ML15264B095

UNITED STATES 

NUCLEAR REGULATORY COMMISSION 

OFFICE OF NUCLEAR MATERIALS SAFETY AND SAFEGUARDS 

WASHINGTON, D.C. 20555-0001 

January 12, 2016 

NRC INFORMATION NOTICE 2016-03: REVISION TO THE NATIONAL INSTITUTE OF 

 STANDARDS AND TECHNOLOGY STANDARD 

 FOR RADIUM-223 AND IMPACT ON DOSE 

 CALIBRATION FOR THE MEDICAL USE OF 

 RADIUM-223 DICHLORIDE 

ADDRESSEES 

All U.S. Nuclear Regulatory Commission (NRC) medical licensees, NRC Master Materials 

Licensees, Agreement State Radiation Control Program Directors, and State Liaison Officers. 

PURPOSE 

The NRC is issuing this Information Notice (IN) to alert addressees that the National Institute of 

Standards and Technology (NIST) revised its primary standard for radium-223 (Ra-223) and to 

convey the impact this revision will have on the calibration of patient doses of Ra-223 dichloride 

(trade name Xofigo®). Recipients should review the information contained in this notice for 

applicability to their facilities and consider taking appropriate action, if necessary. However, the 

information conveyed in this notice is not a new NRC requirement; therefore, no specific action 

or written response to this notice is required. 

The NRC is providing this notice to the Agreement States for information and distribution to 

medical use licensees, as appropriate. 

BACKGROUND 

Ra-223 dichloride is an injectable radiopharmaceutical used to treat skeletal metastases in 

advanced, castration-resistant prostate cancer. Ra-223 emits alpha particles and has a half-life 

of 11.4 days. Once in the body, Ra-223 dichloride mimics calcium and forms complexes in 

areas of increased bone turnover, such as sites of bone metastases. Ra-223 dichloride kills 

tumor cells through highly localized, short-range alpha irradiation. Although Ra-223 is primarily 

an alpha-emitter, the activity of Ra-223 can be measured in a radioisotope dose calibrator that 

has been calibrated with NIST-traceable Ra-223 reference material. 
IN 2016-03 

Page 2 of 3 

Following U.S. Food and Drug Administration approval in May 2013, Bayer Pharma AG (Bayer), 

began commercial distribution of Xofigo® domestically. Bayer provided Xofigo® customers with a 

NIST-traceable Ra-223 standard syringe and an appropriate dial setting for dose calibrators 

based on NIST data published in 2010.1

DESCRIPTION OF CIRCUMSTANCES 

In 2013, NIST was made aware of studies performed by the National Physical Laboratory (NPL) 

(the National Measurement Institute of the United Kingdom) in which an approximately 10 

percent difference was found between NPL’s activities obtained using several primary methods 

and those obtained with the calibration factors published by NIST from 2010. Subsequently, 

NIST performed additional testing using more robust methods than previously available to verify 

NPL’s results and confirmed that activity readings were lower than expected. On March 11, 

2015, NIST published information2 regarding the revised primary standard for Ra-223 resulting 

in a numerical increase of 10.5 percent for the new primary standard. This change was only to 

the numerical value of the quantity of Ra-223, as the actual amount of Ra-223 in the primary 

standard did not change. 

Bayer notified Xofigo® customers of the NIST standardization change and future labeling and 

calibration impacts in a letter dated March 18, 2015. See “Bayer Letter to Healthcare 

Professionals for Ra-223 NIST Standardization Issue,” available in ADAMS under Accession 

No. ML15264B158. In the letter, Bayer stated that they will provide customers with a new NISTtraceable Ra-223 standard syringe and dose calibration dial setting based on the NIST revised 

primary standard. Bayer also stated that they will increase the numerical values listed on the 

package label by approximately 10 percent. For example, the labeling of the patient dosage will 

be updated from 50kBq/kg of body weight to 55kBq/kg of body weight. Additionally, Bayer 

stated that the manufacturing and product documentation will be updated and labeled as 1100 

kBq/mL (previously 1000 kBq/mL) and 6.6 MBq/vial (previously 6.0 MBq/vial). 

The NRC’s licensees are typically authorized for the possession and medical use of Ra-223 

dichloride in the millicurie range. Xofigo® doses are administered in the microcurie range, so 

the NRC does not anticipate the need to update licenses as a result of the new primary NIST 

standard. Furthermore, Bayer stated in its March 18, 2015, letter that the revised NIST standard 

for Ra-223 does not change the actual amount of Ra-223 dichloride being administered to 

patients and will not impact the safety and efficacy of Xofigo®. 

 

1 J. T. Cessna and B. E. Zimmerman, Standardization of radium-223 by liquid scintillation counting, Appl. Radiat. Isot. 

68, 1523-1528 (2010) and D. E. Bergeron, B. E. Zimmerman, and J. T. Cessna, Development of secondary 

standards for 223Ra, Appl. Radiat. Isot. 68, 1367-1370 (2010). 

2 B. E. Zimmerman, D. E. Bergeron, J. T. Cessna, R. Fitzgerald, and L. Pibida, Revision of the NIST Standard for 

223Ra: New Measurements and Review of 2008 Data, Journal of Research of NIST, 120, 37-57 (2015).
IN 2016-03 

Page 3 of 3 

As stated in the purpose section of this IN, this notice does not convey any new NRC 

requirements. Therefore, licensees are not required to take any action based on this notice. As 

stated in its March 18, 2015 letter, Bayer is contacting healthcare providers to provide 

information on how to obtain an updated NIST-traceable standard and to prepare for future 

changes in the dose calibrator dial setting. The new dial setting should not be used for verifying 

the activity in patient dosages until Bayer implements label changes in 2016. Bayer will notify 

Xofigo® customers of the label change via letter a few weeks before the implementation date. 

When the label change occurs and the new dial setting is to be implemented, licensees may 

update internal procedures, as needed (e.g., to reflect the new dial setting on the dose 

calibrator). 

CONCLUSION 

Bayer's March 18, 2015, letter emphasizes that no immediate action on the part of its customers 

is necessary for meeting the new calibration standard. NRC advises affected licensees to 

continue to use the existing NIST-traceable Ra-223 standard syringe and calibration dial setting 

until notified otherwise by Bayer. 

CONTACT 

This notice requires no specific action or written response. Licensees may contact Bayer at 

(888) 842-2937 or visit www.xofigo.us.com for additional information on how to obtain an 

updated NIST-traceable Ra-223 standard syringe and to prepare for future changes in the dose 

calibrator dial setting. For regulatory questions, please contact the technical contact below. 

 

 /RA Pamela Henderson for/ 

 Daniel S. Collins, Director 

Division of Material Safety, State, Tribal 

 and Rulemaking Programs 

Office of Nuclear Material Safety 

 and Safeguards 

Technical Contact: Michael Fuller, NMSS 

 Phone: (301) 415-0520 

 Email: Michael.Fuller@nrc.gov 

Note: NRC generic communications may be found on the NRC public Web site, 

http://www.nrc.gov, under “NRC Library” > “Document Collections 
IN 2016-03 

Page 3 of 3 

As stated in the purpose section of this IN, this notice does not convey any new NRC 

requirements. Therefore, licensees are not required to take any action based on this notice. As 

stated in their March 18, 2015 letter, Bayer is contacting healthcare providers to provide 

information on how to obtain an updated NIST-traceable standard and to prepare for future 

changes in the dose calibrator dial setting. The new dial setting should not be used for verifying 

the activity in patient dosages until Bayer implements label changes in 2016. Bayer will notify 

Xofigo® customers via letter a few weeks before the implementation date of the label change. 

When the label change occurs and the new dial setting is to be implemented, licensees may 

update internal procedures, as needed (e.g. to reflect the new dial setting on the dose 

calibrator). 

CONCLUSION 

Bayer's March 18, 2015, letter emphasizes that no immediate action on the part of its customers 

is necessary for meeting the new calibration standard. NRC advises affected licensees to 

continue to use the existing NIST-traceable Ra-223 standard syringe and calibration dial setting 

until notified otherwise by Bayer. 

CONTACT 

This notice requires no specific action or written response. Licensees may contact Bayer at 

(888) 842-2937 or visit www.xofigo.us.com for additional information on how to obtain an 

updated NIST-traceable Ra-223 standard syringe and to prepare for future changes in the dose 

calibrator dial setting. For regulatory questions, please contact the technical contact below. 

 

 /RA Pamela Henderson for/ 

 Daniel S. Collins, Director 

Division of Material Safety, State, Tribal 

 and Rulemaking Programs 

Office of Nuclear Material Safety 

 and Safeguards 

Technical Contact: Michael Fuller, NMSS 

 Phone: (301) 415-0520 

 Email: Michael.Fuller@nrc.gov 

Note: NRC generic communications may be found on the NRC public Web site, 

http://www.nrc.gov, under “NRC Library” > “Document Collections

ADAMS Accession No. ML15264B095 *via email 

OFFICE MSTR/MSEB MSTR/MSEB MSTR/MSEB OGC MSTR 

NAME *ACockerham AMcIntosh DBollock *NLO PHenderson for 

DCollins 

DATE 9/25/15 10/14/15 10/1/15 1/7/16 1/12/16 

OFFICIAL RECORD DOCUMENT