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

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)].

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)]

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.

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%)

7.1 Drugs 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 5 half-lives before administration of either the dosimetry or a therapeutic dose of AZEDRA. Do not administer these drugs until at least 7 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, buproprion, duloxetine, mirtazapine, venlafaxine)
• Botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St John’s Wort, yohimbine)

Risk Summary

Based 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 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. Advise pregnant women of the risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Risk Summary

There are no data on the presence of iobenguane I 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.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating AZEDRA [see Use in Specific Populations (8.1)].

Contraception

AZEDRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise women of reproductive potential to use effective contraception during treatment with AZEDRA and for 7 months following the final dose of AZEDRA.

Males

Based on its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment with AZEDRA and for 4 months following the final dose of AZEDRA [see Dosage and Administration (2.6)].

Infertility

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)].

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.

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.

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.