Xofigo^® (Solution) Instructions for Use

Marketing Authorization Holder

Bayer, AG (Germany)

Manufactured By

Agilera Pharma, AS (Norway)

Quality Control Release

BAYER, AS (Norway)

ATC Code

V10XX03 (Radium (223Ra) dichloride)

Active Substance

Radium chloride [223 Ra]

Radium chloride [223 Ra] (Grouping name)

Dosage Form

Xofigo®

Solution for intravenous administration 1100 kBq/ml: fl. 6 ml

Dosage Form, Packaging, and Composition

Solution for intravenous administration colorless, transparent.

The content of radium chloride [223Ra] is indicated as calculated for radium-223 at the reference date**.

Excipients : sodium chloride – 6.3 mg, sodium citrate – 7.2 mg*, hydrochloric acid – 0.2 mg, water for injections – up to 1 ml.

6 ml (6600 kBq^#) – colorless glass vials with a capacity of 10 ml (1) complete with 2 moisture-absorbent cellulose discs – lead containers (1) with tables of radioactive decay coefficient values – type A cardboard boxes for transporting radioactive substances.

* the amount of anhydrous sodium citrate is indicated; sodium citrate dihydrate is used in the manufacturing process;
** reference date – the date set as “12:00 Central European Time 14 days after the drug manufacturing date” and corresponding to the calibration date.

Clinical-Pharmacological Group

Radiopharmaceutical drug for the palliative treatment of bone metastases

Pharmacotherapeutic Group

Therapeutic radiopharmaceuticals; other therapeutic radiopharmaceuticals

Pharmacological Action

Therapeutic radiopharmaceutical. The therapeutic effect is due to the emission of alpha particles.

Radium chloride [223 Ra] mimics calcium and forms a complex with the bone mineral hydroxyapatite. Due to this, the radium isotope selectively affects bone tissue, in particular bone metastatic lesions of prostate cancer. The high linear energy transfer value of alpha particles (80 keV/μm) leads to a high frequency of double-stranded DNA breaks and causes a strong cytotoxic effect. In vivo models have shown an additional effect of the drug on the tumor microenvironment, including osteoclasts and osteoblasts, which contributed to its additional efficacy. The range of action of the alpha particles of radium chloride [223 Ra] is less than 100 μm (less than ten cell diameters), which minimizes damage to healthy surrounding tissues.

Pharmacokinetics

After intravenous administration of the drug containing radium chloride [223 Ra], its bioavailability is 100%.
After intravenous administration, the radium isotope (radium-223) is rapidly cleared from the systemic circulation and accumulates primarily in the bones and bone metastases or is directly excreted into the intestine.
Approximately 20% of the administered dose remained in the systemic circulation 15 minutes after administration. Approximately 4% of the administered dose remained in the systemic circulation 4 hours after administration, decreasing to less than 1% after 24 hours. V_d exceeded the blood volume, indicating distribution to peripheral compartments. Radiopharmaceutical activity was noted in the bones and intestine 10 minutes after administration. At 4 hours after administration, the mean values of the radioactive dose determined in the bones and intestine were about 61% and 49%, respectively. No significant accumulation of the radium isotope was observed in organs such as the heart, liver, kidneys, bladder, and spleen 4 hours after injection.

The radium isotope (radium-223) undergoes radioactive decay and is not metabolized.
The radium isotope is mainly eliminated from the body through the intestine. About 5% is excreted by the kidneys. Data on hepatobiliary excretion are not available.
Results of whole-body radioactivity measurements 7 days after administration (taking into account the decay factor) show that 76% of the administered dose is eliminated from the body. The rate of elimination of radium-223 from the gastrointestinal tract is influenced by the high variability of intestinal transit time in the population. The normal range of bowel movement frequency is from once a day to once a week.

Indications

Castration-resistant prostate cancer with bone metastases and no visceral metastases.

ICD codes

Dosage Regimen

For intravenous administration.

The drug containing radium chloride [223­Ra] should be prescribed only by a physician experienced in the use of radiopharmaceuticals. Before prescribing the drug, the patient must be examined. The use of the drug can only be carried out in specialized medical institutions by personnel authorized to handle radiopharmaceuticals.

The activity dose is 55 kBq/kg. Six injections are prescribed at 4-week intervals.

Adverse Reactions

Blood and lymphatic system disorders very common – thrombocytopenia; common – neutropenia, pancytopenia, leukopenia; uncommon – lymphopenia.

Gastrointestinal disorders very common – diarrhea, vomiting, nausea.

Other common – injection site reactions.

Contraindications

Hypersensitivity to the active substance, age under 18 years.

With caution

In patients with impaired bone marrow function; in patients with prostate cancer at the stage of progressive diffuse bone infiltration; in patients at risk of spinal cord compression or with established spinal cord compression; in patients with bone fractures; in patients with Crohn’s disease and ulcerative colitis; in patients with impaired liver function; in patients with severe renal impairment (CrCl <30 ml/min).

Use in Pregnancy and Lactation

Not used in women.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

A complete blood count should be performed before each injection. Before the first administration of the drug, the absolute neutrophil count (ANC) should be ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, and hemoglobin ≥10.0 g/dL. Before subsequent administrations of the drug, ANC should be ≥1.0×10⁹/L, platelet count ≥50×10⁹/L. If, despite supportive therapy, these parameters do not normalize within 6 weeks after the last administration, further therapy should be continued only after careful assessment of the benefit-risk ratio.

Treatment should be carried out with caution in patients with impaired bone marrow function (e.g., after prior cytotoxic chemotherapy and/or external beam radiotherapy (EBRT)), or in patients with prostate cancer at the stage of progressive diffuse bone infiltration.

Since the active substance is excreted through the intestine, radioactive radiation may lead to exacerbation of acute inflammatory bowel disease. The benefit-risk ratio should be carefully assessed when prescribing this agent to patients with acute inflammatory bowel disease.

Standard supportive therapy, administered according to clinical indications, in patients with untreated threatening or identified spinal cord compression should be completed before initiating or resuming therapy with this agent.

In patients with bone fractures, orthopedic stabilization of fractures should be performed before initiating or resuming therapy with this agent.

Therapy with this agent leads to long-term cumulative radiation exposure in patients. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary malformations. In particular, the risk of developing osteosarcoma, myelodysplastic syndrome, and leukemias may increase.

Diarrhea, nausea, and vomiting, which may occur during treatment, can cause dehydration. It is necessary to monitor timely fluid intake and control the body’s water balance. In case of severe or persistent diarrhea, nausea, and vomiting, patients should be advised to seek medical attention.
Treatment of patients with signs or symptoms of dehydration or hypovolemia should be initiated as soon as possible.

Data from animal studies have shown a potential risk of negative effects of this agent on fertility. Men should be counseled regarding sperm preservation before starting therapy.

Due to the possible effect on spermatogenesis associated with radioactive exposure, men should be advised to use reliable methods of contraception during treatment and for 6 months after therapy with this agent.

The use of this agent must comply with the requirements for radiation safety and drug quality.

The radium-223 isotope emits predominantly alpha particles; however, beta and gamma radiation are generated during the decay of radium-223 and its daughter isotopes. Due to the gamma radiation, the use of special devices allows measuring the radioactivity of this agent and determining the degree of radioactive contamination.

Personnel working with radiopharmaceuticals and at risk of radioactive contamination from external exposure or contamination from spilled patient waste (e.g., urine, feces, vomit) must observe radiation protection measures in accordance with regulatory requirements. Caution should be exercised when handling materials (e.g., bed linen) used by patients. Since the administered activity dose is typically less than 8 MBq, the external exposure to personnel from contact with a patient receiving therapy with this agent is significantly lower compared to other radiopharmaceuticals used for therapeutic purposes. Nevertheless, following the ALARA principles (“As Low As Reasonably Achievable”), to minimize radiation exposure to personnel, it is recommended to minimize the time spent in the radiation area, maximize the distance from the radiation source, and use radiation protection means.

Drug Interactions

There is a possibility of interaction with calcium and phosphates. Intake of drugs containing these substances and/or vitamin D should be discontinued several days before starting therapy with this agent.

Concomitant chemotherapy and therapy with radium chloride [223­Ra] may have an additive effect on bone marrow suppression. The safety and efficacy of concomitant chemotherapy and therapy with radium chloride [223­Ra] have not been established.

Use in combination with abiraterone acetate and prednisone/prednisolone is not recommended.

In patients receiving therapy with bisphosphonates and this agent, an increased risk of osteonecrosis of the jaw cannot be excluded.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.