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  • CLASSES

    Other Antineoplastic Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Alpha-particle emitting radiotherapeutic drug FDA-approved for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.
    In combination with best standard of care (which included antiandrogen therapy), improved overall survival compared to placebo and best standard of care in a double-blind, randomized trial.
    Bone marrow failure may occur; hematologic evaluation should be performed prior to each dose.

    COMMON BRAND NAMES

    Xofigo

    HOW SUPPLIED

    Xofigo Intravenous Inj Sol: 1mL, 1100kBq

    DOSAGE & INDICATIONS

    For the treatment of castration-resistant prostate cancer, in patients with symptomatic bone metastases and no known visceral metastatic disease.
    Intravenous dosage
    Adults

    55 Kilobecquerel (kBq) (equal to 1.49 microcurie) per kg of body weight by slow IV injection over 1 minute, every 4 weeks for 6 injections. The safety and efficacy beyond 6 injections has not been studied. When calculating the dose, a decay correction factor must be used to account for the physical decay of radium-223 after packaging (see below). Immediately before and after administration, measure the net patient dose in a radioisotope dose calibrator that has been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-223 standard and corrected for decay using the date and time of calibration. After initial calibration, re-calibrate the dose calibrator at least yearly, and after any maintenance that could affect the dosimetry.
    Volume to be administered (mL) = Body weight in kg x 55 kBq/kg
                                                      Decay factor x 1,100 kBq/mL
    or
    Volume to be administered (mL) = Body weight in kg x 1.49 microcurie/kg
                                                      Decay factor x 30 microcurie/mL
    Number of days from reference date on vial (Decay factor)
    -14 (2.296)     0 (0.982)
    -13 (2.161)     1 (0.925)
    -12 (2.034)     2 (0.87)
    -11 (1.914)     3 (0.819)
    -10 (1.802)     4 (0.771)
    -9 (1.696)      5 (0.725)
    -8 (1.596)      6 (0.683)
    -7 (1.502)      7 (0.643)
    -6 (1.414)      8 (0.605)
    -5 (1.33)        9 (0.569)
    -4 (1.252)      10 (0.536)
    -3 (1.178)      11 (0.504)
    -2 (1.109)      12 (0.475)
    -1 (1.044)      13 (0.447)
                         14 (0.42)

    MAXIMUM DOSAGE

    Adults

    55 kBq/kg (1.49 microcurie/kg).

    Geriatric

    55 kBq/kg (1.49 microcurie/kg).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Since radium-223 dichloride is not metabolized in the liver and does not undergo biliary excretion, it does not appear that hepatic impairment should affect the pharmacokinetics. A dedicated trial in patients with hepatic impairment has not been conducted; however, based on a subgroup analysis in the randomized clinical trial, dose adjustment is not needed in patients with mild hepatic impairment. Insufficient data exists to make a recommendation in patients with moderate or severe hepatic impairment.

    Renal Impairment

    A dedicated trial in patients with renal impairment has not been conducted; however, based on a subgroup analysis in the randomized clinical trial, dose adjustment is not needed in patients with mild or moderate renal impairment (CrCl >= 30 ml/min). Insufficient data exists to make a recommendation in patients with severe renal impairment (CrCl < 30 ml/min).

    ADMINISTRATION

    Radium-223 dichloride (an alpha particle-emitting pharmaceutical) should only be received, used and administered by authorized persons in designated clinical settings, and is subject to the regulations and/or appropriate licenses of the competent official organization.

    Injectable Administration

    Radium-223 dichloride is available in 6 mL single use vials containing 1,100 kBq/mL (30 microcurie/mL) at the reference date.
    Use universal precautions to avoid contamination, including gloves and barrier gowns, when handling blood and body fluids. Minimize the time spent in radiation areas, maximize the distance to radiation sources, and use adequate shielding
    In case of exposure to skin or eyes, flush immediately with water.
    In case of a spill, contact the local radiation safety officer immediately to begin decontamination procedures. Ethylene-diaminetetraacetic acid (EDTA, 0.01M) is recommended to remove contamination.
    There is a risk for radiation exposure or contamination from spills of bodily fluids (e.g., feces, urine, and vomit). Medical staff, caregivers, and patient's household members should take appropriate radiation protection precautions, including multiple flushes after using the toilet, washing soiled clothing separately from other clothing, and wearing gloves when handling body fluids.
    Do not mix or dilute radium-223 dichloride with other solutions.
    Dispose of any unused product or contaminated materials in accordance with local regulations on radioactive waste.

    Intravenous Administration

    Use aseptic technique during preparation and administration, as well as appropriate precautions for radiopharmaceuticals.
    Visually inspect product for particulate matter and discoloration.
    Flush the line with isotonic saline before and after administration.
    Administer as a slow intravenous injection over 1 minute.

    STORAGE

    Xofigo:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Store below 104 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    Radium-223 dichloride is classified as FDA pregnancy category X. This agent is contraindicated for use in women who are or may become pregnant. Although there are not human or animal data on its in pregnancy and radium-223 dichloride is not indicated for use in women, maternal use of radiopharmaceuticals can affect fetal development. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the potential hazard to the fetus and risk for pregnancy loss should be discussed with the patient. Females of reproductive potential should be advised to avoid becoming pregnant during treatment.

    Anemia, bone marrow suppression, chemotherapy, neutropenia, thrombocytopenia

    In a randomized, double blind, placebo controlled phase III trial, hematologic adverse effects occurred more frequently in patients treated with radium-223 dichloride than placebo, including bone marrow failure (with 2 associated deaths), ongoing anemia, neutropenia, and thrombocytopenia (pancytopenia), and vascular hemorrhage. Prior to the first dose of radium-223 dichloride, the absolute neutrophil count (ANC) should be >= 1.5 x 109/L, platelet count >= 100 x 109/L, and hemoglobin >= 10 g/dL. Before each subsequent dose, the ANC should be >= 1 x 109/L and platelet count >= 50 x 109/L. Discontinue treatment if labs have not recovered within 6 to 8 weeks of the last dose or if patients experience life-threatening complications despite supportive care for bone marrow suppression. The safety and efficacy of administering radium-223 dichloride in combination with chemotherapy is unknown. Due to the risk of additive myelosuppression, combination therapy is not recommended.

    Breast-feeding

    Radium-223 dichloride is not indicated for use in women. According to the manufacturer, it is unknown whether radium-223 dichloride is excreted in human milk; however, there is potential for serious radiation-related adverse effects in nursing infants. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Accidental exposure

    Radium-223 dichloride is primarily (95.3%) an alpha particle-emitter, with 3.6% beta-particle emission and 1.1% gamma-particle emission. Alpha-particles are unable to penetrate skin; therefore, the radiation exposure associated with handling of patient doses is expected to be low. Take appropriate precautions for handling and administering radiopharmaceuticals and minimize the time spent in areas of radiation. In the event of accidental exposure of the skin or eyes to radium-223 dichloride, flush the affected area immediately with water. If a spill occurs, 0.01 M ethylene-diamine-tetraacetic acid (EDTA) may be used to remove contamination.

    Children, infants, neonates

    The safety and efficacy of radium-223 dichloride in neonates, infants, children, and adolescents have not been established. In animal studies, single and repeat doses (20 to 80 kBq/kg, or 0.541 to 2.16 microcurie/kg) caused depletion of osteocytes, osteoblasts, and osteoclasts; fibro-osseous lesions; disruption of growth; and missing or irregular teeth.

    Infertility, male-mediated teratogenicity

    Because radiopharmaceuticals can affect spermatogenesis, there is potential for male-mediated teratogenicity. Male patients should use barrier contraception (latex condom) during sexual intercourse with a woman of reproductive potential, and female partners of reproductive potential should use a highly effective contraceptive method during and for 6 months after stopping therapy. There is no data regarding the potential effects of radium-223 dichloride on fertility, however, it is possible that radiation could cause infertility.

    ADVERSE REACTIONS

    Severe

    nausea / Early / 2.0
    diarrhea / Early / 2.0
    vomiting / Early / 2.0
    peripheral edema / Delayed / 2.0
    infection / Delayed / 2.0

    Moderate

    secondary malignancy / Delayed / 0-1.0
    dehydration / Delayed / 3.0
    erythema / Early / 1.0

    Mild

    injection site reaction / Rapid / 1.0

    DRUG INTERACTIONS

    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.

    PREGNANCY AND LACTATION

    Pregnancy

    Radium-223 dichloride is classified as FDA pregnancy category X. This agent is contraindicated for use in women who are or may become pregnant. Although there are not human or animal data on its in pregnancy and radium-223 dichloride is not indicated for use in women, maternal use of radiopharmaceuticals can affect fetal development. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the potential hazard to the fetus and risk for pregnancy loss should be discussed with the patient. Females of reproductive potential should be advised to avoid becoming pregnant during treatment.

    Radium-223 dichloride is not indicated for use in women. According to the manufacturer, it is unknown whether radium-223 dichloride is excreted in human milk; however, there is potential for serious radiation-related adverse effects in nursing infants. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Radium-223 dichloride is an alpha particle-emitting radiopharmaceutical administered via intravenous injection. When new bone formation occurs around bone metastases, radium-223 dichloride mimics calcium to form complexes with hydroxyapatite, a calcium-containing component of the bone matrix. Once incorporated into the bone matrix, adjacent tumor cells are irradiated, resulting in double-strand DNA breaks. Alpha-particle emitters such as radium-223 dichloride have very short penetration of tissue (less than 100 micrometers, or 2 to 10 cell diameters), resulting in minimal damage to surrounding tissue.

    PHARMACOKINETICS

    Intravenous Route

    After intravenous administration, radium-223 exhibits linear pharmacokinetics and is rapidly cleared from the bloodstream and distributed primarily into bone or excreted into the intestine. Based on calculations from data in 5 patients with castration-resistant prostate cancer, radioactivity to bone approximates 4262.6 rad/mCi, red marrow and upper and lower large intestine walls each absorb < 515 rad/mCi of radiation, and other organs absorb < 27 rad/mCi per dose. Fifteen minutes after administration, 20% of the injected radioactive dose remained in the blood; after 4 hours, 4% remained in the blood (61% in bone, no significant uptake in heart, liver, kidneys, urinary bladder, and spleen); after 24 hours, < 1% remained in the blood.
    Radium-223 dichloride is a radiopharmaceutical isotope that decays and is not metabolized. After correcting for decay, approximately 63% of the administered radioactivity was excreted from the body within 7 days of administration, with 13% (range, 0 to 34%) in fecal matter at 48 hours and 2% (range, 1% to 5%) in urine. The rate of elimination is influenced by intestinal transit rates; it is unknown whether patients with slower transit rates will receive higher intestinal radiation exposure and thus increased gastrointestinal toxicity. Radium-223 dichloride has a physical half-life of 11.4 days.