [see Adverse Reactions ( 6.1 ) ]. The time to worsening of hypothyroidism was 4 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 1 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 a therapeutic dose of AZEDRA [see Adverse Reactions ( 6.1 )] experienced a 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 a therapeutic dose of AZEDRA [see Adverse Reactions ( 6.1 )] , 7% developed renal failure or acute kidney injury and 22% demonstrated a clinically significant decrease in glomerular filtration rate (GFR) measured at 6 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 9 weeks after a 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 I 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 a fetus. Advise females of reproductive potential to use effective contraception during treatment with AZEDRA and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 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 a 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 )] .

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 )] 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 a 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 a 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 a 12-month efficacy phase with a 1 year follow-up. Twenty-one patients received a 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), a 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 3 months of study entry, were also excluded. The safety data described below are based on pooled safety data from studies IB12 and IB12B. A 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 a NCI CTCAE version 3.0. b Based on laboratory data. c Includes vomiting and retching. d Includes sialoadenitis, salivary gland pain, and salivary gland enlargement. e Includes abdominal pain, abdominal pain upper, and abdominal pain lower. f Incudes fatigue, asthenia. g Includes upper respiratory tract infection, sinusitis, rhinorrhea, upper-airway cough syndrome, nasopharyngitis. h Only assessed in Study IB12B (N=68). i Includes dizziness and dizziness postural. j Includes dysgeusia, hypogeusia and ageusia. k Includes blood pressure increased and hypertension. Adverse Reaction All Grades a , (%) Grades a 3 - 4, (%) Hematologic b Lymphopenia 96 78 Anemia 93 24 Thrombocytopenia 91 50 Neutropenia 84 59 Gastrointestinal Nausea 78 16 Vomiting c 58 10 Dry mouth 48 2 Sialadenitis d 39 1 Diarrhea 25 3 Abdominal pain e 23 6 Constipation 19 7 Oropharyngeal pain 14 0 Dyspepsia 10 0 General Fatigue f 71 26 Pyrexia 14 2 Injection site pain 10 0 Hyperhidrosis 10 0 Alopecia 10 0 Infections Upper respiratory tract infection g 16 2 Urinary tract infection 11 1 Investigations b Increased international normalized ratio h 85 18 Increased blood alkaline phosphatase 53 5 Increased aspartate aminotransferase 50 2 Increased alanine aminotransferase 43 2 Metabolism and nutrition Decreased appetite 30 5 Dehydration 16 4 Decreased weight 16 1 Musculoskeletal and connective tissue disorders Back pain 17 2 Pain in extremity 15 0 Nervous system Dizziness i 34 13 Headache 32 6 Dysgeusia j 24 1 Respiratory, thoracic, and mediastinal disorders Cough 18 0 Dyspnea 18 7 Vascular Hypotension 24 4 Hypertension k 20 11 Tachycardia 10 3 The 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%)

<table ID="table5" width="750" styleCode="Noautorules"><caption>Table 5: Adverse Reactions Occurring in &#x2265;10% of Patients with PPGL Receiving Therapeutic Dose of AZEDRA in Studies IB12B and IB12 </caption><col width="54%" align="left"/><col width="23%" align="center"/><col width="23%" align="center"/><tfoot><tr valign="top"><td colspan="3" align="left"><paragraph styleCode="footnote">^aNCI CTCAE version 3.0.</paragraph><paragraph styleCode="footnote">^bBased on laboratory data.</paragraph><paragraph styleCode="footnote">^cIncludes vomiting and retching.</paragraph><paragraph styleCode="footnote">^dIncludes sialoadenitis, salivary gland pain, and salivary gland enlargement.</paragraph><paragraph styleCode="footnote">^eIncludes abdominal pain, abdominal pain upper, and abdominal pain lower.</paragraph><paragraph styleCode="footnote">^fIncudes fatigue, asthenia. </paragraph><paragraph styleCode="footnote">^gIncludes upper respiratory tract infection, sinusitis, rhinorrhea, upper-airway cough syndrome, nasopharyngitis.</paragraph><paragraph styleCode="footnote">^hOnly assessed in Study IB12B (N=68).</paragraph><paragraph styleCode="footnote">ⁱIncludes dizziness and dizziness postural.</paragraph><paragraph styleCode="footnote">^jIncludes dysgeusia, hypogeusia and ageusia.</paragraph><paragraph styleCode="footnote">^kIncludes blood pressure increased and hypertension.</paragraph></td></tr></tfoot><tbody><tr valign="bottom"><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">All Grades^a, (%)</content></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">Grades^a 3 - 4, (%)</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Hematologic^b</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Lymphopenia</td><td styleCode="Botrule Rrule">96</td><td styleCode="Botrule Rrule">78</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Anemia</td><td styleCode="Botrule Rrule">93</td><td styleCode="Botrule Rrule">24</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Thrombocytopenia</td><td styleCode="Botrule Rrule">91</td><td styleCode="Botrule Rrule">50</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Neutropenia</td><td styleCode="Botrule Rrule">84</td><td styleCode="Botrule Rrule">59</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Gastrointestinal</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Nausea</td><td styleCode="Botrule Rrule">78</td><td styleCode="Botrule Rrule">16</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Vomiting^c</td><td styleCode="Botrule Rrule">58</td><td styleCode="Botrule Rrule">10</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Dry mouth</td><td styleCode="Botrule Rrule">48</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Sialadenitis^d</td><td styleCode="Botrule Rrule">39</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Diarrhea</td><td styleCode="Botrule Rrule">25</td><td styleCode="Botrule Rrule">3</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Abdominal pain^e</td><td styleCode="Botrule Rrule">23</td><td styleCode="Botrule Rrule">6</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Constipation</td><td styleCode="Botrule Rrule">19</td><td styleCode="Botrule Rrule">7</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Oropharyngeal pain</td><td styleCode="Botrule Rrule">14</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Dyspepsia</td><td styleCode="Botrule Rrule">10</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">General</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Fatigue^f</td><td styleCode="Botrule Rrule">71</td><td styleCode="Botrule Rrule">26</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Pyrexia</td><td styleCode="Botrule Rrule">14</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Injection site pain</td><td styleCode="Botrule Rrule">10</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Hyperhidrosis</td><td styleCode="Botrule Rrule">10</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Alopecia</td><td styleCode="Botrule Rrule">10</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Infections</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Upper respiratory tract infection^g</td><td styleCode="Botrule Rrule">16</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Urinary tract infection</td><td styleCode="Botrule Rrule">11</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Investigations^b</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Increased international normalized ratio^h</td><td styleCode="Botrule Rrule">85</td><td styleCode="Botrule Rrule">18</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Increased blood alkaline phosphatase</td><td styleCode="Botrule Rrule">53</td><td styleCode="Botrule Rrule">5</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Increased aspartate aminotransferase</td><td styleCode="Botrule Rrule">50</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Increased alanine aminotransferase</td><td styleCode="Botrule Rrule">43</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Metabolism and nutrition</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Decreased appetite</td><td styleCode="Botrule Rrule">30</td><td styleCode="Botrule Rrule">5</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Dehydration</td><td styleCode="Botrule Rrule">16</td><td styleCode="Botrule Rrule">4</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Decreased weight </td><td styleCode="Botrule Rrule">16</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Musculoskeletal and connective tissue disorders</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Back pain</td><td styleCode="Botrule Rrule">17</td><td styleCode="Botrule Rrule">2</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Pain in extremity </td><td styleCode="Botrule Rrule">15</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Nervous system</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Dizzinessⁱ</td><td styleCode="Botrule Rrule">34</td><td styleCode="Botrule Rrule">13</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Headache</td><td styleCode="Botrule Rrule">32</td><td styleCode="Botrule Rrule">6</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Dysgeusia^j</td><td styleCode="Botrule Rrule">24</td><td styleCode="Botrule Rrule">1</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Respiratory, thoracic, and mediastinal disorders</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Cough</td><td styleCode="Botrule Rrule">18</td><td styleCode="Botrule Rrule">0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Dyspnea</td><td styleCode="Botrule Rrule">18</td><td styleCode="Botrule Rrule">7</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule">Vascular</td><td styleCode="Botrule Rrule"/><td styleCode="Botrule Rrule"/></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Hypotension</td><td styleCode="Botrule Rrule">24</td><td styleCode="Botrule Rrule">4</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Hypertension^k</td><td styleCode="Botrule Rrule">20</td><td styleCode="Botrule Rrule">11</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"> Tachycardia</td><td styleCode="Botrule Rrule">10</td><td styleCode="Botrule Rrule">3</td></tr></tbody></table>