CardioSource WorldNews | Page 12
REPATHA® (evolocumab)
BRIEF SUMMARY OF PRESCRIBING INFORMATION
Please see package insert for full Prescribing Information
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 placebo-controlled
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 REPATHAtreated 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 rate 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
Nasopharyngitis
Upper respiratory tract infection
Influenza
Back pai n
Injection site reactions†
Cough
Urinary tract infection
Sinusitis
Headache
Myalgia
Dizziness
Musculoskeletal pain
Hypertension
Diarrhea
Gastroenteritis
Placebo
(N=302)
%
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
REPATHA
(N=599)
%
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, placebo-controlled 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.
Table 2. Adverse Reactions Occurring in Greater than 1% of REPATHA-treated
Patients and More Frequently than with Placebo in Pooled 12-Week Studies
Placebo
REPATHA†
(N=1224)
(N=2052)
%
%
Nasopharyngitis
3.9
4.0
Back pain
2.2
2.3
Upper respiratory tract infection
2.0
2.1
Arthralgia
1.6
1.8
Nausea
1.2
1.8
Fatigue
1.0
1.6
Muscle spasms
1.2
1.3
Urinary tract infection
1.2
1.3
Cough
0.7
1.2
Influenza
1.1
1.2
Contusion
0.5
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 52-week 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 REPATHA-treated
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 placebo-treated patients were 0.1% and 0%, respectively.
Allergic Reactions
Allergic reactions occurred in 5.1% and 4.7% of REPATHA-treated and placebotreated 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 h uman 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 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, placebocontrolled 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 sensitivity 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 evolocumabrelated 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.
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/
© 2015 Amgen Inc. All rights reserved. Not for reproduction. v2 09/15