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NPLATE(romiplostim)injection, powder, lyophilized, for solut
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Nplate safely and effectively. See full prescribing information for Nplate.
Nplate® (romiplostim)
For subcutaneous injection
Initial U.S. Approval: 2008
RECENT MAJOR CHANGES
Indications and Usage 07/2011
Dosage and Administration 07/2011
Warnings and Precautions: Progression of MDS 07/2011
Warnings and Precautions: Thrombotic/Thromboembolic Events 07/2011
INDICATIONS AND USAGE
Nplate is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.
Limitations of Use:
Nplate is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.
Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk for bleeding.
Nplate should not be used in an attempt to normalize platelet counts. (1)
DOSAGE AND ADMINISTRATION
Initial dose of 1 mcg/kg once weekly as a subcutaneous injection. (2.1)
Adjust weekly dose by increments of 1 mcg/kg to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. (2.1)
Do not exceed the maximum weekly dose of 10 mcg/kg. Do not dose if platelet count is > 400 x 109/L. (2.1)
Discontinue Nplate if platelet count does not increase after 4 weeks at the maximum dose. (2.1)
Do not shake during reconstitution; protect reconstituted Nplate from light; administer reconstituted Nplate within 24 hours. (2.2)
The injection volume may be very small. Use a syringe with gradations to 0.01 mL. (2.2)
Discard any unused portion of the single-use vial. (2.2)
DOSAGE FORMS AND STRENGTHS
250 mcg or 500 mcg of deliverable romiplostim in single-use vials (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS
Nplate increases blast cell counts and increases the risk of progression to acute myelogenous leukemia in patients with myelodysplastic syndromes. (5.1)
Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate. Use with additional caution in ITP patients with chronic liver disease. (5.2)
Nplate increases the risk for reticulin deposition within the bone marrow; clinical studies have not ruled out the possibility that reticulin and other fiber deposition may result in bone marrow fibrosis with cytopenias. Monitor peripheral blood for signs of marrow fibrosis. (5.3)
Discontinuation of Nplate may result in worsened thrombocytopenia than was present prior to Nplate therapy. Monitor complete blood counts (CBCs), including platelet counts, for at least 2 weeks following Nplate discontinuation. (5.4)
If severe thrombocytopenia develops during Nplate treatment, assess patients for the formation of neutralizing antibodies. (5.5)
Monitor CBCs, including platelet counts and peripheral blood smears, weekly until a stable Nplate dose has been achieved. Thereafter, monitor CBCs, including platelet counts and peripheral blood smears, at least monthly. (5.6)
Nplate is available only through a restricted distribution program called the Nplate® NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program. Under the Nplate® NEXUS Program, only prescribers and patients registered with the program are able to prescribe, administer, and receive product. To enroll in the Nplate® NEXUS Program, call 1-877-Nplate1 (1-877-675-2831). (5.7)
ADVERSE REACTIONS
The most common adverse reactions (≥ 5% higher patient incidence in Nplate versus placebo) are arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, and paresthesia. Headache was the most commonly reported adverse reaction that did not occur at ≥ 5% higher patient incidence in Nplate versus placebo. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-877-Nplate1 (1-877-675-2831) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, Nplate may cause fetal harm. Enroll pregnant patients in the Nplate pregnancy registry by calling 1-877-Nplate1 (1-877-675-2831). (8.1)
Nursing Mothers: A decision should be made to discontinue Nplate or nursing, taking into account the importance of Nplate to the mother. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Revised: 07/2011
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Back to Highlights and TabsFULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage Regimen
2.2 Preparation and Administration
2.3 Use of Nplate With Concomitant Medical ITP Therapies
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia
5.2 Thrombotic/Thromboembolic Complications
5.3 Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis
5.4 Worsened Thrombocytopenia After Cessation of Nplate
5.5 Lack or Loss of Response to Nplate
5.6 Laboratory Monitoring
5.7 Nplate Distribution Program
6 ADVERSE REACTIONS
6.1 Clinical Studies Experience
6.2 Postmarketing Experience
6.3 Immunogenicity
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Chronic ITP
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Information for Patients
MEDICATION GUIDE
How should I take Nplate?
General information about the safe and effective use of Nplate.
What are the ingredients in Nplate?
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - VIAL, 250 MCG
PACKAGE LABEL - PRINCIPAL DISPLAY PANEL - VIAL, 500 MCG
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FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Nplate is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.
Limitations of use:
-
Nplate is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP [see Warnings and Precautions (5.1)].
-
Nplate should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding [see Warnings and Precautions (5.2)].
-
Nplate should not be used in an attempt to normalize platelet counts [see Warnings and Precautions (5.2)].
2 DOSAGE AND ADMINISTRATION
Only prescribers enrolled in the Nplate® NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program may prescribe Nplate [see Warnings and Precautions (5.7)]. Nplate must be administered by the enrolled prescribers or healthcare providers under their direction.
2.1 Recommended Dosage Regimen
Use the lowest dose of Nplate to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Administer Nplate as a weekly subcutaneous injection with dose adjustments based upon the platelet count response.
The prescribed Nplate dose may consist of a very small volume (eg, 0.15 mL). Administer Nplate only with a syringe that contains 0.01 mL graduations.
Initial Dose
The initial dose for Nplate 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 Nplate 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 10mcg/kg. In clinical studies, most patients who responded to Nplate achieved and maintained platelet counts ≥ 50 x 109/L with a median dose of 2 mcg/kg.
During Nplate therapy, assess CBCs, including platelet count and peripheral blood smears, 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 and peripheral blood smears, monthly thereafter.
Adjust the dose as follows:
-
If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
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If platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
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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 Nplate at a dose reduced by 1 mcg/kg.
Discontinuation
Discontinue Nplate if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Nplate therapy at the maximum weekly dose of 10mcg/kg [see Warnings and Precautions (5.4)]. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate [see Warnings and Precautions (5.6)].
2.2 Preparation and Administration
Nplate is supplied in single-use 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 Nplate with preservative-free Sterile Water for Injection, USP as described in Table 1. Do not use bacteriostatic water for injection.
Table 1. Reconstitution of Nplate Single-Use Vials
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|
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Nplate Single-Use Vial |
Total Vial Content
of Romiplostim |
|
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 |
Gently swirl and invert the vial to reconstitute. Avoid excess or vigorous agitation: DO NOT SHAKE. Generally, dissolution of Nplate takes less than 2 minutes. The reconstituted Nplate solution should be clear and colorless. Visually inspect the reconstituted solution for particulate matter and/or discoloration. Do not administer Nplate if particulate matter and/or discoloration is observed.
Reconstituted Nplate can be kept at room temperature (25°C/77°F) or refrigerated at 2° to 8°C (36° to 46°F) for up to 24hours 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 Nplate solution that is given to the patient by dividing the microgram dose by the concentration of the reconstituted Nplate 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.
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 Nplate With Concomitant Medical ITP Therapies
Nplate 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 Clinical Studies (14.1)].
3 DOSAGE FORMS AND STRENGTHS
Single-use vials contain 250 or 500 mcg of deliverable romiplostim as a sterile, lyophilized, solid white powder.
5 WARNINGS AND PRECAUTIONS
5.1 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 Nplate. 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 romiplostim treatment arm. At the time of an interim analysis, among 219 MDS patients randomized 2:1 to treatment with Nplate or placebo (147 Nplate: 72 placebo), eleven patients showed progression to AML, including nine on the Nplate arm versus two on the placebo arm. In addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28 patients, 25 of whom were on the romiplostim treatment arm. Of the 28 patients who had an increase in circulating myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML, and 20 patients have not progressed to AML. In four patients, increased peripheral bloodblast cell counts decreased to baseline after discontinuation of Nplate. In a single-arm trial of Nplate given to 72 patients with thrombocytopenia related to MDS, eight (11%) patients were reported as having possible disease progression, and three patients had confirmation of AML during follow-up. In addition, in three patients, increased peripheral bloodblast cell counts decreased to baseline after discontinuation of Nplate.
Nplate is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
5.2 Thrombotic/Thromboembolic Complications
Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate. Nplate should be used with caution in patients with ITP and chronic liver disease.
To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L [see Dosage and Administration (2.1)].
5.3 Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis
Nplate administration increases the risk for development or progression of reticulin fiber deposition within the bone marrow. In clinical studies, Nplate was discontinued in four of the 271 patients because of bone marrow reticulin deposition. Six additional patients had reticulin observed upon bone marrow biopsy. All 10 patients with bone marrow reticulin deposition had received Nplate doses ≥ 5 mcg/kg and six received doses ≥ 10 mcg/kg. Progression to marrow fibrosis with cytopenias was not reported in the controlled clinical studies. In the extension study, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate therapy. Clinical studies have not excluded a risk of bone marrow fibrosis with cytopenias.
Prior to initiation of Nplate, examine the peripheral blood smear closely to establish a baseline level of cellular morphologic abnormalities. Following identification of a stable Nplate dose, examine peripheral blood smears and CBCs monthly for new or worsening morphological abnormalities (eg, teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Nplate and consider a bone marrow biopsy, including staining for fibrosis [see Adverse Reactions (6.1)].
5.4 Worsened Thrombocytopenia After Cessation of Nplate
In clinical studies of patients with chronic ITP who had Nplate discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Nplate therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of Nplate, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines [see Adverse Reactions (6.1)].
5.5 Lack or Loss of Response to Nplate
Hyporesponsiveness or failure to maintain a platelet response with Nplate should prompt a search for causative factors, including neutralizing antibodies to Nplate [see Adverse Reactions (6.2)]. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Nplate and thrombopoietin (TPO). Discontinue Nplate 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 10mcg/kg.
5.6 Laboratory Monitoring
Monitor CBCs, including platelet counts and peripheral blood smears, prior to initiation, throughout, and following discontinuation of Nplate therapy. Prior to the initiation of Nplate, examine the peripheral blood differential to establish the baseline extent of red and white blood cell abnormalities. Obtain CBCs, including platelet counts and peripheral blood smears, weekly during the dose adjustment phase of Nplate therapy and then monthly following establishment of a stable Nplate dose. Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Nplate [see Dosage and Administration (2.1) and Warnings and Precautions (5.1, 5.2)].
5.7 Nplate Distribution Program
Nplate is available only through a restricted distribution program called Nplate® NEXUS (Network of Experts Understanding and Supporting Nplate and Patients) Program. Under the Nplate® NEXUS Program, only prescribers and patients registered with the program are able to prescribe, administer, and receive Nplate. This program provides educational materials and a mechanism for the proper use of Nplate. To enroll in the Nplate® NEXUS Program, call 1-877-Nplate1 (1-877-675-2831). Prescribers and patients are required to understand the risks of Nplate therapy. Prescribers are required to understand the information in the prescribing information and be able to:
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Educate patients on the benefits and risks of treatment with Nplate, ensure that the patient receives the Medication Guide, instruct them to read it, and encourage them to ask questions when considering Nplate. Patients may be educated by the enrolled prescriber or a healthcare provider under that pres
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