Side Effects of Xofigo (radium Ra 223)

Xofigo (radium Ra 223) is a radioactive medicine (radiotherapeutic drug) used to treat male patients with symptoms of advanced prostate cancer that has spread to the bones, but not to other parts of the body.

The radioactive particles emitted by Xofigo help kill cancer cells in the bone by damaging their DNA. Xofigo causes minimal damage to the nearby healthy cells. Xofigo can help some patients live longer. 

Common side effects of Xofigo include

• nausea,
• vomiting,
• diarrhea,
• swelling of the arms or legs, and
• low blood cell counts.

Serious side effects of Xofigo include

• bone marrow suppression (a potentially serious condition in which blood cell counts decrease),
• a drop in red blood cells,
• white blood cells, and
• platelets. 

Information on potential drug-drug interactions with Xofigo is not available as no formal drug interaction studies have been performed.

Xofigo can cause harm to a fetus and should not be used in women who are or may become pregnant.

Women who are pregnant or who may become pregnant should not handle Xofigo without wearing gloves or proper protection. Male patients who are sexually active should use condoms and their female partners should use a highly effective method of birth control (for example, birth control pills) during treatment and for 6 months after stopping treatment.

Xofigo should not be used by women. It is not known if Xofigo is excreted in breast milk.

The most common side effects of radium Ra 223 are:

• nausea,
• vomiting,
• diarrhea,
• swelling of the arms or legs (peripheral edema), and
• low blood cell counts.

To avoid dehydration caused by diarrhea, nausea, or vomiting, patients are advised to drink plenty of water and report any signs of dehydration such as dry mouth or increased thirst.

Radium Ra 223 can cause bone marrow suppression, a potentially serious condition in which blood cell counts decrease.

In clinical studies, use of radium Ra 223 caused a drop in red blood cells, white blood cells, and platelets in some patients. Because of serious bone marrow problems, some patients had to permanently discontinue treatment, required blood transfusions, and some deaths were reported.

The following serious adverse reactions are discussed in greater detail in another section of the label:

• Bone Marrow Suppression

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%, Table 3) in patients receiving Xofigo were

• nausea,
• diarrhea,
• vomiting, and
• peripheral edema.

Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebotreated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%, Table 4) were

• anemia,
• lymphocytopenia,
• leukopenia,
• thrombocytopenia, and
• neutropenia.

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

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

• 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 naive patients and in 4% of patients who had received prior docetaxel.
• Grade 3-4 neutropenia occurred in 1% of docetaxel naive 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.
• 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.

• 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.