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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
NPLATE (BLA-125268)
(ROMIPLOSTIM)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/21/2025 (SUPPL-176)
5 Warnings and Precautions
5.2 Thrombotic/Thromboembolic ComplicationsAdditions and revisions underlined:
Thrombotic/thromboembolic complications have resulted from increases in platelet counts with Nplate use secondary to drug-induced thrombocytosis, regardless of the underlying disease. Thrombotic/ thromboembolic events including deep vein thrombosis (1.4%), pulmonary embolism (1.2%) and myocardial infarction (0.8%) have been observed with the use of Nplate in the ITP population. Other thrombotic events including transient ischemic attack have been reported. These events have occurred regardless of platelet counts. Portal vein thrombosis has been reported in patients with and without chronic liver disease receiving Nplate.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication GuideAdditions and revisions underlined:
Nplate can cause serious side effects, including:
. . .
Blood clots in the veins of your legs (deep vein thrombosis, DVT), lungs (pulmonary embolism, PE),
heart attack and strokes have happened in people with ITP during treatment with Nplate.
o You may get blood clots in the veins of your liver (portal vein thrombosis) with or without chronic liver disease.
. . .
02/10/2021 (SUPPL-168)
6 Adverse Reactions
6.1 Clinical Trials Experience
(Additions and/or revisions underlined)
Pediatric Patients
The data described below reflect median exposure to Nplate of 168 days for 59 pediatric patients (aged 1 to 17 years) with ITP for at least 6 months, of whom 47.5% were female, across the randomized phase of two placebo- controlled trials. Table 4 presents the most common adverse reactions experienced by at least 5% of the pediatric patients (1 year and older) receiving Nplate across the two placebo-controlled trials with at least a 5% higher incidence in patients who received Nplate compared to those who received placebo.
In pediatric patients of age greater than or equal to 1 year receiving Nplate for ITP, adverse reactions with an incidence of greater than or equal to 25% in the two randomized trials were: contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%).
Among 203 pediatric patients with ITP who received Nplate in a single arm, open-label, long-term (median duration of 3 years on therapy) study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies. In this single arm, open-label, long-term study, headache occurred in 78 patients (38%), 3% (n=6) being severe and 1% (n=2) resulting in discontinuation of drug.
Bone Marrow Reticulin Formation and Collagen Fibrosis
The open-label long-term study also evaluated changes in bone marrow reticulin and collagen formation. The modified Bauermeister grading scale was used for both assessments. Based on cohort assignment at the time of study enrollment, patients were evaluated for bone marrow reticulin and collagen at year 1 (cohort 1) or year 2 (cohort 2) in comparison to the baseline bone marrow at the start of the study. From the total of 79 patients enrolled in the 2 cohorts, 27 (90%) patients in cohort 1 and 36 (73.5%) patients in cohort 2 had evaluable on-study bone marrow biopsies. Increased reticulin fiber formation was reported for 18.5% (5 of 27) of patients in cohort 1 and 47.2% (17 of 36) of patients in cohort 2, with a maximum grade of 2. No patients in either cohort developed collagen fibrosis (defined as grade 4) or a bone marrow abnormality that was inconsistent with an underlying diagnosis of ITP.
6.3 Immunogenicity
(Additions and/or revisions underlined)
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Nplate in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. 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 adult clinical studies in adult patients with ITP, the incidence of pre-existing antibodies to romiplostim was 3.3% (35/1046) and the incidence of binding antibody development during treatment with Nplate or a non-US approved romiplostim product was 5.7% (60/1046). The incidence of pre-existing antibodies to endogenous TPO was 3% (31/1046) and the incidence of binding antibody development to endogenous TPO during treatment was 3.2% (33/1046). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, four patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No apparent correlation was observed between antibody activity and clinical effectiveness or safety.
In pediatric studies, data on antibody formation was collected from 282 patients (20 from early phase studies, 59 from phase 3 studies with duration of 6 months and 203 from a long-term study with median duration of 3 years). The incidence of binding antibodies to Nplate at any time was 9.6% (27/282), of which 2 patients (0.7%) had pre-existing binding non-neutralizing Nplate antibodies at baseline. and 11 patients (3.9%) had persistent bindingantibody positivity at end of study. Additionally, 2.8% (8/282) developed neutralizing antibodies to Nplate, with 4 patients (1.4%) having persistent neutralizing antibody positivity at end of study, despite discontinuation of Nplate.
The incidence of binding antibodies to TPO at any time was 3.9% (11/282), of which 2 patients (0.7%) had pre-existing binding non-neutralizing antibodies to TPO at baseline and 1 patient (0.4%) had binding persistent antibody positivity at end of study. One patient (0.4%) had a weakly positive postbaseline result for neutralizing antibodies against TPO while on study (with positive non-neutralizing antibodies to Nplate) with a negative result at baseline for both antibodies. The patient showed a transient antibody response for neutralizing antibodies against TPO, with a negative result at the patient’s last timepoint tested within the study period after discontinuation of Nplate.
8 Use in Specific Populations
8.4 Pediatric Use
(Additions and/or revisions underlined)
Safety and effectiveness have been established in pediatric patients age 1 year and older with ITP for at least 6 months evaluated in two randomized, placebo-controlled studies. Long-term safety in the same population using Nplate for a median duration of 3 years was also evaluated in a single arm, open-label study [see Adverse Reactions (6.1), Clinical Studies (14.2)].
01/28/2021 (SUPPL-167)
5 Warnings and Precautions
5.2 Thrombotic/Thromboembolic Complications(Additions and/or revisions underlined)
Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate use secondary to drug-induced thrombocytosis, regardless of the underlying disease. There is insufficient evidence to establish a relationship between maximum platelet threshold and risk of thrombotic/thromboembolic complications. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate.
In patients with ITP, to minimize the risk for thrombotic/thromboembolic complications, do not use Nplate in an attempt to normalize platelet counts. Follow the dose adjustment guidelines [see Dosage and Administration (2.1)].
In the absence of myelosuppression induced by acute exposure to radiation, Nplate administration might cause excessive increases in platelet counts and may cause thrombotic and thromboembolic complications [see Clinical Pharmacology (12.2)].
8 Use in Specific Populations
8.4 Pediatric Use(Newly added information)
The use of Nplate to increase survival in pediatric patients (including term neonates) acutely exposed to myelosuppressive doses of radiation is based on efficacy studies conducted in adult animals. Efficacy studies of Nplate could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. A similar response to romiplostim is expected in the pediatric and adult patients based on the mechanism of action of the drug and pharmacokinetics of romiplostim in pediatric patients 1 year and older with ITP [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide(Newly added section)
(Newly added information)
Advise patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) that efficacy studies of Nplate for this indication could not be conducted in humans for ethical and feasibility reasons and that, therefore, approval of this use was based on efficacy studies conducted in animals [see Clinical Studies (14.3)].
11/23/2020 (SUPPL-169)
6 Adverse Reactions
6.2 Postmarketing ExperienceAddition underlined
…
Hypersensitivity reactions including angioedema and anaphylaxis.
10/17/2019 (SUPPL-164)
5 Warnings and Precautions
Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous LeukemiaIn this subsection, all instances of ‘subjects’ are replaced by ‘patients’.
6 Adverse Reactions
Additions and/or revisions underlined:
The following clinically significant adverse reactions are discussed in greater detail in other sections:
· Progression of Myelodysplastic Syndromes
· Thrombotic/Thromboembolic Complications
· Loss of Response to Nplate
Additions and/or revisions underlined:
In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate and 32% of patients receiving placebo. For those patients receiving Nplate, 14 (48%) of headaches were mild, 9 (31%) were moderate, and 6 (21%) were severe. Table 3 presents adverse drug reactions from Studies 1 and 2 with a greater than or equal to 5% higher patient incidence in Nplate versus placebo.
The safety profile of Nplate was similar across patients, regardless of ITP duration. The following adverse reactions (at least 5% incidence and at least 5% more frequent with Nplate compared with placebo or standard of care) occurred in Nplate patients with ITP duration up to 12 months: bronchitis, sinusitis, vomiting, arthralgia, myalgia, headache, dizziness, diarrhea, upper respiratory tract infection, cough, nausea and oropharyngeal pain. The adverse reaction of thrombocytosis occurred with an incidence of 2% in adults with ITP duration up to 12 months.
In adult clinical studies in adult patients with ITP, the incidence of pre-existing antibodies to romiplostim was 3.3% (35/1046) and the incidence of binding antibody development during treatment with Nplate or a non-US approved romiplostim product was 5.7% (60/1046). The incidence of pre-existing antibodies to endogenous TPO was 3% (31/1046) and the incidence of binding antibody development to endogenous TPO during treatment was 3.2% (33/1046). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, four patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No apparent correlation was observed between antibody activity and clinical effectiveness or safety.
A postmarketing registry study involving patients with thrombocytopenia on Nplate or a non-US approved romiplostim product was conducted to assess the long-term consequences of the anti-romiplostim antibodies. Adult patients who lacked response or lost response to Nplate or a non-US approved romiplostim product were enrolled. The incidence of new binding antibody development was 3.8% (7/184) to romiplostim and 2.2% (4/184) were positive for binding, non-neutralizing antibodies to TPO; two patients were positive for binding antibodies to both romiplostim and TPO. Of the seven patients with positive binding antibodies to romiplostim, one patient (0.5%; 1/184) was positive for neutralizing antibodies to romiplostim only.
8 Use in Specific Populations
LactationRisk Summary
Additions and/or revisions underlined:
There is no information regarding the presence of romiplostim in human milk, the effects on the breastfed child, or the effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to romiplostim are unknown. Due to the potential for serious adverse reactions in a breastfed child from Nplate, advise women not to breastfeed during treatment with Nplate.
Additions and/or revisions underlined:
Risk Summary
Based on findings from animal reproduction studies, Nplate may cause fetal harm when administered to a pregnant woman. Available data with Nplate use in pregnant women are insufficient to draw conclusions about any drug- associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEExtensive changes; please refer to label for complete information.
12/14/2018 (SUPPL-163)
5 Warnings and Precautions
5.1 Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous LeukemiaAdditions and/or revisions underlined:
Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in adult clinical trials with Nplate.
A randomized, double-blind, placebo-controlled trial enrolling adult patients …
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
Adults
The data described below reflect Nplate exposure to 271 adult patients with chronic ITP …
Among 291 adult patients with chronic ITP …
Pediatric Patients
The data described below reflect median exposure to Nplate of 168 days for 59 pediatric patients (aged 1 to 17 years) with ITP for at least 6 months, of whom 47.5% were female, across the randomized phase of two placebo- controlled trials. Table 4 presents the most common adverse reactions experienced by at least 5% of the pediatric patients (1 year and older) receiving Nplate across the two placebo-controlled trials with at least a 5% higher incidence in patients who received Nplate compared to those who received placebo.
Table 4. Common Adverse Reactions (? 5% Incidence and ? 5% More Frequent on the Nplate Arm) from Two Placebo-Controlled Trials in Pediatric Patients with ITP for at least 6 months
Newly added Table; please see label for complete information.
In pediatric patients of age ? 1 year receiving Nplate for ITP, adverse reactions with an incidence of ? 25% in the two randomized trials were: contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%).
6.3 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Nplate in the studies described below with the incidence of antibodies in other studies or to other products may be misleading …
In clinical studies in adult patients with ITP …
In pediatric studies, the incidence of binding antibodies to Nplate at any time was 7.8% (22/282). Of the 22 patients, 2 patients had pre-existing binding non-neutralizing Nplate antibodies at baseline. Additionally, 2.5% (7/282) developed neutralizing antibodies to Nplate. A total of 3.2% (9/282) patients had binding antibodies to TPO at any time during Nplate treatment. Of these 9 patients, 2 patients had pre-existing binding non-neutralizing antibodies to TPO. All patients were negative for neutralizing activity to TPO.
A post marketing registry study involving patients …
Nineteen confirmed pediatric patients were included in the post marketing registry study. The incidence of binding antibody post treatment was 16% (3/19) to romiplostim, of which 5.3% (1/19) were positive for neutralizing antibodies to romiplostim. There were no antibodies detected to TPO.
7 Drug Interactions
Additions and/or revisions underlined:
Nplate may be used with other medical ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin.
8 Use in Specific Populations
8.1 Pregnancy
8.2 Lactation
PLLR conversion; extensive changes. Please refer to label for complete information.
8.4 Pediatric Use
Additions and/or revisions underlined:
Safety and effectiveness have been established in pediatric patients age 1 year and older with ITP for at least 6 months evaluated in two randomized, placebo-controlled studies. The pharmacokinetics of romiplostim have been evaluated in pediatric patients 1 year and older with ITP. See Dosage and Administration (2.1) for dosing recommendations for pediatric patients 1 year and older. The safety and efficacy of Nplate in pediatric patients younger than 1 year with ITP have not been established. Serum concentrations of romiplostim in pediatric patients with ITP were within the range observed in adult patients with ITP receiving the same dose range of romiplostim.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAddition of the following:
Pregnancy:
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their prescriber of a known or suspected pregnancy.
Lactation:
Advise women not to breastfeed during treatment with Nplate.
06/05/2017 (SUPPL-160)
5 Warnings and Precautions
5.1 5.1 Risk of Progression of Myelodysplastic Syndromes to Acute Myelogenous Leukemia(Additions and/or revisions are underlined)
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 Nplate arm. This trial consisted of a 58-week study period with a 5-year long-term follow- up phase. The subjects were randomized 2:1 to treatment with Nplate or placebo (167 Nplate, 83 placebo). During the 58-week study period, progression to AML occurred in 10 (6.0%) subjects in the Nplate arm and 4 (4.8%) subjects in the placebo arm(hazard ratio [95%CI] = 1.20 [0.38, 3.84]). Of the 250 subjects, 210 (84.0%) entered the long-term follow-up phase of this study. With 5-years of follow-up, 29 (11.6%) subjects showed progression to AML, including 20/168 (11.9%) subjects in the Nplate arm versus 9/82 (11.0%) subjects in the placebo arm (HR [95% CI] = 1.06 [0.48, 2.33]). The incidence of death (overall survival) was 55.7% (93/167) in the Nplate arm versus 54.2% (45/83) in the placebo arm (HR [95% CI] = 1.03 [0.72, 1.47]). In the baseline low IPSS group, there was a higher incidence of death in the Nplate arm [41.3% (19/46)] compared to the placebo arm [30.4% (7/23)] [HR (95% CI) = 1.59 (0.67, 3.80)]. In a single-arm trial of Nplate given to 72 subjects with thrombocytopenia-related MDS, 8 (11.1%) subjects were reported as having possible disease progression, of which 3 (4.2%) had confirmation of AML during follow-up. In addition, in 3 (4.2%) subjects, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate.
04/19/2016 (SUPPL-155)
5 Warnings and Precautions
ImmunogenicityAddition of the following:
- 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 Nplate 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 antibody activity and clinical effectiveness or safety.
- A post marketing registry study involving patients with thrombocytopenia on Nplate 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 Nplate 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.
04/19/2016 (SUPPL-156)
6 Adverse Reactions
Clinical Trials ExperienceBone Marrow Reticulin Formation and Collagen Fibrosis
- Nplate administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Nplate. In a clinical trial, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Nplate therapy.
- An open-label clinical trial prospectively evaluated changes in bone marrow reticulin formation and collagen fibrosis in adult patients with ITP treated with Nplate 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.
8 Use in Specific Populations
Pregnancy- In rat and rabbit developmental toxicity studies, no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred. In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses. Women who become pregnant during Nplate treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.