Description
Release form
Powder for preparing solution for sc administration
Packing
1 bottle 5 ml.
Pharmacological action of
Romiplostim is an Fc-peptidylated protein (peptide antibody), involved in signaling and activation of intracellular transcription by binding to thrombopoietin receptors (TPO) (also known as cMpl) and inducing an increase in platelet formation. A peptide antibody molecule consists of an Fc fragment of human IgG1 immunoglobulin, in which each single chain subunit is connected by a covalent bond at the C-terminus to a peptide chain containing two TPO receptor-binding fragments.
The amino acid sequence of romiplostim is not homologous to the amino acid sequence of endogenous TPO. In preclinical and clinical studies, there was no cross-reaction of antibodies to romiplostim with endogenous TPO.
Clinical efficacy of
The efficacy and safety of romiplostim was evaluated with a treatment duration of up to 3 years. In clinical studies, treatment with romiplostim led to a dose-dependent increase in platelet count. The time to reach the maximum effect with respect to the platelet count was about 10-14 days and was not dose dependent. After a single sc administration of romiplostim at a dose of 1 to 10 μg / kg in patients with idiopathic (immune) thrombocytopenic purpura (ITP), the peak platelet count exceeded the initial platelet count by 1.3-14.9 times for 2-3 weeks. The response to treatment in all patients was different. In most patients with ITP who received romiplostim within a dose range of 1 to 3 μg / kg for 6 weeks, the platelet count ranged from 50 to 450 109 / l. Of the 271 patients with ITP who received romiplostim in clinical trials, 55 people (20%) were 65 years of age or older, and 27 people (10%) – at the age of 75 years and older. In placebo-controlled studies, no differences in safety and efficacy were found between elderly and young patients.
Results of fundamental placebo-controlled studies
The safety and efficacy of romiplostim was evaluated in two placebo-controlled double-blind studies in adult patients with ITP who received at least one course of treatment before participating in the study and represented a full range groups of patients with ITP. Both studies were conducted on a similar design. Patients (over 18 years old) were randomized at a 2: 1 ratio and received a starting dose of romiplostim 1 μg / kg or placebo, respectively. For 24 weeks, patients received a single injection weekly. Doses were adjusted in order to maintain platelet count (from 50 to 200 à 109 / L). In both studies, efficacy was determined by an increase in the number of patients in whom a sustained increase in platelet count was achieved. The average weekly dose in patients with splenectomy was 3 μg / kg, and 2 μg / kg in patients with preserved spleen.
In both studies, a significantly larger proportion of patients receiving romiplostim showed a persistent response in the form of an increase in platelet count compared with patients receiving placebo. In a placebo-controlled study, after the first 4 weeks of using romiplostim, was the platelet count maintained at fifty 109 / L in 50-70% of patients during the 6-month treatment period. In the placebo group, an increase in platelet count was observed in only 0 7% of patients during the 6-month treatment period. In both studies, patients already receiving ITP therapy according to the established schedule continued to use these drugs throughout the study period (corticosteroids, danazole and / or azathioprine). At the beginning of the study, 21 patients with a preserved spleen and 18 patients who underwent splenectomy received therapy with drugs for the treatment of ITP (mainly corticosteroids). In all patients (100%) after splenectomy receiving romiplostim, it became possible to reduce the dose of corticosteroids by more than 25%, or even cancel standard therapy for ITP at the end of treatment, compared with 17% of patients receiving placebo. In 73% of patients with preserved spleen receiving romiplostim, it became possible to reduce the dose by more than 25%, or even to cancel the standard therapy for the treatment of ITP at the end of treatment, compared with 50% of patients receiving placebo.
Cases of bleeding
Throughout the clinical program for treating ITP, there has been an inverse relationship between cases of bleeding and platelet count. All clinically significant cases of bleeding ( 3 degrees) occurred with platelet counts <30 109 / l. All cases of cro All clinically significant cases of bleeding ( 3 degrees) occurred with platelet counts <30 109 / l. All cases of cro All clinically significant cases of bleeding ( 3 degrees) occurred with platelet counts <30 109 / l. All cases of croincidents 2 degrees occurred with platelet counts <50 109 / l. There were no statistically significant differences between all observed cases of bleeding among patients receiving Enplate or placebo. In two placebo-controlled studies, bleeding was noted in 9 patients, which was regarded as serious (5 [6%] romiplostim, 4 [9.8%] placebo relative risk [romiplostim / placebo] = 0.59 95% confidence interval = (0.15 2.31) ) Bleeding events of degree 2 or higher were observed in 15% of patients receiving romiplostim and 34% of patients receiving placebo (relative risk [romiplostim / placebo] = 0.35 95% confidence interval = (0.14 0.85)). Indications Chronic idiopathic (immune) thrombocytopenic purpura in adult patients after splenectomy resistant to other types of treatment (for example, corticosteroids, immunoglobulins) The drug can be used as a second-line therapy in patients with splenic splenic splenic infection. Contraindications Hypersensitivity to the active ingredient of the drug Enplate, to any of the excipients or to the proteins of Escherichia coli. Use during pregnancy and lactation Clinical data on the use of romiplostim during pregnancy are not available. In experimental animal studies, a transplacental passage and an increased platelet count in the rat fetus were noted, in particular. The potential risk to humans is unknown. Romiplostim should not be used during pregnancy, unless necessary. There is no data on the penetration of romiplostim into breast milk. However, it is possible and the risk to the infant cannot be ruled out. The decision to continue / stop breastfeeding or to continue / stop therapy with romiplostim should be taken into account, taking into account the benefits of breastfeeding for the baby and the benefit of treatment with romiplostim for the mother. Special instructions The following special instructions and precautions are based on phenomena that have been observed or may occur as a result of the pharmacological effects of thrombopoietin receptor stimulants (TPO). Relapse of thrombocytopenia and bleeding after withdrawal of treatment After withdrawal of romiplostim, a relapse of thrombocytopenia is possible. In the event that the withdrawal of romiplostim occurs against the background of the use of anticoagulants or antiplatelet agents, the risk of bleeding increases. Patients should be closely monitored to timely detect a decrease in platelet count and to prevent bleeding after discontinuation of romiplostim. Upon termination of romiplostim therapy, it is recommended that the ITP therapy be started again in accordance with the current treatment guidelines. Additional medical appointments may include withdrawal of anticoagulants and / or antiplatelet agents or transfusion of thrombomas. An increase in bone marrow reticulin An increase in bone marrow reticulin concentration is believed to be due to stimulation of TPO receptors, leading to an increase in the number of megakaryocytes in the bone marrow, which may subsequently contribute to the release of cytokines. An increase in the concentration of reticulin can be suspected by morphological changes in peripheral blood cells, and determined by bone marrow biopsy. Thus, it is recommended that studies of peripheral blood smear and counting of the number of blood cells be performed before and during treatment with romiplostim. In case of loss of effectiveness, or detection of pathology in a smear of peripheral blood in a patient, romiplostim should be canceled, a physical examination should be performed, and a bone marrow biopsy with staining for reticulin should be considered. If possible, a comparison of the results of the biopsy with previous results should be made. If effectiveness persists, and a pathology is observed in a smear of peripheral blood, the doctor should conduct an adequate clinical assessment, including resolving the issue of a bone marrow biopsy. It is also necessary to determine the risk / benefit ratio for romiplostim, and review the options for prescribing alternative ITP therapy. Thrombotic / thromboembolic complications An excess of normal platelet count is a theoretical risk factor for thrombotic / thromboembolic complications. The number of cases of thrombotic / thromboembolic complications observed in clinical trials was the same for romiplostim and placebo, and a relationship between these complications and an increase in platelet count has not been established. Follow the dose adjustment guidelines. Progression of existing malignant diseases of the hematopoietic system or myelodysplastic syndrome (MDS) TPO receptor stimulants are growth factors that lead to the growth of hematopoietic progenitor cells, differentiation, and platelet production. TPO receptors are predominantly located on the surface of cells of the myeloid series. There is a theoretical risk that TPO receptor stimulants may stimulate the progression of existing malignant diseases of the hematopoietic system or MDS. Romiplostim should not be used to treat thrombocytopenia associated with MDS or any other cause other than ITP outside of clinical trials. In groups of patients with thrombocytopenia associated with MDS or any other reason than ITP, the risk / benefit ratio for romiplostim is not defined. In an incomparable open-label clinical trial treating patients with romiplostim MDS, cases of disease progression to acute myeloid leukemia (AML) were observed, although this pathology is the expected outcome of MDS and no association with romiplostim has been established. Moreover, in this study, cases of transient increase in blast cells were observed. The transient increase in blast cells was reversible, and disappeared after the abolition of romiplostim. This fact does not confirm the progression of AML, since it is impossible to distinguish leukemic blast cells from normal blast cells. Lack of response to romiplostim therapy If there is a loss of response to treatment or the inability to maintain a stable platelet count during treatment with romiplostim at recommended doses, it is necessary to establish causative factors, including immunogenicity and an increase in the concentration of reticulin in the bone marrow. Effect of romiplostim on red and white blood cells Changes in the number of red (decrease) and white (increase) blood cells were observed during preclinical studies of the toxicity of the drug (in rats and monkeys), but not in patients with ITP. The need to control these parameters in patients receiving romiplostim treatment should be determined. Influence on the ability to drive vehicles and control mechanisms With respect to the impact on the ability to drive cars and control mechanisms, no studies have been conducted. During clinical studies, some patients experienced transient episodes of dizziness, which may affect the ability to drive a car and control mechanisms. Composition of 1 vial contains romiplostim 250 ?g Dosage and administration of Treatment should be carried out under the supervision of a physician, who has experience in the treatment of hematological patients. Application should be given once a week as a sc injection. The initial dose of romiplostim is 1 mcg / kg of actual body weight. Calculation of dose Initial or subsequent weekly dose Body weight * (kg)? dose (mcg / kg) = individual patient dose (mcg) Volume of administration Dose (mcg)? 1 ml / 500 μg = amount for administration (ml) * – when calculating the dose of romiplostim at the beginning of treatment, you should always use the calculation relative to body weight. In subsequent dose adjustments, only platelet changes in the number of platelets should be based and the dose increased by 1 μg. Example: A patient with a body weight of 75 kg is prescribed 1 μg / kg of romiplostim. Individual dose of the patient = 75 kg? 1 mcg = 75 mcg. Respectively, the amount of the solution of the drug Enplate for injection = 75 mcg? 1 ml / 500 μg = 0.15 ml. When calculating the dose of romiplostim at the beginning of treatment, you should always use a calculation relative to body weight. With subsequent dose adjustment, it should be based solely on changes in platelet count, and increase the dosage by 1 μg / kg (see table below). Side effects of Based on an analysis of data from all adult patients with ITP who received romiplostim in 4 controlled and 5 uncontrolled clinical trials, the total incidence of adverse reactions in patients in the romiplostim group was 91.5% (248/271). The average duration of exposure to romiplostim in these studies was 50 weeks. Adverse reactions, listed in the table below were associated, according to researchers with the treatment, and were observed with a frequency of> 1% of cases (n = 271).
The frequency of occurrence is defined as follows: very often (? 1/10) and often (? 1/100 – <1/10). Adverse reactions are presented in decreasing order of occurrence in each class of organ system. From the hemopoietic system: often – changes in the bone marrow, thrombocytopenia. From the side of the central nervous system: very often headache often – insomnia, dizziness, paresthesia, migraine. From the respiratory system: often – pulmonary embolism. From the digestive system: often – nausea, diarrhea, abdominal pain, dyspepsia, constipation. From the skin: often – itching, ecchymosis, rash. From the musculoskeletal system: often – arthralgia, myalgia, pain in the limbs, muscle spasm, back pain, bone pain. On the part of the body as a whole: often – hyperemia, fatigue, peripheral edema, flu-like syndrome, pain, asthenia, fever, chills. Local reactions: often – redness at the injection site, pain at the injection site, hematoma at the injection site, induration at the injection site. Other: often – bruises. In addition, the adverse reactions listed below have also been associated with treatment by research physicians. Thrombocytosis Based on an analysis of data from all adult patients with ITP receiving romiplostim in 4 controlled and 5 uncontrolled clinical trials, 3 cases of thrombocytosis were recorded, n = 271. All three patients had no clinical consequences due to an increase in platelet count. Thrombocytopenia after discontinuation of treatment Based on an analysis of data from all adult patients with ITP who received romiplostim in 4 controlled and 5 uncontrolled clinical trials, 4 cases of thrombocytopenia after discontinuation of treatment were recorded, n = 271. Increased bone marrow reticulin concentration In clinical trials, treatment with romiplostim was discontinued in 4 of 271 patients due to deposition of reticulin in the bone marrow. In another 6 patients, reticulin was detected by a bone marrow biopsy. Immunogenicity Antibodies to romiplostim were determined in clinical studies. In ITP clinical trials involving 537 adult patients, in 6% and 4% of cases, antibodies to romiplostim and TPO were determined, respectively, and only 2 studies (0.4%) were positive for neutralizing antibodies to romiplostim. Both studies gave a negative result for the neutralization of antibodies to romiplostim 4 months after the end of the drug. The level of preexisting antibodies to romiplostim and TPO was 8% and 5%, respectively. Like all therapeutic proteins, romiplostim has potential immunogenicity. In case of suspicion of the formation of neutralizing antibodies, you should contact the official representative of the company in the Russian Federation for analysis on antibodies. Adverse reactions from spontaneous reporting (not reported in clinical trials) The frequency of adverse reactions from spontaneous reporting cannot be estimated (frequency, unknown). Adverse reactions derived from spontaneous reporting include erythromelalgia. Drug Interactions No studies on interaction with other drugs have been conducted. Possible interactions of romiplostim with concomitantly taken drugs that occur when bound to plasma proteins are unknown. Medications used to treat ITP in combination with romiplostim during clinical trials included corticosteroids, danazol and / or azathioprine, iv immunoglobulin and anti-D immunoglobulin. It is necessary to control the platelet count while prescribing romiplostim with other drugs for the treatment of ITP, in order to prevent an increase in the number of platelets outside the recommended range. The use of corticosteroids, danazol and azathioprine can be reduced or discontinued while using these drugs with romiplostim. It is necessary to control the platelet count when reducing or discontinuing other drugs for the treatment of ITP, in order to prevent a decrease in platelet count below the recommended. Overdose In rats given a single dose of 1000 μg / kg or in monkeys, no adverse reactions were observed after re-administration of romiplostim at a dose of 500 μg / kg (exceeding the maximum clinical dose of 10 μg / kg – 100 or 50 times, respectively). In the event of an overdose, platelet counts may increase and lead to thromboembolic complications. If platelet counts increase rapidly, discontinue Enplate and then carefully monitor platelet counts. Resumption of the drug is possible only according to the recommendations for the method of administration and dosage. Storage conditions The product should be stored out of the reach of children, in the original package in order to protect from light, at 2 ° -8 ° C. Expiration – 3 years. Do not use after the expiry date. Specific storage instructions: After dilution, the chemical and physical stability of the diluted preparation is maintained for 24 h at 25 ° C and for 24 h at 2 ° -8 ° C, in a dark place and in the original packaging. From a microbiological point of view, the drug should be used immediately. If immediate use is not followed, the terms and conditions of storage of the diluted drug prior to use remain at the responsibility of the consumer. The Expiration of the diluted drug should not exceed 24 h at 25 ° C or 24 h in the refrigerator (2 ° -8 ° C). The product should be stored in a dark place. Shelf life 3 years. Deystvuyushtee substance Romiplostim Pharmacy conditions prescription Dosage form injection for injection Possible product names Application 250 mcg No. 1 s / c Application pore d / in s / c 250 μg v 5ml N1 Application powder d / prig. solution for p / leather. introduced. 250 mcg vial 1 pc. supplement bottle 250 mg, 5 ml
