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BRIEF SUMMARY OF PRESCRIBING INFORMATION
NPLATE ® (romiplostim) for injection, for subcutaneous use
1 INDICATIONS AND USAGE
Nplate ® 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:
• 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)].
4 CONTRAINDICATIONS
The data described below reflect Nplate ® exposure to 271 patients
with chronic ITP, aged 18 to 88, of whom 62% were female. Nplate ®
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 Nplate ® over
an extended period of time. Overall, Nplate ® was administered to 114
patients for at least 52 weeks and 53 patients for at least 96 weeks. 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.
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. 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 Nplate ®
versus placebo. The majority of these adverse drug reactions were
mild to moderate in severity. 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.
Table 2. Adverse Drug Reactions Identified in Two Placebo
Controlled Studies
Preferred Term Nplate ® (n = 84) Placebo (n = 41)
None. Arthralgia 26% 20%
5 WARNINGS AND PRECAUTIONS Dizziness 17% 0%
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 Nplate ® treatment 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. Insomnia 16% 7%
2%
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 ® .
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)].
5.3 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 (6.3)]. 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 10 mcg/kg.
5.4 Laboratory Monitoring
Obtain CBCs, including platelet counts, 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)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail
in other sections:
• Progression of Myelodysplastic Syndromes [see Warnings and
Precautions (5.1)]
• Thrombotic/Thromboembolic Complications [see Warnings and
Precautions (5.2)]
• Loss of Response to Nplate ® [see Warnings and Precautions (5.3)]
• Laboratory Monitoring [see Warnings and Precautions (5.4)]
6.1 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.
Myalgia 14% Pain in Extremity 13% 5%
Abdominal Pain 11% 0%
Shoulder Pain 8% 0%
Dyspepsia 7% 0%
Paresthesia 6% 0%
Among 142 patients with chronic ITP who received Nplate ® 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
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 (cohort 1), 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.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval
use of Nplate ® . 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
6.3 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 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 postmarketing registry study involving patients with thrombocytopenia
7 DRUG INTERACTIONS
No formal drug interaction studies of Nplate ® have been performed.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies of Nplate ® use in
pregnant women. 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. Nplate ® should be used during pregnancy only if the
potential benefit to the mother justifies the potential risk to the fetus.
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.
8.3 Nursing Mothers
It is not known whether Nplate ® is excreted in human milk; however,
human IgG is excreted in human milk. Published data suggest that
breast milk antibodies do not enter the neonatal and infant circulation
in substantial amounts. Because many drugs are excreted in human
milk and because of the potential for serious adverse reactions in
nursing infants from Nplate ® , a decision should be made whether to
discontinue nursing or to discontinue Nplate ® , taking into account the
importance of Nplate ® to the mother and the known benefits of nursing.
8.4 Pediatric Use
The safety and effectiveness in pediatric patients (< 18 years) have
not been established.
8.5 Geriatric Use
Of the 271 patients who received Nplate ® in ITP clinical studies,
55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No
overall differences in safety or efficacy have been observed between
older and younger patients in the placebo-controlled studies, but greater
sensitivity of some older individuals cannot be ruled out. In general,
dose adjustment for an elderly patient should be cautious, reflecting
the greater frequency of decreased hepatic, renal, or cardiac function,
and of concomitant disease or other drug therapy.
8.6 Renal Impairment
No clinical studies were conducted in patients with renal impairment.
8.7 Hepatic Impairment
No clinical studies were conducted in patients with hepatic impairment.
10 OVERDOSAGE
Overdoses due to medication errors have been reported in patients
receiving Nplate ® . In the event of overdose, platelet counts may increase
excessively and result in thrombotic/thromboembolic complications. In
this case, discontinue Nplate ® and monitor platelet counts. Reinitiate
treatment with Nplate ® in accordance with dosing and administration
recommendations [see Dosage and Administration (2.1, 2.2)].
This Brief Summary using USPIv11 06/2017
Nplate ® (romiplostim)
Manufactured by:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
U.S. License No. 1080
Patent: http://pat.amgen.com/nplate/
© 2008–2017 Amgen Inc. All rights reserved.