FERUMOXYTOL: 147 Adverse Event Reports & Safety Profile

FERABRIGHT (ferumoxytol injection) is an iron-based contrast agent for intravenous use. Ferumoxytol is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size ranges from 31 nm to 43 nm in diameter. The chemical formula of ferumoxytol is Fe 5874 O 8752 -C 11719 H 18682 O 9933 Na 414 with an apparent molecular weight of 750 kDa. Each mL contains 30 mg of elemental iron and 30 mg of polyglucose sorbitol carboxymethylether as ferumoxytol, and 44 mg of mannitol. It contains no preservatives. FERABRIGHT is a sterile, aqueous, black to reddish brown, isotonic colloidal solution with an osmolality of 270 mOsm/kg to 330 mOsm/kg, magnetic susceptibility of 27,250 to 39,000 x 10 -6 cgs/g Fe, and a pH of 6 to 8.

AND USAGE FERABRIGHT is indicated for magnetic resonance imaging (MRI) of the brain in adults with known or suspected malignant neoplasms in the brain to visualize lesions with a disrupted blood-brain barrier. FERABRIGHT is an iron-based contrast agent indicated for magnetic resonance imaging (MRI) of the brain in adults with known or suspected malignant neoplasms in the brain to visualize lesions with a disrupted blood-brain barrier.

AND ADMINISTRATION The recommended dose of FERABRIGHT is based on patient weight: 50 kg or less: 300 mg of elemental iron administered as a single intravenous infusion over at least 15 minutes. 51 kg or more: 510 mg of elemental iron administered as a single intravenous infusion over at least 15 minutes. ( 2.1 ) FERABRIGHT must be diluted before administration in either 0.9% sodium chloride injection or 5% dextrose injection to achieve concentrations of 2 mg/mL to 8 mg/mL of elemental iron. ( 2.2 ) Obtain post-contrast T1-weighted images approximately 24 hours after administration. ( 2.3 )

2.1 Recommended Dosage and Administration Instructions The recommended dose of FERABRIGHT is based on patient body weight as follows: 50 kg or less: 300 mg of elemental iron diluted in 0.9% sodium chloride injection or 5% dextrose injection <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . 51 kg or more: 510 mg of elemental iron diluted in 0.9% sodium chloride injection or 5% dextrose injection <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>. Administer diluted FERABRIGHT by intravenous infusion over at least 15 minutes while the patient is in a reclined or semi-reclined position approximately 24 hours prior to imaging <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.1 )]</span> . Allow at least 30 minutes after FERABRIGHT infusion for administration of any other medications that may cause serious hypersensitivity reactions or hypotension (e.g., chemotherapeutic agents or monoclonal antibodies) <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.2 )]</span>.

2.2 Dilution Instructions To achieve a final concentration of 2 mg/mL to 8 mg/mL of elemental iron, add the recommended dose of FERABRIGHT to 0.9% sodium chloride injection or 5% dextrose injection as follows: For a 300 mg dose, add 10 mL of FERABRIGHT to 50 mL to 140 mL diluent. For a 510 mg dose, add 17 mL of FERABRIGHT to 50 mL to 200 mL diluent. Inspect diluted FERABRIGHT visually for the absence of particulate matter and discoloration prior to administration. Use diluted FERABRIGHT solution immediately. If not used immediately, store the diluted FERABRIGHT solution at controlled room temperature (25°C ± 2°C) for up to 4 hours or refrigerated (2°C to 8°C) for up to 48 hours. Each vial of FERABRIGHT is for a single dose. Discard any unused portion.

2.3 Imaging Obtain post-contrast T1-weighted images approximately 24 hours after FERABRIGHT administration.

FERABRIGHT is contraindicated in patients with known hypersensitivity to ferumoxytol, any of FERABRIGHT’s components, or any other intravenous iron products. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.1 )] . Known hypersensitivity to ferumoxytol, any of FERABRIGHT’s components, or any other intravenous iron products ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Anaphylaxis and Other Serious Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Hypotension [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥0.65%) are nausea, pruritus, constipation, headache, diarrhea, increased blood pressure, bleeding, hyperpigmentation, vein injury, taste alteration, burning/tingling sensation with injection, red sclera, allergic rhinitis, back pain, vomiting, and increased ALT. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449, 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 safety of FERABRIGHT was evaluated in three blinded read studies (Study 001, Study 002, and Study 003) in 225 patients with known or suspected neoplasms in the brain who received FERABRIGHT by intravenous infusion for MRI.

In Study

001, 153 patients weighing between 45 kg and 140 kg received a FERABRIGHT median dose of 506 mg [see Clinical Studies ( 14 )] .

The

510 mg dose is recommended in patients weighing 51 kg or more [see Dosage and Administration ( 2.1 )] . The mean (range) age was 52 (18 to 83) years; patients were 57% male, 92% White, 2% Black or African American, 3% Asian, 1% American Indian or Alaska Native, 2% of other race, and 93% Not Hispanic or Latino ethnicity.

In Study

002, 17 patients weighing between 60 kg and 135 kg received a FERABRIGHT median dose of 435 mg. Doses below 510 mg are not recommended in patients weighing 51 kg or more [see Dosage and Administration ( 2.1 )] . The mean (range) age was 52 (32 to 72) years; patients were 65% male, 100% White, and 100% Not Hispanic or Latino ethnicity.

In Study

003, 55 patients weighing between 62 kg and 129 kg received a FERABRIGHT median dose of 312 mg. Doses below 510 mg are not recommended in patients weighing 51 kg or more [see Dosage and Administration ( 2.1 )] . The mean (range) age was 51 (23 to 73) years; patients were 64% male, 91% White, 4% Asian, 2% Native Hawaiian or Other Pacific Islander, 4% of other race, and 93% Not Hispanic or Latino ethnicity. Adverse reactions reported in patients (≥0.65%) in Study 001 are shown in Table 1.

Table

1: Adverse Reactions Reported in Brain Neoplasm Patients who Received FERABRIGHT for MRI in Study 001* *Median dose of 506 mg.

The

510 mg dose is recommended in patients weighing 51 kg or more [see Dosage and Administration ( 2.1 )] .

Adverse

Reaction FERABRIGHT (N = 153) n (%)

Nausea Pruritus Constipation Headache Diarrhea

Increased blood pressure Bleeding Hyperpigmentation Vein injury Taste alteration Burning/tingling sensation with injection Red sclera Allergic rhinitis 3 (1.96%) 2 (1.31%) 2 (1.31%) 1 (0.65%) 1 (0.65%) 1 (0.65%) 1 (0.65%) 1 (0.65%) 1 (0.65%) 1 (0.65%) 1 (0.65%) 1 (0.65%) 1 (0.65%) Additional adverse reactions reported in Studies 002 and 003 were back pain (3 patients), vomiting (1 patient), and increased ALT (1 patient). Additional adverse reactions reported in ≥1% of patients with IDA (FERABRIGHT is not approved to treat IDA) in a randomized clinical trial that administered two doses of 510 mg ferumoxytol 3 to 8 days apart by intravenous infusion (not an approved dosing regimen for FERABRIGHT) were dizziness and fatigue. Additional adverse reactions reported in ≥1% of patients with IDA and CKD (FERABRIGHT is not approved to treat IDA or CKD) in three randomized clinical trials that administered two doses of 510 mg ferumoxytol 3 to 8 days apart by rapid intravenous injection (not an approved dosing regimen for FERABRIGHT) were peripheral edema, edema, abdominal pain, cough, pyrexia, dyspnea, and muscle spasm.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ferumoxytol products, which contain the same active ingredient as FERABRIGHT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular disorders: cardiac/cardiorespiratory arrest, ischemic myocardial events, acute myocardial ischemia with or without myocardial infarction or with in-stent thrombosis in the context of a hypersensitivity reaction, congestive heart failure, clinically significant hypotension, tachycardia/rhythm abnormalities General disorders and administration site conditions: cyanosis Immune system disorders: anaphylaxis and hypersensitivity reactions Nervous system disorders: syncope, unresponsiveness, loss of consciousness Skin and system disorders: angioedema These adverse reactions have usually occurred within 30 minutes after the administration of ferumoxytol.

AND PRECAUTIONS Hypotension: Monitor for signs and symptoms of hypotension following administration. ( 5.2 )

Iron

Overload: Avoid use of FERABRIGHT in patients with iron overload. ( 5.3 )

Magnetic Resonance Imaging Test

Interference: Conduct anticipated MRI studies (other than the intended FERABRIGHT brain imaging) prior to the administration of FERABRIGHT or use T1- or proton density-weighted pulse sequences if MRI is required within 3 months after administration. ( 5.4 ) Differences in Magnetic Resonance Imaging Appearance Compared to Gadolinium-Based Contrast: Be aware of the potentially limited interpretability of changes in lesion contrast appearance if prior images were not obtained with FERABRIGHT. ( 5.5 )

5.1 Anaphylaxis and Other Serious Hypersensitivity Reactions Fatal and serious hypersensitivity reactions, including anaphylaxis presenting with cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness, have occurred in patients receiving ferumoxytol products, which contain the same active ingredient as FERABRIGHT. Other adverse reactions potentially associated with hypersensitivity have occurred, including pruritus, rash, urticaria, and wheezing. These reactions have occurred in patients who had no prior exposure to ferumoxytol as well as in patients who previously tolerated ferumoxytol. Patients with a history of multiple drug allergies may have a greater risk of anaphylaxis with FERABRIGHT. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of ferumoxytol including FERABRIGHT may have more severe outcomes. Carefully consider the potential risks and benefits before administering FERABRIGHT to these patients. FERABRIGHT is contraindicated in patients with known hypersensitivity to ferumoxytol, any of FERABRIGHT’s components, or any other intravenous iron products <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . Only administer FERABRIGHT as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Closely observe patients for signs and symptoms of hypersensitivity including monitoring of blood pressure and pulse during and after FERABRIGHT administration for at least 30 minutes and until clinically stable following completion of infusion. Allow at least 30 minutes after FERABRIGHT infusion for administration of any other medications that may cause serious hypersensitivity reactions or hypotension <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> . In a clinical study in patients with iron deficiency anemia (IDA) (FERABRIGHT is not approved to treat IDA), regardless of etiology, hypersensitivity reactions were reported in 0.4% (4/997) of patients administered ferumoxytol as an intravenous infusion over at least 15 minutes. These included one patient with severe hypersensitivity reaction and three patients with moderate hypersensitivity reactions. In clinical studies predominantly in patients with IDA and chronic kidney disease (CKD) (FERABRIGHT is not approved to treat IDA or CKD), serious hypersensitivity reactions were reported in 0.2% (4/1,806) of patients administered ferumoxytol as a rapid intravenous injection (not an approved method of administration for FERABRIGHT). Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria, or wheezing) were reported in 3.5% (63/1,806) of these patients. In postmarketing experience with ferumoxytol, fatal and serious anaphylactic type reactions presenting with cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

5.2 Hypotension FERABRIGHT may cause clinically significant hypotension. Monitor patients for signs and symptoms of hypotension following FERABRIGHT administration <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ) and Warnings and Precautions ( 5.1 )]</span> . In a clinical study in patients with IDA (FERABRIGHT is not approved to treat IDA), moderate hypotension was reported in 0.2% (2/997) of patients administered ferumoxytol as an intravenous infusion over 15 minutes. In clinical studies in patients with IDA and CKD (FERABRIGHT is not approved to treat IDA or CKD), hypotension was reported in 1.9% (35/1,806) of patients, including three patients with serious hypotensive reactions, who were administered ferumoxytol as a rapid intravenous injection (not an approved method of administration for FERABRIGHT). Hypotension has also been reported in postmarketing experience <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

5.3 Iron overload Use of FERABRIGHT can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Avoid use of FERABRIGHT in patients with iron overload.

5.4 Magnetic Resonance Imaging Test Interference Administration of FERABRIGHT may transiently affect the diagnostic ability of MRI. Conduct anticipated MRI studies (other than the intended FERABRIGHT brain imaging) prior to the administration of FERABRIGHT. Alteration of MRI studies may persist for up to 3 months following the FERABRIGHT dose. If MRI is required within 3 months after FERABRIGHT administration, use T1- or proton density-weighted pulse sequences to minimize the FERABRIGHT effects. MRI imaging using T2-weighted pulse sequences should not be performed earlier than 4 weeks after the administration of FERABRIGHT. Maximum alteration of vascular MRI signal is evident for 1 to 2 days following FERABRIGHT administration <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . FERABRIGHT will not interfere with X-ray, computed tomography (CT), positron emission tomography (PET), single photon emission computed tomography (SPECT), planar nuclear medicine imaging, or ultrasound.

5.5 Differences in Magnetic Resonance Imaging Appearance Compared to Gadolinium-Based Contrast MRI obtained with FERABRIGHT may demonstrate different size, intensity, and pattern of contrast signal in lesions compared to images obtained with gadolinium-based contrast <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> . Be aware of the potentially limited interpretability of changes in lesion contrast appearance if prior images were not obtained with FERABRIGHT.