SPC

Question 1

The dose of Praluent can be individualised based on which patient?

Answer 1

Based on baseline LDL-C level, goal of the therapy & response by the patient.

Question 2

Why are lipid levels assessed at the 4 week time point to consider adjusting dose?

Answer 2

When steady state LDC-C is usually achieved

Question 3

When alirocumab is used concomitantly with statins, how much lower is the exposure to alirocumab?

Answer 3

The exposure to alirocumab is 40% because statins & other lipid modifying therapy are known to increase the production of PCSK9, the protein targeted by alirocumab

Question 4

How many patients aged 65 & over and 75 and over were included in the safety analysis of patients and what differences were observed in these groups?

Answer 4

There were 1158 patients over 65yrs

There were 241 patients over 75yrs and no sig differences were observed in S&E

Question 5

What % of patients treated with Praluent had two consecutive values of LDL-C of less than 0.65%

Answer 5

796 patients from 3340 patients i.e. 23.8% treated with Praluent had 2 consecutive values of LDL-C

Question 6

What % of pts. had a treatment emergent anti-drug antibody(ADA) response & what % of pts. exhibited neutralising antibodies?

Answer 6

4.8% of pts. has ADA and 1.2% had neutralising antibodies.

Question 7

What is the median half life of alirocumab as a monotherapy and in combination with a statin

Answer 7

Median half life is 17-20 days

With statins its 12 days

Question 8

What is the clinical impact of a body weight of over 100kg vs 50-100kg on alirocumab LDL-C lovering?

Answer 8

No clinical impact

Question 9

In an analysis of the phase III pooled data that allowed up-titration, what impact did up-titration from 75mg Q2W have on LDC-C levels(on a background of statin therapy)?

Answer 9

Gives additional lowering in LDL-C of 14%.

Question 10

In the Long Term pre-specified analysis adjudicated major adverse cardiovascular events were reported in what % of pts. in the alirocumab and placebo groups?

Answer 10

Alirocumab: 1.7%
Placebo: 3.3%
Reduction in MACE

Question 11

Pharmaceutical form

Answer 11

clear, colourless to pale yellow solution

Question 12

Prior to the use of Alirocumab, what secondary causes of hyperlipidaemia or mixed dyslipidaemia should be excluded?

Answer 12

Nephrotic syndrome and hypothyroidism should be excluded.

Question 13

S&E in Paediatric popluation

Answer 13

S&E of Alirocumab in children less than 18yrs have not been established.

Question 14

Id dose adjustment needed for elderly patients?

Answer 14

No dose adjustment id needed for the elderly

Question 15

Recommendations for adminstration

Answer 15

1. Injection site should be rotated with each injection
2. Alirocumab should not be injected into areas of active skin disease or injury such as sunburn, skin rashes, inflammation or skin infection

Question 16

Precautions to be taken before handling

Answer 16

Praluent should be allowed to warm to room temp prior to use. Praluent should be used as soon as possible after it has warmed up.

Question 17

Renal impairment

Answer 17

In clinical studies, there was limited representation of patients with severe renal impairment i.e. eGFR of less than 30 ml/min/1.73m2. Praluent should be used with caution in pts. with severe renal impairment.

Question 18

Hepatic impairment

Answer 18

Pts. with severe hepatic impairment i.e Child Pugh C have not been studied.

Question 19

Effects of other medicinal products on Alirocumab

Answer 19

1. Statins & other LMT increase production of PCSK9.
   The exposure to alirocumab is about 40%, 15% and 35% lower when used concomitantly with statins, ezetimibe and fenofibrate.

Question 20

Pregancy

Answer 20

It is a recombinant IgG1 antibody, therefore it is expected to cross the placental barrier. Animal studies do not indicate direct or indirect harmful effects with respect to maintenance of pregnancy or embroy-fetal development, maternal toxicity was noted in rats but not in monkeys. The use of Praluent is not recommended during pregnancy unless the clinical condition of the women requires treatment with alirocumab

Question 21

Breast Feeding

Answer 21

It is not known whether Alirocumab is excreted in human milk. Human immunoglobulin G(IgG) antibody is excreted in human milk, in particular in colostrum: the use use of Praluent is not recommended in breast feeding women.

Question 22

Most common adverse events

Answer 22

injection site reactions - erthema/reddness, itching, swelling, pain/tenderness
upper respiratory tract signs & symtoms
Pruritus

Question 23

Rare adverse events

Answer 23

Hypersensitivity,
hypersensitivity vasculitis
Urticaria
Eczema nummular

Question 24

local injection site reactions %

Answer 24

6.1% with Alirocumab
4.1% with Placebo
Most injection site reactions are transient and mild intensity.

Question 25

Discontinuation rates

Answer 25

0. 2% in Alirocumab | 0. 3% in Placebo

Question 26

No of over 65 and 75yrs in controlled studies

Answer 26

In controlled studies, 1158 patients (23.8%) treated were over 65yrs and 241 patients(7.2%) treated with Praluent were over 75yrs. No sig differences in SE were seen between the two doses.

Question 27

What % of pts. had LDL-C levels less than 0.65 mmol/l

Answer 27

796 of 3340 pts(23.8%) treated with Alirocumab has 2 consecutive values of 0.65. These occurred when patients were initiated and maintained on 150mg Q2W regardless of the baseline LCL-C levels. No adverse reaction was identified related to these LDL-C values.

Question 28

Anti-drug-antibodies (ADA)

Answer 28

In phase 3 studies, 4.8% of pts. had ADA response compared to 0.6% in controlled group (placebo or ezetimibe) The majority of those pts. exhibited transient low titer ADA responses with no neutralising activity.

Question 29

What does PCSK9 stand for?

Answer 29

Proprotein convertase subtilisin kexin type 9

Question 30

Which lipids does Alirocumab reduce?

Answer 30

``` Alirocumab treatment can produce reductions in ApoB non-HDL-C TG Lp(a) ```

Question 31

What is loss of function mutation?

Answer 31

Individuals with single allele PCSK9 loss of function mutation have lower levels of LDL-C, which correlated with a sig lower incidence of CHD

Question 32

What is gain of function mutation?

Answer 32

leads to increased levels of LDL-C such as FH patients

Question 33

How long does it take for max serum levels to be achieved?

Answer 33

T-max 3-7days.

Question 34

The absolute bioavailiability of alirocumab is?

Answer 34

85%

Question 35

When is steady state with alirocumab achieved?

Answer 35

Steady state was reached after 2-3 doses with an accumulation ratio of about 2 fold

Question 36

How is alirocumab broken down in the body

Answer 36

Alirocumab is expected to degrade to small peptides and individual amino acids. At low concentrations the elimination is via a saturable binding to target, while at higher concentration alirocumab is largely eliminated through a non-saturable proteolytic pathway.

Question 37

What is the self life of Alirocumab?

Answer 37

2 years

Question 38

Special precautions for storage?

Answer 38

Store at 2 to 8 degrees Do not freeze Time out of the refrigeration should not exceed a maximum of 24hrs at temperatures at below 25% Keep the pen or syringe in the outer carton in order to protect it from sun light

Question 39

In mild to moderate renal impairment, what is the alirocumab % exposure ?

Answer 39

At steady state at both 75mg and 150mg Q2W dosing regimen was increased by 22%-35% and 49%-50%

Question 40

Special precaution before using alirocumab?

Answer 40

The solution should be clear, colourless to pale yellow. If solution is discoloured or contains visible particulate matter, the solution should not be used.

Question 41

What is the 75mg and 150mg PEN appearance

Answer 41

``` 75mg = blue cap with light green activation button 150mg = blue cap with dark grey activation button ```