Instruction for use: Nplate

Dosage form: Powder for the preparation of a solution for subcutaneous administration

Active substance: Romiplostimum

ATX

B02BX04 Romiplostim

Pharmacological group:

Antihemorrhagic means [Coagulants (including factors of blood coagulation), hemostatics]

The nosological classification (ICD-10)

D69.3 Idiopathic Thrombocytopenic Purpura: Werlhof's Disease; Idiopathic autoimmune thrombocytopenia; Idiopathic thrombocytopenic purpura of adults; Idiopathic thrombocytopenic purpura in adults; Immune idiopathic thrombocytopenic purpura; Immune thrombocytopenia; Bleeding in patients with thrombocytopenic purpura; Evans Syndrome; Thrombocytopenic purpura; Thrombocytopenia of immune origin; Chronic idiopathic thrombocytopenic purpura; Essential thrombocytopenia; Autoimmune thrombocytopenic purpura in pregnancy; Posttransfusion purpura

Composition and release form

Powder for the preparation of injection solution for subcutaneous administration 1 fl.

Romiplostim 250 mcg; 500 μg

Auxiliary substances: mannitol (E421); Sucrose; L-histidine; Polysorbate 20; Hydrochloric acid (for pH adjustment)

In glass vials with an elastomeric plug, an aluminum cap and a breakable polypropylene cap; In the planar cell pack 1 bottle; In a pack of cardboard 1 package.

Description of dosage form

White lyophilizate.

Reconstituted drug: a clear, colorless liquid, virtually free of inclusions.

Characteristic

Romiplostim is produced by recombinant DNA technology using the strain Escherichia coli (E. Coli).

Pharmachologic effect

Mode of action - Stimulating thrombopoiesis.

Pharmacodynamics

Romiplostim is an Fc-peptidylated protein (peptide antibody) involved in signaling and activating intracellular transcription by binding to the receptors of thrombopoietin (TPO) (also known as cMpl) and inducing an increase in platelet formation. The peptide antibody molecule consists of an Fc fragment of the human IgGl immunoglobulin in which each single-stranded subunit is linked by a covalent bond at the C-terminus to a peptide chain containing 2 TPO receptor-binding fragments.

The amino acid sequence of the romiplostym is not homologous to the amino acid sequence of the endogenous TPO. In pre-clinical and clinical studies, there was no cross-reacting of antibodies to Romiplostim with endogenous TPO.

Clinical efficacy

The efficacy and safety of Romiplostima was evaluated with a treatment duration of up to 3 years. In clinical trials, treatment with Romiplostim resulted in a dose-dependent increase in the number of platelets. The time to reach the maximum effect relative to the number of platelets was about 10-14 days and did not depend on the dose. After a single administration of Romiplostim in a dose of 1 to 10 μg / kg in patients with ITP, the peak of the platelet count was 1.3-14.9 times the initial platelet count for 2-3 weeks. The response to treatment in all patients was different. In most patients with ITP who received within 6 weeks of Romiplostim at a dose range of 1 to 3 μg / kg, the platelet count varied between 50 and 450 · 109 / L. Of the 271 patients with ITP who received Romiplot in clinical studies, 55 (20%) were 65 years of age or older and 27 (10%) were 75 years of age or older. In placebo-controlled studies, no difference in safety and efficacy between elderly and young patients was identified.

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 representing the full spectrum of the ITP patient group. Both studies were conducted in a similar design. Patients (over 18 years of age) were randomized in a 2: 1 ratio and received a starting dose of Romiblastim 1 μg / kg or placebo, respectively. For 24 weeks, a single injection was administered weekly. Doses were adjusted to maintain the number of platelets (from 50 to 200 · 109 / l). In both studies, efficacy was determined by the increase in the number of patients in whom a sustained increase in the number of platelets 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 demonstrated a persistent response in the form of an increase in the number of platelets compared to patients receiving a placebo. In placebo-controlled studies, after the first 4 weeks of romiplostim, the platelet count was maintained at ≥50 · 109 / L in 50-70% of patients during the 6-month treatment period. In the placebo group during the 6-month treatment period, only 0-7% of patients were noted to have an increase in the number of platelets. In both studies, patients already receiving therapy for ITP according to the established scheme continued to use these drugs throughout the study period (corticosteroids, danazol and / or azathioprine). At the beginning of the study, 21 patients with preserved spleen and 18 patients with splenectomy received therapy for the treatment of ITP (mainly corticosteroids). In all patients (100%) after splenectomy receiving Romiplostim, it was possible to reduce the dose of corticosteroids by more than 25%, or even to abolish standard therapy for the treatment of ITP at the end of treatment, compared with 17% of patients receiving placebo. In 73% of patients with preserved spleen who received Romiplostim, a dose reduction of more than 25% was possible, or even a cancellation of standard therapy for treatment of ITP at the end of treatment, compared with 50% of patients receiving placebo.

Cases of bleeding

Throughout the clinical program of treatment of ITP, there was an inverse relationship between cases of bleeding and the number of platelets. All clinically significant cases of bleeding (≥3 degrees) occurred at a platelet level <30 · 109 / L. All cases of bleeding ≥2 degree occurred at a platelet level <50 · 109 / l. There were no statistically significant differences between all observed cases of bleeding among patients who received the Enplet or placebo.

In two placebo-controlled trials, 9 patients experienced bleeding, which was considered to be serious (5 [6.0%] Romiplostim, 4 [9.8%] placebo, relative risk [Romiplostim / placebo] = 0.59, 95% Confidence interval = [0,15; 2,31]). Cases of bleeding of grade 2 or higher were noted in 15% of patients receiving Romiplostim and 34% of patients receiving placebo (relative risk; [Romiplotim / placebo] = 0.35; 95% confidence interval = [0.14; 0.85 ]).

Pharmacokinetics

The pharmacokinetics of Romiplostim is based on a target-mediated distribution of the drug, which is probably due to the receptors for thrombopoietin (TPO) located on the surface of platelets and other platelet cells, such as megakaryocytes.

Suction

After SC administration, from 3 to 15 μg / kg of Rommoplasm Cmax in blood plasma in patients with idiopathic (immune) thrombocytopenic purpura (ITP) was observed after 7-50 hours (on average, after 14 hours). The concentrations of the drug in the blood plasma varied in different patients and did not correlate with the prescribed dose. Concentrations of Romiplostima in blood plasma, probably, have feedback with the number of platelets.

Distribution

The volume of distribution of Romiplostima in healthy volunteers after IV injections decreases nonlinearly from 122; 78.8 to 48.2 ml / kg for IV doses of 0.3; 1.0 and 10 μg / kg, respectively. Such a non-linear decrease in the volume of distribution corresponds to a target-mediated binding of Romiplostim (receptors for megakaryocytes and platelets), which can be saturated at higher doses.

Excretion

T1 / 2 Romiplostima in patients with ITP varies from 1 to 34 days (average, 3.5 days). Removal of Romiplostima from the blood plasma is partially dependent on the expression of TPO receptors on platelets. As a consequence of the dose received, in patients with a high number of platelets, low plasma concentrations and vice versa are detected. In another study involving patients with ITP, no cumulation was observed after 6 weeks of weekly application of Romiplostim (3 μg / kg).

Special patient groups

There have been no studies of the pharmacokinetics of Romiplostima in patients with renal and hepatic insufficiency. Presumably, the pharmacokinetics of Romiplostima does not depend on age, body weight and sex in a clinically significant degree.

Indications of the Nplate

Chronic idiopathic (immune) thrombocytopenic purpura in adult patients after splenectomy resistant to other types of treatment (eg GCS, immunoglobulins).

The therapist can be used as second-line therapy in patients with preserved spleen with contraindications to splenectomy.

Contraindications

Hypersensitivity to the active substance, to any of the excipients or to E. Coli proteins.

Application in pregnancy and lactation

Clinical data on the use of Romiplostima during pregnancy are absent. In experiments on animals, in particular, the transplacental passage and an increased number of platelets in a rat fetus were noted. The potential risk to humans is unknown.

Romiplostim should not be used during pregnancy, except for absolute necessity.

There is no data on the penetration of Romiplostim into breast milk. Nevertheless, this is possible, and the risk for an infant cannot be ruled out.

The decision to continue / stop breastfeeding or continue / stop therapy with romiplothym should be taken, given the benefits of breastfeeding for the baby and the benefit of Romiplostim treatment for the mother.

Side effects

Based on the analysis of data for all adult patients with ITP who received Romiplast in 4 controlled and 5 uncontrolled clinical trials, the total number of cases of undesirable reactions in patients in the romiplostym group was 91.5% (248/271). The average exposure time for romiplostim in these studies was 50 weeks. The undesired reactions listed in the table below were related, according to the researchers, to the treatment being administered, and were observed with a frequency> 1% of cases (n = 271). The frequency of occurrence is defined as follows: very often (≥1 / 10) and often (≥1 / 100- <1/10). Undesirable reactions are presented in order of decreasing incidence in each class of organ system in terms of the Medical Regulatory Dictionary (MedDRA).

* See «Special instruction»

In addition, the undesirable reactions listed below were also linked by the investigating physicians with the treatment being administered.

Thrombocytosis

Based on the analysis of data for all adult patients with ITP who received Romiplost in 4 controlled and 5 uncontrolled clinical trials, 3 cases of thrombocytosis, n = 271, were recorded. All three patients had no clinical consequences due to increased platelet count.

Thrombocytopenia after discontinuation of treatment

Based on the analysis of data for all adult patients with ITP who received Romiplost in 4 controlled and 5 uncontrolled clinical trials, 4 cases of thrombocytopenia after cessation of treatment were recorded, n = 271.

Increased concentration of reticulin in the bone marrow

In clinical trials, the treatment with romiplostim was discontinued in 4 of the 271 patients due to the deposition of reticulin in the bone marrow. In 6 patients, reticulin was detected with bone marrow biopsy.

Immunogenicity

In clinical studies, antibodies to romiplostim were determined.

In clinical trials of ITP, with antibodies to Romiplotimus and TPO, respectively, in 537 adult patients, only 2 studies (0.4%) were positive for neutralizing antibodies to Romiplostim. Both studies gave a negative result for the neutralization of antibodies to Romiplostoma 4 months after the end of the drug. The level of antibodies to Romiplotimus and TPO previously existing was 8.0 and 5.0%, 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 the analysis of antibodies.

Unwanted reactions from spontaneous reporting (not reported in clinical studies)

The frequency of adverse reactions from spontaneous reporting cannot be estimated (the frequency is unknown). Adverse reactions from spontaneous reporting include disorders of the vascular system: erythromelalgia.

Interaction

There have been no studies on interactions with other drugs.

Possible interactions of Romiplostim with concomitantly taken preparations, arising when binding to plasma proteins, are unknown.

Drugs used to treat ITP in combination with Romiplostim during clinical trials included SCS, danazol and / or azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. It is necessary to control the number of platelets with simultaneous appointment of romiplostim with other drugs for the treatment of ITP, in order to prevent an increase in the number of platelets beyond the recommended range.

The use of GCS, danazol and azathioprine can be reduced or discontinued while using these drugs with romiplostim. It is necessary to control the number of platelets with the reduction or elimination of other drugs for the treatment of ITP, in order to prevent a decrease in the number of platelets below the recommended level.

Dosing and Administration

Treatment should be conducted under the supervision of a doctor who has experience in the treatment of hematological patients.

The therapist should be administered once a week as a subcutaneous injection.

The initial dose of Romiplostima is 1 μg / kg of actual body weight.

Calculation of dose:

Initial or subsequent weekly dose Body weight * in kg × dose in μg / kg = individual dose of patient in μg

Volume of administration - Dose in μg × 1 ml / 500 μg = amount for administration in ml

Example: A patient with a body weight of 75 kg is prescribed 1 μg / kg of Romiplostim.

Individual patient dose = 75 kg × 1 μg = 75 μg.

Accordingly, the amount of solution of the drug Enplet for injection = 75 μg × 1 ml / 500 μg = 0.15 ml

* When calculating the dose of Romiplostim at the beginning of treatment, the calculation should always be based on body weight. With subsequent correction of the dose should be based exclusively on changes in the number of platelets, and increase the dosage by 1 μg (see table below).

Dose selection

The weekly dose of romiplostime should be increased in 1 μg / kg body weight until the patient's platelet count reaches ≥50 · 109 / L. The number of platelets should be assessed weekly until a stable amount is achieved (≥50 · 109 / L for at least 4 weeks without dose adjustment). In the future, the number of platelets should be evaluated on a monthly basis. Do not exceed the maximum weekly dose of 10 mcg / kg.

The dose should be adjusted as follows:

Number of platelets

(× 109 / L) Correction of the dose

<50 Increase the weekly dose by 1 mcg / kg

> 200

2 weeks in a row Reduce the weekly dose by 1 mcg / kg

> 400 Do not prescribe a drug, continue to evaluate the number of platelets weekly.

After the platelet count is reduced to <200 · 109 / L, continue treatment with a weekly dose reduced by 1 μg / kg

If the response to treatment fails or if it is impossible to maintain a stable amount of platelets when treated with Romiplotome in the recommended doses, it is necessary to establish the cause of the loss of response.

Discontinuation of treatment

Treatment with romiplostim should be discontinued if the platelet count does not increase to a level sufficient to prevent clinically significant bleeding after 4 weeks of romiplostim at a maximum dose of 10 μg / kg. Periodic clinical examination of the patient is necessary, and on an individual basis the doctor must decide on continuing treatment. After the withdrawal of treatment, a relapse of thrombocytopenia is possible.

Mode of application

After the powder is diluted, the injectable solution should be injected. The injection volume can be very small. Use a syringe with 0.01 ml divisions.

Patients of advanced age (≥65 years)

In general, there was no difference in efficacy and safety in the groups of patients younger than 65 and over 65 years of age. Despite the fact that no dose adjustment for elderly patients is required based on these data, care must be taken when treating them. This is due to the fact that at the present time a small number of elderly patients have participated in clinical trials.

Children and adolescents (<18 years)

The drug is not recommended for use in children younger than 18 years due to insufficient data on safety and efficacy. In this group, the lack of data does not allow us to formulate recommendations for dosing.

Hepatic and renal insufficiency

In this group of patients there were no controlled clinical trials. Caution should be used with the Enplet in such patients.

Preparation of the solution

The product is a sterile preparation, does not contain preservatives or stabilizers and is intended for use immediately after the preparation of the solution. The therapist should be planted in accordance with proper asepsis rules.

The 250 mcg envelope, a powder for the preparation of a solution for s / c injection, should be diluted in 0.72 ml of sterile water for injection to obtain a volume of 0.5 ml. Each vial contains a sufficient amount of Romiplostim to ensure a solution with a concentration of 250 μg / 0.5 ml.

The 500 micrograms, a powder for the preparation of a solution for administration, should be diluted in 1.2 ml of sterile water for injection to obtain a volume of 1 ml. Each vial contains a sufficient amount of Romiplostim to ensure a solution with a concentration of 500 μg / ml.

Do not use sodium chloride or bacteriostatic water to dilute the drug.

Water for injection should be injected into the vial. The bottle can be turned gently to dissolve the contents. The bottle should not be shaken or vigorously mixed with its contents. Usually the dissolution of the drug Enplet takes less than 2 minutes. The finished solution should be clear and colorless. Before use, you should visually check that there are no foreign particles and the color of the solution. Do not use a colored solution or solution containing foreign particles.

Unused product or waste must be disposed of in accordance with the requirements.

In the absence of studies on pharmaceutical compatibility, this preparation should not be diluted with other solvents, except as noted above.

Overdose

In rats receiving a single dose of 1000 μg / kg or in monkeys, after repeated application of Romiplostim at a dose of 500 μg / kg (exceeding the maximum clinical dose of 10 μg / kg - 100 or 50 times, respectively), no undesirable reactions were observed.

In case of an overdose, the number of platelets may increase and lead to thromboembolic complications. If the number of platelets increases rapidly, you should stop taking the drug Enplet and then carefully monitor the level of platelets. Renewal of the drug is possible only according to the recommendations for the method of administration and dosage.

Special instructions

The following special instructions and precautions are based on events that have been observed, or can occur as a result of the pharmacological action of receptor stimulators to TPO.

Recurrent thrombocytopenia and bleeding after withdrawal of treatment

After the abolition of Romiplostima, recurrent thrombocytopenia is possible. In the event that the abolition of romiplostime occurs against the background of anticoagulants or antiplatelet agents, the risk of bleeding increases. Patients should be closely monitored for the timely detection of a decrease in the number of platelets and to prevent bleeding after the abolition of Romiplostima. When discontinuing therapy with Romiplotomy, it is recommended that the therapy of the ITP be re-started in accordance with the current treatment guidelines. Additional medical purposes may include the abolition of anticoagulants and / or antiaggregants or transfusion of thrombomass.

Increased reticulin in the bone marrow

An increase in the concentration of reticulin in the bone marrow is considered a consequence of stimulation of TPO receptors, which leads 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 the morphological changes in peripheral blood cells, and determined by bone marrow biopsy. Thus, before and during treatment with Romiplotome, it is recommended that a study of the smear of peripheral blood and counting the number of blood cells is recommended. In case of loss of efficacy, or detection of pathology in the peripheral blood smear in a patient, it is necessary to cancel the romipliplim, conduct a physical examination, and consider the question of conducting a bone marrow biopsy with staining on the reticulin.

If possible, biopsy results should be compared with previous results. If the efficacy persists, and pathology is observed in the peripheral blood smear, the physician should conduct an adequate clinical evaluation, including the decision to conduct bone marrow biopsy. It is also necessary to determine the risk / benefit ratio for romiplostima, and to re-evaluate the possibility of prescribing an alternative therapy for ITPs.

Thrombotic / thromboembolic complications

The number of platelets exceeding the norm is a theoretical risk factor for the development of thrombotic / thromboembolic complications. The number of thrombotic / thromboembolic complications observed in clinical trials was the same for romiplostim and placebo, and the relationship between these complications and the increase in the number of platelets was not established. Follow the guidelines for dose adjustment.

Progression of existing malignant diseases of the hemopoietic system or myelodysplastic syndrome (MPS)

TPO receptor stimulators are growth factors that lead to growth of hematopoietic progenitor cells, differentiation, and platelet production. TPO receptors are predominantly located on the surface of myeloid cells. There is a theoretical risk that stimulants of TPO receptors can stimulate the progression of existing malignant diseases of the hematopoiesis system or MDS.

Do not apply romiplostim for the treatment of thrombocytopenia associated with MDS or any other cause other than ITP beyond clinical trials. In groups of patients with thrombocytopenia associated with MDS or any other cause other than ITP, the risk / benefit relationship for Romiplostima is not defined. In a non-comparative open clinical study of the treatment of patients with MDS Romiplasm, cases of progression to acute myeloid leukemia (OMJI) have been observed, although this pathology is an expected outcome of MDS, and the relationship with romiplostym has not been established. In addition, in this study there have been cases of transient growth of blast cells. 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 the response to treatment is lost or it is impossible to maintain a stable amount of platelets in the treatment with Romiplostim at the recommended doses, it is necessary to establish causative factors, including immunogenicity and an increase in the concentration of reticulin in the bone marrow.

The effect of Romiplostim on red and white blood cells

Changes in the number of red (decrease) and white (increase) in blood cells were observed during preclinical studies of drug toxicity (in rats and monkeys), but not in patients with ITP. It should be determined whether these parameters should be monitored in patients receiving rhyplostimic treatment.

Influence on the ability to drive a car and to handle machinery

The impact on the ability to drive a car and control the mechanisms of research has not been carried out.

During clinical trials, some patients experienced transient dizziness attacks, which could affect the ability to drive and control machinery.

Special instructions on the condition of storage

After dilution: the chemical and physical stability of the diluted drug is maintained for 24 hours at 25 ° C and for 24 hours at 2-8 ° C, in a dark place and in the original package.

From the microbiological point of view, the drug should be used immediately. If no immediate application is forthcoming, the terms and conditions for keeping the diluted drug before use remain the responsibility of the consumer. Shelf life of the diluted product should not exceed 24 hours at a temperature of 25 ° C, or 24 hours in the refrigerator (at a temperature of 2-8 ° C). The drug should be stored in a place protected from light.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Nplate

In the dark place at a temperature of 2-8 ° C (do not freeze). (In a sealed package)

Keep out of the reach of children.

Shelf life of Nplate

3 years.

Do not use after the expiry date printed on the package.