Xofigo
(radium chloride Ra-223)Dosage & Administration
The dose regimen of Xofigo is 55 kBq (1.49 microcurie) per kg body weight, given at 4 week intervals for 6 injections.
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Xofigo Prescribing Information
Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
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 |
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.
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)].
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 As Low As Reasonably Achievable (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 (Organ Level INternal Dose Assessment/EXponential Modeling), 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.
| |||
|
|
|
|
| 1152 | 4263 |
|
| 139 | 514 |
|
| 46 | 172 |
|
| 38 | 142 |
|
| 32 | 120 |
|
| 7.3 | 27 |
|
| 4.0 | 15 |
|
| 3.2 | 12 |
|
| 3.0 | 11 |
|
| 1.7 | 6.4 |
|
| 1.2 | 4.5 |
|
|
| 1.8 |
|
|
| 0.94 |
|
|
| 0.85 |
|
|
| 0.51 |
|
|
| 0.44 |
|
|
| 0.44 |
|
|
| 0.41 |
|
|
| 0.37 |
|
|
| 0.33 |
|
|
| 0.31 |
|
|
| 0.27 |
|
|
| 0.26 |
|
|
| 0.21 |
|
|
| 0.18 |
|
|
| 86 |
|
Xofigo (radium Ra 223 dichloride injection) is available in single-dose vials containing 6 mL of clear, colorless solution at a concentration of 1,100 kBq/mL (30 microcurie/mL) at the reference date with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the referencedate.
Pregnancy
Risk Summary
The safety and efficacy of Xofigo have not been established in females. Based on mechanism of action, Xofigo can cause fetal harm when administered to a pregnant female [see Clinical Pharmacology ( 12.1)]. While there are no human or animal data on the use of Xofigo in pregnancy, maternal use of a radioactive therapeutic agent could affect development of a fetus. Advise pregnant females and females of reproductive potential of the potential risk to a fetus.
Lactation
Risk Summary
The safety and efficacy of Xofigo have not been established in females. There is no data on the presence of radium-223 dichloride in human milk, the effects on the breastfed child, or the effects on milk production.
Females and Males of Reproductive Potential
Contraception
Males
Because of potential effects on spermatogenesis associated with radiation, advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo [see Use in Specific Populations ].
Infertility
Males
Based on mechanism of action, Xofigo may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1) and Nonclinical Toxicology ].
Pediatric Use
The safety and efficacy of Xofigo in pediatric patients have not been established.
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 22 – 88 kBq (0.59 - 2.38 microcurie) per kg body weight.
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.
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 ]. 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.
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 ].
None.
Bone Marrow Suppression
In the randomized trial, 2% of patients on the Xofigo arm experienced bone marrow failure or ongoing pancytopenia compared to no patients treated with placebo. There were two deaths due to bone marrow failure and for 7 of 13 patients treated with Xofigo, bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients on the Xofigo arm and 2% on the placebo arm permanently discontinued therapy due to bone marrow suppression.
In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% 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. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Xofigo. In the randomized trial, complete blood counts (CBCs) were obtained every 4 weeks prior to each dose and the nadir CBCs and times of recovery were not well characterized. In a separate single-dose phase 1 study of Xofigo, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Xofigo administration at doses that were up to 1 to 5 times the recommended dose, and most patients recovered approximately 6 to 8 weeks after administration [see Adverse Reactions ].
Hematologic evaluation of patients must be performed at baseline and prior to every dose of Xofigo. Before the first administration of Xofigo, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet count ≥ 100 x 109/L and hemoglobin ≥ 10 g/dL. Before subsequent administrations of Xofigo, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. If there is no recovery to these values within 6 to 8 weeks after the last administration of Xofigo, despite receiving supportive care, further treatment with Xofigo should be discontinued. Patients with evidence of compromised bone marrow reserve should be monitored closely and provided with supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.
The safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use with chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued.
Increased Fractures and Mortality in Combination with Abiraterone plus Prednisone/Prednisolone
Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials.
The clinical efficacy and safety of concurrent initiation of Xofigo treatment and abiraterone acetate plus prednisone/prednisolone treatment was assessed in a randomized, placebo-controlled multicenter phase 3 study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation.
At the primary analysis, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established.
-167640120650005.3 Embryo-Fetal Toxicity
The safety and efficacy of Xofigo have not been established in females. Based on its mechanism of action, Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo [see Use in Specific Populations and Clinical Pharmacology ].