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B:8.375 in
T:8.125 in
S:7 in
REPATHA™ (evolocumab)
BRIEF SUMMARY OF PRESCRIBING INFORMATION
Please see package insert for full Prescribing Information
9.6
6.3
6.3
5.6
5.0
3.6
3.6
3.0
3.6
3.0
2.6
3.0
2.3
2.6
2.0
10.5
9.3
7.5
6.2
5.7
4.5
4.5
4.2
4.0
4.0
3.7
3.3
3.2
3.0
3.0
†
includes erythema, pain, bruising
Adverse Reactions in Seven Pooled 12-Week Controlled Trials
In seven pooled 12-week, double-blind, randomized, placebocontrolled trials, 993 patients received 140 mg of REPATHA
subcutaneously every 2 weeks and 1059 patients received 420 mg
of REPATHA subcutaneously monthly. The mean age was 57 years
(range: 18 to 80 years), 29% were older than 65 years, 49% women,
85% White, 5% Black, 9% Asian, and 5% Hispanic. Adverse reactions
reported in at least 1% of REPATHA-treated patients, and more
frequently than in placebo-treated patients, are shown in Table 2.
3.9
2.2
2.0
1.6
1.2
1.0
1.2
1.2
0.7
1.1
0.5
4.0
2.3
2.1
1.8
1.8
1.6
1.3
1.3
1.2
1.2
1.0
140 mg every 2 weeks and 420 mg once monthly combined
Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week
Trials and One 52-Week Trial)
The adverse reactions described below are from a pool of the 52week trial (Study 2) and seven 12-week trials. The mean and median
exposure durations of REPATHA in this pool of eight trials were 20
weeks and 12 weeks, respectively.
Local Injection Site Reactions
Injection site reactions occurred in 3.2% and 3.0% of REPATHAtreated and placebo-treated patients, respectively. The most
common injection site reactions were erythema, pain, and bruising.
The proportions of patients who discontinued treatment due to local
injection site reactions in REPATHA-treated patients and placebotreated patients were 0.1% and 0%, respectively.
Allergic Reactions
Allergic reactions occurred in 5.1% and 4.7% of REPATHA-treated
and placebo-treated patients, respectively. The most common allergic
reactions were rash (1.0% versus 0.5% for REPATHA and placebo,
respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus
0.2%), and urticaria (0.4% versus 0.1%).
Neurocognitive Events
In placebo-controlled trials, neurocognitive events were reported in less
than or equal to 0.2% in REPATHA-treated and placebo-treated patients.
Low LDL-C Levels
In a pool of placebo- and active-controlled trials, as well as open-label
extension studies that followed them, a total of 1988 patients treated
with REPATHA had at least one LDL-C value < 25 mg/dL. Changes to
background lipid-altering therapy were not made in response to low
LDL-C values, and REPATHA dosing was not modified or interrupted
on this basis. Although adverse consequences of very low LDL-C were
not identified in these trials, the long-term effects of very low levels of
LDL-C induced by REPATHA are unknown.
Musculoskeletal Events
Musculoskeletal adverse reactions were reported in 14.3% of REPATHAtreated patients and 12.8% of placebo-treated patients. The most common
adverse reactions that occurred at a rate greater than placebo were
back pain (3.2% versus 2.9% for REPATHA and placebo, respectively),
arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia
In a 12-week, double-blind, randomized, placebo-controlled trial
of 49 patients with HoFH (Study 4), 33 patients received 420 mg of
REPATHA subcutaneously once monthly [see Clinical Studies (14.3)].
The mean age was 31 years (range: 13 to 57 years), 49% were women,
90% White, 4% Asian, and 6% other. The adverse reactions that
occurred in at least two (6.1%) REPATHA-treated patients, and more
frequently than in placebo-treated patients, included:
• Upper respiratory tract infection (9.1% versus 6.3%)
• Influenza (9.1% versus 0%)
• Gastroenteritis (6.1% versus 0%)
• Nasopharyngitis (6.1% versus 0%)
6.2 Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity.
The immunogenicity of REPATHA has been evaluated using an
electrochemiluminescent bridging screening immunoassay for the
detection of binding anti-drug antibodies. For patients whose sera
tested positive in the screening immunoassay, an in vitro biological
assay was performed to detect neutralizing antibodies.
In a pool of placebo- and active-controlled clinical trials, 0.1% of
patients treated with at least one dose of REPATHA tested positive for
binding antibody development. Patients whose sera tested positive for
binding antibodies were further evaluated for neutralizing antibodies;
none of the patients tested positive for neutralizing antibodies.
There was no evidence that the presence of anti-drug binding
antibodies impacted the pharmacokinetic profile, clinical response,
or safety of REPATHA, but the long-term consequences of continuing
REPATHA treatment in the presence of anti-drug binding antibodies
are unknown.
The detection of antibody formation is highly dependent on the
sensitivity and specificity of the assay. Additionally, the observed
incidence of 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 REPATHA with the incidence of antibodies to other
products may be misleading.
8. USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no data available on use of REPATHA in pregnant women
to inform a drug-associated risk. In animal reproduction studies,
there were no effects on pregnancy or neonatal/infant development
when monkeys were subcutaneously administered evolocumab from
organogenesis through parturition at dose exposures up to 12 times
the exposure at the maximum recommended human dose of 420 mg
every month. In a similar study with another drug in the PCSK9 inhibitor
antibody class, humoral immune suppression was observed in infant
monkeys exposed to that drug in utero at all doses. The exposures
where immune suppression occurred in infant monkeys were greater
than those expected clinically. No assessment for immune suppression
†
© 2015 Amgen Inc. All rights reserved. Not for reproduction. v2 09/15
This Brief Summary is based on the REPATHA™ Prescribing Information
v2, 09/15
REPATHA™ (evolocumab)
Manufactured by: Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320-1799
U.S. License Number 1080
Patent: http://pat.amgen.com/repatha/
T:10.875 in
REPATHA
(N=599)
%
REPATHA†
(N=2052)
%
B:11.125 in
Nasopharyngitis
Upper respiratory tract infection
Influenza
Back pain
Injection site reactions†
Cough
Urinary tract infection
Sinusitis
Headache
Myalgia
Dizziness
Musculoskeletal pain
Hypertension
Diarrhea
Gastroenteritis
Placebo
(N=302)
%
Nasopharyngitis
Back pain
Upper respiratory tract infection
Arthralgia
Nausea
Fatigue
Muscle spasms
Urinary tract infection
Cough
Influenza
Contusion
Placebo
(N=1224)
%
was conducted with evolocumab in infant monkeys. Measurable
evolocumab serum concentrations were observed in the infant
monkeys at birth at comparable levels to maternal serum, indicating
that evolocumab, like other IgG antibodies, crosses the placental barrier.
FDA’s experience with monoclonal antibodies in humans indicates that
they are unlikely to cross the placenta in the first trimester; however, they
are likely to cross the placenta in increasing amounts in the second and
third trimester. Consider the benefits and risks of REPATHA and possible
risks to the fetus before prescribing REPATHA to pregnant women.
In the U.S. general population, the estimated background risk of major
birth defects and miscarriage in clinically recognized pregnancies is
2-4% and 15-20%, respectively.
Data
Animal Data
In cynomolgus monkeys, no effects on embryo-fetal or postnatal
development (up to 6 months of age) were observed when evolocumab
was dosed during organogenesis to parturition at 50 mg/kg once every
2 weeks by the subcutaneous route at exposures 30- and 12-fold the
recommended human doses of 140 mg every 2 weeks and 420 mg once
monthly, respectively, based on plasma AUC. No test of humoral immunity
in infant monkeys was conducted with evolocumab.
8.2 Lactation
Risk Summary
There is no information regarding the presence of evolocumab in
human milk, the effects on the breastfed infant, or the effects on milk
production. The development and health benefits of breastfeeding should
be considered along with the mother’s clinical need for REPATHA and any
potential adverse effects on the breastfed infant from REPATHA or from
the underlying maternal condition. Human IgG is present in human milk,
but published data suggest that breast milk antibodies do not enter the
neonatal and infant circulation in substantial amounts.
8.4 Pediatric Use
The safety and effectiveness of REPATHA in combination with diet and
other LDL-C-lowering therapies in adolescents with HoFH who require
additional lowering of LDL-C were established based on data from a
12-week, placebo-controlled trial that included 10 adolescents (ages 13
to 17 years old) with HoFH [see Clinical Studies (14.3)]. In this trial, 7
adolescents received REPATHA 420 mg subcutaneously once monthly
and 3 adolescents received placebo. The effect of REPATHA on LDL-C
was generally similar to that observed among adult patients with HoFH.
Including experience from open-label, uncontrolled studies, a total of 14
adolescents with HoFH have been treated with REPATHA, with a median
exposure duration of 9 months. The safety profile of REPATHA in these
adolescents was similar to that described for adult patients with HoFH.
The safety and effectiveness of REPATHA have not been established in
pediatric patients with HoFH who are younger than 13 years old.
The safety and effectiveness of REPATHA have not been established in
pediatric patients with primary hyperlipidemia or HeFH.
8.5 Geriatric Use
In controlled studies, 1420 patients treated with REPATHA were ≥ 65
years old and 171 were ≥ 75 years old. No overall differences in safety
or effectiveness were observed between these patients and younger
patients, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but
greater sensiti vity of some older individuals cannot be ruled out.
8.6 Renal Impairment
No dose adjustment is needed in patients with mild to moderate
renal impairment. No data are available in patients with severe renal
impairment [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dose adjustment is needed in patients with mild to moderate hepatic
impairment (Child-Pugh A or B). No data are available in patients with
severe hepatic impairment [see Clinical Pharmacology (12.3)].
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic potential of evolocumab was evaluated in a lifetime
study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg
administered every 2 weeks. There were no evolocumab-related tumors
at the highest dose at systemic exposures up to 38- and 15-fold the
recommended human doses of 140 mg every 2 weeks and 420 mg once
monthly, respectively, based on plasma AUC. The mutagenic potential of
evolocumab has not been evaluated; however, monoclonal antibodies are
not expected to alter DNA or chromosomes.
There were no adverse effects on fertility (including estrous cycling,
sperm analysis, mating performance, and embryonic development)
at the highest dose in a fertility and early embryonic developmental
toxicology study in hamsters when evolocumab was subcutaneously
administered at 10, 30, and 100 mg/kg every 2 weeks. The highest
dose tested corresponds to systemic exposures up to 30- and 12-fold
the recommended human doses of 140 mg every 2 weeks and 420
mg once monthly, respectively, based on plasma AUC. In addition, there
were no adverse evolocumab-related effects on surrogate markers of
fertility (reproductive organ histopathology, menstrual cycling, or sperm
parameters) in a 6-month chronic toxicology study in sexually mature
monkeys subcutaneously administered evolocumab at 3, 30, and 300
mg/kg once weekly. The highest dose tested corresponds to 744- and
300-fold the recommended human doses of 140 mg every 2 weeks and
420 mg once monthly, respectively, based on plasma AUC.
13.2 Animal Toxicology and/or Pharmacology
During a 3-month toxicology study of 10 and 100 mg/kg once every 2
weeks evolocumab in combination with 5 mg/kg once daily rosuvastatin
in adult monkeys, there were no effects of evolocumab on the humoral
immune response to keyhole limpet hemocyanin (KLH) after 1 to 2
months exposure. The highest dose tested corresponds to exposures
54- and 21-fold higher than the recommended human doses of 140
mg every 2 weeks and 420 mg once monthly, respectively, based on
plasma AUC. Similarly, there were no effects of evolocumab on the
humoral immune response to KLH (after 3 to 4 months exposure) in a
6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg
once weekly evolocumab corresponding to exposures 744- and 300-fold
greater than the recommended human doses of 140 mg every 2 weeks
and 420 mg once monthly, respectively, based on plasma AUC.
S:10 in
1. INDICATIONS AND USAGE
1.1 Primary Hyperlipidemia
REPATHA is indicated as an adjunct to diet and maximally tolerated
statin therapy for the treatment of adults with heterozygous familial
hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular
disease (CVD), who require additional lowering of low density lipoprotein
cholesterol (LDL-C).
1.2 Homozygous Familial Hypercholesterolemia
REPATHA is indicated as an adjunct to diet and other LDL-lowering
therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of
patients with homozygous familial hypercholesterolemia (HoFH) who
require additional lowering of LDL-C.
1.3 Limitations of Use
The effect of REPATHA on cardiovascular morbidity and mortality has
not been determined.
4. CONTRAINDICATIONS
REPATHA is contraindicated in patients with a history of a serious
hypersensitivity reaction to REPATHA [see Warnings and Precautions (5.1)].
5. WARNINGS AND PRECAUTIONS
5.1 Allergic Reactions
Hypersensitivity reactions (e.g., rash, urticaria) have been reported
in patients treated with REPATHA, including some that led to
discontinuation of therapy. If signs or symptoms of serious allergic
reactions occur, discontinue treatment with REPATHA, treat according
to the standard of care, and monitor until signs and symptoms resolve.
6. ADVERSE REACTIONS
The following adverse reactions are also discussed in other sections
of the label:
• Allergic Reactions [see Warnings and Precautions (5.1)]
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 clinical practice.
Adverse Reactions in Patients with Primary Hyperlipidemia and in
Patients with Heterozygous Familial Hypercholesterolemia
REPATHA is not indicated for use in patients without familial hypercholesterolemia or atherosclerotic CVD [see Indications and Usage (1.1)].
The data described below reflect exposure to REPATHA in 8 placebocontrolled trials that included 2651 patients treated with REPATHA,
including 557 exposed for 6 months and 515 exposed for 1 year (median
treatment duration of 12 weeks). The mean age of the population
was 57 years, 49% of the population were women, 85% White,
6% Black, 8% Asians, and 2% other races.
Adverse Reactions in a 52-Week Controlled Trial
In a 52-week, double-blind, randomized, placebo-controlled trial
(Study 2), 599 patients received 420 mg of REPATHA subcutaneously
once monthly [see Clinical Studies (14.1)]. The mean age was 56 years
(range: 22 to 75 years), 23% were older than 65 years, 52% women,
80% White, 8% Black, 6% Asian, and 6% Hispanic. Adverse reactions
reported in at least 3% of REPATHA-treated patients, and more
frequently than in placebo-treated patients in Study 2, are shown in
Table 1. Adverse reactions led to discontinuation of treatment in 2.2%
of REPATHA-treated patients and 1% of placebo-treated patients.
The most common adverse reaction that led to REPATHA treatment
discontinuation and occurred at a ra te greater than placebo was
myalgia (0.3% versus 0% for REPATHA and placebo, respectively).
Table 1. Adverse Reactions Occurring in Greater than or Equal to
3% of REPATHA-treated Patients and More Frequently than with
Placebo in Study 2
Table 2. Adverse Reactions Occurring in Greater than 1% of
REPATHA-treated Patients and More Frequently than with
Placebo in Pooled 12-Week Studies