ive 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
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.
12.6 Cardiac Electrophysiology
The effect of a single dose of 50 kBq/kg of radium-223 dichloride on the QTc interval was eva luated in a subgroup of 29 patients (21 received Xofigo and 8 received placebo) in the randomized clinical trial. No large changes in the mean QTc interval (i.e., greater than 20 ms) were detected up to 6 hours post-dose. The potential for delayed effects on the QT interval after 6 hours was not eva luated.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal studies have not been conducted to eva luate the carcinogenic potential of radium-223 dichloride. However, in repeat-dose toxicity studies in rats, osteosarcomas, a known effect of bone-seeking radionuclides, were observed at clinically relevant doses 7 to 12 months after the start of treatment. The presence of other neoplastic changes, including lymphoma and mammary gland carcinoma, was also reported in 12- to 15-month repeat-dose toxicity studies in rats.
Genetic toxicology studies have not been conducted with radium-223 dichloride. However, the mechanism of action of radium-223 dichloride involves induction of double-strand DNA breaks, which is a known effect of radiation.
Animal studies have not been conducted to eva luate the effects of radium-223 dichloride on male or female fertility or reproductive function. Xofigo may impair fertility and reproductive function in humans based on its mechanism of action.
14 CLINICAL STUDIES
The efficacy and safety of Xofigo were eva luated in a double-blind, randomized, placebo-controlled phase 3 clinical trial of patients with castration-resistant prostate cancer with symptomatic bone metastases. Patients with visceral metastases and malignant lymphadenopathy exceeding 3 cm were excluded. The primary efficacy endpoint was overall survival. A key secondary efficacy endpoint was time to first symptomatic skeletal event (SSE) defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention. There were no scheduled radiographic assessments performed on study. All patients were to continue androgen deprivation therapy. At the cut-off date of the pre-planned interim analys |
