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Medically reviewed by Kovalenko Svetlana Olegovna, PharmD. Last updated on 17.03.2022
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Энплейт is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Limitations Of Use
- Энплейт is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.
- Энплейт should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding.
- Энплейт should not be used in an attempt to normalize platelet counts.
Recommended Dosage Regimen
Use the lowest dose of Энплейт to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Administer Энплейт as a weekly subcutaneous injection with dose adjustments based upon the platelet count response.
The prescribed Энплейт dose may consist of a very small volume (eg, 0.15 mL). Administer Энплейт only with a syringe that contains 0.01 mL graduations.
Initial Dose
The initial dose for Энплейт is 1 mcg/kg based on actual body weight.
Dose Adjustments
Use the actual body weight at initiation of therapy, then adjust the weekly dose of Энплейт by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; do not exceed a maximum weekly dose of 10 mcg/kg. In clinical studies, most patients who responded to Энплейт achieved and maintained platelet counts ≥ 50 x 109/L with a median dose of 2 mcg/kg.
During Энплейт therapy, assess CBCs, including platelet counts, weekly until a stable platelet count (≥ 50 x 109/L for at least 4 weeks without dose adjustment) has been achieved. Obtain CBCs, including platelet counts, monthly thereafter.
Adjust the dose as follows:
- If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
- If platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
- If platelet count is > 400 x 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 x 109/L, resume Энплейт at a dose reduced by 1 mcg/kg.
Discontinuation
Discontinue Энплейт if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Энплейт therapy at the maximum weekly dose of 10 mcg/kg. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Энплейт.
Preparation And Administration
To mitigate against medication errors (both overdose and underdose), ensure that these preparation and administration instructions are followed.
Calculate the dose and reconstitute with the correct volume of sterile water for injection. Withdraw the appropriate volume of the calculated dose from the vial. Only administer subcutaneously.
Энплейт is supplied in single-dose vials as a sterile, preservative-free, white lyophilized powder that must be reconstituted as outlined in Table 1 and administered using a syringe with 0.01 mL graduations. Using aseptic technique, reconstitute Энплейт with preservative-free Sterile Water for Injection, USP, as described in Table 1. Do not use bacteriostatic water for injection.
Table 1. Reconstitution of Энплейт Single-Dose Vials
Энплейт Single-Dose Vial | Total Vial Content of Энплейт* | Sterile Water for Injection** | Deliverable Product and Volume | Final Concentration | ||
250 mcg | 375 mcg | add | 0.72 mL | = | 250 mcg in 0.5 mL | 500 mcg/mL |
500 mcg | 625 mcg | add | 1.2 mL | = | 500 mcg in 1 mL | 500 mcg/mL |
* Total vial content includes overfill to ensure delivery of 250 mcg or 500 mcg. ** Use preservative-free Sterile Water for Injection. |
Gently swirl and invert the vial to reconstitute. Avoid excess or vigorous agitation: DO NOT SHAKE. Generally, dissolution of Энплейт takes less than 2 minutes. The reconstituted Энплейт solution should be clear and colorless. Visually inspect the reconstituted solution for particulate matter and/or discoloration. Do not administer Энплейт if particulate matter and/or discoloration is observed.
Reconstituted Энплейт can be kept at room temperature (25°C/77°F) or refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours prior to administration. Protect the reconstituted product from light.
To determine the injection volume to be administered, first identify the patient’s total dose in micrograms (mcg) using the dosing information in Section 2.1. For example, a 75 kg patient initiating therapy at 1 mcg/kg will begin with a dose of 75 mcg. Next, calculate the volume of Энплейт solution that is given to the patient by dividing the microgram dose by the concentration of the reconstituted Энплейт solution (500 mcg/mL). For this patient example, the 75 mcg dose is divided by 500 mcg/mL, resulting in an injection volume of 0.15 mL.
As the injection volume may be very small, use a syringe with graduations to 0.01 mL. Verify that the syringe contains the correct dosage.
Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than one dose from a vial.
Use Of Энплейт With Concomitant Medical ITP Therapies
Энплейт may be used with other medical ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. If the patient’s platelet count is ≥ 50 x 109/L, medical ITP therapies may be reduced or discontinued.
None.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Risk Of Progression Of Myelodysplastic Syndromes To Acute Myelogenous Leukemia
Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in clinical trials with Энплейт.
A randomized, double-blind, placebo-controlled trial enrolling patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated due to more cases of AML observed in the Энплейт arm. This trial consisted of a 58-week study period with a 5-year long-term follow-up phase. The subjects were randomized 2:1 to treatment with Энплейт or placebo (167 Энплейт, 83 placebo). During the 58-week study period, progression to AML occurred in 10 (6.0%) subjects in the Энплейт arm and 4 (4.8%) subjects in the placebo arm (hazard ratio [95%CI] = 1.20 [0.38, 3.84]). Of the 250 subjects, 210 (84.0%) entered the long-term follow-up phase of this study. With 5-years of follow-up, 29 (11.6%) subjects showed progression to AML, including 20/168 (11.9%) subjects in the Энплейт arm versus 9/82 (11.0%) subjects in the placebo arm (HR [95% CI] = 1.06 [0.48, 2.33]). The incidence of death (overall survival) was 55.7% (93/167) in the Энплейт arm versus 54.2% (45/83) in the placebo arm (HR [95% CI] = 1.03 [0.72, 1.47]). In the baseline low IPSS group, there was a higher incidence of death in the Энплейт arm [41.3% (19/46)] compared to the placebo arm [30.4% (7/23)] [HR (95% CI) = 1.59 (0.67, 3.80)].
In a single-arm trial of Энплейт given to 72 subjects with thrombocytopenia-related MDS, 8 (11.1%) subjects were reported as having possible disease progression, of which 3 (4.2%) had confirmation of AML during follow-up. In addition, in 3 (4.2%) subjects, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Энплейт.
Энплейт is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
Thrombotic/Thromboembolic Complications
Thrombotic/thromboembolic complications may result from increases in platelet counts with Энплейт use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Энплейт.
To minimize the risk for thrombotic/thromboembolic complications, do not use Энплейт in an attempt to normalize platelet counts. Follow the dose adjustment guidelines.
Loss Of Response To Энплейт
Hyporesponsiveness or failure to maintain a platelet response with Энплейт should prompt a search for causative factors, including neutralizing antibodies to Энплейт. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Энплейт and thrombopoietin (TPO). Discontinue Энплейт if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
Laboratory Monitoring
Obtain CBCs, including platelet counts, weekly during the dose adjustment phase of Энплейт therapy and then monthly following establishment of a stable Энплейт dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Энплейт.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Information For Patients
Prior to treatment, patients should fully understand the risks and benefits of Энплейт. Inform patients that the risks associated with long-term administration of Энплейт are unknown.
Inform patients of the following risks and considerations for Энплейт:
- Энплейт therapy is administered to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; Энплейт is not used to normalize platelet counts.
- Following discontinuation of Энплейт, thrombocytopenia and risk of bleeding may develop that is worse than that experienced prior to the Энплейт therapy.
- Энплейт therapy may increase the risk of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation. Detection of peripheral blood cell abnormalities may necessitate a bone marrow examination.
- Too much Энплейт may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
- Энплейт stimulates certain bone marrow cells to make platelets and increases the risk of progression to acute myelogenous leukemia in patients with myelodysplastic syndromes.
- Platelet counts and CBCs must be performed weekly until a stable Энплейт dose has been achieved; thereafter, platelet counts and CBCs must be performed monthly while taking Энплейт.
- Patients must be closely monitored with weekly platelet counts and CBCs for at least 2 weeks following Энплейт discontinuation.
- Even with Энплейт therapy, patients should continue to avoid situations or medications that may increase the risk for bleeding.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
The carcinogenic potential of romiplostim has not been evaluated. The mutagenic potential of romiplostim has not been evaluated. Romiplostim had no effect on the fertility of rats at doses up to 37 times the MHD based on systemic exposure.
Use In Specific Populations
Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Энплейт use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Энплейт should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
In rat and rabbit developmental toxicity studies, no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred.
In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses.
Women who become pregnant during Энплейт treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.
Nursing Mothers
It is not known whether Энплейт is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Энплейт, a decision should be made whether to discontinue nursing or to discontinue Энплейт, taking into account the importance of Энплейт to the mother and the known benefits of nursing.
Pediatric Use
The safety and effectiveness in pediatric patients (< 18 years) have not been established.
Geriatric Use
Of the 271 patients who received Энплейт in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Renal Impairment
No clinical studies were conducted in patients with renal impairment.
Hepatic Impairment
No clinical studies were conducted in patients with hepatic impairment.
The following serious adverse reactions are discussed in greater detail in other sections:
- Progression of Myelodysplastic Syndromes
- Thrombotic/Thromboembolic Complications
- Loss of Response to Энплейт
- Laboratory Monitoring
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.
The data described below reflect Энплейт exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Энплейт was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received Энплейт over an extended period of time. Overall, Энплейт was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks.
In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Энплейт and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5% higher patient incidence in Энплейт versus placebo. The majority of these adverse drug reactions were mild to moderate in severity.
Table 2. Adverse Drug Reactions Identified in Two Placebo-Controlled Studies
Preferred Term | Энплейт (n = 84) | Placebo (n = 41) |
Arthralgia | 26% | 20% |
Dizziness | 17% | 0% |
Insomnia | 16% | 7% |
Myalgia | 14% | 2% |
Pain in Extremity | 13% | 5% |
Abdominal Pain | 11% | 0% |
Shoulder Pain | 8% | 0% |
Dyspepsia | 7% | 0% |
Paresthesia | 6% | 0% |
Among 142 patients with chronic ITP who received Энплейт in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies.
Bone Marrow Reticulin Formation And Collagen Fibrosis
Энплейт administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Энплейт. In a clinical trial, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Энплейт therapy.
An open-label clinical trial prospectively evaluated changes in bone marrow reticulin formation and collagen fibrosis in adult patients with ITP treated with Энплейт or a non-US approved romiplostim product. Patients were administered romiplostim by SC injection once weekly for up to 3 years. Based on cohort assignment at time of study enrollment, patients were evaluated for bone marrow reticulin and collagen at year 1 (cohort 1), year 2 (cohort 2), or year 3 (cohort 3) in comparison to the baseline bone marrow at start of the trial. Patients were evaluated for bone marrow reticulin formation and collagen fibrosis using the modified Bauermeister grading scale. From the total of 169 patients enrolled in the 3 cohorts, 132 (78%) patients were evaluable for bone marrow collagen fibrosis and 131 (78%) patients were evaluable for bone marrow reticulin formation. Two percent (2/132) of patients (both from cohort 3) developed Grade 4 findings (presence of collagen). There was no detectable bone marrow collagen in one patient on repeat testing 12 weeks after discontinuation of romiplostim. Progression of bone marrow reticulin formation (increase greater than or equal to 2 grades or more) or an increase to Grade 4 (presence of collagen) was reported in 7% (9/131) of patients.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of Энплейт. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Erythromelalgia
- Hypersensitivity
- Angioedema
Immunogenicity
As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high-and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay.
In clinical studies in patients with ITP, the incidence of preexisting antibodies to romiplostim was 5% (53/1112) and the incidence of binding antibody development during treatment with Энплейт or a non-US approved romiplostim product was 4% (50/1112). The incidence of preexisting antibodies to endogenous TPO was 4% (40/1112) and the incidence of binding antibody development to endogenous TPO during treatment was 3% (38/1112). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, five patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No apparent correlation was observed between antibody activity and clinical effectiveness or safety.
A postmarketing registry study involving patients with thrombocytopenia on Энплейт or a non-US approved romiplostim product was conducted to assess the long-term consequences of the anti-romiplostim antibodies. Patients who lacked response or lost response to Энплейт or a non-US approved romiplostim product were enrolled. The incidence of new binding antibody development was 3% (5/186) to romiplostim and 1% (2/186) to TPO. One patient was positive for binding antibodies to both romiplostim and TPO. Of the five patients with positive binding antibodies to romiplostim, two (1%) were positive for neutralizing antibodies to romiplostim only.
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading.
Overdoses due to medication errors have been reported in patients receiving Энплейт. In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue Энплейт and monitor platelet counts. Reinitiate treatment with Энплейт in accordance with dosing and administration recommendations.
In clinical studies, treatment with Энплейт resulted in dose-dependent increases in platelet counts. After a single subcutaneous dose of 1 to 10 mcg/kg Энплейт in patients with chronic ITP, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2-to 3-week period. The platelet counts were above 50 x 109/L for seven out of eight patients with chronic ITP who received six weekly doses of Энплейт at 1 mcg/kg.
In the long-term extension study in patients with ITP receiving weekly treatment of Энплейт subcutaneously, the pharmacokinetics of romiplostim over the dose range of 3 to 15 mcg/kg indicated that peak serum concentrations of romiplostim were observed about 7 to 50 hours post dose (median: 14 hours) with half-life values ranging from 1 to 34 days (median: 3.5 days). The serum concentrations varied among patients and did not correlate with the dose administered. The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a result, for a given dose, patients with high platelet counts are associated with low serum concentrations and vice versa. In another ITP clinical study, no accumulation in serum concentrations was observed (n = 4) after six weekly doses of Энплейт (3 mcg/kg). The accumulation at higher doses of romiplostim is unknown.