Index of drugs

Treatment of adult patients with refractory prostate cancer with symptomatic bone metastases without known visceral metastases.

1 ml of solution contains 1000 kBq radium dichloride Ra 223 (radium-223 dichloride), which corresponds to 0.53 ng radium-223 on the day of calibration. Radium is present in the solution in the form of a free ion. Rad-223 is the emitter of alpha particles and its half-life is 11.4 days. The specific activity of radium-223 is 1.9 MBq / ng. The six-step decay of radium-223 to lead-207 occurs through short-lived decay products and is accompanied by alpha, beta and gamma emissions with different energies and emission probabilities. Some of the energy emitted from radium-223 and its decay products in the form of alpha particles is 95.3% (energy range 5.0-7.5 MeV). Part emitted in the form of beta particles is 3.6% (average energy is 0.445 MeV and 0.492 MeV), and the part emitted in the form of gamma radiation is 1.1% (energy range 0.01-1,27 MeV). 1 vial contains 6 ml of solution (6.0 MBq radium-223 dichloride on the calibration day). 1 ml of solution contains 0.194 mmol sodium (corresponding to 4.5 mg of sodium).

Therapeutic radiopharmaceutical, emitting alpha particles. Its active part, radium-223 (in the form of radium-223 dichloride), mimics Calcium and selectively targets the bone, especially bone metastases, by forming complexes with the bone mineral - hydroxyapatite. Highly linear energy transfer of alpha emitters (80 keV / micrometer) leads to a high frequency of DNA double chain cracking in neighboring tumor cells, leading to a strong cytotoxic effect. Additional effects of the product on the tumor microenvironment, including osteoblasts and osteoclasts, may contribute to the effectiveness of the observedin vivo. The range of alpha radium-223 particles is below 100 micrometres (less than 10 cell diameters), which minimizes damage to the surrounding normal tissues. The preparation is administered as an intravenous injection and is therefore 100% bioavailable. Following intravenous injection, rad-223 rapidly clears the blood and is mainly introduced into the bones and bone metastases or is excreted into the intestine. 15 minutes after injection, about 20% of the injected activity remained in the blood. After 4 hours, approximately 4% of the injected activity remained in the blood, decreasing to less than 1% 24 h after the injection. The volume of distribution was greater than the volume of blood indicating distribution to peripheral compartments. After 10 min after the injection, the activity was observed in bone and in the intestine. The level of bone activity was in the range of 44% to 77% after 4 hours after injection. No significant uptake was observed in other organs, such as the heart, liver, kidneys, bladder and spleen, 4 hours after the injection. Rad-223 is a disintegrating isotope and is not metabolised. Excretion with faeces is the main route of elimination from the body. Approx. 5% are excreted in the urine and there is no evidence of excretion via the liver and bile ducts. Whole body measurements 7 days after the injection (with the correction of the number of breakdowns) indicate that the median of 76% of the administered activity was excreted from the body. The rate of elimination of radium-223 dichloride from the gastrointestinal tract is influenced by the high variability of intestinal transit rate among the population, with the normal range of emptying the intestine from once a day to once a week.

There is no known contraindication in the use of the preparation.

Due to the risk of bone marrow suppression, it is necessary to perform a hematological assessment before starting treatment and before each dose of the preparation. Before the first administration, the absolute neutrophil count (ANC) should be ≥ 1.5 x 10⁹/ l, number of plates ≥ 100 x 10⁹/ l and hemoglobin ≥ 10.0 g / dl. Before the Next administrations, the ANC should be ≥ 1.0 x 10⁹/ l, and the number of plates ≥ 50 x 10⁹/ L. If these values ​​are not improved within 6 weeks after the last dose of the preparation despite receiving standard treatment, further treatment with the preparation should be continued only after careful assessment of the risk / benefit ratio. Caution should be exercised in patients with a confirmed reduction in myeloid reserve, e.g.after previous treatment with cytotoxic and / or post-radiation therapy (EBRT) and in patients with prostate cancer and advanced bone dissemination (EOD4 "superscan"). In these patients, the Phase III study reported an increased number of side effects seen in the blood picture, such as neutropenia and thrombocytopenia. The efficacy and safety of chemotherapy with cytotoxic chemotherapy after Xofigo treatment have not been determined. Limited data are available to indicate that patients receiving cytotoxic therapy after treatment with the medicinal product exhibit a similar haematological profile compared to patients receiving chemotherapy after using a placebo. The safety and efficacy of the preparation have not been studied in patients with Crohn's disease and ulcerative colitis. Considering the excretion of the drug in the feces, the radiation may cause an increase in acute intestinal inflammation. It should only be used after a thorough benefit / risk assessment in patients with acute enteritis. In patients with untreated or confirmed spinal cord compression, standard treatment should be discontinued as clinically indicated before initiation or resumption of therapy with the product. Patients with bone fractures should undergo orthopedic stabilization of fractures before starting or resuming therapy with the product. Elevated risk of osteonecrosis of the jaw (ONJ) ​​can not be excluded in patients treated with bisphosphonates and the preparation. The preparation contributes to the overall long-term, accumulating exposure of the patient to radiation. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and the development of hereditary defects. In particular, the risk of osteosarcoma may be increased (osteosarcoma), myelodysplastic syndrome and leukemia. In clinical trials, no cases of cancer induced by the preparation have been reported during follow-up up to 3 years. The safety and efficacy of the medicine in children and adolescents under 18 years have not been studied; use in children and adolescents in the indication of prostate cancer is not appropriate. Depending on the volume administered, the preparation may contain up to 2.35 mmol (54 mg) sodium per dose - should be taken into account in patients controlling the sodium content of the diet.

Because of the potential for radiation-related spermatogenesis, men should be advised to use effective contraception during and up to 6 months after treatment. The drug is not indicated for use in women. There are no data on the effects of the preparation on human fertility. Based on animal studies, there is a potential risk that the radiation from the preparation could cause adverse effects affecting fertility. Patients should seek advice on the possibility of collecting sperm for storage before treatment.

Very common: thrombocytopenia, diarrhea, vomiting, nausea. Common: neutropenia, pancytopenia, leukopenia, reactions at the injection site (erythema, pain and swelling). Uncommon: lymphopenia. In the Phase I study, the lowest points of the number (nadir) of neutrophils and platelets occurred 2-3 weeks after intravenous administration of a single dose of the preparation. The drug contributes to the overall long-term, accumulating exposure of the patient to radiation. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and the development of hereditary defects. In particular, the risk of osteosarcoma may be increased (osteosarcoma), myelodysplastic syndrome and leukemia. In clinical trials, no cases of cancer induced by the preparation have been reported during follow-up up to 3 years.

Intravenously. Adults. It should only be administered by personnel authorized to use radiopharmaceuticals in designated clinical settings and after the patient has been assessed by a qualified doctor. The dosing schedule for the preparation is 50 kBq per kg body weight, administered at 4-week intervals. in 6 injections. The safety and efficacy of the medicine beyond 6 injections has not been studied. In the elderly, dose adjustment is not considered necessary. The safety and efficacy of this medicine have not been studied in patients with hepatic impairment. Because rad-223 is neither metabolized by the liver nor excreted through bile, hepatic dysfunction is not expected to affect the pharmacokinetics of radium-223 dichloride. Dose adjustment is not considered necessary in patients with impaired hepatic function. There were no significant differences in the safety of use or efficacy between patients with mild renal impairment (creatinine clearance 50-80 ml / min) and patients with normal renal function. Data on patients with moderate renal impairment (creatinine clearance 30-50 ml / min) are limited.There are no data available in patients with severe renal impairment (creatinine clearance <30 ml / min) or end-stage renal disease. However, due to the fact that urinary excretion is minimal and the main elimination pathway is excretion in the faeces, renal dysfunction is not expected to affect the pharmacokinetics of radium-223 dichloride. In patients with impaired renal function, dose adjustment is not considered necessary. The preparation should be given as a slow intravenous injection (usually up to 1 minute). Use an isotonic sodium chloride 9 mg / ml (0.9%) solution for injection prior to injection and after the injection.