Romiplostim

Romiplostim 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:

• Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.

• Romiplostim should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding.

• Romiplostim should not be used in an attempt to normalize platelet counts.

Romiplostim is a man-made form of a protein that increases production of platelets (blood-clotting cells) in your body.

Romiplostim is used to prevent bleeding episodes in people with chronic immune thrombocytopenic purpura (ITP), a bleeding condition caused by a lack of platelets in the blood.

Romiplostim is usually given after other medications have been tried without successful treatment of symptoms.

Romiplostim is not a cure for ITP and it will not make your platelet counts normal if you have this condition.

Romiplostim may also be used for purposes not listed in this medication guide.

2.1 Recommended Dosage Regimen

Use the lowest dose of Romiplostim to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Administer Romiplostim as a weekly subcutaneous injection with dose adjustments based upon the platelet count response.

The prescribed Romiplostim dose may consist of a very small volume (eg, 0.15 mL). Administer Romiplostim only with a syringe that contains 0.01 mL graduations.

Initial Dose

The initial dose for Romiplostim 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 Romiplostim 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 Romiplostim achieved and maintained platelet counts ≥ 50 x 109/L with a median dose of 2 mcg/kg.

During Romiplostim 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 Romiplostim at a dose reduced by 1 mcg/kg.

Discontinuation

Discontinue Romiplostim if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Romiplostim therapy at the maximum weekly dose of 10 mcg/kg. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Romiplostim.

2.2 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.

Romiplostim 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 Romiplostim with preservative-free Sterile Water for Injection, USP, as described in Table 1. Do not use bacteriostatic water for injection.

* 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 Romiplostim takes less than 2 minutes. The reconstituted Romiplostim solution should be clear and colorless. Visually inspect the reconstituted solution for particulate matter and/or discoloration. Do not administer Romiplostim if particulate matter and/or discoloration is observed.

Reconstituted Romiplostim 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 Romiplostim solution that is given to the patient by dividing the microgram dose by the concentration of the reconstituted Romiplostim 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.

2.3 Use of Romiplostim With Concomitant Medical ITP Therapies

Romiplostim 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.

See also:
What is the most important information I should know about Romiplostim?

Romiplostim is available only under a special program called Romiplostim NEXUS. You must be registered in the program and sign documents stating that you understand the risks and benefits of taking this medication.

Romiplostim is not a cure for ITP and it will not make your platelet counts normal if you have this condition.

Before you use Romiplostim, tell your doctor if you have kidney or liver disease.

Using Romiplostim long-term can cause harmful effects on your bone marrow that may result in serious blood cell disorders. To be sure this medication is helping your condition and not causing harmful effects, your blood will need to be tested often. Do not miss any scheduled visits to your doctor.

It may take up to 4 weeks of using this medicine before it is completely effective in preventing bleeding episodes. Talk with your doctor if you have any bruising or bleeding episodes after 4 weeks of treatment.

After you stop using Romiplostim, your risk of bleeding may be even higher than it was before you started treatment. Be extra careful to avoid cuts or injury for at least 2 weeks after you stop using Romiplostim. Your blood will need to be tested weekly during this time.

Use Romiplostim as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Romiplostim comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again before each time you use Romiplostim.
• Romiplostim is given as an injection at your doctor's office, hospital, or clinic. You should receive Romiplostim only under direct medical supervision by a doctor experienced in the use of Romiplostim.
• If you miss a dose of Romiplostim, contact your doctor right away.

Ask your health care provider any questions you may have about how to use Romiplostim.

Use: Labeled Indications

Immune thrombocytopenia: Treatment of thrombocytopenia in adult patients with immune thrombocytopenia (ITP) who have had insufficient response to corticosteroids, immune globulin, or splenectomy; treatment of thrombocytopenia in pediatric patients ≥1 year of age with ITP for ≥6 months who have had insufficient response to corticosteroids, immune globulin, or splenectomy.

Limitations of use: Romiplostim should be used only when the degree of thrombocytopenia and clinical condition increase the risk for bleeding; Romiplostim should not be used in attempt to normalize platelet counts; Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome or any cause of thrombocytopenia other than ITP.

See also:
What other drugs will affect Romiplostim?

No formal drug interaction studies of Romiplostim have been performed.

See also:
What are the possible side effects of Romiplostim?

The following serious adverse reactions are discussed in greater detail in other sections:

• Progression of Myelodysplastic Syndromes
• Thrombotic/Thromboembolic Complications
• Loss of Response to Romiplostim
• 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 Romiplostim exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Romiplostim 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 Romiplostim over an extended period of time. Overall, Romiplostim 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 Romiplostim 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 Romiplostim 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

Among 142 patients with chronic ITP who received Romiplostim 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

Romiplostim administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Romiplostim. In a clinical trial, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Romiplostim therapy.

An open-label clinical trial prospectively evaluated changes in bone marrow reticulin formation and collagen fibrosis in adult patients with ITP treated with Romiplostim 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 (cohort1), 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 Romiplostim. 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 Romiplostim 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 antibod y activity and clinical effectiveness or safety.

A post marketing registry study involving patients with thrombocytopenia on Romiplostim 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 Romiplostim 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.