Romiplostim is a parenteral thrombopoietin receptor agonist indicated for the treatment of immune thrombocytopenia (ITP) in patients who have had insufficient response to corticosteroids, immunoglobulins, or splenectomy and to increase survival in patients with hematopoietic syndrome of acute radiation syndrome (ARS). Romiplostim is produced by recombinant DNA technology in E. coli and increases platelet production by binding and activating the thrombopoietin (TPO) receptor, similar to endogenous TPO. As compared to recombinant human TPO (rhTPO), romiplostim shares no sequence homology to endogenous TPO. Patients receiving rhTPO have developed antibodies causing severe thrombocytopenia. The unique peptide sequence of romiplostim significantly limits, but does not completely remove, the risk of antibody formation. In clinical studies of non-splenectomized and splenectomized patients with chronic ITP, romiplostim produced response rates of 79% to 88% and increased platelet counts in a dose-dependent fashion. Romiplostim should only be used in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk of bleeding. It should not be used in an attempt to normalize platelet counts. Additionally, romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS), due to the potential for MDS progression during treatment. Efficacy studies could not be conducted in humans with ARS for ethical and feasibility reasons; hence, approval for this indication was based on efficacy studies in animals, romiplostim's effect on platelet count in healthy human volunteers, and on efficacy data supporting its effect on thrombocytopenia in patients with ITP. In patients with ITP, monitor CBC weekly during the dose adjustment phase, and then monthly once a stable dose has been achieved. Also, because platelets can drop and increase the risk of bleeding, monitor CBC weekly for at least 2 weeks after treatment discontinuation.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Romiplostim should be clear and colorless.
Subcutaneous Administration
Reconstitution
-For doses 23 mcg and more: Reconstitute with Sterile Water for Injection; dilution is not required.
-Dilute the 125 mcg vial (total vial content, 230 mcg) with 0.44 mL of Sterile Water for Injection (final concentration of 500 mcg/mL).
-Dilute the 250 mcg vial (total vial content, 375 mcg) with 0.72 mL of Sterile Water for Injection (final concentration of 500 mcg/mL).
-Dilute the 500 mcg vial (total vial content, 625 mcg) with 1.2 mL of Sterile Water for Injection (final concentration of 500 mcg/mL).
-For doses less than 23 mcg: Reconstitute with Sterile Water for Injection, then dilute with 0.9% Sodium Chloride Injection.
--Dilute the 125 mcg vial (total vial content, 230 mcg) with 0.44 mL of Sterile Water for Injection. Additional dilution with 1.38 mL of 0.9% Sodium Chloride Injection is required (final concentration of 125 mcg/mL).
-Dilute the 250 mcg vial (total vial content, 375 mcg) with 0.72 mL of Sterile Water for Injection. Additional dilution with 2.25 mL of 0.9% Sodium Chloride Injection is required (final concentration of 125 mcg/mL).
-Dilute the 500 mcg vial (total vial content, 625 mcg) with 1.2 mL of Sterile Water for Injection. Additional dilution with 3.75 mL of 0.9% Sodium Chloride Injection is required (final concentration of 125 mcg/mL).
-Gently swirl and invert the vial. Do not shake. Dissolution should occur within 2 minutes.
-Do not pool unused portions from vials or administer more than 1 dose from a vial.
-Storage: Protect from light. Product reconstituted with Sterile Water for Injection and not further diluted can remain in the original vial at room temperature or refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours, or held in a syringe at room temperature for up to 4 hours. Reconstituted product further diluted with Sodium Chloride Injection can be held in a syringe at room temperature or in the original vial refrigerated for no longer than 4 hours prior to administration.
Subcutaneous Injection
-Overdoses have been reported due to medication errors. Withdraw the appropriate volume from the vial.
-Administer only in a syringe with 0.01 mL graduations, and verify that the syringe contains the correct dosage.
-Inject romiplostim subcutaneously into the outer aspect of the upper arm, abdomen (except for 2 inches around the navel), or front aspect of the middle thighs. Do not inject into an area that has scars or stretch marks or is tender, red, bruised, or hard. Rotate injection sites.
Romiplostim may increase the risk for development or progression of reticulin fiber deposition in the bone marrow, which may improve upon discontinuation of romiplostim. In a clinical trial, 1 patient with immune thrombocytopenic purpura (ITP) and hemolytic anemia developed bone marrow fibrosis with collagen during romiplostim therapy. A prospective, open-label trial evaluated changes in bone marrow reticulin formation (n = 131) and collagen fibrosis (n = 132) in adults with ITP treated with romiplostim. After 3 years of treatment, 2% of patients developed bone marrow collagen fibrosis. Upon repeat testing 12 weeks after romiplostim discontinuation, bone marrow collagen was not detected in 1 patient. Progression of bone marrow reticulin formation was reported in 7% of patients.
Discontinuation of romiplostim may result in more severe thrombocytopenia or risk of bleeding than was present before initiation of therapy. Patients should continue to avoid situations or medications that may increase the risk for bleeding. After romiplostim discontinuation, obtain weekly complete blood counts including platelet counts for at least 2 weeks.
Thrombosis and thromboembolism may result from increases in platelet counts with romiplostim use. Portal vein thrombosis has been reported in patients with chronic liver disease. Thrombocytosis occurred in 2% of adult patients treated for up to 12 months. Follow romiplostim dose guidelines to achieve and maintain platelet counts of 50,000/mm3 or more; do not use romiplostim in an attempt to normalize platelet counts.
Antibody formation may occur as a result of romiplostim treatment; neutralizing antibodies to romiplostim and/or thrombopoietin (TPO) may develop. Lack of response or failure to maintain a response to romiplostim should prompt a search for causative factors including neutralizing antibodies to romiplostim. To detect antibody formation, submit blood samples to the manufacturer. Discontinue romiplostim if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the maximum dose (10 mcg/kg/week). In adult clinical studies (n = 1,112), the incidence of preexisting antibodies to romiplostim was 5%, and the incidence of binding antibody development during romiplostim treatment was 4%. The incidence of preexisting antibodies to endogenous TPO was 4%, and the incidence of binding antibody development to endogenous TPO during treatment was 3%. Of the patients with positive antibodies to romiplostim or TPO, 5 had neutralizing activity to romiplostim, and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety. In pediatric studies (n = 282), the incidence of binding antibodies to romiplostim at any time was 7.8% (22/282); of these patients, 2 had preexisting binding non-neutralizing romiplostim antibodies at baseline. Overall, 2.5% developed neutralizing antibodies to romiplostim. A total of 3.2% (9/282) had binding antibodies to TPO at any time during treatment; of these patients, 2 had preexisting binding non-neutralizing antibodies to TPO. All patients were negative for neutralizing activity to TPO. In a postmarketing registry of patients who lacked or lost response to romiplostim (n = 186), the incidence of new binding antibody development was 3% to romiplostim and 1% to TPO. One patient was positive for binding antibodies to both romiplostim and TPO. Of the patients with positive binding antibodies to romiplostim, 1% was positive for neutralizing antibodies to romiplostim only. In the pediatric subpopulation (n = 19), the incidence of binding antibody after treatment was 16% to romiplostim; 5.3% of these patients were positive for neutralizing antibodies to romiplostim. There were no antibodies detected to TPO.
Headache was the most commonly reported adverse reaction, occurring in 35% of adult patients receiving romiplostim during clinical trials; 48% of headaches were mild, 31% were moderate, and 21% were severe. Arthralgia (26%), dizziness (17%), insomnia (16%), myalgia (14%), pain in extremity (13%), shoulder pain (8%), dyspepsia (7%), and paresthesias (6%) were reported in 5% or more of patients treated with romiplostim for up to 12 months and at least 5% more frequent with romiplostim vs. placebo.
Contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%) were the most commonly reported adverse reactions in pediatric patients treated with romiplostim for at least 6 months. Ear infection (5%), gastroenteritis (5%), sinusitis (5%), diarrhea (20%), upper abdominal pain (14%), rash (15%), purpura (7%), urticaria (5%), fever (24%), and peripheral edema (7%) were also reported in 5% or more of pediatric patients treated with romiplostim for up to 6 months and at least 5% more frequent with romiplostim vs. placebo. Abdominal pain (11%) has also been reported in adult clinical trials. Bronchitis, sinusitis, vomiting, diarrhea, upper respiratory tract infection, cough, nausea, and oropharyngeal pain were reported in 5% or more of adult patients treated with romiplostim for up to 12 months and at least 5% more frequent with romiplostim vs. placebo.
Progression from myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML) has been observed in adult clinical trials with romiplostim. Romiplostim may increase the risk of new primary malignancy as romiplostim stimulates the TPO receptor on the surface of hematopoietic cells. A randomized, double-blind, placebo-controlled trial (n = 250) of patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated early because of more cases of AML seen in the romiplostim treatment arm. During the 58-week study period, 14 patients (10 in the romiplostim group; 4 in placebo) progressed to AML (HR 1.2, 95% CI 0.38 to 3.84). Of the 250 patients, 210 entered a long-term follow-up study. With 5 years of follow-up, 29 patients (20 in the romiplostim group; 9 in placebo) progressed to AML (HR 1.06, 95% CI 0.48 to 2.33). The incidence of death (overall survival) was 55.7% in the romiplostim arm compared to 54.2% in the placebo arm (HR 1.03, 95% CI 0.72 to 1.47). There was a higher incidence of death in the romiplostim arm in the baseline low IPSS group (41.3% vs. 30.4%; HR 1.59, 95% CI 0.67 to 3.8). In a single-arm study of 72 patients with MDS, 8 patients developed possible disease progression, 3 of which had confirmation of AML. In addition, 3 patients experienced a decrease to baseline in peripheral blood blast cell counts after discontinuation of therapy.
Erythromelalgia, hypersensitivity, and angioedema have been reported with postmarketing use.
After discontinuation of romiplostim, thrombocytopenia and risk of bleeding may be more severe than that experienced prior to romiplostim therapy. Patients with immune thrombocytopenia should continue to avoid situations or medications that may increase the risk of bleeding. Obtain weekly complete blood counts including platelet counts for at least 2 weeks after stopping romiplostim.
Progression from myelodysplastic syndrome (MDS) to acute myelogenous leukemia (AML) has been observed in adult clinical trials with romiplostim. Romiplostim should not be used for the treatment of thrombocytopenia secondary to any cause other than chronic idiopathic thrombocytopenic purpura (ITP). A randomized, double-blind, placebo-controlled trial (n = 250) of patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated early because of more cases of AML seen in the romiplostim treatment arm. During the 58-week study period, 14 patients (10 in the romiplostim group; 4 in placebo) progressed to AML (HR 1.2, 95% CI 0.38 to 3.84). Of the 250 patients, 210 entered a long-term follow-up study. With 5 years of follow-up, 29 patients (20 in the romiplostim group; 9 in placebo) progressed to AML (HR 1.06, 95% CI 0.48 to 2.33). The incidence of death (overall survival) was 55.7% in the romiplostim arm compared to 54.2% in the placebo arm (HR 1.03, 95% CI 0.72 to 1.47). There was a higher incidence of death in the romiplostim arm in the baseline low IPSS group (41.3% vs. 30.4%; HR 1.59, 95% CI 0.67 to 3.8). In a single-arm study of 72 patients with MDS, 8 patients developed possible disease progression, 3 of which had confirmation of AML. In addition, 3 patients experienced a decrease to baseline in peripheral blood blast cell counts after discontinuation of therapy.
Use romiplostim with caution in patients with risk factors for thrombotic or thromboembolic disease. Thromboembolic/thrombotic complications may occur due to increases in platelet counts with romiplostim use secondary to drug-induced thrombocytopenia, regardless of the underlying disease. Portal vein thrombosis has been reported in patients with chronic hepatic disease. To minimize the risk of thromboembolic complications in patients with immune thrombocytopenia, do not use romiplostim to normalize platelet counts. Follow dose adjustment guidelines to achieve and maintain a platelet count of at least 50,000/mm3. To decrease the risk of overdose and its complications, ensure preparation and administration instructions are followed.
Romiplostim may cause fetal harm when administered during human pregnancy. Limited data in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta; adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Women who become pregnant during romiplostim treatment should enroll in the manufacturer's pregnancy surveillance program by calling 1-800-772-6432.
Advise women to avoid breast-feeding during treatment with romiplostim, due to the potential for serious adverse reactions. There is no information regarding the presence of romiplostim in human milk, the effects on the breastfed child, or the effects on milk product. Human IgG is present in human milk, but published data suggest breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For the treatment of chronic immune thrombocytopenic purpura (ITP) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy:
NOTE: Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome or any cause of thrombocytopenia other than ITP. Only use romiplostim in ITP patients who are at an increased risk of bleeding. Do not use romiplostim in an attempt to normalize platelet counts.
Subcutaneous dosage:
Adults: 1 mcg/kg/week subcutaneously initially; adjust dose based on platelet counts only. Adjust dose in 1 mcg/kg/week increments to achieve a platelet count of 50,000/mm3 or more. Median effective dose: 2 mcg/kg/week. Max: 10 mcg/kg/week. Monitor CBC weekly during the dose adjustment phase and then monthly thereafter. Use the lowest dose needed. If the platelet count is less than 50,000/mm3, increase the dose by 1 mcg/kg/week. If the platelet count is more than 200,000/mm3 for 2 consecutive weeks, reduce the dose by 1 mcg/kg/week. If the platelet count is more than 400,000/mm3, temporarily withhold treatment and monitor the platelet count weekly; resume at a dose reduced by 1 mcg/kg/week after the platelet count is less than 200,000/mm3. Discontinue romiplostim if the platelet count does not increase to a level sufficient to avoid clinically significant bleeding after 4 weeks at the maximum dose of 10 mcg/kg/week. Monitor CBC weekly for at least 2 weeks after discontinuation.
Children and Adolescents: 1 mcg/kg/week subcutaneously initially; adjust dose based on platelet counts and changes in body weight. Adjust dose in 1 mcg/kg/week increments to achieve a platelet count of 50,000/mm3 or more. Median effective dose: 5.5 mcg/kg/week. Max: 10 mcg/kg/week. Monitor CBC weekly during the dose adjustment phase and then monthly thereafter. Reassess weight every 12 weeks. Use the lowest dose needed. If the platelet count is less than 50,000/mm3, increase the dose by 1 mcg/kg/week. If the platelet count is more than 200,000/mm3 for 2 consecutive weeks, reduce the dose by 1 mcg/kg/week. If the platelet count is more than 400,000/mm3, temporarily withhold treatment and monitor the platelet count weekly; resume at a dose reduced by 1 mcg/kg/week after the platelet count is less than 200,000/mm3. Discontinue romiplostim if the platelet count does not increase to a level sufficient to avoid clinically significant bleeding after 4 weeks at the maximum dose of 10 mcg/kg/week. Monitor CBC weekly for at least 2 weeks after discontinuation.
For the treatment of hematopoietic syndrome of acute radiation syndrome to increase survival:
NOTE: Estimate the patient's absorbed whole body radiation dose based on information from public heatlh authorities, biodosimetry if available, or clinical findings, such as time to onset of vomiting or lymphocyte depletion kinetics.
Subcutaneous dosage:
Adults: 10 mcg/kg subcutaneously once, as soon as possible after suspected or confirmed exposure to radiation concentrations more than 2 gray.
Infants, Children, and Adolescents: 10 mcg/kg subcutaneously once, as soon as possible after suspected or confirmed exposure to radiation concentrations more than 2 gray.
Neonates: 10 mcg/kg subcutaneously once, as soon as possible after suspected or confirmed exposure to radiation concentrations more than 2 gray.
Maximum Dosage Limits:
-Adults
10 mcg/kg/week subcutaneously.
-Geriatric
10 mcg/kg/week subcutaneously.
-Adolescents
10 mcg/kg/week subcutaneously.
-Children
10 mcg/kg/week subcutaneously.
-Infants
10 mcg/kg subcutaneously once for hematopoietic syndrome.
-Neonates
10 mcg/kg subcutaneously once for hematopoietic syndrome.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Romiplostim products.
Romiplostim is a thrombopoietin-mimetic Fc-peptide fusion protein (peptibody) produced by recombinant DNA technology in Escherichia coli. Romiplostim shares no amino acid sequence homology with endogenous thrombopoietin (TPO) and therefore is not expected to elicit cross-reacting antibodies that cause thrombocytopenia, a problem that has occurred with previously studied recombinant TPO agents. The peptibody molecule contains 2 identical single-chain subunits, each consisting of human immunoglobulin IgG1 Fc domain (constant region), covalently linked at the C-terminus to 2 identical peptide sequences that each bind and activate the TPO receptor. The Fc component of the romiplostim peptibody extends the half-life, allowing it to remain active in the circulation much longer than endogenous TPO; it is eventually removed by the reticuloendothelial system.
In vitro, romiplostim binds to the TPO receptor (also known as cMpl), which consists of 2 cytokine receptor modules (CRMs). Romiplostim binds to the distal CRM, allowing the cMpl receptor to become active. As a result of this, romiplostim induces phosphorylation of JAK2 and STAT5 in TPO-dependent cell lines, promotes growth of TPO-dependent cell lines and megakaryocyte-colony forming cells, and increases megakaryocyte ploidy and maturation. Increased megakaryocyte production may lead to bone marrow reticulin deposition as transforming growth-factor beta (TGF-beta) is released from megakaryocytes. TGF-beta has previously been shown to increase reticulin fiber formation. Elimination of romiplostim is platelet-dependent; increased platelet counts will cause decreased serum concentrations of romiplostim.
Romiplostim is administered subcutaneously. Elimination is partially dependent on the thrombopoietin (TPO) receptor on platelets. Half-life ranges from 1 to 34 days (median: 3.5 days). No accumulation in serum concentrations (n = 4) was observed after 6 weekly doses of 3 mcg/kg.
-Route-Specific Pharmacokinetics
Subcutaneous Route
Peak serum concentrations are observed approximately 7 to 50 hours (median: 14 hours) after administration. Romiplostim displays dose-dependent increases in platelets. After a single dose of 1 to 10 mcg/kg in patients with chronic immune thrombocytopenic purpura (ITP), platelet counts were 1.3 to 14.9 times higher than baseline over a 2 to 3 week period. Patients with higher platelet counts exhibit lower serum concentrations of romiplostim, and patients with lower platelet counts exhibit higher serum concentrations of romiplostim. Serum concentrations of romiplostim do not correlate with doses administered.
-Special Populations
Pediatrics
Similar to adults, romiplostim pharmacokinetics are highly variable in pediatric patients. During pharmacokinetic trials, serum concentrations of romiplostim in pediatric patients were within the range observed in adult patients receiving the same dose.