HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` XOFIGO safely and effectively. See full prescribing information for
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` XOFIGO.
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` Xofigo (radium Ra 223 dichloride) Injection, for intravenous use
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` Initial U.S. Approval: 2013
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` --------------------------- INDICATIONS AND USAGE --------------------------
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` Xofigo is an alpha particle-emitting radioactive therapeutic agent indicated for
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` the treatment of patients with castration-resistant prostate cancer, symptomatic
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` bone metastases and no known visceral metastatic disease. (1)
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`---------------------- DOSAGE AND ADMINISTRATION ---------------------­
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`The dose regimen of Xofigo is 50 kBq (1.35 microcurie) per kg body weight,
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`given at 4 week intervals for 6 injections. (2.1)
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`--------------------- DOSAGE FORMS AND STRENGTHS -------------------­
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`Single-use vial at a concentration of 1,000 kBq/mL (27 microcurie/mL) at the
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`reference date with a total radioactivity of 6,000 kBq/vial (162
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`microcurie/vial) at the reference date (3)
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`------------------------------ CONTRAINDICATIONS ----------------------------­
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`
`Pregnancy (4, 8.1)
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`1 INDICATIONS AND USAGE
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`2 DOSAGE AND ADMINISTRATION
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`2.1 Recommended Dosage
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`2.2 Administration
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`2.3 Instructions for Use / Handling
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`3 DOSAGE FORMS AND STRENGTHS
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`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
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`5.1 Bone Marrow Suppression
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`6 ADVERSE REACTIONS
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`6.1 Clinical Trials Experience
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`7 DRUG INTERACTIONS
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`8 USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`8.3 Nursing Mothers
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`8.4 Pediatric Use
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`8.5 Geriatric Use
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` FULL PRESCRIBING INFORMATION
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` 1 INDICATIONS AND USAGE
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` ----------------------- WARNINGS AND PRECAUTIONS ---------------------­
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`Bone Marrow Suppression: Measure blood counts prior to treatment initiation
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`and before every dose of Xofigo. Discontinue Xofigo if hematologic values do
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`not recover within 6 to 8 weeks after treatment. Monitor patients with
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`compromised bone marrow reserve closely. Discontinue Xofigo in patients
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`who experience life-threatening complications despite supportive care
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`measures. (5.1)
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`------------------------------ ADVERSE REACTIONS ----------------------------­
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`The most common adverse drug reactions (≥ 10%) in patients receiving
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`
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`Xofigo were nausea, diarrhea, vomiting, and peripheral edema.
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`The most common hematologic laboratory abnormalities (≥ 10%) were
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`anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia
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`(6.1).
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`To report SUSPECTED ADVERSE REACTIONS, contact Bayer
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`HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800­
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`
`FDA-1088 or www.fda.gov/medwatch
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`
`SEE 17 FOR PATIENT COUNSELING INFORMATION
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`Revised: 05/2013
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`8.6 Patients with Hepatic Impairment
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`8.7 Patients with Renal Impairment
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`8.8 Males of Reproductive Potential
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`10 OVERDOSAGE
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`12.2 Pharmacodynamics
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`12.3 Pharmacokinetics
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`12.6 Cardiac Electrophysiology
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`15 REFERENCES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the full prescribing information are not listed.
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` Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases
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` and no known visceral metastatic disease.
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` 2 DOSAGE AND ADMINISTRATION
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` 2.1 Recommended Dosage
` The dose regimen of Xofigo is 50 kBq (1.35 microcurie) per kg body weight, given at 4 week intervals for 6 injections.
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`
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` Safety and efficacy beyond 6 injections with Xofigo have not been studied.
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` The volume to be administered to a given patient should be calculated using the:
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` Patient’s body weight (kg)
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`
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`•
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` • Dosage level 50 kBq/kg body weight or 1.35 microcurie/kg body weight
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` • Radioactivity concentration of the product (1,000 kBq/mL; 27 microcurie/mL) at the reference date
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` • Decay correction factor to correct for physical decay of radium-223.
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`Reference ID: 3308326
`
`AVENTIS EXHIBIT 2175
`Mylan v. Aventis IPR2016-00712
`
`1
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`

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`The total volume to be administered to a patient is calculated as follows:
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` Body weight in kg × 50 kBq/kg body weight
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`Volume to be administered (mL)
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`=
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` or
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`Volume to be administered (mL)
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`=
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` Decay factor × 1,000 kBq/mL
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` Body weight in kg × 1.35 microcurie/kg body weight
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` Decay factor × 27 microcurie/mL
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`Table 1: Decay Correction Factor Table
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` Decay Factor
` Days from Reference Date
` Decay Factor
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` Days from Reference Date
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` 0.982
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` 0
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` 2.296
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` -14
`
` 0.925
`
` 1
`
` 2.161
`
` -13
`
` 0.870
`
` 2
`
` 2.034
`
` -12
`
` 0.819
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` 3
`
` 1.914
`
` -11
`
` 0.771
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` 4
`
` 1.802
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` -10
`
` 0.725
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` 5
`
` 1.696
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` -9
`
` 0.683
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` 6
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` 1.596
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` -8
`
` 0.643
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` 7
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` 1.502
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` -7
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` 0.605
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` 8
`
` 1.414
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` -6
`
` 0.569
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` 9
`
` 1.330
`
` -5
`
` 0.536
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` 10
`
` 1.252
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` -4
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` 0.504
`
` 11
`
` 1.178
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` -3
`
` 0.475
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` 12
`
` 1.109
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` -2
`
` 0.447
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` 13
`
` 1.044
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` -1
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` 0.420
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` 14
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` The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the
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` number of days before or after the reference date. The Decay Correction Factor Table includes a correction to account for the 7 hour time difference
` between 12 noon Central European Time (CET) at the site of manufacture and 12 noon US CST, which is 7 hours earlier than CET.
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` Immediately before and after administration, the net patient dose of administered Xofigo should be determined by
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` measurement in an appropriate radioisotope dose calibrator that has been calibrated with a National Institute of Standards
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` and Technology (NIST) traceable radium-223 standard (available upon request from Bayer) and corrected for decay using
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` the date and time of calibration. The dose calibrator must be calibrated with nationally recognized standards, carried out at
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` the time of commissioning, after any maintenance procedure that could affect the dosimetry and at intervals not to exceed
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` one year.
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` 2.2 Administration
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` Administer Xofigo by slow intravenous injection over 1 minute.
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` Flush the intravenous access line or cannula with isotonic saline before and after injection of Xofigo.
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` 2.3 Instructions for Use/Handling
` General warning
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` Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons
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` in designated clinical settings. The receipt, storage, use, transfer and disposal Xofigo are subject to the regulations and/or
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` appropriate licenses of the competent official organization.
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`Reference ID: 3308326
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`2
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`

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`Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality
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`requirements. Appropriate aseptic precautions should be taken.
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`Radiation protection
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`The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and
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`patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit.
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`Therefore, radiation protection precautions must be taken in accordance with national and local regulations.
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`For drug handling
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`Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for
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`handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid
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`contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the
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`event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary
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`measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine­
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`tetraacetic acid (EDTA) solution is recommended to remove contamination.
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`For patient care
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`Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When
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`handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or
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`patient fecal matter or urine should be washed promptly and separately from other clothing.
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`Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted
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`as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated
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`with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216
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`microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation
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`exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources,
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`and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration
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`are to be treated as radioactive waste and should be disposed of in accordance with local regulations.
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`The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement
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`of Xofigo and the detection of contamination with standard instruments.
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`Instructions for preparation
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`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration,
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`whenever solution and container permit.
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`Xofigo is a ready-to-use solution and should not be diluted or mixed with any solutions. Each vial is for single use only.
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`Dosimetry
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`The absorbed radiation doses in major organs were calculated based on clinical biodistribution data in five patients with
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`castration-resistant prostate cancer. Calculations of absorbed radiation doses were performed using OLINDA/EXM
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`(Organ Level INternal Dose Assessment/EXponential Modeling), a software program based on the Medical Internal
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`Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting radionuclides. For
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`radium-223, which is primarily an alpha particle-emitter, assumptions were made for intestine, red marrow and
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`bone/osteogenic cells to provide the best possible absorbed radiation dose calculations for Xofigo, considering its
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`observed biodistribution and specific characteristics.
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`The calculated absorbed radiation doses to different organs are listed in Table 2. The organs with highest absorbed
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`radiation doses were bone (osteogenic cells), red marrow, upper large intestine wall, and lower large intestine wall. The
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`calculated absorbed doses to other organs are lower.
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`Reference ID: 3308326
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`3
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`

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`Table 2: Calculated Absorbed Radiation Doses to Organs
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` Mean
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` (Gy/MBq)
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` Mean
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` (rad/mCi)
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`
` 0.00012
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` 0.00010
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` 0.00005
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` 0.00023
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` 0.04645
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` 0.00726
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` 0.00014
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` 0.03232
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` 0.00173
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` 0.00320
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` 0.00298
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` 0.00007
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` 0.00012
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` 0.00049
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` 0.00011
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` 0.13879
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` 1.15206
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` 0.00007
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` 0.00009
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` 0.00008
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` 0.00006
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` 0.00007
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` 0.00403
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` 0.00026
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` 0.02311
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`
` 0.44
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` 0.37
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` 0.18
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` 0.85
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` 171.88
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` 26.87
` 0.51
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` 119.58
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` 6.40
` 11.86
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`
` 11.01
` 0.27
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`
` 0.44
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` 1.80
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` 0.41
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` 513.51
` 4262.60
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`
` 0.27
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` 0.33
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` 0.31
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` 0.21
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` 0.26
` 14.90
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` 0.94
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` 85.50
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`
`
` Coefficient of
`
` Variation
`
` (%)
`
` 56
`
` 80
`
` 120
`
` 14
`
` 83
`
` 45
`
` 22
`
` 50
`
` 42
`
` 36
`
` 36
`
` 90
`
` 41
`
` 40
`
` 43
`
` 41
`
` 41
`
` 79
`
` 54
`
` 59
`
` 109
`
` 96
`
` 63
`
` 28
`
` 16
`
`
`
` Target Organ
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` Adrenals
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` Brain
` Breasts
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` Gallbladder wall
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`
` LLI1 Wall
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`
` Small intestine wall
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` Stomach wall
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`
` ULI2 wall
` Heart wall
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`
` Kidneys
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` Liver
` Lungs
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`
` Muscle
`
` Ovaries
` Pancreas
`
` Red marrow
`
` Osteogenic cells
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`
` Skin
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` Spleen
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` Testes
`
` Thymus
`
` Thyroid
` Urinary bladder wall
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` Uterus
` Whole body
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` 1LLI: lower large intestine
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`2ULI: upper large intestine
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` 3 DOSAGE FORMS AND STRENGTHS
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` Xofigo (radium Ra 223 dichloride injection) is available in single-use vials containing 6 mL of solution at a concentration
`
` of 1,000 kBq/mL (27 microcurie/mL) at the reference date with a total radioactivity of 6,000 kBq/vial (162
`
`
` microcurie/vial) at the reference date.
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`
`4 CONTRAINDICATIONS
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` Xofigo is contraindicated in pregnancy.
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` Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Xofigo is not
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`indicated for use in women. Xofigo is contraindicated in women who are or may become pregnant. If this drug is used
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` during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to
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` the fetus [see Use in Specific Populations (8.1)].
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`Reference ID: 3308326
`
`4
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`

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` 5 WARNINGS AND PRECAUTIONS
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` 5.1 Bone Marrow Suppression
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` In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia
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` compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients
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` treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone
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` marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo
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` arm permanently discontinued therapy due to bone marrow suppression.
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` In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1%
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` of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths
` (2%), serious infections (10%), and febrile neutropenia (<1%) were similar for patients treated with Xofigo and placebo.
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`
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` Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients
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` treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each
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` dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of
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` Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1
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` to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see
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` Adverse Reactions (6)].
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`Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first
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`administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L
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`and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet
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`count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo,
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`despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of
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`compromised bone marrow reserve should be monitored closely and provided with supportive care measures when
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`clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care
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`for bone marrow failure.
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`The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial,
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`concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If
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`chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment
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`period, Xofigo should be discontinued.
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` 6 ADVERSE REACTIONS
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`
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` The following serious adverse reactions are discussed in greater detail in another section of the label:
`
` • Bone Marrow Suppression [see Warnings and Precautions (5.1)]
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`
`
` 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.
` In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600
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`
`
` patients received intravenous injections of 50 kBq/kg (1.35 microcurie/kg) of Xofigo and best standard of care and 301
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` patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58%
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` and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of
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` treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo.
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`Reference ID: 3308326
`
`5
`
`

`
`The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral
`
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`
`
`
`
`
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`edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-
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`treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia,
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`lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4).
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`Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients
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`who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo
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`were anemia (2%) and thrombocytopenia (2%).
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`Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the
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`incidence for placebo.
`
`
`Table 3: Adverse Reactions in the Randomized Trial
`
`
`
`
`
`
` System/Organ Class
`
` Preferred Term
`
`
`
`
`
`
`
`
`
` 3
`
` Placebo (n=301)
`
`
`
` Grades 1-4
` Grades 3-4
`
` %
`
` %
`
`
`
`
`
` 1
`
`
` 2
`
` 2
`
` 2
`
`
`
` 2
`
`
`
` 1
`
`
`
` 0
`
`
` 35
`
` 15
`
` 14
`
`
`
` 10
`
`
`
` 1
`
`
`
` 0
`
`
` 2
`
` 2
`
` 2
`
`
`
` 1
`
`
`
` 1
`
`
` Xofigo (n=600)
`
`
`
` Grades 1-4
`
` Grades 3-4
`
` %
`
` %
` Blood and lymphatic system disorders
`
`
`
` Pancytopenia
` 2
` Gastrointestinal disorders
`
` Nausea
`
` 36
` Diarrhea
`
`
` 25
` Vomiting
`
` 19
`
` General disorders and administration site conditions
`
`
` Peripheral edema
` 13
` Renal and urinary disorders
`
` Renal failure and
`
` impairment
`
`
`Laboratory Abnormalities
`
`
`
`
`
`
`
`
`Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for
`
`
`
`Xofigo exceeds the incidence for placebo.
`
`
`
`
`
`Table 4: Hematologic Laboratory Abnormalities
`
`
`
` Xofigo (n=600)
`
` Hematologic
`
` Laboratory
`
` Grades 3-4
`
`
` Grades 1-4
` Abnormalities
`
` %
`
` %
`
`
` 93
`
` Anemia
` 6
`
` 20
`
` 72
` Lymphocytopenia
`
` 3
`
` 35
`
` Leukopenia
`
` 3
`
` 31
` Thrombocytopenia
`
` 2
`
` 18
`
` Neutropenia
` Laboratory values were obtained at baseline and prior to each 4-week cycle.
`
`
`
`
`
`
`
`
`
` Placebo (n=301)
`
`
`
` Grades 1-4
` Grades 3-4
`
` %
`
` %
`
` 88
`
` 6
`
` 53
`
` 7
`
` 10
`
` <1
`
` 22
`
` <1
`
`
` <1
` 5
`
`
`
`
`
`
`
` As an adverse reaction, grade 3-4 thrombocytopenia was reported in 6% of patients on Xofigo and in 2% of patients on
`
`
`
`
` placebo. Among patients who received Xofigo, the laboratory abnormality grade 3-4 thrombocytopenia occurred in 1% of
` docetaxel naïve patients and in 4% of patients who had received prior docetaxel. Grade 3-4 neutropenia occurred in 1% of
`
`
` docetaxel naïve patients and in 3% of patients who have received prior docetaxel.
`
`
`
`Reference ID: 3308326
`
`6
`
`

`
`
`Fluid Status
`
`
`
`
`
`Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such
`
`
`
`
`as diarrhea, nausea, and vomiting which may result in dehydration. Monitor patients’ oral intake and fluid status carefully
`
`
`
`and promptly treat patients who display signs or symptoms of dehydration or hypovolemia.
`
`
`Injection Site Reactions
`
`
`
`Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo.
`
`
`Secondary Malignant Neoplasms
`
`
`Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation
`
`
`
`
`
`exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and
`neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may
`increase the risk of osteosarcoma or other secondary malignant neoplasms [see Nonclinical Toxicology (13.1)]. However,
`
`
`
`
`
`
`
`
`
`
`
`the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo
`
`
`
`
`
`
`(<1% vs. 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the
`
`
`duration of follow up for patients on the trial.
`
`
`Subsequent Treatment with Cytotoxic Chemotherapy
`
`
`
`
`
`In the randomized clinical trial, 16% patients in the Xofigo group and 18% patients in the placebo group received
`
`
`
`
`
`
`cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not
`
`
`
`
`performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy.
`
`
`
` 7 DRUG INTERACTIONS
`
` No formal clinical drug interaction studies have been performed.
`
`
`
` Subgroup analyses indicated that the concurrent use of bisphosphonates or calcium channel blockers did not affect the
` safety and efficacy of Xofigo in the randomized clinical trial.
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
`
` 8.1 Pregnancy Category X [see Contraindications (4)]
`
`
`
` Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are
`
`
`
`
`
` no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of
` a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may
`
`
`
`
` become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while
`
`
`
` taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise
` females of reproductive potential to avoid becoming pregnant during treatment with Xofigo.
`
`
`
`
`
`
` 8.3 Nursing Mothers
`
` Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk.
`
`
`
`
`
` Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants
` from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the
`
`
`
`
`
` importance of the drug to the mother.
`
`
`
`
`
`
` 8.4 Pediatric Use
`
`
` The safety and efficacy of Xofigo in pediatric patients have not been established.
`
`
`
`
`
`
`
`Reference ID: 3308326
`
`
`
`
`
`
`
`
`
`7
`
`

`
`In single- and repeat-dose toxicity studies in rats, findings in the bones (depletion of osteocytes, osteoblasts, osteoclasts,
`
`
`
`fibro-osseous lesions, disruption/disorganization of the physis/growth line) and teeth (missing, irregular growth, fibro­
`
`
`osseous lesions in bone socket) correlated with a reduction of osteogenesis that occurred at clinically relevant doses
`
`
`
`
`
`beginning in the range of 20 – 80 kBq (0.541 - 2.16 microcurie) per kg body weight.
`
`
`
`
`
` 8.5 Geriatric Use
`
`
`
`
`
`
` Of the 600 patients treated with Xofigo in the randomized trial, 75% were 65 years of age and over and while 33% were
` 75 years of age and over. No dosage adjustment is considered necessary in elderly patients. No overall differences in
`
`
`
`
`
`
`
`
`
`
`
` safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience
` has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older
`
`
`
`
` individuals cannot be ruled out.
`
`
`
`
`
` 8.6 Patients with Hepatic Impairment
`
`
`
`
` No dedicated hepatic impairment trial for Xofigo has been conducted. Since radium-223 is neither metabolized by the
`
`
` liver nor eliminated via the bile, hepatic impairment is unlikely to affect the pharmacokinetics of radium-223 dichloride
`
`
`
`
`
`
` [see Clinical Pharmacology (12.3)]. Based on subgroup analyses in the randomized clinical trial, dose adjustment is not
`
`
`
`
`
`
`needed in patients with mild hepatic impairment. No dose adjustments can be recommended for patients with moderate or
`
`
`
`
`
`
`severe hepatic impairment due to lack of clinical data.
`
`
` 8.7 Patients with Renal Impairment
`
`
`
` No dedicated renal impairment trial for Xofigo has been conducted. Based on subgroup analyses in the randomized
` clinical trial, dose adjustment is not needed in patients with existing mild (creatinine clearance [CrCl] 60 to 89 mL/min) or
`
`
`
`
`
`
`
`
` moderate (CrCl 30 to 59 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe
` renal impairment (CrCl less than 30 mL/min) due to limited data available (n = 2) [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
`
`
`
` 8.8 Males of Reproductive Potential
`
` Contraception
`
`
`
`
`
` Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use
` condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for
`
`
`
`
`
`
` 6 months after completing treatment with Xofigo.
`
`
`
`Infertility
`
`
`
`
`
`There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could
`impair human fertility [see Nonclinical Toxicology (13.1)].
`
`
`
`
`
`
`
` 10 OVERDOSAGE
`
`
`
`
`
`
`
`
`
`
`
`
` There have been no reports of inadvertent overdosing of Xofigo during clinical studies.
`
`
` There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures,
`
`
`
` including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical
`
`
`
`
`
` countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate,
`
`
`
`
`or sodium alginate.1
`
`
`
`
` Single Xofigo doses up to 250 kBq (6.76 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no
` dose-limiting toxicities were observed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3308326
`
`8
`
`

`
`
`
` 11 DESCRIPTION
`
`
`
`
`
`
`
`
`
`
` Radium Ra 223 dichloride, an alpha particle-emitting pharmaceutical, is a radiotherapeutic drug.
` Xofigo is supplied as a clear, colorless, isotonic, and sterile solution to be administered intravenously with pH between 6
`
`
`
`
`
` and 8.
`
`
`
` Each milliliter of solution contains 1,000 kBq radium-223 dichloride (27 microcurie), corresponding to 0.53 ng radium­
`
` 223, at the reference date. Radium is present in the solution as a free divalent cation.
`
`
`
`
` Each vial contains 6 mL of solution (6,000 kBq (162 microcurie) radium-223 dichloride at the reference date). The
`
`
`
`
`
` inactive ingredients are 6.3 mg/mL sodium chloride USP (tonicity agent), 7.2 mg/mL sodium citrate USP (for pH
`
`
`
`
`
`
`
`
` adjustment), 0.2 mg/mL hydrochloric acid USP (for pH adjustment), and water for injection USP.
`
`
`
`
`The molecular weight of radium-223 dichloride, 223RaCl2, is 293.9 g/mol.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Radium-223 has a half-life of 11.4 days. The specific activity of radium-223 is 1.9 MBq (51.4 microcurie)/ng.
`
`
`
`
`
`The six-stage-decay of radium-223 to stable lead-207 occurs via short-lived daughters, and is accompanied predominantly
`
`
`
`
`
`
`
`
`by alpha emissions. There are also beta and gamma emissions with different energies and emission probabilities. The
`
`
`
`
`
`fraction of energy emitted from radium-223 and its daughters as alpha-particles is 95.3% (energy range of 5 - 7.5 MeV).
`
`
`
`The fraction emitted as beta-particles is 3.6% (average energies are 0.445 MeV and 0.492 MeV), and the fraction emitted
`
`
`
`as gamma-radiation is 1.1% (energy range of 0.01 - 1.27 MeV).
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
`
` 12.1 Mechanism of Action
`
`
`
`
`
`
`
` The active moiety of Xofigo is the alpha particle-emitting isotope radium-223 (as radium Ra 223 dichloride), which
`
`
`
` mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as
`
`
`
`
`
`
`
`
` bone metastases (see Table 2). The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high
`
`
`
`
`
`
`
`
`
`
` frequency of double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha
`
`
`
`
`
`
` particle range from radium-223 dichloride is less than 100 micrometers (less than 10 cell diameters) which limits damage
`
`
`
`
`
`
`to the surrounding normal tissue.
`
`
`
`
` 12.2 Pharmacodynamics
`
`
`
`
`
`
`
`
` Compared with placebo, there was a significant difference in favor of Xofigo for all five serum biomarkers for bone
`
` turnover studied in a phase 2 randomized study (bone formation markers: bone alkaline phosphatase [ALP], total ALP
`
`
`
`
`
`
`
` and procollagen I N propeptide [PINP], bone resorption markers: C-terminal crosslinking telopeptide of type I collagen
`
`
`
` [S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]).
`
` 12.3 Pharmacokinetics
`
` The pharmacokinetics of radium-223 dichloride in blood was linear in terms of dose proportionality and time
`
`
`
`
`
`
`
` independence in the dose range investigated (46 to 250 kBq [1.24 to 6.76 microcurie] per kg body weight).
`
`
`
`
` Distribution
`
`
`
`
`
` After intravenous injection, radium-223 is rapidly cleared from the blood and is distributed primarily into bone or is
`
` excreted into intestine. Fifteen minutes post-injection, about 20% of the injected radioactivity remained in blood. At 4
`
`
` hours, about 4% of the injected radioactivity remained in blood, decreasing to less than 1% at 24 hours after the injection.
`
`
`
`
`
`
` At 10 minutes post-injection, radioactivity was observed in bone and in intestine. At 4 hours post-injection, the percentage
`
`
`
`
`
` of the radioactive dose present in bone and intestine was approximately 61% and 49%, respectively. No significant uptake
`
`
`
`
`
`
`Reference ID: 3308326
`
`9
`
`

`
`was seen in other organs such as heart, liver, kidneys, urinary bladder, and spleen at 4 hours post-injection [see Dosage
`
`
`and Administration (2.3)].
`
`
`Metabolism
`
`Radium-223 is an isotope that decays and is not metabolized.
`
`
`
`
`
`
`Elimination
`
`The whole body measurements indicated that approximately 63% of the administered radioactivity was excreted from the
`
`
`
`
`
`body within 7 days after injection (after correcting for decay). Fecal excretion is the major route of elimination from the
`
`
`
`
`
`
`
`body. At 48 hours after injection, the cumulative fecal excretion was 13% (range 0 - 34%), and the cumulative urine
`
`
`
`
`
`
`
`excretion was 2% (range 1 - 5%). There was no evidence of hepato-biliary excretion based on imaging data.
`
`
`
`
`
`
`
`The rate of elimination of radium-223 dichloride from the gastrointestinal tract is influenced by the high variability in
`
`
`
`intestinal transit rates across the population. Patients with a slower int