Nplate

Generic Name: Romiplostim
Class: Hematopoietic Agents
VA Class: BL400
CAS Number: 267639-76-9

Warning(s)

REMS:

FDA approved a REMS for romiplostim to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of romiplostim and consists of the following: medication guide, elements to assure safe use, communication plan, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Biosynthetic (recombinant DNA-derived) Fc-peptide fusion protein; thrombopoietin-receptor agonist.1 3

Uses for Nplate

Idiopathic Thrombocytopenic Purpura

Treatment of chronic idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura) in patients who have had an inadequate response to corticosteroids, immunoglobulins, or splenectomy and in whom the degree of thrombocytopenia and clinical status increase bleeding risk.1 3

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Do not use to normalize platelet counts since excessive increases in platelet count may increase the risk of thromboembolic complications.1

Not indicated for the treatment of thrombocytopenia associated with myelodysplastic syndrome or thrombocytopenia associated with any condition other than chronic ITP.1

Nplate Dosage and Administration

General

  • Monitor CBC, including platelet count and peripheral blood smear, weekly until achieve a stable platelet count (≥50,000/mm3 for ≥4 weeks without dosage adjustment); monitor at least monthly thereafter.1

  • After romiplostim discontinuance, monitor CBC, including platelet count, weekly for at least 2 weeks; potential for worsening thrombocytopenia following discontinuance.1

  • May be used with other drugs to treat ITP such as corticosteroids, danazol, azathioprine, immune globulin IV (IGIV), and Rho(D) immune globulin.1 If the platelet count increases to ≥50,000/mm3, medical therapies for ITP may be reduced or discontinued.1

Restricted Distribution Program

  • FDA required and approved a Risk Evaluation and Mitigation Strategy (REMS) for romiplostim.9 Goals are to promote informed risk-benefit decisions before initiating the drug; to ensure its appropriate use while patients are receiving therapy; and to establish the overall long-term safety and safe use of romiplostim by periodically monitoring all patients for various adverse effects.9 The REMS program consists of a medication guide, a communication plan, and elements to ensure safe use.9

  • Romiplostim is prescribed and distributed under a restricted distribution program, the Nplate NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) program.1 4 5 Only prescribers and patients registered with the program are able to prescribe, administer, and receive romiplostim.1 5 Clinicians may contact 877-675-2831 (877-Nplate1) or visit for additional information and to enroll in Amgen’s Nplate NEXUS program for romiplostim.1

Administration

Reconstitution

Romiplostim lyophilized powder is supplied in single-use vials containing 375 mcg (to deliver 250 mcg) or 625 mcg (to deliver 500 mcg) of the drug.1 Reconstitute lyophilized romiplostim using only sterile water for injection without preservatives; do not use bacteriostatic water for injection.1 (See Storage under Stability.) Reconstitute the powder by adding 0.72 or 1.2 mL of preservative-free sterile water for injection to a vial labeled as containing 250 or 500 mcg, respectively, of romiplostim.1

Gently swirl and invert the vial to facilitate dissolution, which generally takes <2 minutes; do not shake or vigorously agitate the vial.1

Reconstitution of the lyophilized drug as directed provides a clear and colorless solution containing 250 or 500 mcg per 0.5 or 1 mL, respectively, for sub-Q administration.1

Sub-Q Administration

Administer by sub-Q injection.1

A clinician should administer romiplostim;1 5 the patient should not self-administer the drug.2

Injection volumes of the drug may be very small; administer romiplostim using a syringe calibrated in increments of 0.01 mL.1 Exercise extra care to ensure the accuracy of the administered dose because of the potential for serious adverse effects following administration of excessive doses.1 5

Dosage

Adults

Idiopathic Thrombocytopenic Purpura
Sub-Q

Initially, 1 mcg/kg weekly based on actual body weight.1

Adjust dosage at weekly intervals in increments of 1 mcg/kg (up to a maximum dosage of 10 mcg/kg weekly) until a platelet count of ≥50,000/mm3 is achieved.1

Reduce dosage by 1 mcg/kg weekly if platelet count is >200,000/mm3 for 2 consecutive weeks.1 Do not administer if platelet count is >400,000/mm3; assess the platelet count weekly and resume romiplostim at a dosage reduced by 1 mcg/kg weekly once the platelet count is <200,000/mm3.1 Discontinue romiplostim if, after 4 weeks of therapy at the maximum recommended dosage of 10 mcg/kg weekly, the platelet count has not increased to a level sufficient to avoid clinically important bleeding.1

Monitor CBC, including platelet count and peripheral blood smear, weekly until a stable platelet count (≥50,000/mm3 for ≥4 weeks without dosage adjustment) has been achieved; monitor CBC, including platelet count and peripheral blood smear, at least monthly thereafter.1 Because of the potential for worsening thrombocytopenia following discontinuance of romiplostim, monitor CBC, including platelet count, weekly for at least 2 weeks after drug discontinuance.1

Prescribing Limits

Adults

Idiopathic Thrombocytopenic Purpura
Sub-Q

Maximum 10 mcg/kg weekly.1

Special Populations

No special population dosage recommendations at this time.1

Cautions for Nplate

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

General Precautions

Bone Marrow Reticulin Deposition and Bone Marrow Fibrosis

Thrombopoietin (TPO)-receptor agonists (e.g., romiplostim) increase the risk of development or progression of reticulin fiber deposition within the bone marrow, thereby increasing the risk for bone marrow fibrosis or myelofibrosis.1 Risk of development of bone marrow fibrosis with cytopenias not excluded in clinical studies of romiplostim.1

Evaluate a peripheral blood smear prior to starting romiplostim therapy and monthly thereafter once a stable dosage has been achieved.1 Examination of the peripheral blood smear should include establishment of a baseline level of cellular morphologic abnormalities and monthly evaluations to detect new or worsening morphologic abnormalities (e.g., teardrop or nucleated erythrocytes, immature leukocytes). 1 Perform CBC monthly to evaluate new or worsening cytopenias.1 If a new or worsening morphologic abnormality or cytopenia develops, discontinue romiplostim and consider a bone marrow biopsy, with additional staining for fibrosis.1

Thrombocytopenia Following Romiplostim Discontinuance

Risk of thrombocytopenia, which may be more severe than prior to therapy, after discontinuance of romiplostim.1 May result in increased risk of bleeding, especially if romiplostim is discontinued while the patient is receiving concomitant antiplatelet or anticoagulation therapy.1

Following discontinuance of romiplostim, perform CBC including platelet count weekly for at least 2 weeks.1 Consider additional ITP therapy for worsening thrombocytopenia.1

Thrombosis/Thromboembolism

Risk of thrombosis or a thromboembolic complication as a result of excessive increase in platelet count secondary to excessive dosages of romiplostim.1 To minimize the risk, do not use romiplostim to normalize platelet counts; use drug only to maintain a platelet count of ≥50,000/mm3 according to the dosage adjustment guidelines.1 (See Dosage under Dosage and Administration.)

Malignancy

Romiplostim stimulates the TPO receptor present on the surface of hematopoietic cells; may increase the risk for a hematologic malignancy, especially in patients with myelodysplastic syndrome (MDS). 1 Do not use romiplostim to treat or correct thrombocytopenia related to an underlying hematologic cause (e.g., myelodysplasia) or resulting from chemotherapy; use romiplostim only for thrombocytopenia associated with chronic ITP.1

Laboratory Monitoring

Obtain CBC, including platelet count and peripheral blood smear, prior to starting therapy and weekly during the dosage adjustment phase, then monthly once a stable dosage has been achieved.1 Baseline peripheral blood smears should establish the presence and extent of red blood cell and leukocyte abnormalities.1 After romiplostim is discontinued, evaluate CBC with platelet count weekly for at least 2 weeks to monitor for worsening thrombocytopenia.1

Lack or Loss of Response

In cases of lack of response (i.e., hyporesponsiveness) or failure to maintain a platelet response, consider performing an evaluation of possible causative factors (e.g., presence of neutralizing antibodies, evidence of bone marrow fibrosis).1 Blood samples for detection of antibody formation can be sent to Amgen to determine if antibodies to either romiplostim or TPO are present.1

Discontinue romiplostim if the platelet count does not increase sufficiently after 4 weeks of treatment at the highest recommended dosage of 10 mcg/kg weekly.1

Immunogenicity

Binding antibodies to romiplostim and TPO reported, including anti-romiplostim neutralizing antibodies.8 No clinical impact on safety or efficacy observed in patients who tested positive for antibodies.8

Specific Populations

Pregnancy

Category C.1 Pregnancy registry at 1-887-Nplate1 (1-887-675-2831).1

Lactation

Not known whether romiplostim is distributed into human milk; however, human immunoglobulin G antibody (IgG) is distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No substantial differences in safety and efficacy in geriatric patients ≥65 years of age relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Not studied in hepatic impairment.1 Use with caution.1

Renal Impairment

Not studied in patients with renal impairment.1 Use with caution.1

Common Adverse Effects

Arthralgia,1 dizziness,1 insomnia,1 myalgia,1 extremity pain,1 abdominal pain.1

In the extension study: headache, nasopharyngitis, confusion, fatigue.6

Interactions for Nplate

No formal drug interaction studies to date.1

Nplate Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations attained approximately 7–50 hours (median: 14 hours) following sub-Q administration of romiplostim doses of 3–15 mcg/kg.1

Distribution

Extent

Not known whether romiplostim is distributed into milk.1

Elimination

Elimination Route

Elimination of the drug is partly dependent on the TPO receptor on platelets.1 High platelet counts are associated with low serum romiplostim concentrations.1

Half-life

Approximately 1–34 days (median: 3.5 days).1

Stability

Storage

Parenteral

Powder for Injection

2–8°C; do not freeze.1 Store vials in carton to protect from light until used.1

Protect reconstituted solutions from light and store at 25°C or refrigerated at 2–8°C for up to 24 hours prior to administration.1 Do not administer more than one dose from each single-use vial; discard any unused portions of the solution.1

Actions

  • Biosynthetic (recombinant DNA-derived) Fc-peptide fusion protein; thrombopoietin receptor agonist.1 3 Produced by recombinant DNA technology in Escherichia coli.1

  • Contains 2 identical single-chain subunits, each consisting of human IgG1 Fc domain covalently linked at the C-terminus to a peptide containing 2 thrombopoietin receptor-binding domains.1

  • Has no amino acid sequence homology to endogenous thrombopoietin.1 3

  • Binds to the thrombopoietin receptor (also known as cMp1) and activates intracellular transcriptional pathways leading to increased platelet production.1 3

Advice to Patients

  • Importance of understanding that romiplostim treatment can only be administered by a clinician enrolled in the Nplate NEXUS program; all patients receiving romiplostim must be enrolled in the NEXUS program.1 (See Restricted Distribution Program under Dosage and Administration.)

  • Under the REMS program approved by FDA, medication guide must be provided prior to each dose of romiplostim.9 Importance of carefully reading medication guide before initiating therapy and prior to receiving each dose.1 2 9

  • Importance of understanding that the goal of therapy is to achieve and maintain a platelet count of ≥50,000/mm3 to reduce the risk of bleeding, not to normalize platelet counts.1

  • Risk of worsening thrombocytopenia with possible bleeding following discontinuance of romiplostim, compared with such risks prior to starting therapy; increased risk if patient is receiving concomitant anticoagulant or antiplatelet drugs.1

  • Risk of reticulin fiber formation in bone marrow with possible progression to bone marrow fibrosis.1

  • Risk of thrombosis or thromboembolism.1

  • Risk of progression of underlying MDS or hematologic malignancy.1

  • Risk of adverse events associated with long-term administration not fully known.1

  • Importance of avoiding situations or drug therapies that may increase risk of bleeding.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Distribution of romiplostim is restricted.1 4 5 (See Restricted Distribution Program under Dosage and Administration.)

Romiplostim

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for subcutaneous use

375 mcg (to deliver 250 mcg)

Nplate

Amgen

625 mcg (to deliver 500 mcg)

Nplate

Amgen

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Amgen. Nplate (romiplostim) for injection prescribing information. Thousand Oaks, CA; 2008 Aug.

2. Amgen. Nplate (romiplostim) for injection medication guide. Thousand Oaks, CA; 2008 Aug.

3. Kuter DJ, Bussel JB, Lyons RM et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008: 371:395-403.

4. Pazdur R. Letter regarding approval of biologics license application for romiplostim (BL 125268/0). Rockville, MD: US Food and Drug Administration; 2008 Aug 22.

5. Amgen. Nexus healthcare professional brochure: Understanding and supporting Nplate (romiplostim) and patients. Available at: . Accessed 2008 Oct 3.

6. Bussel JB, Kuter DJ, Pullarkat V et al. Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009; 113:2161-71. [PubMed 18981291]

7. Kuter DJ, Phil D, Mufti G et al. Evaluation of bone marrow reticulin formation in romiplostim-treated adult patients with chronic immune thrombocytopenic purpura (ITP). Blood. 2008; 112: Abstract 3416.

8. Jawa V, Hokom M, Hu J et al. Low immunogenicity to romiplostim in clinical studies with ITP subjects. Blood. 2008; 112: Abstract 3425.

9. Amgen. BLA 125268 Nplate (romiplostim): risk evaluation and mitigation strategy (REMS). Thousand Oaks, CA; 2010 Mar 23. Available from FDA website (). Accessed 2011 Feb 8.

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