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Evolocumab side effects: Repatha® (evolocumab) Side Effects & Safety Information

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Repatha® (evolocumab) Side Effects & Safety Information

Do not use Repatha® if you are allergic to evolocumab or to any of the ingredients in Repatha®.

Before you start using Repatha®, tell your healthcare provider about all your medical conditions, including if you are allergic to rubber or latex, are pregnant or plan to become pregnant, or are breastfeeding or plan to breastfeed. The needle covers on the single-dose prefilled syringes and the inside of the needle caps on the single-dose prefilled SureClick® autoinjectors contain dry natural rubber. The single-dose Pushtronex® system (on-body infusor with prefilled cartridge) is not made with natural rubber latex.

Tell your healthcare provider or pharmacist about any prescription and over-the-counter medicines, vitamins, or herbal supplements you take.

What are the possible side effects of Repatha®?

Repatha® can cause serious side effects including, serious allergic reactions. Stop taking Repatha® and call your healthcare provider or seek emergency help right away if you have any of these symptoms: trouble breathing or swallowing, raised bumps (hives), rash or itching, swelling of the face, lips, tongue, throat or arms.

The most common side effects of Repatha® include: runny nose, sore throat, symptoms of the common cold, flu or flu-like symptoms, back pain, high blood sugar levels (diabetes), and redness, pain, or bruising at the injection site.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Repatha®. Ask your healthcare provider or pharmacist for more information. Call your healthcare provider for medical advice about side effects.

Evolocumab (Subcutaneous Route) Side Effects

Side Effects

Drug information provided by: IBM Micromedex

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Incidence not known

  1. Difficulty with breathing or swallowing

  2. fever

  3. hives, itching, or rash

  4. large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or genitals

  5. nausea

  6. reddening of the skin, especially around the ears

  7. swelling of the eyes, face, or inside of the nose

  8. unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  1. Back pain

  2. bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site

  3. blurred vision

  4. body aches or pain

  5. chills

  6. cough

  7. dry mouth

  8. ear congestion

  9. flushed, dry skin

  10. fruit-like breath odor

  11. general feeling of discomfort or illness

  12. headache

  13. loss of voice

  14. muscle aches

  15. sneezing

  16. sore throat

  17. stomach ache

  18. stuffy or runny nose

  19. sweating

  20. trouble breathing

  21. unexplained weight loss

  22. vomiting
Less common

  1. Bladder pain

  2. bloody or cloudy urine

  3. diarrhea

  4. difficult, burning, or painful urination

  5. difficulty with moving

  6. dizziness

  7. frequent urge to urinate

  8. loss of appetite

  9. lower back or side pain

  10. muscle or joint pain

  11. muscle stiffness

  12. nervousness

  13. pain or tenderness around the eyes and cheekbones

  14. pounding in the ears

  15. slow or fast heartbeat

  16. swollen joints

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

 

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Portions of this document last updated: Nov. 01, 2021

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.

Adverse Events Associated With PCSK9 Inhibitors: A Real‐World Experience

Clin Pharmacol Ther. 2019 Feb; 105(2): 496–504.

,
1
,
2
,
3
,
3
,
1
and
3

Muhammed T. Gürgöze

1
Erasmus MC,
University Medical Centre Rotterdam,
Department of Cardiology,
Rotterdam,
The Netherlands,

Annemarie H.G. Muller‐Hansma

2
Netherlands Pharmacovigilance Centre Lareb,
‘s‐Hertogenbosch,
The Netherlands,

Michelle M. Schreuder

3
Erasmus MC,
University Medical Centre Rotterdam,
Department of Internal Medicine,
Rotterdam,
The Netherlands,

Annette M.H. Galema‐Boers

3
Erasmus MC,
University Medical Centre Rotterdam,
Department of Internal Medicine,
Rotterdam,
The Netherlands,

Eric Boersma

1
Erasmus MC,
University Medical Centre Rotterdam,
Department of Cardiology,
Rotterdam,
The Netherlands,

Jeanine E.

Roeters van Lennep

3
Erasmus MC,
University Medical Centre Rotterdam,
Department of Internal Medicine,
Rotterdam,
The Netherlands,

1
Erasmus MC,
University Medical Centre Rotterdam,
Department of Cardiology,
Rotterdam,
The Netherlands,

2
Netherlands Pharmacovigilance Centre Lareb,
‘s‐Hertogenbosch,
The Netherlands,

3
Erasmus MC,
University Medical Centre Rotterdam,
Department of Internal Medicine,
Rotterdam,
The Netherlands,

Corresponding author.

Received 2018 Jun 14; Accepted 2018 Jul 19.

Copyright © 2018 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. This article has been cited by other articles in PMC.

Supplementary Materials
Figure S1. Flowchart of patient inclusion and exclusion for the Lareb database.

Table S1. Baseline patient characteristics for EMC database split by drug.

Table S2. Patient characteristics for Lareb database split by drug.

Table S3. Patient characteristics for VigiLyze database split by drug.

Table S4. AEs split by PCSK9 inhibitor for EMC database.

Table S5. Adverse events split by PCSK9 inhibitor for Lareb database.

Table S6. Adverse events split by PCSK9 inhibitor for VigiLyze database.

Table S7. Drug discontinuation.

GUID: C095BDA2-2AF3-4464-9F2E-B8082FB96F88

Abstract

In randomized clinical trials (RCTs) proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors showed a favorable safety profile, however, “real‐world” data on adverse events (AEs) is scarce. Three datasets, a hospital registry (n = 164), and two Pharmacovigilance databases, Lareb (n = 149) and VigiLyze (n = 15,554), reporting AEs attributed to PCSK9 inhibitors (alirocumab or evolocumab) prescribed in clinical practice were analyzed. In the hospital registry, 41.5% of the patients reported any AE, most often injection‐site reactions (33.8%) and influenza‐like illness (27.9%). Twelve patients (7%) discontinued PCSK9 inhibitor treatment. Most common AE reported in the Lareb and VigiLyze database was myalgia (12.8% and 8.3%, respectively). No clinically relevant differences in gender or between drugs were observed. No specific subgroup of patients could be identified at risk of developing AEs. During follow‐up, AEs resolved in most patients (71.1%). In a real‐world setting, PCSK9 inhibitors are well tolerated with an overall safety profile comparable to RCTs.

Study Highlights

☑ RCTs assessing clinical effects of PCSK9 inhibitors alirocumab and evolocumab showed a favorable safety profile with a low rate of AEs. Most common reported AEs in RCTs are nasopharyngitis, upper respiratory tract infection, influenza‐like illness, myalgia, back pain, arthralgia, headache, and ISRs.

☑ What are (the most common) AEs associated with the use of the PCSK9 inhibitors alirocumab and evolocumab prescribed in a real‐world setting?

☑ In a real‐world setting, PCSK9 inhibitors are well tolerated with an overall safety profile comparable to RCTs. Most common AEs are influenza‐like illness, nasopharyngitis, myalgia, and ISRs, which often resolve over time. No clinical relevant differences in gender or between drugs were observed. No specific subgroup of patients could be identified at risk of developing AEs.

☑ Safety monitoring of PCSK9 inhibitors is indispensable to assess long‐term effects and reactions occurring in specific subgroups of patients. Therefore, healthcare providers should contribute to report to pharmacovigilance centers.

High low‐density lipoprotein‐cholesterol (LDL‐C) levels are associated with risk of cardiovascular disease (CVD). 1 Lipid‐lowering therapy (LLT), including statins and ezetimibe, proved to be very effective in lowering CVD events.2 Cardiovascular prevention guidelines provide recommendations for optimal LDL‐C levels for patients at high risk of CVD.3 However, despite maximum tolerated LLT, only a minority of these patients reach the desired LDL‐C targets.4

Proprotein convertase subtilisin/kexin 9 (PCSK9) has been identified as a new player within the lipid metabolism.5 PCSK9 binds to the LDL‐receptor and promotes its lysosomal degradation, hence increasing LDL‐C plasma levels.6 People with hereditary high PCSK9 levels have a higher risk of cardiovascular events, whereas the opposite is true for people with hereditary low PCSK9 compared to the general population.7

Monoclonal antibodies binding PCSK9 have been successfully developed as a new class of LLT.6 In 2015, two PCSK9 inhibitors (alirocumab and evolocumab) have been approved by the US Food and Drug Administration and European Medicines Agency. In multiple large randomized placebo‐controlled trials, PCSK9 inhibitors showed reductions of LDL‐C levels up to 60% and recently also a decrease in cardiovascular outcomes.8, 9

According to current literature, alirocumab and evolocumab have a favorable safety profile and are generally well tolerated.10 However, real‐word data on adverse events (AEs) of PCSK9 inhibitors prescribed outside clinical trials is scarce. At present, real‐world observational studies are considered indispensable to provide complementary information to randomized clinical trials (RCTs), especially about AEs, as these studies involve a large and diverse population of patients in a real‐world setting beyond the rather homogenous group of patients who participated in RCTs. This allows for detection of rare complications, long‐term effects, and reactions occurring in specific subgroups of patients.11

The aim of this study is to assess the main AEs reported by patients using PCSK9 inhibitors alirocumab and evolocumab in clinical practice.

Results

Baseline characteristics per database are shown in Table 
and Tables

S1–S3
for data on alirocumab and evolocumab separately.

Table 1

Characteristics EMC, n = 164a Lareb, n = 149 VigiLyze, n = 15,554
Age (year), median (IQR) 58 (48–65) 63 (56–69)
Age groups, n (%)
0–17 years 0 (0) 0 (0. 0) 8 (0.1) d
18–44 years 24 (15) 5 (3.4) 289 (1.9)
45–64 years 91 (56) 71 (47.7) 4,210 (27.1)
65–74 years 46 (28) 56 (37.6) 4,835 (31.1)
≥ 75 years 3 (2) 8 (5.4) 2,670 (17. 2)
Age unknown, n (%) 0 (0) 9 (6) c 3,542 (22.8)
Gender, n (%)
Male 90 (55) 70 (47) 5,975 (38.4)
Female 74 (45) 78 (52) 8,772 (56.4)
Unknown 0 (0) 1 (1) 807 (5. 2)
BMI (kg/m2), median (IQR) 27.4 (24.4–30.2)
Diabetes, n (%) 29 (18)
Hypertension, n (%) 75 (46)
Ever smoker, n (%) 78 (48)
Current smoker, n (%) 24 (15)
History of CVD, n (%) 108 (66)
Familial hypercholesterolemia, n (%) 148 (90)
Heterozygous 98 (60)
Homozygousb 7 (4)
Clinical 43 (26)
Lipid‐lowering therapy, n (%)
Statin use 100 (61)
High intensity 63 (38)
Moderate intensity 30 (18)
Low intensity 7 (4)
Ezetimibe 164 (100)
Ezetimibe monotherapy 64 (39)
LDL‐C (mmol/L), median (IQR) 4. 28 (3.34–5.14)

Erasmus Medical Centre hospital registry

Of the 183 patients registered in the database, 19 were excluded; 10 lacked follow‐up data, 8 participated in PCSK9 trials, and 1 patient had missing baseline data. Therefore, 164 patients were included in the current analysis (Table 
). The median age was 58 years (interquartile range (IQR) = 48–65 years), 55% were men. The majority of patients (90%) was diagnosed with familial hypercholesterolemia (FH). Sixty‐six percent of the patients had a history of CVD. All patients used LLT, however, more than a third of the patients (39%) used ezetimibe monotherapy because of statin intolerance. Baseline median LDL‐C was 4.28 mmol/l (166 mg/dL). Alirocumab and evolocumab were used by 49.4% and 50.6% of the patients, respectively. There was no difference between baseline characteristics of patients using alirocumab and evolocumab (Table

S1
).

Lareb database

Of the 152 patients in the database, 149 patients were included in the analysis (Table 
). Main reasons for exclusion were AEs not related to PCSK9 inhibitors (Figure

S1
). The median age was 63 years (IQR = 56–69 years) and 52% were women. Forty‐three patients used alirocumab and 110 evolocumab (Table

S2
). Age and gender distribution was similar between both groups.

VigiLyze database

The VigiLyze database contained 15,554 patients of AEs associated with PCSK9 inhibitors. Most patients (31.1%) were 65–74 years, 56.4% were women. A total of 4,650 patients used alirocumab and 10,931 evolocumab (Table

S3
). Age and gender distribution was similar between both groups.

Adverse events

Most common AEs are presented in Table 
and Tables

S4–S6
for data on alirocumab and evolocumab separately.

Table 2

Overall frequencies of adverse events for both PCSK9 inhibitors with gender differences

ERASMUS MC Total (n = 68a) OR (95% CI) male vs. female Lareb Total (n = 149) OR (95% CI) male vs. female VigiLyze Total (n = 15,554) OR (95% CI) male vs. female
Any TEAE, n (%) 68 (100. 0) 0.58 (0.31–1.09)b Any TEAE, n (%) 149 (100.0) Any TEAE, n (%) 15,554 (100.0)
1 event 37 (54.4) 1 event 51 (34.2)
2 events 21 (30. 9) 2 events 41 (27.5)
≥3 events 10 (14.7) ≥ 3 events 61 (38.3)
Events, median (IQR) 1.0 (1.0–2.0) Events, median (IQR) 2. 0 (1.0–3.0)
Total no. of TEAEs reported 116 Total no. of TEAEs reported 375 Total no. of TEAEs reported 29,956
TEAEs leading to discontinuation 11 (16.2) TEAEs leading to discontinuation 60 (40. 3) TEAEs leading to discontinuation N/A
TEAEs leading to death 0 (0.0) TEAEs leading to death 1 (0.7) TEAEs leading to death N/A
Most common (≥4%) TEAEs, n (%) Most common (≥4%) TEAEs, n (%) Most common (≥4%) TEAEs, n (%)
Influenza‐like illness 19 (27. 9) 0.56 (0.19–1.66) Myalgia 19 (12.8) 1.63 (0.62–4.32) Myalgia 1,287 (8.3) 1.11 (0.99–1.25)
Injection‐site hematoma 13 (19.1) 0.43 (0.12–1.56) Influenza like illness 14 (9.4) 2.15 (0.69–6.77) Drug dose omission 1,151 (7.4) 0.87 (0.770. 99)
Nasopharyngitis 11 (16.2) 0.52 (0.16–2.25) Fatigue 12 (8.1) 1.13 (0.35–3.67) Injection‐site pain 959 (6.2) 0.55 (0.480.65)
Abdominal discomfort 8 (11.8) 2.04 (0.45–9.31) Headache 12 (8.1) 0.20 (0.040.95) Influenza like illness 818 (5. 3) 1.06 (0.91–1.23)
Myalgia 7 (10.3) 0.41 (0.07–2.30) Arthralgia 10 (6.7) 1.73 (0.47–6.42) Back pain 816 (5.2) 0.95 (0.82–1.09)
Cognitive disorder 6 (8.8) 2.43 (0.41–14.25) Dyspnea 9 (6.0) 0.13 (0.02–1.04) Arthralgia 789 (5. 1) 1.01 (0.87–1.17)
Fatigue 6 (8.8) 2.43 (0.41–14.25) Nausea 9 (6.0) 0.54 (0.13–2.24) Fatigue 764 (4.9) 0.92 (0.79–1.06)
Headache 6 (8.8) 0.53 (0.09–3.13) Malaise 8 (5.4) 0.35 (0.07–1.81) Pain in extremity 755 (4.9) 0.77 (0.660.90)
Injection‐site pain 6 (8.8) 1.14 (0.21–6.08) Muscle spasms 8 (5.4) 0.65 (0.15–2.84) Muscle spasms 719 (4.6) 0.81 (0.690.95)
Injection‐site swelling 6 (8.8) 2.43 (0.41–14.25) Pain in extremity 8 (5.4) 0.35 (0.07–1.81) Pain 703 (4.5) 0.66 (0.560.78)
Rash 4 (5.9) 0.36 (0.04–3.60) Diarrhea 6 (4.0) 0.54 (0.10–3.07) Headache 651 (4.2) 0.72 (0.610.86)
Dizziness 6 (4.0) 0.54 (0.10–3.07)
Injection‐site reactions, n (%) 23(33.8) 0.62 (0.22–1.71) Injection‐site reactions, n (%) 3 (2.0) 2.27 (0.20–25.53) Injection‐site reactions (≥ 1.0%), n (%) 3,291 (21.2) 0.55 (0.500.60)
Injection‐site hematoma 13 (19.1) 0.43 (0.12–1.56) Injection‐site hematoma 1 (0.7) Injection‐site pain 959 (6.2) 0.55 (0.480.65)
Injection‐site pain 6 (8.8) 1.14 (0.21–6.08) Injection‐site hemorrhage 1 (0.7) Injection‐site bruising 526 (3.4) 0.56 (0.460.67)
Injection‐site swelling 6 (8.8) 2.43 (0.41–14.25) Injection‐site swelling 1 (0.7) Injection‐site hemorrhage 373 (2.4) 0.72 (0.580.89)
Injection‐site erythema 2 (2.9) 1.13 (0.07–18.8) Injection‐site erythema 268 (1.7) 0.49 (0.370.65)
Injection‐site infection 1 (1.5) Injection‐site swelling 229 (1.5) 0.61 (0.450.81)
Injection‐site pruritus 152 (1.0) 0.42 (0.290.62)

Erasmus Medical Centre hospital registry

At first follow‐up, 68 patients (41.5%) reported ≥1 AE. A total of 116 events were reported with most patients reporting one event (54.4%; Table 
). Most common AEs were influenza‐like illness (27.9%), nasopharyngitis (16.2%), abdominal discomfort (11.8%), and myalgia (10.3%). Twenty‐three patients (33.8%) reported ≥1 injection‐site reactions (ISRs), most commonly injection‐site hematoma. No significant gender differences in AEs were observed.

The percentage of patients reporting AEs were similar for the alirocumab group and the evolocumab group (43.2% and 39.8%, respectively; Table

S4
). Influenza‐like illness was the most reported AE for both alirocumab and evolocumab (28.6% and 27.3%, respectively). The AE profile did not significantly differ between alirocumab and evolocumab.

Lareb database

A total of 375 events were reported by 149 patients of whom 38% reported ≥3 AEs (Table 
). The most common reported AEs were myalgia (12.8%), influenza‐like illness (9.4%), fatigue (8.1%), and headache (8.1%). ISRs were infrequently reported by 2.0% of the patients.

No significant differences in gender were observed, except for men reporting headache less frequently than women (odds ratio (OR) = 0.20, 95% confidence interval (CI) = 0.04–0.95; P = 0.042). The overall AE profile for alirocumab and evolocumab was similar (Table

S5
).

VigiLyze database

A total of 29,956 AEs were collected, reported by 15,554 patients (Table 
). Most common documented AEs were myalgia (8.3%), influenza‐like illness (5.3%), back pain (5.2%), and arthralgia (5.1%). ISRs were frequently reported (21.2%), and were most often injection‐site pain (6.2%). Most AEs, including pain in extremity (< 0.001), muscle spasms (= 0.010), pain (< 0.001), headache (< 0.001), diarrhea (= 0.002), and nausea (< 0.001), and the overall total of ISRs (< 0.001) were significantly more often reported by women than men. Drug dose omission (7.4%) was not considered a drug‐related AE that was relevant for this study.

Myalgia was the most reported AE for both alirocumab and evolocumab (9.4% and 7.8%, respectively; Table

S6
). Back pain was reported nearly three times as frequent for evolocumab (6.4%) compared to alirocumab (2.4%). ISRs were reported at a similar rate (21.6% vs. 21.3%).

Predictors and time course of AEs

In the Erasmus Medical Centre (EMC) hospital registry, we analyzed for possible predictors of AEs, such as gender, statin use, or a very low LDL‐C. Univariate logistic regression analyses did not show any significant predictors for AEs, in particular very low LDL‐C and statin intolerance (Table 
).

Table 3

Univariate logistic regression of possible predictors of adverse events at follow‐up 1

OR (95% CI) P value
Age 0.98 (0.96–1.01) 0.202
Gender (male) 0.58 (0.31–1.09) 0.091
BMI 0.99 (0.92–1.07) 0.740
Hypertension (yes) 1.34 (0.72–2.50) 0.356
Current smoker (yes) 0.63 (0.25–1.57) 0.320
Diabetes (yes) 1.00 (0.44–2.25) 0.992
History of CVD (yes) 1.44 (0.74–2.80) 0.283
FH (yes) 0.90 (0.32–2.56) 0.845
FH – Genetic mutation (yes) 1.46 (0.70–3.04) 0.318
Statin use (yes) 1.18 (0.62–2.23) 0.618
Statin intensity (high vs. low + mod) 1.68 (0.73–3.88) 0.225
Statin intolerance 0.85 (0.45–1.61) 0.618
LDL‐C at baseline 1.05 (0.88–1.24) 0.590
LDL‐C at follow‐up 1 1.14 (0.94–1.38) 0.187
LDL‐C <0.5 mmol/La at follow‐up 1 1.83 (0.47–7.07) 0.383
PCSK9 inhibitor (EVO vs. ALI) 0.87 (0.47–1.62) 0.654

To study the time course of reported AEs we compared the reported AEs at the first, second, and third follow‐up visits (Table 
). Of the 164 patients with a first follow‐up visit, 131 had a second follow‐up visit and 94 had a third follow‐up visit. Nearly 60% of patients who reported AEs at the first follow‐up visit also had AEs at the second follow‐up visit. Notably, the majority (74%) of these patients reported different AEs at the first and second follow‐up visits. For 40.4% of the patients with AEs at the first follow‐up visit, AEs resolved at the second follow‐up. However, 22.8% of the patients without AEs at the first follow‐up developed new AEs at the second follow‐up. Compared to the first follow‐up visit, AEs resolved in 71.1% at the third follow‐up.

Table 4

Comparison of adverse events occurrence at follow‐up

Follow‐up 2 (n = 131) Follow‐up 3 (n = 94)
AEs No AEs AEs No AEs
Follow‐up 1
AEs 31
59.6%
21
40.4%
11
28.9%
27
71.1%
No AEs 18
22.8%
61
77.2%
7
12.5%
49
87.5%
Follow‐up 2
AEs 1133.3% 22
66.7%
No AEs 711.5% 54
88.5%

Drug discontinuation

In the EMC hospital registry, 12 patients (7%), 5 patients using alirocumab and 7 evolocumab, discontinued PCSK9 inhibitor treatment; 11 because of AEs and 1 due to nonresponse. The majority of patients (67%) who stopped treatment were women and 42% reported ≥3 events. Twenty‐four AEs were reported by 11 patients, which were most often influenza‐like illness (50%), cognitive disorders (25%), abdominal discomfort (17%), fatigue (17%), and malaise (17%; Table

S7
). ISRs did not lead to discontinuation of drug therapy. Notably, most patients with these AEs continued treatment.

In the Lareb database, 60 patients (40%) discontinued treatment due to AEs; 12 patients (20%) were using alirocumab and 48 patients (80%) evolocumab. In line with the hospital registry, most patients discontinued treatment due to ≥3 AEs (57%) and ISRs were not associated with discontinuation (Table

S7
). For alirocumab, discontinuation was higher in women compared to men (67% vs. 33%), whereas the women to men ratio was similar for those who stopped evolocumab treatment. The main reason for drug discontinuation was myalgia; in patients with myalgia 100% were alirocumab users and 70% of evolocumab users discontinued therapy (Figure 
).

Drug action taken for alirocumab and evolocumab in Lareb database. Drug action taken per reported adverse event (AE) by patients who discontinued alirocumab (left) and evolocumab (right) in the Lareb database compared to patients who continued or for whom drug action was unknown. Axis shows number of patients who reported a specific AE. AEs with a frequency of n = 1 have been excluded for evolocumab to allow for better overview and visualization of the most common AEs.

Discussion

In this analysis, based on a hospital registry and two pharmacovigilance databases, the most reported AEs associated with PCSK9 inhibitors prescribed in a clinical setting were influenza‐like illness, nasopharyngitis, myalgia, and ISRs. There were no significant differences between alirocumab and evolocumab or between both genders. The AEs were usually mild and most AEs resolved during follow‐up. The rate of drug discontinuation was infrequent. No specific category of patients could be identified at increased risk of developing AEs.

Pharmacovigilance databases in general contain fewer reports of nonserious AEs or AEs not associated with drug discontinuation because of the threshold to report. Furthermore, it is known that women are at higher risk of developing AEs12 and more often report to pharmacovigilance centers compared to men.13 In our study, we found that women represented 52% of Lareb and 56% of VigiLyze reports. In the Netherlands, 42% of all patients using PCSK9 inhibitors were women14 leading to an AE report ratio of 1.23 supporting that women report AEs more often than men. This is in line with the women to men ratio of AE reports of 1.18 observed in the hospital registry.

RCTs assessing clinical effects of PCSK9 inhibitors showed a favorable safety profile with a low rate of AEs. The most common reported AEs are nasopharyngitis, upper respiratory tract infection, influenza‐like illness, myalgia, back pain, arthralgia, headache, and ISRs.10, 15, 16 Despite these findings, the application of PCSK9 inhibitors might be limited by their high costs, even in patients with FH. Hence, in daily clinical practice, cost and benefit need to be weighed against potential AEs.10, 15, 16Although meta‐analyses of published RCTs showed no significant difference in (serious) AE occurrence between patients receiving PCSK9 inhibitors and control,10, 17, 18 real‐world data are limited. Five studies published data of AEs associated with PCSK9 inhibitors in a limited number of patients.19, 20, 21, 22, 23 These previous studies described a similar set of AEs associated with PCSK9 inhibitors in 15–39% of the patients. The method of acquisition of AEs was often not described in detail. Only Saborowski et al.23 indicated that AEs were acquired by self‐reported questionnaires available in 31 of 38 patients (82%). We observed a higher (41.5%) incidence of AEs, which might be explained by the fact that patients were systematically questioned about AEs specifically attributed to PCSK9 inhibitors at every visit.

AEs related to monoclonal antibodies (mAbs) can be distinguished in nonspecific AEs and AEs specifically related to the mAb target, for example, infections with infliximab due to reduced activity of immune cells.24 The use of mAbs can lead to an immune response and even immunogenicity such as the development of neutralizing antibodies, depending on the type of mAb.24 The effect of a mAb on the immune system can range from immune suppression to immune stimulation leading to a wide variety of AEs.25 The cytokine‐mediated type alpha immune response is likely to be the main mechanism for common AEs associated with mAbs, such as flu‐like symptoms and ISRs.26

Alirocumab and evolocumab are fully humanized, which substantially reduces the risk of immunogenicity.24 The use of PCSK9 inhibitors is not related to target‐specific AEs. Very low LDL‐C levels achieved with PCSK9 inhibitors were not significantly associated with an increase in overall AE rates27, 28 or neurocognitive AEs.29, 30 Moreover, levels of vitamin E, steroid, or gonadal hormones were not affected in patients using PCSK9 inhibitors even at very low LDL‐C levels of <0.4 mmol/L (15 mg/dL).31

In RCTs, among the most reported AEs were nasopharyngitis (5.9–12.2%) and influenza (2.1–7.3%) in patients randomized to PCSK9 inhibitors.10, 15, 16 In the EMC registry, influenza‐like illness and nasopharyngitis were reported by 27.9% and 16.2%, respectively, and often resolved during follow‐up. Influenza‐like illness was also among the most frequent reported reactions in both the Lareb and VigiLyze databases.

ISRs were reported by 3.1–7.4% of patients randomized to PCSK9 inhibitors and in general occurred more often in patients randomized to a PCSK9 inhibitor compared to placebo.10, 15, 16 Overall, ISRs in RCTs were mild and transient and did not lead to drug discontinuation. In the EMC registry, ISRs were reported more frequently (33.8%) compared to RCTs, and were also mild and did not lead to drug discontinuation. Remarkably, ISRs were reported much more frequently in the VigiLyze database than in the Lareb database, which might be explained by differences in the types of information source between different countries.

In RCTs, myalgia was reported by 3.5–7.2% of patients randomized to a PCSK9 inhibitor.10, 15, 16 No significant differences were observed in myalgia between PCSK9 inhibitor and comparator arm.10, 17, 18 In the EMC hospital registry, myalgia was reported more frequently, whereas in the Lareb and the VigiLyze databases it was the most commonly reported AE. In the Lareb database, myalgia was a major reason for drug discontinuation. The number of reports in these databases reflects the reporting behavior and not incidence on a suspected AE. We do not have a conclusive explanation for the differences concerning myalgia between the RCTs and the hospital registry. A possible pathogenic mechanism of the development of myalgia as a result of the use of a PCSK9 inhibitor is unclear.

Two meta‐analyses showed that the use of PCSK9 inhibitors was associated with a significantly increased incidence of neurocognitive AEs compared to controls.32, 33 These results raised initial concern about the effect of PCSK9 inhibitors and led to a recommendation of the US Food and Drug Administration in 2014 to perform a long‐term trial prospectively evaluating neurocognitive function.34 The evaluating PCSK9 binding antibody influence on cognitive health in high cardiovascular risk subjects (EBBINGHAUS) study prospectively assessed cognitive function using formal tests and showed no effect on cognitive function in patients randomized to evolocumab compared to placebo.29 Moreover, no significant differences in neurocognitive AE rates were found between alirocumab vs. controls.30 Finally, a recent meta‐analysis, including a larger number of trials, showed no significant differences between the PCSK9 inhibitor and the control arm on neurocognitive outcomes.

In our study, cognitive disorders were reported more frequently (3.7%) than in RCTs and were one of the main reasons for drug discontinuation. An explanation could be that, in contrast to the placebo‐controlled trials, patients were unblinded to treatment and were aware of possible negative cognitive effects attributed to PCSK9 inhibitors via the media. Cognitive AEs reported were mainly mental dullness and forgetfulness and were nonspecific. No formal screening tools have been used in these patients.

Until now, it is not known whether the reported AEs are caused by the PCSK9 inhibition or are specific for the monoclonal antibody that is administered. A novel PCSK9‐based therapy is inclisiran, a small interfering RNA that inhibits translation of the PCSK9 protein. A phase II trial showed a maximum LDL‐C decrease of 41.9% after a single‐dose of 500 mg and 52.6% after two doses of 500 mg.35 The most common AEs of inclisiran were comparable to PCSK9 mAbs, namely myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea, and dizziness. The overall AE rate in the patients who received inclisiran was similar to the patients who received placebo.10, 15, 35

To our knowledge, this is the largest in‐depth study of AEs of PCSK9 inhibitors prescribed in a clinical setting to date. Our study has several strengths. First, in the EMC hospital registry, the treating healthcare professionals enquired about AEs at every visit and only AEs considered to be directly related to the use of the PCSK9 inhibitor were included. Therefore, we consider that reporting bias is prevented as much as possible. We provide data up to a follow‐up duration of 42 weeks, which provides insight on how AEs develop over time. As we combined different data sources utilizing different methods of AE monitoring, a complete overview of possible AEs is provided. General limitations of using real‐world data, such as selection bias, confounding, the lack of a control group, and variable physician‐scheduled appointments, also apply for our study.11 Specific limitations are that the power of the EMC hospital registry was too low to detect significant differences in AEs between genders. A limitation of the Lareb and VigiLyze data was that the amount of available information varied between cases. Moreover, except for the VigiLyze data, this is a single‐country study and experience with these agents is limited. In conclusion, in a real‐world setting, PCSK9 inhibitors are well tolerated. Most common AEs are influenza‐like illness, nasopharyngitis, myalgia, and ISRs, which often resolve over time. ISRs are mild and do not lead to drug discontinuation. However, despite these findings, cost‐effectiveness has still to be taken in account regarding both patients with FH and those without.36 Long‐term safety monitoring of PCSK9 inhibitors prescribed in clinical practice to a diverse population is indispensable to discover new or rare AEs and to assess AE risk in specific subgroups. All healthcare professionals prescribing these medications should contribute to monitor AEs by reporting these to pharmacovigilance agencies and if possible by collecting long‐term data in a local, national, and ultimately an international database.

Methods

Patients and study design

Three different data sources were analyzed: (i) the EMC hospital registry; (ii) the Netherlands Pharmacovigilance Centre Lareb database37; and (iii) VigiLyze38 pharmacovigilance database maintained by the World Health Organization collaborating center for international drug monitoring Uppsala Monitoring Centre (UMC) in Sweden.

EMC hospital registry

Full details of this registry have been published before.20 Briefly, patients with hypercholesterolemia, mostly patients with FH not reaching target LDL‐C levels despite maximally tolerated statin and ezetimibe therapy who were eligible for treatment with PCSK9 inhibitors were recruited from the outpatient clinic in a tertiary university hospital setting. All patients fulfilled the Dutch criteria for reimbursement of PCSK9 inhibitors.39

Patients started with a PCSK9 inhibitor (evolocumab 140 mg subcutaneously every 2 weeks (heterozygous familial hypercholesterolemia) or 420 mg subcutaneously every 2 weeks (homozygous familial hypercholesterolemia) or alirocumab 75, or 150 mg subcutaneously every 2 weeks (heterozygous familial hypercholesterolemia)) between June 2015 and November 2017 as part of clinical care. There was no preference for alirocumab or evolocumab. All patients had at least two PCSK9 inhibitor subcutaneous injections between baseline and on‐treatment measurements. Only patients of whom at least one follow‐up visit was available were included in the analysis. Patients who participated in a PCSK9 trial were excluded from analysis.

Baseline date was defined as the date when the first injection of the PCSK9 inhibitor was administered. Routine laboratory investigations were performed before and after start of PCSK9 inhibitor to monitor treatment effects. Patients had regular appointments for follow‐up at 6 weeks, 18 weeks, and 42 weeks at the outpatient clinic. AEs, including ISRs and adherence to LLT, were systematically discussed during each consultation. Only PCSK9 inhibitor‐related AEs were included, which were defined as AEs not present prior to the start of PCSK9 inhibitor therapy, or an already present symptom that changed or worsened following treatment. AEs were classified using Medical Dictionary for Regulatory Activities terms. One patient may report multiple events. Clinical data, such as age, gender, body mass index (BMI), diabetes mellitus, hypertension, history of CVD, familial hypercholesterolemia, LLT, laboratory values, and AEs were collected from patients’ files and entered into a database.

According to the Medical Ethical Research Committee, this study (MEC‐2016‐698) was not subject to the Medical Research involving Human Subjects Act. We only used data of patients who provided written consent for research and anonymous publication of their clinical information.

Lareb database

The Netherlands Pharmacovigilance Centre Lareb37 identifies risks associated with the use of drugs in daily practice in the Netherlands. This database contains individual case safety reports of suspected AEs reported by healthcare professionals, manufacturers, patients, or others. The submitted reports are reviewed case‐by‐case by Lareb and AEs are defined with the use of Medical Dictionary for Regulatory Activities terms. One single report may refer to multiple AEs. It must be emphasized that the number of reports reflects reporting behavior and not the incidence of a reaction. Furthermore, it must be noted that the likelihood of a causal relationship can differ between cases, because the aim is to collect all reports of suspicions of AEs and reports may be incomplete concerning the provided information. The database was accessed on September 26, 2017, and contained all AE reports for alirocumab and evolocumab since its inception.

VigiLyze database

VigiLyze38 contains individual case safety reports of suspected AEs collected by national drug authorities in over 110 countries, including Lareb data. Similar to the Lareb database, one single report may refer to multiple AEs, the number of reports reflects reporting behavior and not the incidence of a reaction, and causality is not ensured. Collection of data is heterogeneous between countries, due to, for example, differing national legislation and policies. The database was accessed on November 21, 2017, and contained the dataset from inception to November 19, 2017, of all AE reports on alirocumab and evolocumab.

Statistical analysis

Dichotomous variables are reported as numbers and percentages. Continuous variables are presented as mean ± SD or median and IQR. Normality of data was assessed by visually exploring the distribution in normal plots, checking for skewness, and using The Shapiro‐Wilk test. Differences between categorical variables were evaluated using the χ2 or Fisher’s exact test as appropriate. Differences between numeric variables were evaluated using The Student’s t test or Mann‐Whitney U test as appropriate. Gender differences were assessed using ORs, which were obtained using binary logistic regression. Covariates were analyzed using univariate logistic regression to determine possible predictors. McNemar’s test was performed to assess asymmetry in the distribution of AE occurrence during follow‐up. For all tests, a P value < 0.05 was considered statistically significant. Data were analyzed using IBM SPSS Statistics for Windows, version 21. When individual cases were not available for analysis, SAS Statistics version 9.4 was used to obtain ORs from counts.

Disclaimer

The authors are indebted to the national pharmacovigilance centers that contributed data to the worldwide database, maintained by the World Health Organization collaborating center for international drug monitoring UMC in Sweden. The opinions and conclusions, however, are not those of the various centers, or of the UMC in Sweden. The information originates from a variety of sources, and the likelihood that the suspected AEs are drug‐related can vary between cases.

Funding

No funding was received for this work.

Conflict of interest

J.E. Roeters van Lennep reports personal fees from AKCEA, grants from AMRYT, paid to the institution, outside the submitted work. A.M.H. Galema‐Boers reports personal fees from Sanofi‐Aventis Netherlands B.V. for publication of her thesis and Amgen for presentation at congress, outside the submitted work. All other authors declared that there is no conflict of interest regarding the publication of this article.

Author contributions

M.T.G., and J.E.R. wrote the manuscript; M.T.G., A.H.G.M., M.M.S., J.M.H.G., H.B., and J.E.R. made critical revisions to the manuscript; M.T.G., A.H.G.M., J.M.H.G., and J.E.R. designed the research; M.T.G., A.H.G.M., J.M.H.G., and J.E.R. performed the research; M.T.G., A.H.G.M., H.B., and J.E.R. analyzed the data.

Supporting information

Figure S1. Flowchart of patient inclusion and exclusion for the Lareb database.

Table S1. Baseline patient characteristics for EMC database split by drug.

Table S2. Patient characteristics for Lareb database split by drug.

Table S3. Patient characteristics for VigiLyze database split by drug.

Table S4. AEs split by PCSK9 inhibitor for EMC database.

Table S5. Adverse events split by PCSK9 inhibitor for Lareb database.

Table S6. Adverse events split by PCSK9 inhibitor for VigiLyze database.

Table S7. Drug discontinuation.

Acknowledgments

The authors would like to thank K.A. Steward for carefully scanning through patients’ files and data entry in the EMC hospital registry. All authors approved the final version of the submitted manuscript.

Notes

[The copyright line for this article was changed on August 16, 2019 after original online publication.]

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Evolocumab – Subcutaneous Injection | HealthLink BC

Pronunciation: E-voe-LOK-ue-mab

Common Brand Name(s): Repatha

Important: How To Use This Information

This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

Uses

Evolocumab is used to help lower “bad” cholesterol (LDL) in the blood. For people who have high levels of LDL, it is used along with a proper diet, alone or other LDL-lowering treatments (such as “statin” drugs, ezetimibe, LDL apheresis). Evolocumab is also used by people who have heart disease to help prevent heart attacks and strokes. This medication belongs to a class of drugs known as monoclonal antibodies. It works by improving how well your body gets rid of LDL cholesterol.

In addition to eating a proper diet (such as a low-cholesterol/low-fat diet), other lifestyle changes that may help this medication work better include exercising, losing weight if overweight, and stopping smoking. Consult your doctor for more details.

How To Use

Read the Patient Information Leaflet if available from your pharmacist before you start using evolocumab and each time you get a refill. Carefully read and learn the Instructions for Use. If you have any questions, ask your doctor or pharmacist.

Before use, take evolocumab out of the refrigerator. If you are using the prefilled syringe/pen, let it warm up to room temperature for at least 30 minutes. If you are using the on-body infusor, let it warm up to room temperature for at least 45 minutes. Do not heat this medication any other way, such as by heating in the microwave or placing in hot water. Do not shake this medication. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid.

Inject this medication under the skin of the thigh, abdomen, or upper arm as directed by your doctor, usually once every 2 weeks, or once every month. The dosage is based on your medical condition and response to treatment. If your doctor has prescribed the monthly dose and you are using the prefilled syringe/pen, you will use 3 separate injections within 30 minutes. If you are using the on-body infusor, the medication is injected over 9 minutes.

Before injecting each dose, clean the injection site with rubbing alcohol. Change the injection site each time to lessen injury under the skin. Do not inject into any areas of skin that are injured, tender, hard, red, or hot.

Use this medication regularly to get the most benefit from it. To help you remember, mark the days on the calendar when you need to receive the medication.

Learn how to store and discard medical supplies safely.

Side Effects

Redness, pain, or bruising at the injection site may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including:

  • rash
  • itching/swelling (especially of the face/tongue/throat)
  • severe dizziness
  • trouble breathing

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US –

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada – Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Precautions

Before using evolocumab, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients (such as latex or dry natural rubber found in the needle cover on the prefilled syringe/pen) which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is unknown if this medication passes into breast milk. Consult your doctor before breast-feeding.

Drug Interactions

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Overdose

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

Notes

Do not share this medication with others.

Lab and/or medical tests (such as LDL cholesterol levels) should be done while you are using this medication. Keep all medical and lab appointments.

Missed Dose

If you are using this medication every 2 weeks and miss a dose, use it as soon as you remember if it is within 7 days from the missed dose. If it is longer than 7 days from the missed dose, skip the missed dose. Use your next dose at the regular time. Do not double the dose to catch up.

If you are using this medication once a month and miss a dose, use it as soon as you remember if it is within 7 days from the missed dose, then use your next dose at the regular time. If it is longer than 7 days from the missed dose, use it as soon as you remember and start a new monthly schedule based on this date. Do not double the dose to catch up.

Storage

Store in the original package in the refrigerator away from light and moisture. Do not freeze. If you keep this medication at room temperature, make sure to use it within 30 days and keep it in the original package. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Evolocumab (By injection) | Drug Notes | Health Information

Evolocumab (By injection)

Evolocumab (e-voe-LOK-ue-mab)
Treats high levels of LDL cholesterol.

Brand Name(s):

Repatha

There may be other brand names for this medicine.

When This Medicine Should Not Be Used:

This medicine is not right for everyone. Do not use it if you had an allergic reaction to evolocumab.

How to Use This Medicine:

Injectable
  • Your doctor will prescribe your exact dose and tell you how often it should be given. This medicine is given as a shot under your skin.
  • A nurse or other health provider will give you this medicine.
  • You may be taught how to give your medicine at home. Make sure you understand all instructions before giving yourself an injection. Do not use more medicine or use it more often than your doctor tells you to.
  • This medicine comes in 3 forms: single-dose prefilled pen (autoinjector), single-dose prefilled syringe, and single-use Pushtronex? system (on-body infusor with prefilled cartridge). Your doctor will prescribe the type and dose that is right for you.
  • You will be shown the body areas where this shot can be given. Use a different body area each time you give yourself a shot. Keep track of where you give each shot to make sure you rotate body areas. It is usually given in the stomach, thighs, or upper arms. Do not inject into skin has cuts, scrapes, scars, or stretch marks.
  • Allow the autoinjector or syringe to warm to room temperature for at least 30 minutes before you use it, or for at least 45 minutes for single-use Pushtronex? system. Do not heat or shake the medicine.
  • Use a new autoinjector or syringe (device) for each injection. Do not give more than one injection with one device or save leftover medicine in a used device.
  • If you need more than one injection to get your full dose, give all the injections within 30 minutes.
  • Read and follow the patient instructions that come with this medicine. Talk to your doctor or pharmacist if you have any questions.
  • Missed dose:

    • More
      than 7 days until next regular dose: Inject a dose as soon as possible, and then go back to your regular schedule.
    • Fewer
      than 7 days until next regular dose: Skip the missed dose, and inject the medicine on the regular day. Do not use extra medicine to make up for a missed dose.
  • If you store this medicine at home, keep it in the refrigerator. Do not freeze. You may keep the medicine in the original carton at room temperature, but you must use it within 30 days. Throw away any medicine that you did not use in the 30-day period.
  • Throw away used needles in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

Drugs and Foods to Avoid:

Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.

Warnings While Using This Medicine:

  • Tell your doctor if you are pregnant or breastfeeding, or if you have a latex allergy.
  • Your doctor will do lab tests at regular visits to check on the effects of this medicine. Keep all appointments.
  • Keep all medicine out of the reach of children. Never share your medicine with anyone.

Possible Side Effects While Using This Medicine:

Call your doctor right away if you notice any of these side effects:
  • Allergic reaction: Itching or hives, swelling in your face or hands, swelling or tingling in your mouth or throat, chest tightness, trouble breathing
If you notice these less serious side effects, talk with your doctor:
  • Back pain
  • Cough, stuffy or runny nose, sore throat
  • Pain, itching, burning, swelling, or a lump under your skin where the shot was given

If you notice other side effects that you think are caused by this medicine, tell your doctor

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088

Last Updated: 1/27/2017


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Truven Health Analytics. All rights reserved.


Trial Offers Objective Evidence of Muscle Related Side Effects with Statins

Contact: Beth Casteel, [email protected], 202-375-6275

CHICAGO (Apr 03, 2016) –

The first major clinical trial to include a blinded, placebo-controlled “statin re-challenge” in patients with a history of muscle-related side effects sheds new light on statin-associated muscle symptoms, according to research presented at the American College of Cardiology’s 65th Annual Scientific Session. The trial also demonstrates that monthly self-injection of the relatively new non-statin cholesterol-lowering drug evolocumab reduces levels of low-density lipoprotein, or LDL, cholesterol to a greater extent than ezetimibe, a traditional drug used in statin-intolerant patients.

The study showed that 42.6 percent of 491 patients who had previously reported muscle pain with at least two different statins had a recurrence of symptoms during blinded administration of atorvastatin, but not while taking a placebo.

After a 24-week treatment period, patients with confirmed statin intolerance who were given evolocumab on average showed a 52.8 percent reduction in LDL cholesterol, one of the study’s co-primary endpoints, compared with a 16.7 percent reduction for patients taking ezetimibe. For the study’s other co-primary endpoint, the average change in LDL cholesterol for weeks 22 and 24, patients taking evolocumab showed a reduction of 54.5 percent and patients taking ezetimibe showed a reduction of 16.7 percent.

“These findings provide unique insights into the challenging clinical problem of muscle symptoms in statin treated patients,” said Steven Nissen, M.D., MACC, chairman of Cardiovascular Medicine at Cleveland Clinic and the lead author of the trial. “Evolocumab substantially lowered LDL cholesterol with few patients experiencing muscle symptoms. The study has important implications for both guidelines and regulatory policy, because it provides strong evidence that muscle-related statin intolerance is a real and reproducible phenomenon.”

The patients in the GAUSS-3 trial had very high levels of LDL cholesterol, averaging more than 210 mg/dL. Untreated high LDL cholesterol increases the risk of heart disease, and statins are the most effective drugs available, yet some patients report that that they are unable to tolerate statins, mostly due to muscle pain or weakness.

There has been considerable controversy about the prevalence of muscle-related statin intolerance because large randomized trials have reported low rates of muscle symptoms, while observational studies have suggested that 5 to 20 percent of patients experience muscle symptoms when taking statins.

“Statin intolerance has been one of the most vexing problems faced by cardiologists,” Nissen said. “Patients with high levels of LDL cholesterol and a high risk of cardiovascular events are often reluctant or completely unwilling to take statins, the only cholesterol lowering drugs approved to reduce their risk of a cardiovascular event. This situation is extremely frustrating for both patients and physicians because there have not been good alternatives for treatment.”

Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, is a non-statin cholesterol-lowering drug administered by self-injection every two to four weeks. By binding to and inhibiting PCSK9, a protein that degrades LDL cholesterol receptors on the surface of the liver, the drug is designed to increase the number of LDL receptors on the liver, thus allowing the liver to remove LDL cholesterol from the blood more effectively. Ezetimibe, the existing drug used as a control in the trial, lowers blood cholesterol by decreasing the absorption of cholesterol in the small intestine.

The phase 3, randomized, double-blind GAUSS-3 trial enrolled 511 patients at 53 health care centers. Participants had high LDL cholesterol and a history of statin intolerance. A vast majority of participants—82 percent—had tried and failed to tolerate three or more statins.

Previous studies, including the trial’s predecessor, GAUSS-2, have shown evolocumab reduces LDL cholesterol levels more effectively than ezetimibe.

Because the trial was intended to evaluate evolocumab in statin-intolerant patients, it included an initial statin re-challenge procedure designed to confirm that patients had reproducible muscle symptoms when taking a statin. Nineteen of the enrolled participants bypassed this initial segment because they were documented to have creatine kinase levels—a marker of muscle injury—at least 10 times higher than the upper limit of normal when taking a statin.

Those who participated in the statin challenge were given 20 milligrams of atorvastatin or a placebo daily for 10 weeks, then switched over and were given either a placebo or atorvastatin—whichever one they had not been given in the first phase—for 10 more weeks. Of the 491 participants, 209, or 42.6 percent, reported muscle-related side effects while taking atorvastatin but not while taking the placebo. More than a quarter, 26.5 percent, reported muscle pain while taking the placebo but not while taking atorvastatin, suggesting that although statin intolerance can be confirmed in a substantial proportion of patients with self-reported intolerance, there is also a significant proportion who experience muscle pain that cannot be attributed to taking statins.

After that initial phase, 218 patients with confirmed statin intolerance were enrolled in the trial’s second segment, with 145 randomly assigned to receive evolocumab and 73 randomized to receive ezetimibe. Because evolocumab was administered through self-administered injections totaling 420 milligrams per month, and ezetimibe was administered through a 10-milligram daily pill, those randomized to receive evolocumab were given injections of evolocumab and daily placebo pills, and those randomized to receive ezetimibe were given placebo injections and a daily ezetimibe pill.

Participants in the study’s second phase had an average baseline LDL cholesterol level of 220 mg/dl. After 24 weeks, those given evolocumab had an LDL cholesterol level of 104 mg/dl on average; 64.1 percent of patients taking evolocumab finished the trial with LDL cholesterol below 100 mg/dl, and 29.9 percent finished with LDL cholesterol below 70 mg/dl.

Treatment was discontinued during the trial for one patient given evolocumab and five patients given ezetimibe due to muscle-related adverse events.

Longer-term results from another evolocumab trial showing health outcomes may be available by the end of 2016.

The study’s limitations included its modest size and relatively short duration, but Nissen said it was adequately powered to address its primary endpoint.

The trial was funded by Amgen. Nissen has served as a consultant for many pharmaceutical companies and has overseen clinical trials for Amgen, AstraZeneca, Cerenis, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Orexigen, Takeda and Pfizer. However, he does not accept honoraria, consulting fees or other compensation from commercial entities.

This study was simultaneously published online in the Journal of the American Medical Association at the time of presentation.

The ACC’s Annual Scientific Session, which in 2016 will be April 2-4 in Chicago, brings together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCMediaCenter and #ACC16 for the latest news from the meeting.

The American College of Cardiology is a 52,000-member medical society that is the professional home for the entire cardiovascular care team. The mission of the College is to transform cardiovascular care and to improve heart health. The ACC leads in the formation of health policy, standards and guidelines. The College operates national registries to measure and improve care, offers cardiovascular accreditation to hospitals and institutions, provides professional medical education, disseminates cardiovascular research and bestows credentials upon cardiovascular specialists who meet stringent qualifications.

###

Nissen will be available to the media in a press conference on Sunday, April 3, 2016, at 9:30 a.m. CT/10:30 a.m. ET/2:30 p.m. UTC in Room N229.

Nissen will present the study, “Comparison of PCSK9 Inhibitor Evolocumab Versus Ezetimibe in Statin-intolerant Patients: The Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 (GAUSS-3) Trial,” on Sunday, April 3, 2016, at 8 a.m. CT/9 a.m. ET/1 p.m. UTC in the Main Tent (North Hall B1). 

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Evolocumab – Australian Prescriber

Most patients who require drug treatment for raised cholesterol will be prescribed a statin. In some cases this treatment will not achieve the target concentration for cholesterol. The patients may then be given an additional drug such as ezetimibe. The LAPLACE-2 trial looked at adding evolocumab or ezetimibe to treatment with a statin. This trial used evolocumab 140 mg every two weeks or 420 mg monthly. It also used three different statins at different doses so the 2067 patients were randomised to 24 different treatment groups. At the start of the study the patients had LDL-cholesterol concentration around 2.82 mmol/L. After 12 weeks this had reduced to approximately 1.28 mmol/L in patients taking evolocumab with atorvastatin 10 mg. The combination of evolocumab and atorvastatin 80 mg reduced the concentration to approximately 0.93 mmol/L. A primary outcome was the mean percentage change in LDL cholesterol from baseline for weeks 10 and 12 of the trial. For evolocumab these reductions were around 59–66% with moderate or high doses of statins. These changes were greater than those seen in the ezetimibe groups. Combined with atorvastatin, ezetimibe reduced LDL cholesterol by approximately 17–24%. Evolocumab also reduced concentrations of apolipoprotein B and triglycerides.5

The DESCARTES trial investigated treatment with evolocumab over a year. There were 905 patients who had an LDL-cholesterol concentration above 1.94 mmol/L despite lipid-lowering therapy. The patients were allocated to be treated with diet alone, atorvastatin 10 mg, atorvastatin 80 mg or atorvastatin 80 mg plus ezetimibe. Within each of these groups the patients were given evolocumab 420 mg monthly or a placebo. After 52 weeks the mean LDL cholesterol fell from 2.69 mmol/L, across all groups, to 1.32 mmol/L with evolocumab, but was almost unchanged in the placebo groups. The largest percentage change (61.6%) was in the group treated with evolocumab and atorvastatin 10 mg in addition to diet. Treatment with evolocumab was also associated with reductions in apolipoprotein B and triglycerides.6

The MENDEL-2 trial assessed 615 patients who were not taking a statin. These patients had LDL-cholesterol concentrations averaging around 3.7 mmol/L. They were randomised to take evolocumab, ezetimibe or placebo. After 12 weeks patients injecting evolocumab every two weeks had reduced their LDL-cholesterol concentration by 57% compared with a 17.8% reduction with ezetimibe. The corresponding figures for monthly treatment were 56.1% and 18.6%. There was little change in the placebo groups.7

Evolocumab has also been investigated for patients with statin intolerance in the GAUSS placebocontrolled trials.8 The GAUSS-2 trial enrolled 307 patients who had been unable to tolerate at least two statins. They were randomised to take daily ezetimibe, evolocumab 140 mg every two weeks, or evolocumab 420 mg monthly. At the start of the trial the average concentration of LDL cholesterol was approximately 5 mmol/L. After 12 weeks this had reduced by 53–56% with evolocumab and 15–18% with ezetimibe.

90,000 For the first time in Russia, the MEDSI CDC on Belorusskaya used the drug Evolokumab in the treatment of refractory forms of familial hypercholesterolemia

17.02.2016

The innovative drug Evolocumab in the treatment of patients with “familial hypercholesterolemia” on LDL-apheresis was used for the first time in Russia at the Center for Diagnostics and Innovative Medical Technologies of the Clinical Diagnostic Center MEDSI on Belorusskaya under the guidance of Professor , Doctor of Medical Sciences, Chairman of the Scientific Council of the MEDSI Group of Companies Gennady Aleksandrovich Konovalov.Last week, the first injections of this drug were made, developed by Amgen (USA).

Evolocumab belongs to a new class of drugs – monoclonal antibodies that inhibit proprotein convertase subtilisin / kexin type 9 (PCSK9), which binds to low-density lipoprotein receptors in the liver and promotes their destruction. This drug has undergone clinical trials in the US and Europe and has received FDA (US) and European Medicines Control Agency (EMA) approval as the first PCSK9 inhibitor drug to lower LDL levels.It has been shown to be effective in the treatment of patients with familial hypercholesterolemia, as well as as an adjunctive therapy, without significant side effects. Familial hypercholesterolemia is a hereditary disease caused by impaired cholesterol metabolism and characterized by a genetic cause of an increase in the level of low density lipoproteins in the patient’s blood. Evolocumab’s mechanism of action is by blocking the PCSK9 protein, which limits the number of available receptors in the liver, thereby reducing the body’s ability to remove LDL from the bloodstream.The drug is injected subcutaneously every 2 or 4 weeks, depending on the dose used.

“Evolocumab is expected to become an indispensable treatment tool for a wide range of high-risk patients, in particular those with familial hypercholesterolemia, those with intolerance to effective doses of statins, and patients with a very high risk of cardiovascular disease and unable to reach target values concentration of LDL cholesterol against the background of combined lipid-lowering therapy “, – noted the Scientific Supervisor of the Medsi Group, Professor G.A. Konovalov.

Published in The Lancet and other sources, the results of the world’s largest randomized trials have shown that evolocumab lowers LDL cholesterol levels by an average of 60% in patients with heterozygous familial hypercholesterolemia, when only one parent is a carrier of the LDL receptor gene mutation and by 31 % on average in patients with a homozygous form of the disease, when both parents are carriers of the genetic mutation.

CDC MEDSI on Belorusskaya is the only private medical institution in Russia where Evolokumab was approved by the Ministry of Health of the Russian Federation for use in patient therapy.This drug was delivered to Russia with the assistance of MEDSI’s partner, Global Study Management Non-Amgen Sponsored Clinical Research. Specialists of the Center for Diagnostics and Innovative Medical Technologies of the Clinical and Diagnostic Center MEDSI on Belorusskaya are confident that Evolokumab will take an important place in the algorithm for the effective treatment of patients with refractory lipid metabolism disorders and will provide them with a significant improvement in the quality of life and improve the results of treatment of the most severe patients on programmed LDL and Lp (a) – apheresis.

Characteristics of Evolocumab and its efficacy in the treatment of hyperlipidemia. Author – G.A. Konovalov

Active substance EVOLOCUMABUM | Directory of medicines Compendium

evolocumab selectively binds to type 9 proprotein convertase (PCSK9) and inhibits the binding of circulating PCSK9 to the LDL receptor on the surface of liver cells, thus preventing PCSK9-mediated degradation of LDL.An increase in the levels of LDL receptors in the liver leads to a decrease in the plasma concentration of LDL cholesterol.

In clinical trials, evolocumab reduced the concentrations of unbound PCSK9, LDL cholesterol, total cholesterol, apoB, HDL cholesterol, total cholesterol / HDL cholesterol, apoV / apoA1, VLDL cholesterol, triglycerides, and increased LDL cholesterol and apoA1 cholesterol in patients with primary hypersemia and lipolemia.

C max in blood plasma is reached after 3-4 days. T ½ from 11 to 17 days.

hypercholesterolemia and mixed dyslipidemia.

Indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia as adjunctive therapy to diet:

– in combination with statins or statins and other lipid-lowering therapy for patients who are unable to achieve the desired levels of LDL cholesterol with the maximum tolerated dose of statin, or

– alone or in combination with other lipid-lowering therapy for patients with statin intolerance or for whom statins are contraindicated.

Homozygous familial hypercholesterolemia.

Indicated for adults and adolescents over 12 years of age with homozygous familial hypercholesterolemia in combination with other lipid-lowering therapy.

is administered s / c.

Primary hypercholesterolemia and mixed dyslipidemia in adults.

The recommended dose is 140 mg every 2 weeks or 420 mg once a month.

Homozygous familial hypercholesterolemia in adults and adolescents over the age of 12 years.

The starting dose is 420 mg once a month. After 12 weeks of treatment, the frequency of drug use can be increased to 420 mg 1 time every 2 weeks if clinically significant responses have not been achieved.

increased sensitivity.

rhinopharyngitis, upper respiratory tract infection, urticaria, nausea, arthralgia, back pain.

studies of the interaction of evolocumab with other drugs have not been conducted.

In the event of an overdose, the patient should be treated symptomatically and supportive measures taken if necessary.

New drug has shown success in preventing heart attack

Photo author, Getty Images

Scientists have successfully tested an innovative drug that, according to them, can prevent heart attacks and strokes.

International trials of the drug, in which 27 thousand people took part, have shown that it is able to reduce the amount of bad cholesterol in the body to unprecedented levels. The success of the study suggests that the drug will soon be available to millions of people.

The British Heart Foundation, a medical charity, described the findings as a significant advance in the fight against clinical heart disease.

About 15 million people die from heart attacks and strokes every year.

High levels of bad cholesterol in the body clog blood vessels, preventing the heart and brain from getting the oxygen and nutrients they need.

Millions of people use a statin-class drug to lower bad cholesterol.

A new drug – evolocumab – helps the liver to cleanse the blood of harmful cholesterol.

“It is much more effective than statins,” says Professor Peter Sever of Imperial College London.

He organized the UK portion of the drug trial funded by the pharmaceutical company Amgen.

“As a result, the cholesterol level dropped and fell, and eventually reached the lowest values ​​that we have ever seen in medical practice,” – said Professor Sever BBC.

During the trial, patients were already taking statins. “The risk was reduced by an additional 20%, which is a significant effect. This is perhaps the most important test result of a drug for lowering cholesterol in more than 20 years,” added Professor Sever.

In the course of two-year tests, scientists concluded that without taking the drug, about 365 people out of the total number of subjects (all of whom were at high risk) would have had a heart attack or stroke.

How does it work?

Evolocumab is an antibody (antibodies are produced in the body to fight infection).It is designed to block the PCSK9 protein, which prevents the liver from breaking down cholesterol and thus removing it from the blood.

Other trials on the drug have also shown it can lower cholesterol levels by 60%, and Amgen is not the only company developing such a treatment.

The drug is injected into the body by subcutaneous injection every 2-4 weeks.

However, according to Professor Sever, evolocumab is unlikely to completely replace statins.“There are a lot of people with really high cholesterol, and they probably won’t be satisfied with one drug,” he said.

The price of the new drug varies, but some estimates put it at £ 2,000 ($ 2,500) per person per year for the UK National Health Service (NHS). It is already being prescribed for statin refractory patients.

“This test is a very important step forward,” says Professor Nilesh Samani, co-leader of the British Heart Foundation.“However, the trials stopped after just over two years of routine observation, so it is difficult to talk about real benefits in the long term.”

Evalocumab therapy for 5 years is effective and safe: results of the OSLER-1 study

Therapeutic monoclonal antibodies to proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibit its action and reduce the level of LDL, apoliporotein B, LP 9A), triglycerides, increase the level of HDL. The FOURIER study showed that a representative of this group of drugs – evolocumab – reduces the risk of developing cardiovascular complications.Considering that the drug has an active effect on metabolism, the issue of the safety of such treatment for a long time remains extremely important.

In addition, one could fear that the effect would slip away due to the possible accumulation of antibodies neutralizing the drug during prolonged exposure to the drug.

Previously, three-year follow-up data were available. The latest issue of the JACC journal published the results of the OSLER-1 study, in which patients received evolocumab for 5 years.The rationale for prescribing the drug was the failure to achieve the target LDL cholesterol despite the maximum standard therapy. During the first year, patients were randomized to receive standard therapy or standard therapy + evolocumab. After the first year, everyone was transferred to an open intake of evolocumab.

The study included 1255 patients who received at least one dose of evolocumab. Evolocumab therapy (in combination with standard therapy, 20% of patients received maximum statin therapy) remained effective throughout the observation period, no escaping effect was noted: the degree of LDL reduction from baseline values ​​remained at the same level (by 56-57%).The mean LDL cholesterol level in the observed cohort decreased from 140 to 61 mg / dL.

The incidence of serious side effects in the evolocumab group ranged from 6.9-7.9% per year (in the standard therapy group in the first year it was 6.8%). Interestingly, the incidence of a number of side effects (for example, local reactions at the injection site) decreased from year to year.

659 patients received evolocumab for at least 4 years. In total, over the entire observation period, 27% of patients refused to take evolocumab (due to side effects – 5.7%).Antibodies neutralizing the effect of evolocumab were not detected over the entire observation period.

Based on materials:

Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term efficacy and safety of evolocumab in patients with hypercholesterolemia. J Am Coll Cardiol. 2019; 74: 2132-2146.

http://www.onlinejacc.org/

Text: Shakhmatova O.O.

Repata (evolocumab injection for subcutaneous injection): uses, dosage, side effects, interactions, prevention

  • Generic name: Evolocumab injection, subcutaneous injection
  • Brand name: Repata

Product description

What is Repata and how is it used?

Repata (evolocumab) Injection is a human monoclonal immunoglobulin G2 (IgG2) as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerosis.cardiovascular disease (see also Cardiovascular Disease) that requires an additional reduction in low-density lipoprotein cholesterol (LDL-C). Repatha is also indicated as an adjunct to diet and other LDL-lowering drugs (eg, statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial diseases. hypercholesterolemia (HoFH), which require an additional reduction in LDL-C levels.

What are the side effects of Repatha?

Common Repatha side effects include:

  • runny or stuffy nose,
  • Upper respiratory infection,
  • influenza
  • back pain,
  • injection site reactions (redness, pain and bruising),
  • allergic reactions (rash and urticaria),

  • cough,
  • urinary tract infection,
  • sinus infection,
  • Headache,
  • muscle pain,
  • dizziness,
  • 15 high blood pressure,
  • diarrhea stomach upset.

DESCRIPTION

Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against the human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in mammalian (Chinese hamster ovary) cells that are genetically engineered.

REPATHA is a sterile, preservative-free, clear or opalescent, colorless to pale yellow solution for subcutaneous administration.Each SureClick Disposable Prefilled Syringe and Disposable Prefilled Autoinjector contains 140mg Evolocumab, Acetate (1.2mg), Polysorbate 80 (0.1mg), Proline (25mg) in Water for Injection, USP. Sodium hydroxide can be used to adjust the pH to 5.0. Each single-use Pushtronexsystem (body-on infuser with a pre-filled cartridge) delivers 3.5 ml of solution containing 420 mg evolocumab, acetate (4.2 mg), polysorbate 80 (0.35 mg), proline (89 mg) in water for injection, USP.Sodium hydroxide can be used to adjust the pH to 5.0.

Indications and dosage

INDICATIONS

Prevention of cardiovascular diseases

In adults with established cardiovascular disease, REPATHA is indicated to reduce the risk of myocardial infarction, stroke and coronary revascularization.

Primary hyperlipidemia (including heterozygous familial hypercholesterolemia)

Repata is prescribed as an adjunct to the diet, alone or in combination with other drugs.lipid-lowering therapies (eg, statins, ezetimibe) for the treatment of adults with primary hyperlipidemia to lower low-density lipoprotein cholesterol (LDL-C).

Homozygous familial hypercholesterolemia

REPATHA is indicated as an adjunct to diet and other drugs that lower LDL cholesterol levels (eg statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional reduction in LDL cholesterol levels …

DOSAGE AND ADMINISTRATION

Recommended dosage

The recommended subcutaneous dose of REPATHA for adults with established cardiovascular disease or for adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia [HeFH]) is either 420 mg every 2 weeks once a month, depending on the patient’s preference for dosing frequency and injection volume. … When changing dosing regimen, enter the first dose of the new regimen on the next scheduled day of the previous regimen.

The recommended subcutaneous dose of REPATHA in patients with HoFH is 420 mg once a month. In patients with HoFH, measure LDL-C levels 4-8 weeks after starting REPATHA, as response to therapy will depend on the degree of LDL receptor function.

When monitoring LDL-C in patients receiving REPATHA 420 mg once a month, note that LDL-C can vary significantly over the dosing interval in some patients [see. Clinical studies ].

If a dose is missed, instruct patient to administer REPATHA within 7 days of the missed dose and resume the patient’s original schedule.

  • If a dose is not given every 2 weeks for 7 days, ask the patient to wait until the next dose on the original schedule.
  • If a monthly dose is not given within 7 days, instruct the patient to dose and start a new schedule based on that date.
Important Administration Instructions
  • The 420 mg REPATHA dose can be administered:
    • over 9 minutes using a single-use body infuser with a pre-filled cartridge, or
    • by giving 3 injections consecutively over 30 minutes with a single-use pre-filled autoinjector or disposable pre-filled syringe.
  • Ensure that patients and / or caregivers are properly educated on how to prepare and administer REPATHA prior to use in accordance with the directions for use, including aseptic technique. Ask patients and / or carers to read and follow the Instructions for Use each time they use REPATHA.
  • Store REPATHA in the refrigerator. Before use, allow REPATHA to warm to room temperature for at least 30 minutes for a disposable pre-filled autoinjector or disposable pre-filled syringe and at least 45 minutes for a disposable body-on infuser with a pre-filled cartridge.Do not heat in another way. Alternatively, for patients and caregivers, REPATHA can be stored at room temperature between 20 ° C to 25 ° C (68 ° F to 77 ° F) in its original carton. However, under these conditions REPATHA must be used within 30 days [see. HOW SUPPLIED / Storage and handling ].
  • Visually inspect REPATHA for particles and discoloration prior to use. REPATHA is a clear or opalescent solution from colorless to pale yellow.Do not use if solution is cloudy, discolored, or contains particles.
  • Inject REPATHA subcutaneously into the abdomen, thigh, or upper arm that is not painful, bruised, red, or hard, using a disposable pre-filled syringe, disposable pre-filled autoinjector, or disposable body infuser with a pre-filled cartridge.
  • Do not mix REPATHA with other injectables at the same injection site.
  • Change the site of each subcutaneous injection.

HOW SUPPLIED

Dosage Forms and Strengths

REPATHA is a colorless to pale yellow, clear to opalescent sterile solution available in the following versions:

  • Injection: 140 mg / ml solution, single use pre-filled syringe.
  • Injection: 140 mg / ml solution in a single-use, pre-filled SureClick auto-injector.
  • Injection: 420 mg / 3.5 ml in the Pushtronex disposable system (body-on infuser with pre-filled cartridge).
Storage and Handling

REPATHA is a clear to opalescent, colorless to pale yellow, sterile solution for subcutaneous administration, supplied in a disposable pre-filled syringe, a disposable pre-filled SureClick auto-injector or a disposable Pushtr teleonex system with a pre-infuser on filled cartridge).Each SureClick REPATHA single-use pre-filled syringe or single-use pre-filled auto-injector is designed to deliver 1 ml of 140 mg / ml solution. Each Pushtronex Disposable System (Body Infuser with Prefilled Cartridge) is designed to deliver 420 mg evolocumab in 3.5 ml solution.

9028 6 NDC 72511-770-01
NDC 55513-770-01

Disposable pre-filled syringe 140 mg / ml 1 pack NDC 72511-750-01
NDC 55513-750-01
SureClick auto-injector for single use, pre-filled, 140 mg / ml 1 pack NDC 55513-760-01
SureClick autoinjector for single use, pre-filled, 140 mg / ml 2 packs NDC 72511-7603-02
55513-760-02
SureClick Auto-injector, single use, pre-filled, 140 mg / ml 3 packs NDC 55513-760-03
Pushtronex system for single use 420 mg , 5 ml (body-on infuser with pre-filled cartridge) 1 pack
Pharmacy

Store between 2 ° C and 8 ° C (36 ° F to 46 ° F) in original carton to protect from light.Do not freeze. Don’t shake.

Patient / Caregiver

Store at 2 ° C to 8 ° C (36 ° F to 46 ° F) in the original carton. Alternatively, REPATHA can be stored at room temperature 20 ° C to 25 ° C (68 ° F to 77 ° F) in its original carton; however, under these conditions REPATHA must be used within 30 days. If not used within 30 days, discard REPATHA.

Protect REPATHA from direct light and do not expose to temperatures exceeding 25 ° C (77 ° F).

Manufacturer: Amgen Inc. One Amgen Center Drive Thousand Oaks, California

-1799. Corrected: February 2019

Side effects and drug interactions

SIDE EFFECTS

The following adverse reactions are also discussed elsewhere on the label:

Clinical trial experience

drug trials, may not directly compare with clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in Adults with Primary Hyperlipidemia (including Heterozygous Familial Hypercholesterolemia)

The data described below reflect REPATHA exposure in 8 placebo-controlled trials involving 2651 patients who received REPATHA, including 557 patients for 6 months and 515 patients for 1 year (average duration of treatment 12 weeks). The median age of the population was 57 years, 49% of the population were women, 85% were white, 6% were black, 8% were Asian and 2% were of other races.

Adverse Reactions Within 52 Weeks Controlled

Trial In a 52-week, double-blind, randomized, placebo-controlled trial (Study 3 [DESCARTES, NCT01516879]), 599 patients received 420 mg REPATHA subcutaneously once a month [see. Clinical studies ]. The median age was 56 years (range: 22 to 75), 23% over 65, 52% female, 80% white, 8% black, 6% Asian; 6% identified themselves as immigrants from Spain.Adverse reactions reported in at least 3% of REPATHA patients and more frequently than in DESCARTES placebo patients are shown in Table 1. Adverse reactions resulted in discontinuation in 2.2% of REPATHA patients. and 1%. patients receiving placebo. The most common adverse reaction that led to discontinuation of REPATHA treatment and occurred at a higher rate than placebo was myalgia (0.3% versus 0% for REPATHA and placebo, respectively).

Table 1: Adverse reactions occurring in more or equal to 3% of patients treated with REPATHA and more often than with placebo in DESCARTES

9028 9028

9028

Placebo
(N = 302)%
REPATA
(N = 599)%
Nasopharyngitis 9.6 10.5
Upper respiratory tract infection 6.3 9.3
Influenza 6.3 7.5
Back pain 5.6 6.2
Injection site reactions and dagger; 5.0 5.7
Cough 3.6 4.5
Urinary tract infection 3.6 4.5
Headache 3.6 4.0
Myalgia 3.0 4.0
Dizziness 2.6 3.7
Musculoskeletal pain 3.0 3.2
Diarrhea 2.6 3.0
Stomach flu 2.0 3.0
& dagger; includes redness, 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 REPATHA subcutaneously monthly.The median age was 57 (range: 18 to 80), 29% over 65, 49% female, 85% white, 5% black, 9% Asian; 5% identified themselves as Hispanics. Adverse reactions reported in at least 1% of patients treated with REPATHA, and more often than in patients receiving placebo, are shown in Table 2.

Table 2: Adverse reactions occurring in more than 1% of patients receiving REPATHA, and more often than in placebo patients in pooled 12-week studies

Placebo
(N = 1224)%
REPAT and dagger;
(N = 2052)%
Nasopharyngitis 3.9 4.0
Back pain 2.2 2.3
Upper Respiratory Tract Infection 2.0 2.1
Arthralgia 1.628

1.2 1.8
Fatigue 1.0 1.6
Muscle spasms 1.2 1.3
Urinary tract infection 1

&

dger 140 mg every 2 weeks and 420 mg once monthly together

1.3
Cough 0.7 1.2
Influenza 1.1 1.2
Contusion 0.5
Adverse reactions in eight pooled controlled trials (seven 12-week trials and one 52-week trial)

The adverse reactions described below were from a 52-week trial (DESCARTES) and seven 12-week trials.The median and median durations of REPATHA exposure in this pool of eight trials were 20 weeks and 12 weeks, respectively.

Injection site reactions

Injection site reactions were observed in 3.2% and 3.0% of patients receiving REPATHA and receiving placebo, respectively. The most common injection site reactions were erythema, pain, and bruising. The proportion of patients who discontinued treatment due to local injection site reactions in patients receiving REPATHA and patients receiving placebo was 0.1% and 0%, respectively.

Allergic reactions

Allergic reactions occurred in 5.1% and 4.7% of patients who received REPATHA and received placebo, 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%).

Adverse reactions from the cardiovascular system

Study In a double-blind, randomized, placebo-controlled study of cardiovascular outcomes (Study 1 [REPATHA Cardiovascular Outcomes Trial, FOURIER, NCT01764633]) 27,525 patients received at least one dose of REPATHA or placebo [see. Clinical studies ]. The median age was 62.5 years (range: 40 to 86), 45% were 65 or older, 9% were 75 or older, 25% female, 85% white, 2% black, and 10% Asian; 8% identified as Hispanics. Patients received REPATHA or placebo for an average of 24.8 months; 91% of patients were exposed to? 12 months 54% were exposed at & ge; 24 months and 5% were billed for & ge; 36 months

The safety profile of REPATHA in this trial was broadly in line with the safety profile described above in 12- and 52-week controlled trials in patients with primary hyperlipidemia (including HeFH).Serious adverse events occurred in 24.8% and 24.7% of patients receiving REPATHA and receiving placebo, respectively. Side effects led to discontinuation of study drug in 4.4% of patients receiving REPATHA and 4.2% of patients receiving placebo. Common adverse reactions (> 5% of patients treated with REPATHA and more common than placebo) included diabetes mellitus (8.8% REPATHA, 8.2% placebo), nasopharyngitis (7.8% REPATHA, 7.4% placebo) and upper respiratory tract infections (5.1%).% REPATHA, 4.8% placebo).

Among 16676 patients without diabetes mellitus at baseline, the incidence of new-onset diabetes mellitus during the study was 8.1% in patients receiving REPATHA, compared with 7.7% in patients receiving placebo.

Adverse reactions in patients with homozygous familial hypercholesterolemia

In a 12-week, double-blind, randomized, placebo-controlled study, 49 patients with HoFH (Study 6 [TESLA, NCT01588496]), 33 patients received 420 mg REPATHA subcutaneously once a month [see. Clinical studies ]. The median age was 31 years (range 13 to 57), 49% female, 90% white, 4% Asian, and 6% others. Adverse reactions that occurred in at least two (6.1%) patients receiving REPATHA and more frequently than those receiving placebo included:

90 142

  • Upper respiratory tract infection (9.1% vs 6.3 %)
  • Influenza (9.1% versus 0%)
  • Gastroenteritis (6.1% versus 0%)
  • Rhinopharyngitis (6.1% versus 0%)
  • Immunogenicity

    Like all therapeutic proteins, there is potential for immunogenicity.The detection of antibody formation largely depends on the sensitivity and specificity of the assay. In addition, the observed frequency of antibody positivity (including neutralizing antibodies) in an assay can be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparing the frequency of antibodies to REPATHA in the studies described below with the frequency of antibodies in other studies or to other products can be misleading.

    The immunogenicity of REPATHA was assessed using an electrochemiluminescence screening immunoassay for the detection of anti-drug binding antibodies. For patients whose sera were positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.

    In a pool of placebo and actively controlled clinical trials, 0.3% (48 out of 17,992) of patients who received at least one dose of REPATHA tested positive for the development of binding antibodies.Patients whose serum was positive for antibody binding were additionally assessed for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.

    There was no evidence that the presence of drug binding antibodies affected the pharmacokinetic profile, clinical response, or safety of REPATHA, but the long-term consequences of continuing REPATHA treatment in the presence of drug binding antibodies are unknown.

    Post-Marketing Experience

    The following additional adverse reactions have been identified during post-approval use of REPATHA.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 with drug exposure.

    hydrocodone-acetaminophen 5-325

    • Allergic reactions: angioedema.
    • Flu-like illness

    DRUG INTERACTIONS

    No information provided

    Warnings and precautions

    WARNINGS

    Included in PRECAUTIONS section.

    PRECAUTIONS

    Allergic reactions

    Hypersensitivity reactions (eg, angioedema, rash, urticaria) have been reported in patients receiving REPATHA, including some that have led to discontinuation of therapy. If signs or symptoms of a serious allergic reaction develop, discontinue REPATHA treatment, treat according to standard of care, and observe until signs and symptoms disappear [see Table]. CONTRAINDICATIONS ].

    Patient Information

    Advise the patient and / or caregiver to read the FDA Approved Patient Label [ PATIENT INFORMATION and IFU ] before the patient starts using REPATHA and whenever the patient receives an additional dose, as there may be new information that he needs to know.

    Inform patients that severe hypersensitivity reactions (eg, angioedema) have occurred in patients treated with REPATHA.Inform patients of the symptoms of hypersensitivity reactions and instruct them to stop taking REPATHA and seek immediate medical attention if such symptoms appear.

    Provide patient and caregivers with guidance on correct subcutaneous injection technique, including aseptic technique, and how to properly use a disposable pre-filled autoinjector, disposable pre-filled syringe, or disposable body-on infuser with a pre-filled cartridge (see Brochure with instructions for use ). Inform patients that administration of REPATHA with a disposable pre-filled autoinjector or disposable pre-filled syringe can take up to 15 seconds and about 9 minutes for REPATHA administration using a disposable body-on-pump infuser with a pre-filled cartridge.

    Inform latex-sensitive patients that the following components contain dry natural rubber (a latex derivative) that may cause allergic reactions in latex-sensitive individuals: a glass pre-filled syringe needle cap and a disposable pre-filled auto-injector.

    The disposable body-on infuser with a pre-filled cartridge is not made from natural rubber latex.

    For more information on REPATHA, visit www.REPATHA.com or call 1-844-REPATHA (1-844-737-2842).

    REPATA (evolocumab)

    Preclinical toxicology
    Carcinogenesis, mutagenesis, impaired fertility

    The carcinogenic potential of evolocumab was evaluated in a lifelong study conducted on a hamster at dose levels of 10, 30 and 100 mg / kg, administered …Tumors associated with evolocumab were not observed at the maximum dose with systemic exposure 38 and 15 times the recommended human doses of 140 mg every 2 weeks and 420 mg once a month, 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.

    In a study of the toxicology of fertility and early embryonic development in hamsters with subcutaneous administration of evolocumab at doses of 10, 30 and 100 mg, no side effects on fertility were observed (including the estrous cycle, sperm analysis, mating ability and embryonic development)./ kg every 2 weeks. The highest dose tested corresponds to systemic exposure 30 and 12 times the recommended human doses: 140 mg every 2 weeks and 420 mg once a month, respectively, based on plasma AUC. In addition, in a 6-month chronic toxicology study in sexually mature monkeys who were injected with evolocumab subcutaneously at 3, 30 and 300 years old, there were no side effects associated with evolocumab on surrogate fertility markers (histopathology of the reproductive organs, menstrual cycle, or sperm parameters). ).mg / kg once a week. The highest dose tested corresponds to 744 and 300 times the recommended human doses: 140 mg every 2 weeks and 420 mg once a month, respectively, based on plasma AUC.

    Use in specific populations
    Pregnancy
    Pregnancy register

    There is a pregnancy register that tracks pregnancy outcomes in women exposed to REPATHA during pregnancy.

    Contact 1-877-311-8972 or https: // mothertobaby.org / ongoing-study / repatha / to register or get information about the registry.

    Risk Summary

    There are no data available on the use of REPATHA in pregnant women to communicate drug-related risks. Animal reproduction studies have shown no effect on pregnancy or neonatal / infant development when monkeys were injected subcutaneously with evolocumab from organogenesis to childbirth at doses 12 times higher than the maximum recommended human dose of 420 mg every month.In a similar study with another drug from the class of PCSK9 inhibitors, humoral suppression of immunity was observed in baby monkeys exposed to this drug in utero at all doses. The effects of immunosuppression in baby monkeys were greater than clinically assumed. Evolocumab has not been evaluated for immune suppression in baby monkeys. Measurable serum concentrations of evolocumab were observed in baby monkeys at birth at levels comparable to maternal serum levels, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier.FDA experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they can cross the placenta in increasing numbers during the second and third trimester. Before prescribing REPATHA to pregnant women, consider the benefits and risks of REPATHA and the possible risks to the fetus.

    In the general US population, the estimated background risk of serious birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

    Data

    Animal data

    No effect on fetal-fetal or postnatal development (up to 6 months of age) was observed in cynomolgus monkeys when Evolocumab was administered during prepartum organogenesis at a dose of 50 mg / kg once every 2 weeks by the subcutaneous route at exposures of 30 and 12. – increase the recommended human doses to 140 mg every 2 weeks and 420 mg once a month, respectively, based on plasma AUC. A test for humoral immunity in baby monkeys with evolocumab has not been performed.

    Breastfeeding
    Summary of Risks

    There is no information available regarding the presence of evolocumab in breast milk, its effect on the infant or its effect 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 side effects of REPATHA or the underlying mother’s condition to the infant. Human IgG is present in breast milk, but published evidence suggests that antibodies to breast milk do not enter the bloodstream of newborns and infants in significant amounts.

    Pediatric use

    The safety and efficacy of REPATHA in combination with diet and other LDL-C lowering therapies in HoFH adolescents requiring additional LDL-C lowering have been established based on 12-week placebo-controlled data. a study involving 10 adolescents (13 to 17 years old) with HoFH [see. Clinical studies ]. In this study, 7 adolescents received REPATHA 420 mg subcutaneously once a month and 3 adolescents received a placebo.The effect of REPATHA on LDL-C was generally similar to that seen in adult HoFH patients. Based on the experience of open-label, uncontrolled studies, a total of 14 adolescents with HoFH received REPATHA with an average exposure of 9 months. The safety profile of REPATHA in these adolescents was similar to that described for adult HoFH patients.

    The safety and efficacy of REPATHA have not been established in pediatric HoFH patients younger than 13 years of age.

    The safety and efficacy of REPATHA in pediatric patients with primary hyperlipidemia or HeFH have not been established.

    Geriatric use

    In controlled trials, 7656 (41%) patients treated with REPATHA had? 65 years old and 1500 (8%) were & ge; 75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not shown differences in responses between older and younger patients, but higher sensitivity in some older people cannot be ruled out.

    Renal impairment

    No dose adjustment is required in patients with renal impairment. CLINICAL PHARMACOLOGY ].

    Hepatic impairment

    In patients with mild to moderate hepatic impairment (Child-Pugh A or B), dose adjustment is not required. There are no data on patients with severe hepatic impairment [see. CLINICAL PHARMACOLOGY ].

    Overdose and contraindications

    OVERDOSE

    No information provided

    CONTRAINDICATIONS

    REPATHA is contraindicated in patients with a history of serious hypersensitivity reactions to REPATHA.In patients treated with REPATHA [see. WARNINGS AND PRECAUTIONS ].

    Clinical Pharmacology

    CLINICAL PHARMACOLOGY

    Mechanism of Action

    Evolocumab is a human monoclonal IgG2 directed against the human proprotein convertase subtilisin kexin 9 (PCSK9). Evolocumab binds to PCSK9 and interferes with the binding of circulating PCSK9 to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated degradation of LDLR and allowing LDLR to return to the surface of liver cells.By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the amount of LDLR available to remove LDL from the blood, thereby lowering LDL-C levels.

    Pharmacodynamics

    After a single subcutaneous injection of 140 mg or 420 mg of evolocumab, the maximum suppression of circulating unbound PCSK9 occurred after 4 hours. Unbound PCSK9 concentrations returned to baseline when evolocumab concentrations fell below the quantification limit.

    Pharmacokinetics.

    Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9. Dose administration of 140 mg to healthy volunteers resulted in a mean Cmax (standard deviation [SD]) of 18.6 (7.3) μg / ml and a mean AUClast (SD) of 188 (98.6) day → μg / ml. Dose administration of 420 mg to healthy volunteers resulted in a mean Cmax (SD) of 59.0 (17.2) μg / ml and a mean AUClast (SD) of 924 (346) day → μg / ml. After a single intravenous injection of 420 mg, the mean systemic clearance was 12 (2) ml / hour.An approximate 2–3 fold accumulation was observed at trough serum concentrations (Cmin [SD] 7.21 [6.6]) after 140 mg subcutaneous doses every 2 weeks or after 420 mg subcutaneous monthly doses (Cmin [SD ] 11.2 [10.8]]), and the minimum serum concentrations approached stable at 12 weeks of administration.

    Absorption

    After a single subcutaneous injection of evolocumab at a dose of 140 mg or 420 mg to healthy adults, the mean peak serum concentration was reached after 3-4 days, and the calculated absolute bioavailability was 72%.

    Distribution

    After a single intravenous injection of 420 mg, the mean (standard deviation) stationary volume of distribution was 3.3 (0.5) L.

    Metabolism and excretion

    Two phases of excretion were observed for REPATHA. At low concentrations, excretion occurs predominantly through saturable binding to the target (PCSK9), while at higher concentrations, REPATHA is excreted mainly via the unsaturated proteolytic pathway.The half-life of REPATHA is 11 to 17 days.

    Specific populations

    The pharmacokinetics of evolocumab were independent of age, sex, race or creatinine clearance in all approved populations [see. Use in certain population groups ].

    Evolocumab exposure decreased with increasing body weight. These differences are not clinically relevant.

    Renal failure

    Since it is known that monoclonal antibodies are not cleared through the renal tract, renal function does not affect the pharmacokinetics of evolocumab.

    In a clinical study of 18 patients with normal renal function (estimated glomerular filtration rate [eGFR]> 90 ml / min / 1.73 m2, n = 6), severe renal impairment (eGFR, end-stage renal failure (ESRD), on hemodialysis (n = 6), exposure to evolocumab after a single subcutaneous administration of 140 mg was reduced in patients with severe renal impairment or ESRD on hemodialysis The decrease in PCSK9 levels in patients with severe renal failure or ESRD receiving hemodialysis was the same as in patients with normal renal function [see. Use in certain population groups ].

    Liver failure

    After a single subcutaneous injection of evolocumab at a dose of 140 mg in patients with mild to moderate hepatic insufficiency, lower Cmax values ​​by 20-30% and AUC by 40-50% were observed compared with healthy patients; However, there is no need for dose adjustment in these patients.

    Pregnancy

    The effect of pregnancy on the pharmacokinetics of evolocumab has not been studied [see. Use in certain population groups ].

    Studies of drug interactions

    In patients receiving simultaneously with a high-intensity statin regimen, there was a decrease in Cmax and AUC of evolocumab by about 20%. This difference has no clinical significance and does not affect dosage recommendations.

    Animal toxicology and / or pharmacology

    During the 3-month toxicology study, there was no evolocumab at a dose of 10 and 100 mg / kg once every two weeks in combination with rosuvastatin at a dose of 5 mg / kg once a day in adult monkeys. revealed the effects of evolocumab on the humoral immune response to snail saucer hemocyanin (KLH).) after 1-2 months of exposure. The highest dose tested corresponds to exposures 54 and 21 times the recommended human doses: 140 mg every 2 weeks and 420 mg once a month, respectively, based on plasma AUC. Likewise, there were no effects of evolocumab on the humoral immune response to KLH (after 3-4 months of exposure) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg / kg once a week evolocumab corresponding to exposures 744- and B 300 times more than the recommended human dose: 140 mg every 2 weeks and 420 mg once a month, respectively, based on plasma AUC.

    Clinical Trials
    Prevention of Cardiovascular Disease

    Study 1 (FOURIER, NCT01764633) was a double-blind, randomized, placebo-controlled, event-driven trial involving 27,564 (13,784 REPATHA, 13,780 placebo) adult patients with cardiovascular disease and with LDL-C; 70 mg / dl and / or cholesterol without HDL? 100 mg / dL despite high to moderate-intensity statin therapy. Patients were randomly assigned in a 1: 1 ratio for subcutaneous injection of REPATHA (140 mg every 2 weeks or 420 mg once a month) or placebo; 86% used the every 2 weeks regimen throughout the trial.The median follow-up was 26 months. Overall, 99.2% of patients were followed up until the end of the trial or death.

    Mean age (SD) at baseline was 63 (9) years, with 45% being over 65; 25% were women. The study population was 85% White, 2% Black and 10% Asian; 8% identified as Hispanics. With regard to previous diagnoses of cardiovascular disease, 81% had a prior myocardial infarction, 19% had a non-hemorrhagic stroke, and 13% had symptomatic peripheral arterial disease.Additional baseline risk factors selected included hypertension (80%), diabetes mellitus (1% type 1; 36% type 2), current daily cigarette smoking (28%), New York Heart Association class I or II. chronic heart failure (23%) and eGFR

    REPATHA significantly reduced the risk of the primary combined endpoint (time to the first onset of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina pectoris or coronary revascularization; p

    Results of primary and secondary efficacy endpoints are shown in Table 3 below.

    Table 3: Effect of REPATHA on cardiovascular events in patients with established cardiovascular disease in FOURIER

    Placebo REPATA Repatha vs. %) Morbidity rate (per 100 patient-years) N = 13784
    n (%)
    Morbidity rate (per 100 patient-years) Hazard ratio (95% CI)
    Primary component endpoint
    Time to first death from cardiovascular disease, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina 1563 (11.3) 5.2 1344 (9.8) 4.5 0.85 (0.79, 0.92)
    Key secondary compound endpoint
    Time to first death from cardiovascular diseases, myocardial infarction, stroke 1013 (7.4) 3.4 816 (5.9) 2.7 0.80 (0.73, 0.88)
    Other secondary endpoints
    Time of cardiovascular death 240 (1.7) 0.8 251 (1.8) 0.8 1.05 (0.88 , 1.25)
    Time to death for any reason to 426 (3.1) 1.4 444 (3.2) 1.5 1.04 (0.91, 1.19)
    Time to first fatal or nonfatal myocardial infarction 639 (4.6) 2.1 468 (3.4) 1.6 0.73 (0.65, 0.82)
    Time to first fatal or nonfatal stroke 262 (1.9) 0.9 207 (1.5) 0.7 0.79 (0.66, 0.95)
    Time to first coronary revascularization 965 (7.0) 3.2 759 (5.5) 2.5 0.78 (0.71, 0.86)
    Time to first hospitalization for unstable angina b 239 (1.7 ) 0.8 236 (1.7) 0.8 0.99 (0.82, 1.18)
    to Time to death for any reason is not a component of neither a primary composite endpoint, nor a key secondary composite endpoint.
    b Not predefined end point; Special analyzes were performed to ensure that results were obtained for each individual component of the primary endpoint.

    Figure 1: Estimated 3-year primary composite endpoint cumulative frequency in FOURIER

    Figure 2: Calculated 3-year key secondary composite endpoint cumulative frequency in FOURIER
    9000

    The difference between REPATHA and placebo in the mean percent change in LDL-C from baseline before week 12 was -63% (95% CI: -63%, -62%), and from baseline level up to 72 weeks – -57% (95% CI).: -58%, -56%). At week 48, the median [Q1, Q3] LDL-C was 26 [15, 46] mg / dL in the REPATHA group, with 47% of patients having LDL-C.

    Taking all estimates into account, among patients treated with REPATHA, 10401 (76%) had at least one LDL-C value.

    In EBBINGHAUS (NCT02207634), a follow-up study of 1,974 patients enrolled in the FOURIER study, REPATHA was not inferior to placebo in specific areas of cognitive function assessed by neuropsychological functional tests over a mean follow-up of 19 months.

    Primary hyperlipidemia (including heterozygous familial hypercholesterolemia)

    Study 2 (LAPLACE-2, NCT01763866) was a multicenter, double-blind, randomized, 12-week, controlled trial in which patients were initially randomized to an open-label 4-specific statin therapy a weekly period of lipid stabilization, followed by a randomized distribution into groups. subcutaneous injection of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once a month, or placebo for 12 weeks.The study included 1,896 patients with hyperlipidemia who received REPATHA, placebo, or ezetimibe as adjunctive therapy to daily doses of statins (atorvastatin, rosuvastatin, or simvastatin). Ezetimibe was also included as an active control only among those assigned background atorvastatin. Overall, the median age at baseline was 60 years (range: 20 to 80), 35% were & ge; 65 years old, 46% women, 94% white, 4% black and 1% Asian; 5% identified as Hispanic or Latino.After 4 weeks of background statin therapy, mean baseline LDL-C levels ranged from 77 to 127 mg / dL in the five background therapy groups.

    when plan B came out

    The difference between REPATHA and placebo in the mean percentage change in LDL-C from baseline to week 12 was -71% (95% CI: -74%, -67%; p

    Table 4: Effect of REPATHA on parameters lipids in patients with hyperlipidemia on background statins (mean% change from baseline to week 12 in LAPLACE-2)

    9028 every 2 weeks (n = 281)

    ) 59

    Treatment group LDL-C Non-HDL-C Apo B Total cholesterol
    REPATHA every 2 weeks versus placebo every 2 weeks (background statins: atorvastatin 10 mg or 80 mg; rosuvastatin 5 mg or 40 mg; simvastatin 40 mg)
    8 6 5 4
    REPATHA 140 mg every 2 weeks & dagger;, (n = 555) -63 -53 – 49 -36
    Mean difference from placebo (95% CI) -71
    (-74, -67)
    -59
    (-62, -55)
    -55
    (-58, -52)
    -40
    (-43, -38)
    REPATHA once a month versus placebo once a month (background statins: atorvastatin 10 or 80 mg; rosuvastatin 5 or 40 mg; simvastatin 40 mg)
    Placebo once a month (n = 277) 4 5 3 two
    REPATHA 420 mg once a month (n = 562 – -50 -46 -3.4
    Mean difference from placebo (95% CI) -63
    (-68, -57)
    -54
    (-58, – 50)
    -50
    (-53, -47)
    -36
    (-39, -33)
    REPATA every 2 weeks versus ezetimibe 10 mg / day (background statin: atorvastatin 10 mg or 80 mg)
    Ezetimibe 10 mg per day (n = 112) -17 -16 -14 -12
    REPATA 140 mg every 2 weeks’1 (n = 219) -63 -52 -49 -36
    Average difference from ezetimibe (95% CI) -Four five
    (-52, -39)
    -36
    (-41, -31)
    -35
    (-40, -31)
    -24
    (-28, -20)
    REPATHA once a month versus ezetimibe 10 mg per day (background statin: atorvastatin 10 mg or 80 mg)
    Ezetimibe 10 mg per day (n = 109) -19 – 16 -eleven -12
    REPATHA 420 mg once a month (n = 220) -59 -50 -46 -3.4
    Average difference from ezetimibe (95% CI) -41
    (-47, -35)
    -35
    (-40, -29)
    -3.4
    (-39, -30)
    -22
    ( -26, -19)
    Estimates are based on a multiple imputation model that considers adherence to treatment.
    & dagger; 140 mg every 2 weeks or 420 mg once a month leads to a similar decrease in LDL-C levels.

    Figure 3: Effect of REPATHA on LDL-C in patients with hyperlipidemia when combined with statins (change in mean% from baseline to week 12 in LAPLACE-2)

    Estimates based on a multiple imputation model that takes into account adherence to treatment. The error bars indicate the 95% confidence interval.

    Study 3 (DESCARTES, NCT01516879) was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial of 901 hyperlipidemic patients who received protocol-fixed background lipid-lowering therapy, either a cholesterol-lowering diet, or a cholesterol-lowering diet. in addition to atorvastatin (10 mg or 80 mg per day) or a combination of atorvastatin 80 mg per day with ezetimibe. After stabilization with therapy, patients were randomly assigned to either placebo or REPATHA 420 mg administered subcutaneously once a month.Overall, the median age at baseline was 56 years (range: 25 to 75), 23% were & ge; 65 years old, 52% female, 80% white, 8% black, and 6% Asian; 6% identified as Hispanic or Latino. After stabilization on prescribed background therapy, the mean baseline level of LDL-C ranged from 90 to 117 mg / dL in the four background therapy groups.

    In these patients with hyperlipidemia on the background therapy defined by the protocol, the difference between REPATHA 420 mg once a month and placebo in the mean percentage change in LDL-C from baseline before 52 weeks was -55% (95% CI: – 60%, – 50%; n

    Table 5: Effect of REPATHA on lipid parameters in patients with hyperlipidemia * (mean% change from baseline to 52 weeks in DESCARTES)

    one once a month (n = 599)

    Treatment group LDL- X Non-HDL-X Apo B Total cholesterol
    Placebo once a month (n = 302) 8 8 two 90AT 285
    -47 -39 -38 -26
    Mean difference from placebo (95% CI) -55
    (-60, -50)
    -46
    (-50, -42)
    -40
    (-44, -37)
    -31
    (-34, -28)
    Estimates based on a multiple imputation model based on adherence to treatment
    * Prior to randomization, patients were stabilized at baseline therapy consisting of a cholesterol-lowering diet, either alone or in addition to atorvastatin (10 mg or 80 mg per day) or a combination of atorvastatin 80 mg per day with ezetimibe.

    Figure 4: Effect of REPATHA 420 mg once a month on LDL-C in patients with hyperlipidemia in DECARTE

    Estimates based on a multiple imputation model that takes adherence into account. The error bars indicate the 95% confidence interval.

    Study 4 (MENDEL-2, NCT01763827) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial of 614 hyperlipidemic patients who did not receive lipid-lowering therapy at baseline.Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every 2 weeks, REPATHA 420 mg once a month, or placebo for 12 weeks. Blind administration of ezetimibe was also included as an active control. Overall, the median age at baseline was 53 years (range: 20 to 80), 18% were & ge; 65 years old, 66% were women, 83% were white, 7% were black and 9% were Asian; 11% identified as Hispanic or Latino. The mean baseline LDL-C was 143 mg / dL.

    The difference between REPATHA and placebo in the mean percentage change in LDL-C from baseline to week 12 was -55% (95% CI: -60%, -50%; p

    Table 6: Effect of REPATHA on lipid parameters in patients with hyperlipidemia (mean% change from baseline to week 12 in MENDEL-2)

    Treatment group LDL-C Non-HDL-C Apo B General cholesterol
    Placebo every 2 weeks (n = 76) one 0 one 0
    Ezetimibe 10 mg per day (n = 77) -176 -13 -10
    REPATA 140 mg every 2 weeks and dagger; (n = 153) -54 -47 -44 -3.4
    Average difference from placebo (95% CI) -55
    (-60, -50) 9028 5

    -47
    (-52, -43)
    -Four five
    (-50, -41)
    -3.4
    (-37, -30)
    Average difference from ezetimibe (95% CI) -37
    (-42, -32)
    -33
    (-37, -29)
    -32
    (-36, -27)
    -2.3
    (-27, – 20)
    Placebo once a month (n = 78) one two two 0
    Ezetimibe 10 mg per day (n = 77) -18 -13 -12
    REPATHA 420 mg once a month (n = 153) -56 -49 -46 -35
    Average difference from placebo (95 % CI) -57
    (-61, -52)
    -51
    (-54, -47)
    -48
    (-52, -44)
    -35
    (-38, -32 )
    Average difference from ezetimibe (95% CI) -38
    (-42, -34)
    -32
    (-36, -29)
    -33
    (-36, -29)
    -2.3
    (-26, – 20)
    Estimates based on the adherence multiple imputation model
    & dagger; 140 mg every 2 weeks or 420 mg once a month leads to a similar decrease in LDL-C levels.

    Study 5 (RUTHERFORD-2, NCT01763918) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial involving 329 patients with heterozygous familial hypercholesterolemia (HeFH) who were taking statidins with other hypolipolemia drugs or without them … Patients were randomized to receive subcutaneous injections of REPATHA 140 mg every two weeks, 420 mg once a month, or placebo. HeFH was diagnosed by Simon Broome’s criteria (1991).In Study 5, 38% of patients had clinical atherosclerotic cardiovascular disease. The median age at baseline was 51 years (range: 19 to 79 years), 15% of patients were & ge; 65 years old, 42% were female, 90% were white, 5% were Asian and 1% were black. The mean baseline LDL cholesterol was 156 mg / dL, and 76% of patients received high-intensity statin therapy.

    Differences between REPATHA and placebo in mean percent change in LDL-C from baseline to week 12 were -61% (95% CI: -67%, -55%; p

    Table 7: Effect of REPATHA on lipid parameters in patients with HeFH (mean% change from baseline to week 12 in RUTHERFORD-2)

    Treatment group LDL-C Non-HDL-C Apo B General cholesterol
    Placebo every 2 weeks (n = 54) -1 -1 -1 – two
    REPATA 140 mg every 2 weeks and a dagger; (n = 110) -62 -56 -49 -42
    Mean difference from placebo (95% CI) -61
    (-67, -55)
    -54
    (-60, -49 )
    -49
    (-54, -43)
    -40
    (-45, -36)
    Placeb o once a month (n = 55) 4 4 4 two
    REPATHA 420 mg once a month (n = 110) -56 -49 -44 -37
    Mean difference from placebo (95% CI) -60
    (-68, -52)
    -53
    (-60, -46)
    -48
    (-55, -41)
    -39
    (-45, -33)
    Estimates based on the adherence multiple imputation model
    & dagger; 140 mg every 2 weeks or 420 mg once a month leads to a similar decrease in LDL-C levels.

    Figure 5: Effect of REPATHA on LDL-C in HeFH Patients (Mean% change from baseline to week 12 at RUTHERFORD-2)

    N = number of patients , randomized and dosed in a complete set of analyzes. Estimates based on a multiple imputation model that takes into account adherence to treatment. The error bars indicate the 95% confidence interval.

    Homozygous familial hypercholesterolemia (HoFH)

    Study 6 (TESLA, NCT01588496) was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not receiving lipid apheresis therapy) with familial hypercholesterolemia HoFH).In this study, 33 patients received subcutaneous injections of 420 mg REPATHA once a month, and 16 patients received placebo as an adjunct to other lipid-lowering drugs (eg, statins, ezetimibe). The median age at baseline was 31 years, with 49% female, 90% white, 4% Asian, and 6% others. The study included 10 adolescents (ages 13 to 17), 7 of whom received REPATHA. The mean LDL cholesterol at baseline was 349 mg / dL in all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe.The diagnosis of HoFH was based on genetic confirmation or clinical diagnosis based on a history of untreated LDL-C concentrations> 500 mg / dL along with xanthoma before age 10 years or evidence of HeFH in both parents.

    The difference between REPATHA and placebo in the mean percentage change in LDL-C from baseline to week 12 was -31% (95% CI: -44%, -18%; p allele to LDL receptors (residual function is practically absent), did not respond to REPATHA.

    Table 8: Effect of REPATHA on lipid parameters in HoFH patients (mean% change from baseline to week 12 at TESLA)

    Treatment group LDL-C Non-HDL- X Apo B Total cholesterol
    Placebo once a month (n = 16) 9 8 4 8
    REPATHA 420 mg = once a month ) -22 -20 -17 -17
    Mean difference from placebo (95% CI) -31
    (-44, -18)
    -28
    (-41 , -16)
    -21
    (-33, -9)
    -25
    (-36, -14)
    Estimates based on the adherence multiple imputation model

    Drug guidelines

    PATIENT INFORMATION 901 91

    No information provided.Please refer to the WARNINGS AND PRECAUTIONS sections.

    REPATA solution – instructions for use, price, dosages, analogs, contraindications

    Active ingredient

    – evolocumab

    Composition and release form of the drug

    Solution for s / c administration from colorless to yellowish, transparent or slightly opalescent, free from mechanical impurities.

    1 ml
    evolocumab 140 mg

    Excipients: proline – 25 mg, glacial acetic acid – 1.2 mg, polysorbate 80 – 0.1 mg, sodium hydroxide – in the amount necessary to bring the pH to 5.0, water d / i – in the amount required for bringing the volume to 1 ml.

    1 ml – glass syringes (1) – contour packs (1) – cardboard packs.
    1 ml – syringe pens (1) – cardboard packs.
    1 ml – syringe pens (2) – cardboard packs.
    1 ml – syringe pens (2) – cardboard packs (3) – packaging.

    Pharmacological action

    Lipid-lowering agent. Evolocumab selectively binds to PCSK9 and prevents the binding of circulating PCSK9 to the LDL receptor on the surface of liver cells, thus preventing PC8K9-mediated degradation of R-LDL. As a result, an increase in the expression of R-LDL in the liver leads to a decrease in the serum concentration of LDL cholesterol.

    In patients with primary hypercholesterolemia and mixed dyslipidemia, the drug reduces the concentrations of unbound PCSK9, LDL-C, total cholesterol (TC), apolipoprotein B (ApoB), high-density non-lipoprotein cholesterol (non-HDL cholesterol), LDL cholesterol and a) (Lp [a]), increases the concentration of HDL-C and apolipoprotein A1 (ApoA1), improving the ratio of TC / HDL-C, ApoB / apolipoprotein A1 (ApoA1).

    A single SC administration of 140 or 420 mg of evolocumab leads to maximum suppression of circulating unbound PCSK9 after 4 hours, which is accompanied by a decrease in LDL-C, reaching the mean nadir by 14 and 21 days, respectively.Changes in the concentration of unbound PCSK9 and serum lipoproteins are reversible after discontinuation of evolocumab. There was no increase in the concentration of unbound PCSK9 or LDL-C above baseline, which indicates that a compensatory mechanism for an increase in the production of PCSK9 and LDL-C does not occur during treatment.

    With a dosage regimen of 140 mg evolocumab every two weeks or 420 mg evolocumab once a month, the maximum decrease in LDL-C reached -72% to -57% of the initial values ​​compared with placebo.The dosing regimens are equivalent in terms of the mean reduction in LDL-C (mean between weeks 10 and 12).

    A similar decrease in LDL-C was observed both with the use of evolocumab in monotherapy and in combination therapy with other lipid-lowering drugs.

    Related news

    Pharmacokinetics

    The median maximum serum concentration was achieved within 3-4 days after a single subcutaneous injection of evolocumab 140 mg or 420 mg to healthy volunteers.The mean maximum concentration (C max [SD]) was 13 (10.4) μg / ml after a single subcutaneous dose of 140 mg. AUC last [SD] was 96/5 (78/7) days • μg / ml. Similar values ​​for C max (SD) and AUC last (SD) were 46 (17/2) μg / ml and 842 (333) days • μg / ml, respectively, after a 420 mg dose. Three subcutaneous doses of 140 mg were bioequivalent to a subcutaneous dose of 420 mg. The absolute bioavailability was defined as 72% compared to pharmacokinetic models after subcutaneous administration.

    Average V d at equilibrium was 3.3 (0.5) L after a single dose of 420 mg IV evolocumab, suggesting limited tissue distribution of evolocumab.

    It is assumed that the metabolism and excretion of the drug occurs by standard pathways of cleavage of immunoglobulins, the result of which is degradation to small peptides and individual amino acids.

    The calculated effective T 1/2 evolocumab was 11 to 17 days.

    In patients with primary hypercholesterolemia or mixed dyslipidemia receiving high doses of statins, the value of systemic exposure of evolocumab was slightly lower than in patients receiving statin at a low or medium dose (AUC ratio last 0.74 [90% CI: 0.29-1.9] ). The approximately 20% increase in clearance is due in part to an increase in PCSK9 concentration, which in turn is caused by statins, which, however, does not adversely affect the lipid pharmacodynamics of evolocumab.Population pharmacokinetic analysis did not reveal significant differences in the serum concentrations of evolocumab in patients with hypercholesterolemia, including familial ones, while taking statins.

    Indications

    Adults with diagnosed cardiovascular diseases caused by atherosclerosis (myocardial infarction, stroke or lower limb artery disease) in order to reduce the risk of cardiovascular complications by reducing the concentration of LDL-C, in addition to correcting other risk factors : in combination with the maximum tolerated dose of statin, or in combination with the maximum tolerated dose of statin and other lipid-lowering therapy, in monotherapy or in combination with other lipid-lowering therapy in patients with intolerance to statins or with contraindications to their use; hypercholesterolemia and mixed dyslipidemia: in combination with a statin or in combination with a statin and other lipid-lowering therapy in patients who do not achieve target LDL-C levels at the maximum tolerated dose of statin, or in monotherapy or in combination with other lipid-lowering therapy in patients with statin intolerance, or having contraindications to their use; homozygous familial hypercholesterolemia.

    Contraindications

    Age up to 18 years with primary hypercholesterolemia and mixed dyslipidemia; children under 12 years of age with homozygous familial hypercholesterolemia.

    Caution

    Severe renal impairment, severe hepatic impairment (Child-Pugh class C), pregnancy and breastfeeding.

    Dosage

    Subcutaneous.

    Primary hypercholesterolemia and mixed dyslipidemia in adults

    The recommended dose is either 140 mg every 2 weeks or 420 mg monthly.

    Homozygous familial hypercholesterolemia in adults and adolescents aged 12 years and older

    The initial recommended dose is 420 mg once a month. After 12 weeks of treatment, the dosing frequency may be increased to 420 mg every 2 weeks if no clinically significant response is observed.

    Diagnosed cardiovascular disease of atherosclerotic genesis in adults

    The recommended dose is 140 mg every 2 weeks or 420 mg once a month.

    Side effects

    Infectious and parasitic diseases: often – influenza, nasopharyngitis, upper respiratory tract infections.

    From the immune system: often – skin rash; infrequently – urticaria.

    From the gastrointestinal tract: often – nausea.

    From the musculoskeletal system: often – back pain, arthralgia.

    Local reactions: often – reactions at the injection site.

    Drug interactions

    Pharmacokinetic interactions between statins and evolocumab were evaluated in clinical research programs. There was an increase in the clearance of evolocumab by approximately 20% when used concomitantly with statins. The increased clearance is due to statin-mediated increases in PCSK9 concentration, which, however, did not affect the pharmacodynamic effect of evolocumab on lipids. No dose adjustment of statins is required when administered concomitantly with evolocumab.

    Since no compatibility studies have been conducted, evolocumab should not be mixed with other drugs.

    Special instructions

    In patients with severe renal insufficiency, the drug should be used with caution.

    In patients with moderate hepatic impairment, there was a decrease in the exposure to evolocumab, which could potentially lead to a decrease in the effect on LDL-C. Therefore, such patients require careful monitoring.In patients with severe hepatic impairment, the drug should be used with caution.

    The needle cap of the glass pre-filled syringe is made of dry natural rubber (latex derivative), which may cause allergic reactions.

    This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. can in fact be considered “sodium free”.

    Pregnancy and lactation

    Use during pregnancy is possible only if the intended benefit to the mother outweighs the potential risk to the fetus.

    The decision to discontinue the drug or stop breastfeeding should be made based on an assessment of the potential benefits of continuing therapy for the mother or the possible risk of adverse effects on the newborn.

    Use in children

    Use is contraindicated in children under 18 years of age with primary hypercholesterolemia and mixed dyslipidemia.

    Use is contraindicated in children under 12 years of age with homozygous familial hypercholesterolemia.

    The description of the REPATA preparation is based on the officially approved instructions for use and approved by the manufacturer.

    The price information provided for the drugs does not constitute an offer to sell or buy a product. The information is intended solely for comparing prices in inpatient pharmacies operating in accordance with Article 55 of the Federal Law “On Circulation of Medicines”.

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    instructions for use, dosage, composition, analogs, side effects / Pillintrip

    Pharmacotherapeutic group: Other lipid modifying agents.ATC code: C10AX13

    Mechanism of action

    Evolocumab binds selectively to PCSK9 and prevents circulating PCSK9 from binding to the low density lipoprotein receptor (LDLR) on the liver cell surface, thus preventing PCSK9-mediated LDLR degradation. Increasing liver LDLR levels results in associated reductions in serum LDL-cholesterol (LDL-C).

    Pharmacodynamic effects

    In clinical trials, Repatha reduced unbound PCSK9, LDL-C, TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1, VLDL-C, TG and Lp (a), and increased HDL-C and ApoA1 in patients with primary hypercholesterolaemia and mixed dyslipidaemia.

    A single subcutaneous administration of Repatha 140 mg or 420 mg resulted in maximum suppression of circulating unbound PCSK9 by 4 hours followed by a reduction in LDL-C reaching a mean nadir in response by 14 and 21 days, respectively. Changes in unbound PCSK9 and serum lipoproteins were reversible upon discontinuation of Repatha. No increase in unbound PCSK9 or LDL-C above baseline was observed during the washout of evolocumab suggesting that compensatory mechanisms to increase production of PCSK9 and LDL-C do not occur during treatment.

    Subcutaneous regimens of 140 mg every 2 weeks and 420 mg once monthly were equivalent in average LDL-C lowering (mean of weeks 10 and 12) resulting in -72 to -57% from baseline compared with placebo. Treatment with Repatha resulted in a similar reduction of LDL-C when used alone or in combination with other lipid-lowering therapy.

    Clinical efficacy in primary hypercholesterolaemia and mixed dyslipidaemia

    LDL-C reduction of approximately 55% to 75% was achieved with Repatha as early as week 1 and maintained during long-term therapy.Maximal response was generally achieved within 1 to 2 weeks after dosing with 140 mg every 2 weeks and 420 mg once monthly. Repatha was effective in all subgroups relative to placebo and ezetimibe, with no notable differences observed between subgroups, such as age, race, gender, region, body-mass index, National Cholesterol Education Program risk, current smoking status, baseline coronary heart disease ( CHD) risk factors, family history of premature CHD, glucose tolerance status, (ie diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, statin dose and intensity, unbound baseline PCSK9, baseline LDL-C and baseline TG.

    In 80-85% of all primary hyperlipidaemia patients treated with either dose, Repatha demonstrated a> 50% reduction in LDL-C at the mean of weeks 10 and 12. Up to 99% of patients treated with either dose of Repatha achieved an LDL-C of <2.6 mmol / L and up to 95% achieved an LDL-C <1.8 mmol / L at the mean of weeks 10 and 12.

    Combination with a statin and statin with other lipid-lowering therapies

    LAPLACE-2 was an international, multicenter, double-blind, randomized, 12-week study in 1,896 patients with primary hypercholesterolaemia or mixed dyslipidaemia who were randomized to receive Repatha in combination with statins (rosuvastatin, simvastatin or atorvastatin).Repatha was compared to placebo for the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe for the atorvastatin group.

    Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with placebo for the rosuvastatin and simvastatin groups and compared with placebo and ezetimibe for the atorvastatin group (p <0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1, VLDL-C, TG and Lp (a) and increased HDL-C from baseline to mean of weeks 10 and 12 as compared to placebo for the rosuvastatin and simvastatin groups (p <0.05) and significantly reduced TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1 and Lp (a), compared with placebo and ezetimibe for the atorvastatin group (p <0.001) (see tables 2 and 3 ).

    RUTHERFORD-2 was an international, multicenter, double-blind, randomized, placebo-controlled, 12-week study in 329 patients with heterozygous familial hypercholesterolaemia on lipid-lowering therapies. Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with placebo (p <0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1, VLDL-C, TG and Lp (a) and increased HDL-C and ApoA1 from baseline to mean of weeks 10 and 12 compared to placebo (p <0.05) (see table 2).

    Table 2. Treatment effects of Repatha compared with placebo in patients with primary hypercholesterolaemia and mixed dyslipidaemia – mean percent change from baseline to average of weeks 10 and 12 (%, 95% CI)

    Study

    Dose regimen

    LDL-C

    (%)

    Non-HDL-C

    (%)

    ApoB

    (%)

    TC

    (%)

    Lp (a)

    (%)

    VLDL-C

    (%)

    HDL-C

    (%)

    TG

    (%)

    ApoA1

    (%)

    TC / HDL-C ratio

    %

    ApoB / ApoA1 ratio

    %

    LAPLACE-2

    (HMD)

    (combined rosuvastatin, simvastatin, & atorvastatin groups)

    140 mg Q2W

    (N = 555)

    -72 b

    (-75, -69)

    -60 b

    (-63, -58)

    -56 b

    (-58, -53)

    -41 b

    (-43, -39)

    -30 b

    (-35, -25)

    -18 b

    (-23, -14)

    6 b

    (4.8)

    -17 b

    (-22, -13)

    3 b

    (1.5)

    -45 b

    (-47, -42)

    -56 b

    (-59, -53)

    420 mg QM

    (N = 562)

    -69 b

    (-73, -65)

    -60 b

    (-63, -57)

    -56 b

    (-58, -53)

    -40 b

    (-42, -37)

    -27 b

    (-31, -24)

    -22 b

    (-28, -17)

    8 b

    (6.10)

    -23 b

    (-28, -17)

    5 b

    (3.7)

    -46 b

    (-48, -43)

    -58 b

    (-60, -55)

    RUTHERFORD-2

    (HeFH)

    140 mg Q2W

    (N = 110)

    -61 b

    (-67, -55)

    -56 b

    (-61, -51)

    -49 b

    (-54, -44)

    -42 b

    (-46, -38)

    -31 b

    (-38, -24)

    -22 b

    (-29, -16)

    8 b

    (4.12)

    -22 b

    (-29, -15)

    7 a

    (3.12)

    -47 b

    (-51, -42)

    -53

    (-58, -48)

    420 mg QM

    (N = 110)

    -66 b

    (-72, -61)

    -60 b

    (-65, -55)

    -55 b

    (-60, -50)

    -44 b

    (-48, -40)

    -31 b

    (-38, -24)

    -16 b

    (-23, -8)

    9 b

    (5.14)

    -17 b

    (-24, -9)

    5 a

    (1.9)

    -49 b

    (-54, -44)

    -56 b

    (-61, -50)

    Key: Q2W = once every 2 weeks, QM = once monthly, HMD = Primary hypercholesterolaemia and mixed dyslipidaemia; HeFH = Heterozygous familial hypercholesterolaemia; a p value <0.05 when compared with placebo. b p value <0.001 when compared with placebo.

    Statin intolerant patients

    GAUSS-2 was an international, multicenter, double-blind, randomized, ezetimibe-controlled, 12-week study in 307 patients who were statin-intolerant or unable to tolerate an effective dose of a statin. Repatha significantly reduced LDL-C compared with ezetimibe (p <0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1 and Lp (a), from baseline to mean of weeks 10 and 12 compared to ezetimibe (p <0.001) (see table 3).

    Treatment in the absence of a statin

    MENDEL-2 was an international, multicenter, double-blind, randomized, placebo and ezetimibe-controlled, 12-week study of Repatha in 614 patients with primary hypercholesterolaemia and mixed dyslipidaemia. Repatha significantly reduced LDL-C from baseline to mean of weeks 10 and 12 compared with both placebo and ezetimibe (p <0.001). Repatha significantly reduced TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1 and Lp (a), from baseline to mean of weeks 10 and 12 compared with both placebo and ezetimibe (p <0.001) (see table 3).

    Table 3. Treatment effects of Repatha compared with ezetimibe in patients with primary hypercholesterolaemia and mixed dyslipidaemia – mean percent change from baseline to average of weeks 10 and 12 (%, 95% CI)

    Study

    Dose regimen

    LDL-C

    (%)

    Non-HDL-C

    (%)

    ApoB

    (%)

    TC

    (%)

    Lp (a)

    (%)

    VLDL-C

    (%)

    HDL-C

    (%)

    TG

    (%)

    ApoA1

    (%)

    TC / HDL-C ratio

    %

    ApoB / ApoA1 ratio

    %

    LAPLACE-2

    (HMD)

    (combined atorvastatin groups)

    140 mg Q2W

    (N = 219)

    -43 c

    (-50, -37)

    -34 c

    (-39, -30)

    -34 c

    (-38, -30)

    -23 c

    (-26, -19)

    -30 c

    (-35, -25)

    -1

    (-7, 5)

    7 s

    (4, 10)

    -2

    (-9, 5)

    7 s

    (4, 9)

    -27 c

    (-30, -23)

    -38 c

    (-42, -34)

    420 mg QM

    (N = 220)

    -46 c

    (-51, -40)

    -39 c

    (-43, -34)

    -40 c

    (-44, -36)

    -25 c

    (-29, -22)

    -33 c

    (-41, -26)

    -7

    (-20, 6)

    8 s

    (5, 12)

    -8

    (-21, 5)

    7 s

    (2, 11)

    -30 c

    (-34, -26)

    -42 c

    (-47, -38)

    GAUSS-2

    (statin intolerant)

    140 mg Q2W

    (N = 103)

    -38 b

    (-44, -33)

    -32 b

    (-36, -27)

    -32 b

    (-37, -27)

    -24 b

    (-28, -20)

    -24 b

    (-31, -17)

    -2

    (-10, 7)

    5

    (1, 10)

    -3

    (-11, 6)

    5 a

    (2, 9)

    -27 b

    (-32, -23)

    -35 b

    (-40, -30)

    420 mg QM

    (N = 102)

    -39 b

    (-44, -35)

    -35 b

    (-39, -31)

    -35 b

    (-40, -30)

    -26 b

    (-30, -23)

    -25 b

    (-34, -17)

    -4

    (-13, 6)

    6

    (1, 10)

    -6

    (-17, 4)

    3

    (-1, 7)

    -30 b

    (-35, -25)

    -36 b

    (-42, -31)

    MENDEL-2

    (treatment in the absence of a statin)

    140 mg Q2W

    (N = 153)

    -40 b

    (-44, -37)

    -36 b

    (-39, -32)

    -34 b

    (-37, -30)

    -25 b

    (-28, -22)

    -22 b

    (-29, -16)

    -7

    (-14, 1)

    6 a

    (3, 9)

    -9

    (-16, -1)

    3

    (0, 6)

    -29 b

    (-32, -26)

    -35 b

    (-39, -31)

    420 mg QM

    (N = 153)

    -41 b

    (-44, -37)

    -35 b

    (-38, -33)

    -35 b

    (-38, -31)

    -25 b

    (-28, -23)

    -20 b

    (-27, -13)

    -10

    (-19, -1)

    4

    (1, 7)

    -9

    (-18, 0)

    4 a

    (1, 7)

    -28 b

    (-31, -24)

    -37 b

    (-41, -32)

    Key: Q2W = once every 2 weeks, QM = once monthly, HMD = Primary hypercholesterolaemia and mixed dyslipidaemia, a p value <0.05 when compared with ezetimibe, b p value <0.001 when compared with ezetimibe, c nominal p value <0.001 when compared with ezetimibe.

    Long-term efficacy in primary hypercholesterolaemia and mixed dyslipidaemia

    DESCARTES was an international, multicentre, double-blind, randomized, placebo-controlled, 52-week study in 901 patients with hyperlipidaemia who received diet alone, atorvastatin, or a combination of atorvastatin and ezetimibe.Repatha 420 mg once monthly significantly reduced LDL-C from baseline at 52 weeks compared with placebo (p <0.001). Treatment effects were sustained over 1 year as demonstrated by reduction in LDL-C from week 12 to week 52. Reduction in LDL-C from baseline at week 52 compared with placebo was consistent across background lipid-lowering therapies optimized for LDL-C and cardiovascular risk.

    Repatha significantly reduced TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1, VLDL-C, TG and Lp (a), and increased HDL-C and ApoA1 at week 52 compared with placebo (p <0.001) (table 4).

    Table 4. Treatment effects of Repatha compared with placebo in patients with primary hypercholesterolaemia and mixed dyslipidaemia – mean percent change from baseline to week 52 (%, 95% CI)

    Study

    Dose regimen

    LDL-C

    (%)

    Non-HDL-C

    (%)

    ApoB

    (%)

    TC

    (%)

    Lp (a)

    (%)

    VLDL-C

    (%)

    HDL-C

    (%)

    TG

    (%)

    ApoA1

    (%)

    TC / HDL-C ratio

    %

    ApoB / ApoA1 ratio

    %

    DESCARTES

    420 mg QM

    (N = 599)

    -59 b

    (-64, -55)

    -50 b

    (-54, -46)

    -44 b

    (-48, -41)

    -33 b

    (-36, -31)

    -22 b

    (-26, -19)

    -29 b

    (-40, -18)

    5 b

    (3, 8)

    -12 b

    (-17, -6)

    3 a

    (1, 5)

    -37 b

    (-40, -34)

    -46 b

    (-50, -43)

    Key: QM = once monthly, a nominal p value <0.001 when compared with placebo, b p value <0.001 when compared with placebo.

    OSLER and OSLER-2 are two ongoing, randomized, controlled, open-label extension studies to assess the long-term safety and efficacy of Repatha in patients who completed treatment in a ‘parent’ study. In each extension study, patients were randomized 2: 1 to receive either Repatha plus standard of care (evolocumab group) or standard of care alone (control group) for the first year of the study.At the end of the first year (week 52 in OSLER and week 48 in OSLER-2), patients were eligible to enter the all Repatha period in which all patients could receive open-label Repatha for either another 4 years (OSLER) or 1 year (OSLER-2).

    A total of 1,324 patients enrolled in OSLER. Repatha 420 mg once monthly significantly reduced LDL-C from baseline at week 12 and week 52 compared with control (nominal p <0.001). Treatment effects were maintained over 124 weeks as demonstrated by reduction in LDL-C from week 12 in the parent study to week 112 in the open-label extension.A total of 2,928 patients enrolled in OSLER-2. Repatha significantly reduced LDL-C from baseline at week 12 compared with control (nominal p <0.001). Treatment effects were maintained as demonstrated by reduction in LDL-C from week 12 to week 24 in the open-label extension. Repatha significantly reduced TC, ApoB, non-HDL-C, TC / HDL-C, ApoB / ApoA1, VLDL-C, TG and Lp (a), and increased HDL-C and ApoA1 from baseline to week 52 in OSLER and to week 24 in OSLER-2 compared with control (nominal p <0.001). LDL-C and other lipid parameters returned to baseline within 12 weeks after discontinuation of Repatha at the beginning of OSLER or OSLER-2 without evidence of rebound.

    TAUSSIG is an ongoing multicenter, open-label, 5-year extension study to assess the long-term safety and efficacy of Repatha, as an adjunct to other lipid-lowering therapies, in patients with severe familial hypercholesterolaemia, including homozygous familial hypercholesterolaemia. A total of 102 severe familial hypercholesterolaemia patients and 96 homozygous familial hypercholesterolaemia patients enrolled in TAUSSIG.All patients in the study were initially treated with Repatha 420 mg once monthly, except for those receiving apheresis at enrolment who began with Repatha 420 mg once every 2 weeks. Dose frequency in non-apheresis patients could be titrated up to 420 mg once every 2 weeks based on LDL-C response and PCSK9 levels. Long-term use of Repatha demonstrated a sustained treatment effect as evidenced by reduction of LDL-C in patients with severe familial hypercholesterolaemia (table 5).

    Changes in other lipid parameters (TC, ApoB, non-HDL-C, TC / HDL-C, and ApoB / ApoA1) also demonstrated a sustained effect of long-term Repatha administration in patients with severe familial hypercholesterolaemia.

    Table 5. Effect of Repatha on LDL-C in patients with severe familial hypercholesterolaemia – median percent change from baseline to OLE week 36

    Patient population

    (N)

    OLE week 12

    (n = 16)

    OLE week 24

    (n = 8)

    OLE week 36

    (n = 5)

    Severe FH (N = 102)

    -47

    -45

    -48

    Key: OLE = open-label extension, N (n) = Number of evaluable patients (N) and patients with observed LDL values ​​at specific scheduled visit (n) in the severe familial hypercholesterolaemia interim analysis set.

    The long-term safety of sustained very low levels of LDL-C (i.e. <0.65 mmol / L [<25 mg / dL]) has not yet been established.

    Treatment of homozygous familial hypercholesterolaemia

    TESLA was an international, multicenter, double-blind, randomized, placebo-controlled 12-week study in 49 homozygous familial hypercholesterolaemia patients aged 12 to 65 years. Repatha 420 mg once monthly, as an adjunct to other lipid-lowering therapies (e.g., statins, bile-acid sequestrants), significantly reduced LDL-C and ApoB at week 12 compared with placebo (p <0.001) (table 6). Changes in other lipid parameters (TC, non-HDL-C, TC / HDL-C, and ApoB / ApoA1) also demonstrated a treatment effect of Repatha administration in patients with homozygous familial hypercholesterolaemia.

    Table 6. Treatment effects of Repatha compared with placebo in patients with homozygous familial hypercholesterolaemia – mean percent change from baseline to week 12 (%, 95% CI)

    Study

    Dose regimen

    LDL-C

    (%)

    Non-HDL-C

    (%)

    ApoB

    (%)

    TC

    (%)

    Lp (a)

    (%)

    VLDL-C

    (%)

    HDL-C

    (%)

    TG

    (%)

    TC / HDL-C Ratio

    %

    ApoB / ApoA1 Ratio

    %

    TESLA

    (HoFH)

    420 mg QM

    (N = 33)

    -32 b

    (-45, -19)

    -30 a

    (-42, -18)

    -23 b

    (-35, -11)

    -27 a

    (-38, -16)

    -12

    (-25, 2)

    -44

    (-128, 40)

    -0.1

    (-9, 9)

    0.3

    (-15, 16)

    -26 a

    (-38, -14)

    -28 a

    (-39, -17)

    Key: HoFH = homozygous familial hypercholesterolaemia, QM = once monthly, a nominal p value <0.001 when compared with placebo, b p value <0.001 when compared with placebo.

    Long-term efficacy in homozygous familial hypercholesterolaemia

    In TAUSSIG, long-term use of Repatha demonstrated a sustained treatment effect as evidenced by reduction of LDL-C of approximately 20% to 30% in patients with homozygous familial hypercholesterolaemia not on apheresis and approximately 15% to 25% in patients with homozygous familial hypercholesterolaemia on apheresis (table 7).Changes in other lipid parameters (TC, ApoB, non-HDL-C, TC / HDL-C, and ApoB / ApoA1) also demonstrated a sustained effect of long-term Repatha administration in patients with homozygous familial hypercholesterolaemia. Reductions in LDL-C and changes in other lipid parameters in 13 adolescent patients (aged> 12 to <18 years) with homozygous familial hypercholesterolaemia are comparable to those in the overall population of patients with homozygous familial hypercholesterolaemia.

    Table 7.Effect of Repatha on LDL-C in patients with homozygous familial hypercholesterolaemia – mean percent change from baseline to OLE week 36

    Patient population

    (N)

    OLE week 12

    OLE week 24

    OLE week 36

    HoFH

    (N = 96)

    -20

    (n = 70)

    -23

    (n = 46)

    -24

    (n = 30)

    Non-apheresis

    (N = 65)

    -22

    (n = 46)

    -24

    (n = 33)

    -24

    (n = 27)

    Apheresis

    (N = 31)

    -17

    (n = 24)

    -20

    (n = 13)

    -21

    (n = 3)

    Key: OLE = open-label extension.N (n) = Number of evaluable patients (N) and patients with observed LDL values ​​at specific schedule visit (n) in the HoFH interim analysis set.

    Effect on atherosclerotic disease burden

    The effects of Repatha 420 mg once monthly on atherosclerotic disease burden, as measured by intravascular ultrasound (IVUS), were evaluated in a 78-week double-blind, randomized, placebo controlled study in 968 patients with coronary artery disease on a stable background of optimal statin therapy.Repatha reduced both percent atheroma volume (PAV; 1.01% [95% CI 0.64, 1.38], p <0.0001) and total atheroma volume (TAV; 4.89 mm 3 [95% CI 2.53, 7.25], p <0.0001) compared with placebo. Atherosclerotic regression was observed in 64.3% (95% CI 59.6, 68.7) and 47.3% (95% CI 42.6, 52.0) of patients who received Repatha or placebo respectively when measured by PAV. When measured by TAV, atherosclerotic regression was observed in 61.5% (95% CI 56.7, 66.0) and 48.9% (95% CI 44.