DRUGS & SUPPLEMENTS

Radium Bromatum

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1 INDICATIONS AND USAGE

Radium Bromatum is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.

Radium Bromatum is an alpha particle-emitting radioactive therapeutic agent indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. (1)

2 DOSAGE AND ADMINISTRATION

The dose regimen of Radium Bromatum is 55 kBq per kg body weight, given at 4 week intervals for 6 injections. (2.1)

2.1 Recommended Dosage

The dose regimen of Radium Bromatum is 55 kBq (1.49 microcurie) per kg body weight, given at 4 week intervals for 6 injections. Safety and efficacy beyond 6 injections with Radium Bromatum have not been studied.

The volume to be administered to a given patient should be calculated using the:

  • Patient’s body weight (kg)
  • Dosage level 55 kBq/kg body weight or 1.49 microcurie/kg body weight
  • Radioactivity concentration of the product (1,100 kBq/mL; 30 microcurie/mL) at the reference date
  • Decay correction factor to correct for physical decay of radium-223.

The total volume to be administered to a patient is calculated as follows:


Volume to be administered (mL)


=


Body weight in kg × 55 kBq/kg body weight


Decay factor × 1,100 kBq/mL


or


Volume to be administered (mL)


=


Body weight in kg × 1.49 microcurie/kg body weight


Decay factor × 30 microcurie/mL


Days from Reference Date


Decay Factor


Days from Reference Date


Decay Factor


-14


2.296


0


0.982


-13


2.161


1


0.925


-12


2.034


2


0.870


-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


1.330


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


0.420


The Decay Correction Factor Table is corrected to 12 noon Central Standard Time (CST). To determine the decay correction factor, count the number of days before or after the reference date. The Decay Correction Factor Table includes a correction to account for the 7 hour time difference between 12 noon Central European Time (CET) at the site of manufacture and 12 noon US CST, which is 7 hours earlier than CET.


Immediately before and after administration, the net patient dose of administered Radium Bromatum should be determined by measurement in an appropriate radioisotope dose calibrator that has been calibrated with a National Institute of Standards and Technology (NIST) traceable radium-223 standard (available upon request from Bayer) and corrected for decay using the date and time of calibration. The dose calibrator must be calibrated with nationally recognized standards, carried out at the time of commissioning, after any maintenance procedure that could affect the dosimetry and at intervals not to exceed one year.

2.2 Administration

Administer Radium Bromatum by slow intravenous injection over 1 minute.

Flush the intravenous access line or cannula with isotonic saline before and after injection of Radium Bromatum.

2.3 Instructions for Use / Handling

General warning

Radium Bromatum should be received, used and administered only by authorized persons in designated clinical settings. The receipt, storage, use, transfer and disposal Radium Bromatum are subject to the regulations and/or appropriate licenses of the competent official organization.

Radium Bromatum should be handled by the user in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken.

Radiation protection

The administration of Radium Bromatum is associated with potential risks to other persons (e.g., medical staff, caregivers and patient’s household members) from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations.

For drug handling

Follow the normal working procedures for the handling of radiopharmaceuticals and use universal precautions for handling and administration such as gloves and barrier gowns when handling blood and bodily fluids to avoid contamination. In case of contact with skin or eyes, the affected area should be flushed immediately with water. In the event of spillage of Radium Bromatum, the local radiation safety officer should be contacted immediately to initiate the necessary measurements and required procedures to decontaminate the area. A complexing agent such as 0.01 M ethylene-diamine-tetraacetic acid solution is recommended to remove contamination.

For patient care

Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. When handling bodily fluids, simply wearing gloves and hand washing will protect caregivers. Clothing soiled with Radium Bromatum or patient fecal matter or urine should be washed promptly and separately from other clothing.

Radium-223 is primarily an alpha emitter, with a 95.3% fraction of energy emitted as alpha-particles. The fraction emitted as beta-particles is 3.6%, and the fraction emitted as gamma-radiation is 1.1%. The external radiation exposure associated with handling of patient doses is expected to be low, because the typical treatment activity will be below 8,000 kBq (216 microcurie). In keeping with the As Low As Reasonably Achievable (ALARA) principle for minimization of radiation exposure, it is recommended to minimize the time spent in radiation areas, to maximize the distance to radiation sources, and to use adequate shielding. Any unused product or materials used in connection with the preparation or administration are to be treated as radioactive waste and should be disposed of in accordance with local regulations.

The gamma radiation associated with the decay of radium-223 and its daughters allows for the radioactivity measurement of Radium Bromatum and the detection of contamination with standard instruments.

Instructions for preparation

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Radium Bromatum is a ready-to-use solution and should not be diluted or mixed with any solutions. Each vial is for single use only.

Dosimetry

The absorbed radiation doses in major organs were calculated based on clinical biodistribution data in five patients with castration-resistant prostate cancer. Calculations of absorbed radiation doses were performed using OLINDA/EXM (Organ Level INternal Dose Assessment/EXponential Modeling), a software program based on the Medical Internal Radiation Dose (MIRD) algorithm, which is widely used for established beta and gamma emitting radionuclides. For radium-223, which is primarily an alpha particle-emitter, assumptions were made for intestine, red marrow and bone/osteogenic cells to provide the best possible absorbed radiation dose calculations for Radium Bromatum, considering its observed biodistribution and specific characteristics.

The calculated absorbed radiation doses to different organs are listed in Table 2. The organs with highest absorbed radiation doses were bone (osteogenic cells), red marrow, upper large intestine wall, and lower large intestine wall. The calculated absorbed doses to other organs are lower.

Target Organ Mean

(Gy/MBq)

Mean

(rad/mCi)

Coefficient of Variation

(%)


Adrenals


0.00012


0.44


56


Brain


0.00010


0.37


80


Breasts


0.00005


0.18


120


Gallbladder wall


0.00023


0.85


14


LLILLI: lower large intestine wall


0.04645


171.88


83


Small intestine wall


0.00726


26.87


45


Stomach wall


0.00014


0.51


22


ULIULI: upper large intestine wall


0.03232


119.58


50


Heart wall


0.00173


6.40


42


Kidneys


0.00320


11.86


36


Liver


0.00298


11.01


36


Lungs


0.00007


0.27


90


Muscle


0.00012


0.44


41


Ovaries


0.00049


1.80


40


Pancreas


0.00011


0.41


43


Red marrow


0.13879


513.51


41


Osteogenic cells


1.15206


4262.60


41


Skin


0.00007


0.27


79


Spleen


0.00009


0.33


54


Testes


0.00008


0.31


59


Thymus


0.00006


0.21


109


Thyroid


0.00007


0.26


96


Urinary bladder wall


0.00403


14.90


63


Uterus


0.00026


0.94


28


Whole body


0.02311


85.50


16

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3 DOSAGE FORMS AND STRENGTHS

Radium Bromatum (radium Ra 223 dichloride injection) is available in single-use vials containing 6 mL of solution at a concentration of 1,100 kBq/mL (30 microcurie/mL) at the reference date with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the reference date.

Single-use vial at a concentration of 1,100 kBq/mL (30 microcurie/mL) at the reference date with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the reference date (3)

4 CONTRAINDICATIONS

Radium Bromatum is contraindicated in pregnancy.

Radium Bromatum can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Radium Bromatum is not indicated for use in women. Radium Bromatum 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 .

Pregnancy (4, 8.1)

5 WARNINGS AND PRECAUTIONS

Bone Marrow Suppression: Measure blood counts prior to treatment initiation and before every dose of Radium Bromatum. Discontinue Radium Bromatum if hematologic values do not recover within 6 to 8 weeks after treatment. Monitor patients with compromised bone marrow reserve closely. Discontinue Radium Bromatum in patients who experience life-threatening complications despite supportive care measures.

5.1 Bone Marrow Suppression

In the randomized trial, 2% of patients on the Radium Bromatum 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 Radium Bromatum, 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 Radium Bromatum 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 Radium Bromatum and placebo. Myelosuppression; notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia; has been reported in patients treated with Radium Bromatum. 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 Radium Bromatum, neutrophil and platelet count nadirs occurred 2 to 3 weeks after Radium Bromatum 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 Radium Bromatum. Before the first administration of Radium Bromatum, 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 Radium Bromatum, 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 Radium Bromatum, despite receiving supportive care, further treatment with Radium Bromatum 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 Radium Bromatum in patients who experience life-threatening complications despite supportive care for bone marrow failure.

The safety and efficacy of concomitant chemotherapy with Radium Bromatum 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, Radium Bromatum should be discontinued.

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6 ADVERSE REACTIONS

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

  • Bone Marrow Suppression

The most common adverse drug reactions (≥ 10%) in patients receiving Radium Bromatum were nausea, diarrhea, vomiting, and peripheral edema.

The most common hematologic laboratory abnormalities (≥ 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 Radium Bromatum 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 Radium Bromatum and placebo arms, respectively. The median duration of treatment was 20 weeks (6 cycles) for Radium Bromatum and 18 weeks (5 cycles) for placebo.

The most common adverse reactions (≥ 10%) in patients receiving Radium Bromatum 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 (Table 4).

Treatment discontinuations due to adverse events occurred in 17% of patients who received Radium Bromatum and 21% of patients who received placebo. The most common hematologic laboratory abnormalities leading to discontinuation for Radium Bromatum were anemia (2%) and thrombocytopenia (2%).

Table 3 shows adverse reactions occurring in ≥ 2% of patients and for which the incidence for Radium Bromatum exceeds the incidence for placebo.


System/Organ Class

Preferred Term


Radium Bromatum (n=600)


Placebo (n=301)


Grades 1-4

%


Grades 3-4

%


Grades 1-4

%


Grades 3-4

%


Blood and lymphatic system disorders


Pancytopenia


2


1


0


0


Gastrointestinal disorders


Nausea


36


2


35


2


Diarrhea


25


2


15


2


Vomiting


19


2


14


2


General disorders and administration site conditions


Peripheral edema


13


2


10


1


Renal and urinary disorders


Renal failure and impairment


3


1


1


1

Laboratory Abnormalities

Table 4 shows hematologic laboratory abnormalities occurring in > 10% of patients and for which the incidence for Radium Bromatum exceeds the incidence for placebo.

Table 4: Hematologic Laboratory Abnormalities


Hematologic Laboratory Abnormalities


Radium Bromatum


Placebo (n=301)


Grades 1-4

%


Grades 3-4

%


Grades 1-4

%


Grades 3-4

%


Anemia


93


6


88


6


Lymphocytopenia


72


20


53


7


Leukopenia


35


3


10


<1


Thrombocytopenia


31


3


22


<1


Neutropenia


18


2


5


<1


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 Radium Bromatum and in 2% of patients on placebo. Among patients who received Radium Bromatum, 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 Radium Bromatum and 1% of patients on placebo. Radium Bromatum 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 Radium Bromatum.

Secondary Malignant Neoplasms

Radium Bromatum 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, Radium Bromatum 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 Radium Bromatum 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 Radium Bromatum 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 Radium Bromatum will tolerate subsequent cytotoxic chemotherapy.

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7 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 Radium Bromatum in the randomized clinical trial.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Category X

Radium Bromatum 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 Radium Bromatum in pregnancy and Radium Bromatum is not indicated for use in women, maternal use of a radioactive therapeutic agent could affect development of a fetus. Radium Bromatum 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 Radium Bromatum.

8.3 Nursing Mothers

Radium Bromatum 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 Radium Bromatum, a decision should be made whether to discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and efficacy of Radium Bromatum in pediatric patients have not been established.

In single- and repeat-dose toxicity studies in rats, findings in the bones 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 22 – 88 kBq (0.59 - 2.38 microcurie) per kg body weight.

8.5 Geriatric Use

Of the 600 patients treated with Radium Bromatum 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.

8.6 Patients with Hepatic Impairment

No dedicated hepatic impairment trial for Radium Bromatum 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.

8.7 Patients with Renal Impairment

No dedicated renal impairment trial for Radium Bromatum 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) .

8.8 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 Radium Bromatum.

Infertility

There are no data on the effects of Radium Bromatum on human fertility. There is a potential risk that radiation by Radium Bromatum could impair human fertility .

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10 OVERDOSAGE

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

There is no specific antidote. In the event of an inadvertent overdose of Radium Bromatum, 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.1

Single Radium Bromatum doses up to 276 kBq (7.46 microcurie) per kg body weight were evaluated in a phase 1 clinical trial and no dose-limiting toxicities were observed.

11 DESCRIPTION

Radium Bromatum Ra 223 dichloride, an alpha particle-emitting pharmaceutical, is a radiotherapeutic drug.

Radium Bromatum is supplied as a clear, colorless, isotonic, and sterile solution to be administered intravenously with pH between 6 and 8.

Each milliliter of solution contains 1,100 kBq radium-223 dichloride (30 microcurie), corresponding to 0.58 ng radium-223, at the reference date. Radium Bromatum is present in the solution as a free divalent cation.

Each vial contains 6 mL of solution (6,600 kBq (178 microcurie) radium-223 dichloride at the reference date). The inactive ingredients are 6.3 mg/mL sodium chloride USP (tonicity agent), 7.2 mg/mL sodium citrate USP (for pH adjustment), 0.2 mg/mL hydrochloric acid USP (for pH adjustment), and water for injection USP.

The molecular weight of radium-223 dichloride, 223RaCl2, is 293.9 g/mol.

Radium-223 has a half-life of 11.4 days. The specific activity of radium-223 is 1.9 MBq (51.4 microcurie)/ng.

The six-stage-decay of radium-223 to stable lead-207 occurs via short-lived daughters, and is accompanied predominantly by alpha emissions. There are also beta and gamma emissions with different energies and emission probabilities. The fraction of energy emitted from radium-223 and its daughters as alpha-particles is 95.3% (energy range of 5 - 7.5 MeV). The fraction emitted as beta-particles is 3.6% (average energies are 0.445 MeV and 0.492 MeV), and the fraction emitted as gamma-radiation is 1.1% (energy range of 0.01 - 1.27 MeV).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The active moiety of Radium Bromatum is the alpha particle-emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. 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.

12.2 Pharmacodynamics

Compared with placebo, there was a significant difference in favor of Radium Bromatum for all five serum biomarkers for bone turnover studied in a phase 2 randomized study (bone formation markers: bone alkaline phosphatase [ALP], total ALP and procollagen I N propeptide [PINP], bone resorption markers: C-terminal crosslinking telopeptide of type I collagen [S-CTX-I] and type I collagen crosslinked C-telopeptide [ICTP]).

12.3 Pharmacokinetics

The pharmacokinetics of radium-223 dichloride in blood was linear in terms of dose proportionality and time independence in the dose range investigated.

Distribution

After intravenous injection, radium-223 is rapidly cleared from the blood and is distributed primarily into bone or is excreted into intestine. Fifteen minutes post-injection, about 20% of the injected radioactivity remained in blood. At 4 hours, about 4% of the injected radioactivity remained in blood, decreasing to less than 1% at 24 hours after the injection. At 10 minutes post-injection, radioactivity was observed in bone and in intestine. At 4 hours post-injection, the percentage of the radioactive 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 .

Metabolism

Radium-223 is an isotope that decays and is not metabolized.

Elimination

The whole body measurements indicated that approximately 63% of the administered radioactivity was excreted from the body within 7 days after injection. Fecal excretion is the major route of elimination from the body. At 48 hours after injection, the cumulative fecal excretion was 13% (range 0 - 34%), and the cumulative urine excretion was 2% (range 1 - 5%). There was no evidence of hepato-biliary excretion based on imaging data.

The rate of elimination of radium-223 dichloride from the gastrointestinal tract is influenced by the high variability in intestinal transit rates across the population. Patients with a slower intestinal transit rate could potentially receive a higher intestinal radiation exposure. It is not known whether this will result in increased gastrointestinal toxicity.

Special Populations

Pediatric patients

Safety and effectiveness of Radium Bromatum 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 55 kBq/kg of radium-223 dichloride on the QTc interval was evaluated in a subgroup of 29 patients (21 received Radium Bromatum 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 evaluated.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate 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 evaluate the effects of radium-223 dichloride on male or female fertility or reproductive function. Radium Bromatum may impair fertility and reproductive function in humans based on its mechanism of action.

14 CLINICAL STUDIES

The efficacy and safety of Radium Bromatum were evaluated 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 analysis, a total of 809 patients had been randomized 2:1 to receive Radium Bromatum 55 kBq (1.49 microcurie)/kg intravenously every 4 weeks for 6 cycles (n = 541) plus best standard of care or matching placebo plus best standard of care (n = 268). Best standard of care included local EBRT, corticosteroids, antiandrogens, estrogens, estramustine or ketoconazole. Therapy was continued until unacceptable toxicity or initiation of cytotoxic chemotherapy, other systemic radioisotope, hemi-body EBRT or other investigational drug. Patients with Crohn’s disease, ulcerative colitis, prior hemibody radiation or untreated imminent spinal cord compression were excluded from the study. In patients with bone fractures, orthopedic stabilization was performed before starting or resuming treatment with Radium Bromatum.

The following patient demographics and baseline disease characteristics were balanced between the arms. The median age was 71 (range 44-94) with a racial distribution of 94% Caucasian, 4% Asian, 2% Black and <1% Other. Patients were enrolled predominantly from Europe (85%) with 4% of patients enrolled from North America. ECOG performance status was 0-1 in 86% of patients. Eighty-five percent of patients had 6 or more bone scan lesions and of those 40% had > 20 lesions or a superscan. Opiate pain medications were used for cancer-related pain in 54% of patients, non-opiate pain medications in 44% of patients and no pain medications in 2% of patients. Patients were stratified by baseline ALP, bisphosphonate use, and prior docetaxel exposure. Prior bisphosphonates were used by 41% of patients and 58% had received prior docetaxel. During the treatment period, 83% of Radium Bromatum patients and 82% of placebo patients received gonadotropin-releasing hormone agonists and 21% of Radium Bromatum patients and 34% of placebo patients received concomitant antiandrogens. Use of systemic steroids (41%) and bisphosphonates (40%) was balanced between the arms.

The pre-specified interim analysis of overall survival revealed a statistically significant improvement in patients receiving Radium Bromatum plus best standard of care compared with patients receiving placebo plus best standard of care. An exploratory updated overall survival analysis performed before patient crossover with an additional 214 events resulted in findings consistent with the interim analysis (Table 5).


Radium Bromatum


Placebo


Interim Analysis


Subjects randomized


541


268


Number of deaths


191 (35.3%)


123 (45.9%)


Censored


350 (64.7%)


145 (54.1%)


Median survival (months)Survival time is calculated as months from date of randomization to date of death from any cause. Subjects who are not deceased at time of analysis are censored on the last date subject was known to be alive or lost to follow-up.

(95% CI)


14.0

(12.1, 15.8)


11.2

( 9.0, 13.2)


p-valuep-value is from a log-rank test stratified by total ALP, current use of bisphosphonates, and prior use of docetaxel.


0.00185


Hazard ratio (95% CI)Hazard ratio is from a Cox proportional hazards model adjusted for total ALP, current use of bisphosphonates, and prior use of docetaxel. Hazard ratio < 1 favors radium-223 dichloride.


0.695 (0.552, 0.875)


Updated Analysis


Subjects randomized


614


307


Number of deaths


333 (54.2%)


195 (63.5%)


Censored


281 (45.8%)


112 (36.5%)


Median survival (months)

(95% CI)


14.9

(13.9, 16.1)


11.3

(10.4, 12.8)


Hazard ratio (95% CI)


0.695 (0.581, 0.832)


The Kaplan-Meier curves for overall survival based on the updated survival results are shown in Figure 1.

Figure 1: Kaplan-Meier Overall Survival Curves from the Phase 3 Clinical Trial

The survival results were supported by a delay in the time to first SSE favoring the Radium Bromatum arm. The majority of events consisted of external beam radiotherapy to bone metastases.

Figure 1

15 REFERENCES

  • Radiation Emergency Medical Management. [REMM/National Library of Medicine Website.] http://www.remm.nlm.gov/int_contamination.htm#blockingagents

16 HOW SUPPLIED/STORAGE AND HANDLING

Radium Bromatum (radium Ra 223 dichloride injection) is supplied in single-use vials containing 6 mL of solution at a concentration of 1,100 kBq/mL (30 microcurie/mL) with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the reference date (NDC 50419-208-01).

Store at room temperature, below 40° C (104° F). Store Radium Bromatum in the original container or equivalent radiation shielding.

This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.

Follow procedures for proper handling and disposal of radioactive pharmaceuticals.

17 PATIENT COUNSELING INFORMATION

Advise patients:

  • To be compliant with blood cell count monitoring appointments while receiving Radium Bromatum. Explain the importance of routine blood cell counts. Instruct patients to report signs of bleeding or infections.
  • To stay well hydrated and to monitor oral intake, fluid status, and urine output while being treated with Radium Bromatum. Instruct patients to report signs of dehydration, hypovolemia, urinary retention, or renal failure / insufficiency.
  • There are no restrictions regarding contact with other people after receiving Radium Bromatum. Follow good hygiene practices while receiving Radium Bromatum and for at least 1 week after the last injection in order to minimize radiation exposure from bodily fluids to household members and caregivers. Whenever possible, patients should use a toilet and the toilet should be flushed several times after each use. Clothing soiled with patient fecal matter or urine should be washed promptly and separately from other clothing. Caregivers should use universal precautions for patient care such as gloves and barrier gowns when handling bodily fluids to avoid contamination. When handling bodily fluids, wearing gloves and hand washing will protect caregivers.
  • Who are sexually active to use condoms and their female partners of reproductive potential to use a highly effective method of birth control during treatment and for 6 months following completion of Radium Bromatum treatment.

Manufactured for:

Bayer HealthCare Pharmaceuticals Inc.

Whippany, NJ 07981

Radium Bromatum is a trademark of Bayer Aktiengesellschaft.

© 2013, Bayer HealthCare Pharmaceuticals Inc.

All rights reserved.

Revised: March 2016

NDC 50419-208-01

6 mL

Xofigo®

Radium Bromatum Ra 223 dichloride injection

1100 kBq/mL (30 microcurie/mL)

For Intravenous Administration

Sterile

Single-Dose Vial:

Discard Unused Portion

Manufactured for:

Bayer HealthCare

Whippany, NJ 07981

6600 kBq/vial (178 microcurie/vial) at 5AM CST (12 noon CET) on reference date:

LOT:

EXP:

Radium Bromatum pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Radium Bromatum available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Radium Bromatum destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Radium Bromatum Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Radium Bromatum pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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Frequently asked Questions

Can i drive or operate heavy machine after consuming Radium Bromatum?

Depending on the reaction of the Radium Bromatum after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Radium Bromatum not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Radium Bromatum addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Radium Bromatum, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Radium Bromatum consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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