Bayer Appoints Cardinal Health as U.S. Based Contract Manufacturer for Xofigo® (radium Ra 223 dichloride) Injection

WHIPPANY, N.J. and DUBLIN, Ohio, Dec. 18, 2014 /PRNewswire/ -- Bayer HealthCare and Cardinal Health today announced the signing of a 15-year agreement for the contract manufacturing of Xofigo^® (radium Ra 223 dichloride).  As part of the agreement, Cardinal Health will build a state-of-the art, 64,000 square foot facility in Indianapolis, which will be dedicated exclusively to the manufacturing of Xofigo.  Product manufactured at this facility will primarily be distributed in the United States and Canada.

The manufacturing facility will be built near and leverage the capabilities and talent of Cardinal Health's existing Indianapolis radiopharmacy, which is one of the two U.S. locations authorized by Bayer HealthCare to distribute Xofigo. Cardinal Health is the sole distributor of Xofigo in the U.S.

Xofigo is an alpha-particle-emitting radioactive therapeutic agent for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease. Bayer HealthCare is developing and marketing Xofigo worldwide. The current manufacturing site in Norway will continue to be responsible for global supply of the product. 

"This new agreement presents us with an excellent opportunity to leverage our unmatched expertise in the nuclear pharmacy industry to expand access to a therapeutic agent," said Tiffany Olson, president of Cardinal Health's Nuclear Pharmacy Services business. "We look forward to continuing to strengthen our relationship with Bayer HealthCare, and to developing innovative services to expand the use of radiopharmaceuticals in the United States and Canada."

Bayer had started the preparations for a second manufacturing site soon after the first marketing authorization for Xofigo was obtained in May 2013. The new Cardinal Health manufacturing facility, slated for completion in 2017, will be built and equipped for the unique manufacturing needs of Xofigo.  It will be supported by approximately 85 employees, including specialized manufacturing roles, chemists, engineers and other professional positions.

"Cardinal Health has played a pivotal role in distributing Xofigo to medical facilities since the product's launch in the U.S. in May 2013," said Shannon Campbell, vice president and general manager of oncology, Bayer HealthCare. "Cardinal Health's proven track record in radiopharmaceuticals and their experience with Xofigo make them a formidable choice for helping to expand our manufacturing capabilities in North America.  We're pleased to take this important step forward alongside Cardinal Health."

About Castration-Resistant Prostate Cancer (CRPC) and Bone Metastases
Prostate cancer is the most common cancer among men in the United States (other than skin cancer).  Approximately four percent of prostate cancer cases are considered distant, which means that the cancer has spread beyond the prostate to distant areas of the body (metastasized). If prostate cancer starts to spread to other areas of the body, it most commonly goes to the bone. Once the cancer has reached the bone, interactions between tumors cells and the bone cells responsible for breaking down and rebuilding bone result in excessive bone rebuilding.

About Xofigo^® (radium Ra 223 dichloride) Injection
Xofigo is an alpha particle-emitting radioactive therapeutic agent with an anti-tumor effect on bone metastases. The active ingredient in Xofigo is the alpha particle-emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high linear energy transfer of Xofigo may cause double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha particle range from radium Ra 223 dichloride is less than 100 micrometers which may limit the damage to the surrounding normal tissue¹.

The approval of Xofigo is based on data from the pivotal Phase III ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial. At the interim analysis, Xofigo significantly improved overall survival (OS) [HR=0.695 (95% CI 0.552-0.875), p=0.00185]; median OS was 14.0 months with Xofigo plus best standard of care (95% CI 12.1, 15.8) vs. 11.2 months with placebo plus best standard of care (95% CI 9.0, 13.2).¹ Additionally, at the interim analysis there was a delay in time to first symptomatic skeletal event (SSE) for patients treated with Xofigo vs. placebo. The majority of events consisted of external beam radiotherapy to bone metastases

An exploratory updated overall survival analysis performed before patient crossover with an additional 214 events resulted in findings consistent with the interim analysis. The updated analysis showed improvement in overall survival (OS), with a median OS of 14.9 months with Xofigo (95% CI 13.9, 16.1) vs. 11.3 months with placebo (95% CI 10.4, 12.8) [HR=0.695 (95% CI 0.581-0.832)].¹

Important Safety Information for Xofigo^® (radium Ra 223 dichloride) Injection

• Contraindications: Xofigo is contraindicated in women who are or may become pregnant. Xofigo can cause fetal harm when administered to a pregnant woman.
• Bone Marrow Suppression: In the randomized trial, 2% of patients in 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. 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 in the Xofigo arm and 2% in 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%) was similar for patients treated with Xofigo and placebo. Myelosuppression – notably thrombocytopenia, neutropenia, pancytopenia, and leucopenia – has been reported in patients treated with Xofigo.
  Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure.
• Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be >1.5 × 10⁹/L, the platelet count >100 × 10⁹/L, and hemoglobin >10 g/dL. Prior to subsequent administrations, the ANC should be >1 × 10⁹/L and the platelet count >50 × 10⁹/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care.
• Concomitant Use with Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on 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.
• Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons 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.
• 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. 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
• Adverse Reactions: The most common adverse reactions (>10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (>10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%).

For full prescribing information visit http://labeling.bayerhealthcare.com/html/products/pi/Xofigo_PI.pdf

About Cardinal Health
Headquartered in Dublin, Ohio, Cardinal Health, Inc. (NYSE: CAH) is a $91 billion health care services company that improves the cost-effectiveness of health care. As the business behind health care, Cardinal Health helps pharmacies, hospitals, ambulatory surgery centers, clinical laboratories and physician offices focus on patient care while reducing costs, enhancing efficiency and improving quality. Cardinal Health is an essential link in the health care supply chain, providing pharmaceuticals and medical products and services to more than 100,000 locations each day and is also the industry-leading direct-to-home medical supplies distributor. The company is a leading manufacturer of medical and surgical products, including gloves, surgical apparel and fluid management products. In addition, the company operates the nation's largest network of radiopharmacies that dispense products to aid in the early diagnosis and treatment of disease. Ranked #22 on the Fortune 500, Cardinal Health employs 34,000 people worldwide. More information about the company may be found at www.cardinalhealth.com and @CardinalHealth on Twitter.

About Bayer HealthCare Pharmaceuticals Inc. 
Bayer HealthCare Pharmaceuticals Inc. is the U.S.-based pharmaceuticals business of Bayer HealthCare LLC, a subsidiary of Bayer AG. Bayer HealthCare is one of the world's leading, innovative companies in the healthcare and medical products industry, and combines the activities of the Animal Health, Consumer Care, Medical Care, and Pharmaceuticals divisions.  As a specialty pharmaceutical company, Bayer HealthCare Pharmaceuticals Inc. provides products for General Medicine, Hematology, Neurology, Oncology and Women's Healthcare. The company's aim is to discover and manufacture products that will improve human health worldwide by diagnosing, preventing and treating diseases.

© 2014 Bayer HealthCare Pharmaceuticals Inc. 
BAYER, the Bayer Cross, and Xofigo are registered trademarks of Bayer.               

Forward-Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. 

1. XOFIGO® (radium Ra 223 dichloride) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, May 2013.

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SOURCE Cardinal Health