NPlate - Drug Monograph

Introduction

NPlate (romiplostim) is a thrombopoietin receptor agonist approved by the FDA in 2008 for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). It is a genetically engineered fusion protein analog that stimulates platelet production through mechanisms similar to endogenous thrombopoietin. NPlate represents a significant advancement in the management of ITP, particularly for patients who have not responded adequately to conventional treatments such as corticosteroids, immunoglobulins, or splenectomy.

Mechanism of Action

NPlate works by binding to and activating the human thrombopoietin (TPO) receptor, also known as c-Mpl, on the surface of megakaryocytes in the bone marrow. This binding triggers intracellular signaling pathways (primarily JAK2/STAT5) that promote megakaryocyte proliferation, differentiation, and platelet production. Unlike endogenous thrombopoietin, which is a glycoprotein hormone, romiplostim is an Fc-peptide fusion protein ("peptibody") created through recombinant DNA technology. It mimics the biological activity of thrombopoietin but has no amino acid sequence homology to endogenous TPO.

Indications

NPlate is FDA-approved for:

• Treatment of thrombocytopenia in adult and pediatric patients 1 year of age and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy
• Treatment of thrombocytopenia in patients with immune thrombocytopenia for at least 6 months who are not splenectomized and for whom splenectomy is not recommended

• Thrombocytopenia associated with myelodysplastic syndromes (MDS)
• Chemotherapy-induced thrombocytopenia
• Thrombocytopenia in hepatitis C patients undergoing antiviral therapy

Dosage and Administration

• Adults: Start with 1 mcg/kg subcutaneously once weekly
• Pediatric patients (1 year and older): Start with 1 mcg/kg subcutaneously once weekly

• Adjust weekly dose in increments of 1 mcg/kg
• Maximum recommended dose: 10 mcg/kg weekly
• Adjust dose to maintain platelet count ≥50 × 10⁹/L as necessary to reduce bleeding risk
• Do not exceed dose necessary to achieve and maintain target platelet count

• Administer as a subcutaneous injection
• Rotate injection sites (abdomen, thigh, upper arm)
• Reconstitute with preservative-free sterile water for injection
• Use within 24 hours of reconstitution when refrigerated

• Renal impairment: No dose adjustment necessary
• Hepatic impairment: Use with caution; no specific dose recommendations
• Elderly: No dose adjustment necessary
• Pediatric: Safety and efficacy established in children ≥1 year old

Pharmacokinetics

• Peak serum concentrations occur approximately 7-50 hours after subcutaneous administration
• Bioavailability is approximately 50-80%

• Volume of distribution is approximately 2.5-4.5 L
• Binds to TPO receptors with high affinity

• Cleared primarily by the reticuloendothelial system
• Undergoes proteolytic degradation similar to other peptide therapeutics

• Half-life: 1-34 days (median 3.5 days)
• Clearance: Approximately 1.5-4.5 mL/hr/kg
• No renal or hepatic elimination pathways identified

Contraindications

• Hypersensitivity to romiplostim or any component of the formulation
• Use for the normalization of platelet counts in patients with myelodysplastic syndromes (increased risk of progression to acute myeloid leukemia)

Warnings and Precautions

• Risk of progression to myelofibrosis with myeloid metaplasia
• Risk of hematologic malignancies, particularly acute myeloid leukemia (AML) in patients with myelodysplastic syndromes

• Thrombotic/thromboembolic complications: Increased risk of thrombosis, especially at higher platelet counts
• Bone marrow reticulin formation and fibrosis: Monitor peripheral blood smears
• Loss of response: May indicate developing neutralizing antibodies or other pathology
• Worsened thrombocytopenia after discontinuation: Platelet counts may fall below baseline
• Hematologic malignancies: Monitor patients closely
• Laboratory monitoring: Required throughout therapy

Drug Interactions

• No formal drug interaction studies conducted
• Theoretical interactions with medications that affect platelet function or thrombopoietin signaling
• Use caution with anticoagulants and antiplatelet agents due to increased thrombosis risk
• Potential interaction with other thrombopoietin receptor agonists
• No known cytochrome P450 interactions

Adverse Effects

• Headache (35%)
• Arthralgia (26%)
• Dizziness (17%)
• Insomnia (16%)
• Myalgia (14%)
• Pain in extremity (13%)
• Abdominal pain (11%)
• Shoulder pain (8%)
• Dyspepsia (7%)
• Paresthesia (6%)

• Thrombotic/thromboembolic complications
• Bone marrow reticulin formation
• Progression of myelodysplastic syndromes to acute myeloid leukemia
• Worsened thrombocytopenia after discontinuation
• Hypersensitivity reactions
• Hematologic malignancies

Monitoring Parameters

• Complete blood count with differential and peripheral smear
• Baseline bone marrow examination (if clinical indication)
• Assessment of thrombosis risk factors

• Weekly CBC with platelet count until stable dose established
• Thereafter, monthly CBC with platelet count
• Regular peripheral blood smear examination
• Monitor for signs/symptoms of thrombosis
• Monitor for bone pain or other symptoms suggestive of marrow fibrosis
• Assess response and bleeding symptoms regularly

• Weekly CBC for at least 4 weeks
• Monitor for bleeding complications

Patient Education

• Purpose of treatment: To increase platelet count and reduce bleeding risk
• Administration: Teach proper subcutaneous injection technique if self-administering
• Storage: Refrigerate at 2-8°C; protect from light
• Missed dose: Administer as soon as remembered, then resume regular schedule
• Bleeding precautions: Use soft toothbrush, electric razor, avoid contact sports
• Signs to report: Unusual bleeding/bruising, blood in urine/stool, severe headache, shortness of breath, chest pain, leg swelling or pain
• Pregnancy/breastfeeding: Discuss with healthcare provider before conception
• Regular monitoring: Importance of keeping all scheduled appointments
• Drug interactions: Inform all healthcare providers about NPlate use

References

1. FDA Prescribing Information: NPlate (romiplostim). Updated 2021. 2. Kuter DJ, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008;371(9610):395-403. 3. Bussel JB, et al. Long-term efficacy and safety of romiplostim for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;182(5):704-712. 4. Neunert C, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019;3(23):3829-3866. 5. Rodeghiero F, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children. Blood. 2009;113(11):2386-2393. 6. Provan D, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186. 7. Kuter DJ. The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol. 2013;98(1):10-23. 8. ClinicalTrials.gov: Various studies on romiplostim in ITP and other conditions.