Radium Ra 223 Dichloride

1 INDICATIONS AND USAGE Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Xofigo is an alpha particle-emitting radioactive therapeutic agent indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. ( 1 )

2 DOSAGE AND ADMINISTRATION The dose regimen of Xofigo is 55 kBq (1.49 microcurie) per kg body weight, given at 4 week intervals for 6 injections. ( 2.1 ) 2.1 Recommended Dosage The dose regimen of Xofigo is 55 kBq (1.49 microcurie) per kg body weight, given at 4 week intervals for 6 injections. Safety and efficacy beyond 6 injections with Xofigo have not been studied. The volume to be administered to a given patient should be calculated using the: • Patient’s body weight (kg) • Dosage level 55 kBq/kg body weight or 1.49 microcurie/kg body weight • Radioactivity concentration of the product (1,100 kBq/mL; 30 microcurie/mL) at the reference date • Decay correction factor to correct for physical decay of radium-223. The total volume to be administered to a patient is calculated as follows: Volume to be administered (mL) = Body weight in kg × 55 kBq/kg body weight Decay factor × 1,100 kBq/mL or Volume to be administered (mL) = Body weight in kg × 1.49 microcurie/kg body weight Decay factor × 30 microcurie/mL Table 1: Decay Correction Factor Table Days from Reference Date Decay Factor Days from Reference Date Decay Factor -14 2.296 0 0.982 -13 2.161 1 0.925 -12 2.034 2 0.870 -11 1.914 3 0.819 -10 1.802 4 0.771 -9 1.696 5 0.725 -8 1.596 6 0.683 -7 1.502 7 0.643 -6 1.414 8 0.605 -5 1.330 9 0.569 -4 1.252 10 0.536 -3 1.178 11 0.504 -2 1.109 12 0.475 -1 1.044 13 0.447 14 0.420 The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the 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. Immediately before and after administration, the net patient dose of administered Xofigo should be determined by measurement in an appropriate radioisotope dose calibrator that has been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-223 standard (available upon request from Bayer) and corrected for decay using the date and time of calibration. The dose calibrator must be calibrated with nationally recognized standards, carried out at the time of commissioning, after any maintenance procedure that could affect the dosimetry and at intervals not to exceed one year. 2.2 Administration Administer Xofigo by slow intravenous injection over 1 minute. Flush the intravenous access line or cannula with isotonic saline before and after injection of Xofigo. Discard any unused portion, if applicable [see Dosage and Administration (2.3)]. 2.3 Instructions for Use/Handling General warning Xofigo (an alpha particle-emitting pharmaceutical) should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal of Xofigo are subject to the regulations and/or appropriate licenses of the competent official organization. Xofigo should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. Radiation protection The administration of Xofigo is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations. 1 For drug handling Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Xofigo, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid (EDTA) solution is recommended to remove contamination. For patient care Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Xofigo or patient fecal matter or urine should be washed promptly and separately from other clothing. Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the A s L ow A s R easonably A chievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations. The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Xofigo and the detection of contamination with standard instruments. Instructions for preparation Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Xofigo is a ready-to-use solution and should not be diluted or mixed with any solutions. Each vial is for single use only. Dosimetry The absorbed radiation doses in major organs were calculated based on clinical biodistribution data in five patients with castration-resistant prostate cancer. Calculations of absorbed radiation doses were performed using OLINDA/EXM ( O rgan L evel IN ternal D ose A ssessment/ EX ponential M odeling), a software program based on the Medical Internal Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting radionuclides. For radium-223, which is primarily an alpha particle-emitter, assumptions were made for intestine, red marrow and bone/osteogenic cells to provide the best possible absorbed radiation dose calculations for Xofigo, considering its observed biodistribution and specific characteristics. Additional particular modeling was applied for the lungs. The absorbed dose to the lungs is estimated as the dose contribution from 223Ra and daughter decays in the blood-containing fraction of the lung mass and also the dose contribution from 219Rn and daughter decays in the respiratory tract. The calculated absorbed radiation doses to different organs per administered activity are listed in Table 2. The organs with highest absorbed radiation doses are bone (osteogenic cells), red marrow, and large intestine walls. The absorbed doses to other organs are lower. Table 2: Absorbed Radiation Doses per Administered Activity Organ Mean (mGy/MBq) Mean (rad/mCi) Coefficient of Variation (%) Osteogenic cells 1152 4263 41 Red marrow 139 514 41 LLI wall LLI: lower large intestine; ULI: upper large intestine; colon dose = 0.57 × ULI dose + 0.43 × LLI dose2 46 172 83 Colon 38 142 56 ULI wall 32 120 50 Small intestine wall 7.3 27 45 Urinary bladder wall 4.0 15 63 Kidneys 3.2 12 36 Liver 3.0 11 36 Heart wall 1.7 6.4 42 Lungs 1.2 4.5 48 Ovaries 0.49 1.8 40 Uterus 0.26 0.94 28 Gallbladder wall 0.23 0.85 14 Stomach wall 0.14 0.51 22 Adrenals 0.12 0.44 56 Muscle 0.12 0.44 41 Pancreas 0.11 0.41 43 Brain 0.10 0.37 80 Spleen 0.09 0.33 54 Testes 0.08 0.31 59 Skin 0.07 0.27 79 Thyroid 0.07 0.26 96 Thymus 0.06 0.21 109 Breasts 0.05 0.18 120 Whole Body 23 86 16

6 ADVERSE REACTIONS 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 )] The most common adverse drug reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema. The most common hematologic laboratory abnormalities (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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. In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer with bone metastases, 600 patients received intravenous injections of 55 kBq/kg (1.49 microcurie/kg) of Xofigo and best standard of care and 301 patients received placebo and best standard of care once every 4 weeks for up to 6 injections. Prior to randomization, 58% and 57% of patients had received docetaxel in the Xofigo and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Xofigo and 18 weeks (5 cycles) for placebo. The most common adverse reactions (≥ 10%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (Table 4). Treatment discontinuations due to adverse events occurred in 17% of patients who received Xofigo and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Xofigo were anemia (2%) and thrombocytopenia (2%). Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Xofigo exceeds the incidence for placebo. Table 3: Adverse Reactions in the Randomized Trial System/Organ Class Preferred Term Xofigo (n=600) Placebo (n=301) Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 % Blood and lymphatic system disorders Pancytopenia 2 1 0 0 Gastrointestinal disorders Nausea 36 2 35 2 Diarrhea 25 2 15 2 Vomiting 19 2 14 2 General disorders and administration site conditions Peripheral edema 13 2 10 1 Renal and urinary disorders Renal failure and impairment 3 1 1 1 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 Hematologic Laboratory Abnormalities Xofigo (n=600) Placebo (n=301) Grades 1-4 % Grades 3-4 % Grades 1-4 % Grades 3-4 % Anemia 93 6 88 6 Lymphocytopenia 72 20 53 7 Leukopenia 35 3 10 <1 Thrombocytopenia 31 3 22 <1 Neutropenia 18 2 5 <1 Laboratory values were obtained at baseline and prior to each 4-week cycle. 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. 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.

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 (51 to 276 kBq [1.38 to 7.46 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 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 intestinal transit rate could potentially receive a higher intestinal radiation exposure. It is not known whether this will result in increased gastrointestinal toxicity. Special Populations Pediatric patients Safety and effectiveness of Xofigo have not been established in children and adolescents below 18 years of age. Patients with hepatic impairment No dedicated pharmacokinetic study in patients with hepatic impairment has been conducted. However, since radium-223 is not metabolized and there is no evidence of hepato-biliary excretion based on imaging data, hepatic impairment is not expected to affect the pharmacokinetics of radium-223 dichloride. Patients with renal impairment No dedicated pharmacokinetic study in patients with renal impairment has been conducted. However, since excretion in urine is minimal and the major route of elimination is via the feces, renal impairment is not expected to affect the pharmacokinetics of radium-223 dichloride.