Radium chloride

Radium chloride
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Overview

Radium chloride is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Common adverse reactions include nausea, diarrhea, vomiting, and peripheral edema.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Radium chloride FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Radium chloride in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Radium chloride in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Radium chloride FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Radium chloride in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Radium chloride in pediatric patients.

Contraindications

• Xofigo is contraindicated in pregnancy.
• Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
• Xofigo is not indicated for use in women.
• Xofigo is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus

Warnings

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.
• 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.

Adverse Reactions

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 50 kBq/kg (1.35 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%) in patients receiving Xofigo were nausea, diarrhea, vomiting, and peripheral edema (Table 3). Grade 3 and 4 adverse events were reported among 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in Xofigo-treated patients (≥ 10%) 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.

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.

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

Postmarketing Experience

There is limited information regarding Radium chloride Postmarketing Experience in the drug label.

Drug Interactions

• 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): X

• Xofigo can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of Xofigo in pregnancy and Xofigo is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Xofigo is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Xofigo.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Radium chloride in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Radium chloride during labor and delivery.

Nursing Mothers

• Xofigo is not indicated for use in women. It is not known whether radium-223 dichloride is excreted in human milk. Because many drugs are excreted in human milk, and because of potential for serious adverse reactions in nursing infants from Xofigo, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

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 20 – 80 kBq (0.541 - 2.16 microcurie) per kg body weight.

Geriatic 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.

Gender

There is no FDA guidance on the use of Radium chloride with respect to specific gender populations.

Race

There is no FDA guidance on the use of Radium chloride with respect to specific racial populations.

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).

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. 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.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Radium chloride in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Radium chloride in patients who are immunocompromised.

Males of Reproductive Potential

• Contraception: Because of potential effects on spermatogenesis associated with radiation, advise men who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective contraceptive method during and for 6 months after completing treatment with Xofigo.
• Infertility: There are no data on the effects of Xofigo on human fertility. There is a potential risk that radiation by Xofigo could impair human fertility

Administration and Monitoring

Administration

There is limited information regarding Radium chloride Administration in the drug label.

Monitoring

There is limited information regarding Radium chloride Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Radium chloride and IV administrations.

Overdosage

There have been no reports of inadvertent overdosing of Xofigo during clinical studies.

• There is no specific antidote. In the event of an inadvertent overdose of Xofigo, utilize general supportive measures, including monitoring for potential hematological and gastrointestinal toxicity, and consider using medical countermeasures such as aluminum hydroxide, barium sulfate, calcium carbonate, calcium gluconate, calcium phosphate, or sodium alginate.

Single Xofigo doses up to 250 kBq (6.76 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed.

Pharmacology

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Radium chloride

Radium Chloride
Identifiers
CAS Number	10025-66-8 N
3D model (JSmol)	Interactive image
ChemSpider	20138060 Y
ECHA InfoCard
InChI InChI=1S/2ClH.Ra/h2*1H;/q;;+2/p-2 Y Key: RWRDJVNMSZYMDV-UHFFFAOYSA-L Y InChI=1/2ClH.Ra/h2*1H;/q;;+2/p-2 Key: RWRDJVNMSZYMDV-NUQVWONBAG
SMILES [Ra+2].[Cl-].[Cl-]
Properties
Chemical formula	RaCl2
Molar mass	296.094 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Mechanism of Action

• The active moiety of Xofigo is the alpha particle-emitting isotope radium-223 (as radium Ra 223 dichloride), which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases (see Table 2). The high linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of double-strand DNA breaks in adjacent cells, resulting in an anti-tumor effect on bone metastases. The alpha particle range from radium-223 dichloride is less than 100 micrometers (less than 10 cell diameters) which limits damage to the surrounding normal tissue.

Structure

There is limited information regarding Radium chloride Structure in the drug label.

Pharmacodynamics

There is limited information regarding Radium chloride Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Radium chloride Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Radium chloride Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Radium chloride Clinical Studies in the drug label.

How Supplied

There is limited information regarding Radium chloride How Supplied in the drug label.

Storage

There is limited information regarding Radium chloride Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Radium chloride Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Radium chloride interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Radium chloride Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Radium chloride Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Template:Chembox new Radium chloride, RaCl₂, was the first radium compound to be prepared in a pure state and was the basis of Marie Curie's original separation of radium from barium. The first preparation of radium metal was by the electrolysis of a solution of radium chloride using a mercury cathode.

Preparation

Radium chloride crystallises from solution as the dihydrate. It may be dehydrated by heating to 100 °C in air for one hour followed by 5½ hours at 520 °C under argon. If the presence of other anions is suspected, the dehydration may be effectuated by fusion under hydrogen chloride.

Properties

Radium chloride is a white solid with a blue-green luminescence, especially when heated. It is less soluble in water than other alkaline earth metal chlorides, a fact which is used in the first stages of the separation of radium from barium by fractional crystallization. It is only sparingly soluble in azeotropic hydrochloric acid and virtually insoluble in concentrated hydrochloric acid.

Gaseous radium chloride exists as RaCl₂ molecules, as with other alkaline earth metal halides. The gas shows strong absorptions in the visible spectrum at 676.3 nm and 649.8 nm (red): the dissociation energy of the radium–chlorine bond is estimated as 2.9 eV, and its length as 292 pm.

Uses

Radium chloride is still used for the initial stages of the separation of radium from barium during the extraction of radium from pitchblende. The large quantities of material involved (tonnes of ore for milligrams of radium) favour this less costly (but less efficient) method over those based on radium bromide or radium chromate (used for the later stages of the separation).

Sources

• Gmelins Handbuch der anorganischen Chemie (8. Aufl.), Berlin:Verlag Chemie, 1928, pp. 60–61.
• Gmelin Handbuch der anorganischen Chemie (8. Aufl. 2. Erg.-Bd.), Berlin:Springer, 1977, pp. 362–64.