Nplate® [Romiplostim]

Brand Pateon Inc.

In stock 1652 Items

Available since: 2019-09-19

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Clinical Pharmacology

Romiplostim is an Fc-peptidyl protein (peptide antibody) involved in signal transduction and activation of intracellular transcription by binding to thrombopoietin receptors (TPO) (also known as cMpl) and inducing an increase in platelet production. A peptide antibody molecule consists of an Fc fragment of a human IgG1 immunoglobulin, in which each single-stranded subunit is connected by a covalent bond at the C-terminus to a peptide chain containing two TPO receptor-binding fragments.

The romiplostim amino acid sequence is not homologous to the amino acid sequence of endogenous TPO. In preclinical and clinical studies, no cross-reaction of antibodies to romiplostim with endogenous TPO was observed.

Clinical efficacy

The efficacy and safety of romiplostim was assessed with a duration of treatment of up to 3 years. In clinical studies, romiplostim treatment resulted in a dose-dependent increase in platelet count. The time to achieve the maximum effect relative to the platelet count was about 10-14 days and was not dose dependent. After a single sc injection of romiplostim in a dose of 1 to 10 mcg / kg in patients with idiopathic (immune) thrombocytopenic purpura (ITP), the peak of the platelet count exceeded 1.3-14.9 times the initial platelet count within 2-3 weeks. The response to treatment in all patients was different. In the majority of patients with ITP who received romiplostim for 6 weeks in the dose range from 1 to 3 mcg / kg, the number of platelets ranged from 50 to 450 × 109 / l. Of the 271 patients with ITP who received romiplostim in clinical studies, 55 people (20%) were aged 65 and older, and 27 people (10%) were aged 75 and older. In placebo-controlled studies, no differences in safety and efficacy between elderly and young patients were found.

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 taking part in the study, and representing the full range of patients with ITP. Both studies were conducted in a similar design. Patients (older than 18 years) were randomized in 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 to maintain platelet count (from 50 to 200 × 109 / l). In both studies, efficacy was determined by the increase in the number of patients who had achieved a sustained increase in platelet count. The average weekly dose in patients with splenectomy was 3 mcg / kg, and 2 mcg / kg in patients with a preserved spleen.

In both studies, a significantly larger proportion of patients receiving romiplostim showed a strong response in the form of an increase in platelet count compared with patients who received placebo. In placebo-controlled studies after the first 4 weeks of romiplostim, platelet count was maintained at ≥ 50 × 109 / l in 50-70% of patients during the 6-month treatment period. In the placebo group, an increase in the number of platelets was observed only in 0-7% of patients during the 6-month treatment period. In both studies, patients already receiving ITP therapy according to the established regimen continued to use these drugs throughout the study period (corticosteroids, danazol, and / or azathioprine). At the beginning of the study, 21 patients with a preserved spleen and 18 patients who underwent splenectomy were treated with ITP drugs (mainly corticosteroids).In all patients (100%) after splenectomy who received romiplostim, it became possible to reduce the dose of corticosteroids by more than 25%, or even cancel the standard therapy for ITP treatment at the end of treatment, compared with 17% of patients receiving placebo. In 73% of patients with preserved spleen who received romiplostim, it became possible to reduce the dose by more than 25%, or even cancel the standard therapy for ITP treatment at the end of treatment, compared with 50% of patients receiving placebo.

Cases of bleeding

Throughout the entire clinical program of ITP treatment, an inverse relationship was observed between cases of bleeding and the number of platelets. All clinically significant cases of bleeding (≥ 3 degrees) occurred at a platelet level of <30 109="" l="" all="" cases="" of="" bleeding="" 2="" degrees="" occurred="" at="" platelet="" levels="" 50="" there="" were="" no="" statistically="" significant="" differences="" between="" observed="" among="" patients="" who="" received="" enpleit="" or="" placebo="" in="" two="" placebo-controlled="" studies="" 9="" had="" that="" was="" considered="" serious="" 5="" 6="" romiplostim="" 4="" 8="" relative="" risk="" 0="" 59="" 95="" confidence="" interval="(0.14;" 31="" grade="" higher="" 15="" receiving="" and="" 34="" 35="" 85="" p="">

Indications

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

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

Composition

1 bottle contains romiplostim 250 mcg

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Dosage and Administration

Dose calculation

Initial or subsequent weekly dose	Body weight * (kg) × dose (mcg / kg) = individual patient dose (mcg)
Injection volume	Dose (mcg) × 1 ml / 500 mcg = amount for injection (ml)

* - when calculating the dose of romiplostim at the beginning of treatment, you should always use the calculation of body weight. At the subsequent dose adjustment, it should be based solely on changes in platelet count and increase the dose by 1 mcg.

Example: a patient with a body weight of 75 kg was prescribed 1 mcg / kg romiplostim. Individual patient dose = 75 kg × 1 μg = 75 μg. Accordingly, the amount of the solution solution of Inplate for injection = 75 μg × 1 ml / 500 μg = 0.15 ml. When calculating the dose of romiplostim at the beginning of treatment, you should always use the calculation regarding body weight. At the subsequent dose adjustment, one should be based solely on changes in the number of platelets, and increase the dosage by 1 mcg / kg (see table below).

Adverse reactions

Based on the analysis of data for all adult ITP patients receiving romiplostim in 4 controlled and 5 uncontrolled clinical studies, the total number of adverse reactions among patients in the romiplostim group was 91.5% (248/271). The average duration of exposure to romiplostimu in these studies was 50 weeks.

The adverse reactions listed in the table below were, in the opinion of the researchers, related to treatment, and were observed with a frequency of> 1% of cases (n = 271).

Occurrence rate is defined as follows: very often (≥ 1/10) and often (≥ 1/100 - <1/10). Undesirable reactions are presented in decreasing order of the frequency of occurrence in each class of the 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.

On the part of the respiratory system: often - pulmonary embolism.

From the digestive system: often - nausea, diarrhea, abdominal pain, dyspepsia, constipation.

On the part of the skin: often - itching, ecchymosis, rash.

From the musculoskeletal system: often - arthralgia, myalgia, pain in the limbs, muscle spasm, back pain, pain in the bones.

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 were also associated by medical researchers with treatment.

Thrombocytosis

Based on the analysis of data for all adult patients with ITP who received 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 stopping treatment

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

Increased reticulin concentration in the bone marrow

In clinical studies, romiplostim treatment was discontinued in 4 of 271 patients due to the deposition of reticulin in the bone marrow. Another 6 patients reticulin was detected during a bone marrow biopsy.

Immunogenicity

In clinical studies, antibodies to romiplostim were determined.

In clinical studies of ITP, involving 537 adult patients, 6% and 4% of cases detected antibodies to romiplostim and TPO, respectively, and only 2 studies (0.4%) were positive to neutralize antibodies to romiplostim. Both studies gave a negative result to neutralize antibodies to romiplostimu 4 months after the end of the drug. The level of pre-existing antibodies to romiplostim and TPO was 8% and 5%, respectively.

Like all therapeutic proteins, romiplostim has potential immunogenicity.If neutralization antibodies are suspected, contact an official representative of the company in the Russian Federation for an antibody test.

Adverse reactions from spontaneous reportage (not reportable in clinical studies)

The frequency of adverse reactions from spontaneous reproduction cannot be assessed (frequency, unknown). Adverse reactions derived from spontaneous replication include erythromelalgia.

Contraindications

Hypersensitivity to the active substance of the drug Enpleit, to any of the excipients or to the proteins Escherichia coli.

Drug interactions

Research on the interaction with other drugs was not conducted.

The possible interactions of romiplostim with concurrently taking drugs that occur when binding to plasma proteins are unknown.

Drugs used to treat ITP in combination with romiplostim during clinical trials included GCS, danazol and / or azathioprine, IV immunoglobulin and anti-D immunoglobulin. It is necessary to control the number of platelets while prescribing 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 corticosteroids, danazol and azathioprine can be reduced or discontinued with the simultaneous use of these drugs with romiplostim. It is necessary to control the number of platelets in the reduction or cancellation of other drugs for the treatment of ITP, in order to prevent a decrease in the number of platelets below the recommended.

Pregnancy and Lactation

Clinical data on the use of romiplostim during pregnancy are not available.

AT experimental studies animals noted, in particular, transplacental passage and increased platelet count in the rat fetus. The potential risk to humans is unknown.

Romiplostim should not be used during pregnancy, unless necessary.

No data on the penetration of romiplostim in breast milk. However, it is possible, and the risk to the infant cannot be ruled out. The decision to continue / discontinue breastfeeding or continue / discontinue romiplostim therapy should be considered, taking into account the benefits of breastfeeding for the baby and the benefits of the treatment of romiplostim for the mother.

Special instructions

The following special instructions and precautions are based on the phenomena that have been observed, or may occur as a result of the pharmacological action of stimulants of thrombopoietin receptors (TPO).

Relapse of thrombocytopenia and bleeding after discontinuation of treatment

After the abolition of romiplostim possible recurrence of thrombocytopenia. If the cancellation of romiplostim occurs against the background of the use of anticoagulants or antiplatelet agents, the risk of bleeding increases. Patients should be carefully monitored for timely detection of a decrease in platelet count and prevention of bleeding after discontinuation of romiplostim. When discontinuing romiplostim therapy, it is recommended to restart ITP therapy in accordance with the current treatment guidelines. Additional medical appointments may include discontinuation of anticoagulants and / or antiplatelet agents or thrombotic transfusions.

Increase of reticulin in the bone marrow

An increase in reticulin concentration in the bone marrow is considered a consequence of stimulation of TPO receptors, leading to an increase in the number of megakaryocytes in the bone marrow, which may subsequently contribute to the secretion of cytokines. An increase in reticulin concentration can be suspected by morphological changes in peripheral blood cells, and can be determined by bone marrow biopsy.Thus, before and during romiplostim treatment, it is recommended to conduct studies of a peripheral blood smear and counting the number of blood cells. In case of loss of effectiveness, or detection of pathology in a patient’s peripheral blood smear, romiplostim should be canceled, a physical examination should be conducted, and a bone marrow biopsy with staining for reticulin should be considered.

If possible, a comparison of biopsy results with previous results should be made. If efficacy is maintained and pathology is observed in a peripheral blood smear, the physician should conduct an adequate clinical evaluation, including deciding whether to conduct a bone marrow biopsy. It is also necessary to determine the risk / benefit ratio for romiplostim, and to reconsider the possibilities of prescribing alternative ITP therapy.

Thrombotic / thromboembolic complications

A platelet count exceeding the norm is a theoretical risk factor for the development of thrombotic / thromboembolic complications. The number of cases of thrombotic / thromboembolic complications observed in clinical studies was the same for romiplostim and placebo, and the relationship between these complications and the increase in platelet count has not been established. Dose adjustment guidelines should be followed.

The 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 myeloid cells. There is a theoretical risk that stimuli of TPO receptors can 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 studies. In groups of patients with thrombocytopenia associated with MDS or any other cause other than ITP, the risk / benefit ratio for romiplostim has not been determined. In an incomparable open clinical study of 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 the connection with romiplostim has not been established. In addition, in this study there were cases of transient increase in blast cells. 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.

No response to romiplostim therapy

If you lose the response to treatment or cannot maintain a stable platelet count during treatment with romiplostim in recommended doses, it is necessary to establish causative factors, including immunogenicity and an increase in reticulin concentration in the bone marrow.

The effect of romiplostim on red and white blood cells

Changes in the number of red (reduced) and white (increased) blood cells were observed during preclinical studies of the toxicity of the drug (in rats and monkeys), but not in patients with ITP. It is necessary to determine the need to control these parameters in patients receiving romiplostim treatment.

Influence on ability to drive motor transport and control mechanisms

Concerning influence on ability to driving of the car and management of mechanisms of researches it was not conducted. During clinical studies, some patients had transient attacks of vertigo, which may affect the ability to drive a car and control mechanisms.

Overdosage

In rats treated with a single dose of 1000 mcg / kg, or in monkeys, after repeated administration of romiplostim at a dose of 500 mcg / kg (exceeding the maximum clinical dose of 10 mcg / kg - 100 or 50 times, respectively), no adverse reactions were noted. In case of an overdose, the platelet count may increase and lead to thromboembolic complications. If the number of platelets increases rapidly, you should stop taking the drug Enpleit and then carefully monitor the level of platelets. The resumption of the drug is possible only according to the recommendations on the method of use and dosage.