Consumer medicine information

Praluent

Alirocumab

BRAND INFORMATION

Brand name

Praluent

Active ingredient

Alirocumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Praluent.

SUMMARY CMI

Praluent®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Praluent?

Praluent contains the active ingredient alirocumab. Praluent is used to treat high levels of cholesterol in the blood.

For more information, see Section 1. Why am I using Praluent? in the full CMI.

2. What should I know before I use Praluent?

Do not use if you have ever had an allergic reaction to Praluent or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Praluent? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Praluent and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Praluent?

  • Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

More instructions can be found in Section 4. How do I use Praluent? in the full CMI.

5. What should I know while using Praluent?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Praluent.
  • Follow your doctor's instructions carefully.
  • Tell your doctor if you are breastfeeding or become pregnant while you are using Praluent.
Things you should not do
  • Do not stop using this medicine or change the dosage without checking with your doctor.
  • Do not use Praluent if it is not clear to pale yellow or if it contains particles.
  • Do not give Praluent to children.
Looking after your medicine
  • Refrigerate do not freeze, do not expose to heat and do not shake Praluent.
  • Keep in the outer carton in order to protect from light.

For more information, see Section 5. What should I know while using Praluent? in the full CMI.

6. Are there any side effects?

Less serious side effects: allergic reaction symptoms include diarrhoea, rash or purple-coloured spots on the skin, hives and reddish skin spots sometimes with blisters, redness, swelling, pain or bruising where the injection is given, itching, painless swelling under the skin, muscle pain, flu-like symptoms that include sore throat, runny nose or sneezing.

Serious side effects: shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Praluent®

Active ingredient: alirocumab

Consumer Medicine Information (CMI)

This leaflet provides important information about using Praluent. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Praluent.

Where to find information in this leaflet:

1. Why am I using Praluent?
2. What should I know before I use Praluent?
3. What if I am taking other medicines?
4. How do I use Praluent?
5. What should I know while using Praluent?
6. Are there any side effects?
7. Product details

1. Why am I using Praluent?

Praluent contains the active ingredient alirocumab, a protein produced in Chinese hamster ovary cells.

Praluent is an injectable medicine and belongs to a group of medicines called monoclonal antibodies. Monoclonal antibodies are proteins that specifically identify and attach to other proteins in the body. Praluent recognises and attaches to a protein called PCSK9.

PCSK9 lowers the level of a receptor called LDL-R, which is needed to remove LDL cholesterol.

Praluent blocks the PCSK9 protein, thereby increasing the LDL-R receptors that are available to remove LDL cholesterol. This results in lower levels of LDL cholesterol.

Praluent is used with other cholesterol lowering medicines to treat high levels of cholesterol in the blood.

Cholesterol is one of several fatty substances found in the bloodstream. Your total cholesterol is made up of mainly of Low Density Lipoprotein (LDL) and High Density Lipoprotein (HDL) cholesterol. Praluent reduces LDL cholesterol.

LDL cholesterol can build up in the walls of your arteries forming plaque. Eventually this plaque build-up can lead to a narrowing of the arteries.

This narrowing can slow or block blood flow to vital organs such as the heart and brain. This blocking of blood flow can result in a heart attack or stroke and can cause other health problems.

Praluent reduces the risk of heart attack, stroke, and chest pain that may be caused by too little blood and oxygen getting to the heart (angina), in adults with cardiovascular disease and high cholesterol levels in their blood.

Praluent is used in adults who cannot reduce their cholesterol levels by cholesterol lowering diet and exercise.

Praluent should be used with other lipid lowering medicines such as statins to treat high cholesterol and lipid disorders. When a statin cannot be used or does not work well, Praluent can be used alone or together with other cholesterol lowering medicines.

Praluent should be used along with cholesterol lowering diet and exercise as recommended by your doctor.

Your doctor, however, may have prescribed Praluent for another purpose. Ask your doctor if you have any questions about why it has been prescribed for you.

This medicine is only available with a doctor's prescription

2. What should I know before I use Praluent?

Warnings

Do not use Praluent if:

  • you are allergic to alirocumab, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are allergic to medicines or other products that are produced by DNA technology using Chinese Hamster Ovary cells.

Symptoms that may indicate an allergic reaction include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Tell your doctor if you are experiencing these symptoms.

Praluent should not be used after the expiry date (exp) printed on the pack.

If you use this medicine after the expiry date it may have no effect at all, or worse, an unexpected effect.

Praluent should not be used if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start using this medicine, talk to your doctor.

Check with your doctor if you:

  • allergies to any other medicines or substances such as foods, preservatives or dyes
  • take any medicines for any other condition
  • have any kidney or liver problems.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

The effects of Praluent in pregnant women are not known. Therefore the use of this medicine in pregnant women is not recommended.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known whether Praluent passes into breast milk.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Praluent and affect how well it works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Praluent.

4. How do I use Praluent?

How much to use

  • The recommended starting dose of Praluent is either 75mg once every two weeks or 300 mg once every four weeks. Your doctor may adjust your dose depending on your cholesterol levels.
  • To administer the 300 mg dose, inject one 300 mg injection at one injection site, or inject two 150 mg injections, one after the other, at two different injection sites.
  • Follow the instructions provided by your doctor and use Praluent until your doctor tells you to stop.

When to use Praluent

  • Praluent is either used 75mg once every 2 weeks or 300 mg once every 4 weeks (monthly).

How to use Praluent

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label or in this leaflet, ask your doctor or pharmacist for help.

Always check the Praluent label before each injection to make sure you are using the right injection.

Praluent is a clear to pale yellow liquid. Do not shake the Praluent liquid. Do not use Praluent if it is not clear to pale yellow or if it contains particles.

To avoid discomfort, Praluent should be allowed to warm to room temperature (up to 25°C) for 30-40 minutes before injection. Do not use a heat source to warm up Praluent. Do not put Praluent near direct sunlight.

The injection can be self-administered or given by another person, after proper training in injection technique.

  • See the detailed "Instructions for Use" provided with the medicine for instructions about the right way to store, prepare, and use Praluent at home.
  • Praluent is injected under the skin (subcutaneous injection) of your stomach area (abdomen), thigh or upper arm. Change the place that you inject each time so that you do not become sore in one area.
  • After injecting Praluent, immediately throw away the used pre-filled pen or pre-filled syringe in a sharps container as instructed by your doctor or pharmacist.

Do not inject in an area where the skin is tender, reddened, bruised or hard. This may mean there is an infection.

Do not inject into the skin if it is sunburnt or injured.

Do not inject Praluent with other injectable medicines, at the same injection site.

How long to use Praluent

Praluent helps lower your cholesterol levels. It does not cure your condition. Therefore keep using Praluent as directed by your doctor. If you stop taking Praluent, your cholesterol levels may rise again.

If you forget to use Praluent

If you missed a dose of Praluent by less than 7 days, inject your missed dose as soon as you can, then have your next dose at your regular scheduled time. This will keep you on the original schedule.

If you missed a dose of Praluent by more than 7 days and you inject every 2 weeks, wait until your next scheduled dose to re-start Praluent. If you inject every 4 weeks, start a new schedule from the time you inject your missed dose.

If you are not sure when to inject Praluent, call your doctor, pharmacist or nurse.

It is important to use Praluent as prescribed by your doctor.

Do not take a double dose to make up for the dose you missed.

If you use too much Praluent

If you think that you have used too much Praluent, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26) or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Keep telephone numbers of these places handy.

5. What should I know while using Praluent?

Things you should do

Always follow your doctor's instructions carefully.

Keep Praluent in a refrigerator (2°C - 8°C). Do not freeze. Do not expose to extreme heat.

Allow Praluent to warm to room temperature (up to 25°C) for 30-40 minutes before injection. Do not use a heat source to warm up Praluent. Do not put Praluent near direct sunlight.

It is important to keep using Praluent even if you feel well. Praluent helps to control your condition but does not cure it.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are taking Praluent.

Remind any doctor, dentist or pharmacist you visit that you are using Praluent.

Call your doctor straight away if you:

  • become pregnant while you are using Praluent.

Things you should not do

  • Do not stop using this medicine suddenly or change the dosage without checking with your doctor.
  • Do not give Praluent to anyone else, even if they have the same condition as you.
  • Do not use Praluent to treat any other complaints unless your doctor tells you to.
  • Do not shake Praluent.
  • Do not use a heat source to warm up Praluent.
  • Do not put Praluent near direct sunlight.
  • Do not use Praluent if it is not clear to pale yellow or if it contains particles.
  • Do not give Praluent to children. The safety and benefit of Praluent in children under the age of 18 years has not been established.

Looking after your medicine

  • Keep Praluent in the pack to protect from light, until it is time to use it.
  • Keep Praluent in a refrigerator (2°C - 8°C). Do not freeze. Do not expose to extreme heat.
  • Keep Praluent in the refrigerator in an area where children cannot reach it.

If needed, the medicine may be kept outside the refrigerator below 25°C for a maximum of 30 days.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in the refrigerator, away from heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

After removal from the refrigerator, Praluent must be used within 30 days or discarded.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Allergy:
  • a specific form of allergic reaction resulting in narrowing or blockage of blood vessels (hypersensitivity vasculitis). Symptoms include diarrhoea, rash or purple coloured spots on the skin (purpura).
General:
  • muscle pain
  • painless swelling under the skin (angioedema)
  • flu-like symptoms such as sore throat, runny nose, sneezing
Skin-related:
  • itching (pruritis)
  • hives (urticaria)
  • reddish skin spots sometimes with blisters (nummular eczema)
Injection site:
  • redness, swelling, pain or bruising (haematoma) where the injection is given
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergy:
  • shortness of breath
  • wheezing or difficulty in breathing
  • swelling of the face, lips, tongue or other parts of the body.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems.

By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Praluent contains

Active ingredient
(main ingredient)
  • Alirocumab
Other ingredients
(inactive ingredients)
  • histidine
  • sucrose
  • polysorbate 20
  • water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What Praluent looks like

Praluent is a clear to pale yellow sterile solution for injection available in a pre-filled pen or pre-filled syringe. (Aust R 238285, AUST R 238299, AUST R 238304, AUST R 238305, AUST R 377452)

Pre-filled pen:

Each pre-filled pen contains 1 mL or 2 mL of solution and is available in the following strengths:

75 mg/1 mL available in pack sizes of 1, 2 or 6

150 mg/1 mL available in pack sizes of 1, 2 or 6

300 mg/2 mL available in pack sizes of 1 or 3

Pre-filled syringe:

Each pre-filled syringe contains 1 mL of solution and is available in two different strengths:

75 mg/mL available in pack sizes of 1, 2 or 6

150 mg/mL available in pack sizes of 1, 2 or 6

Who distributes Praluent

Praluent is supplied in Australia by:

sanofi-aventis australia pty ltd
12-24 Talavera Road
Macquarie Park NSW 2113
Toll Free No: 1800 818 806

This leaflet was prepared in October 2022.

pral-ccdsv12-cmiv8-17oct22

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Praluent

Active ingredient

Alirocumab

Schedule

S4

 

1 Name of Medicine

Praluent 75 mg/mL, 150 mg/mL and 300 mg/2 mL solution for injection.

2 Qualitative and Quantitative Composition

Alirocumab (rch) 75 mg/mL, 150 mg/mL and 300 mg/2 mL.
Alirocumab is a fully human monoclonal antibody (IgG1 isotype) that targets PCSK9. Alirocumab is produced by recombinant DNA technology in Chinese hamster ovary cell suspension culture.
For full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Solution for injection.
Praluent is a sterile, clear, colourless to pale yellow solution for subcutaneous injection with pH of about 6.0, containing no antimicrobial preservatives.

4 Clinical Particulars

4.1 Therapeutic Indications

Primary hypercholesterolaemia.

Praluent is indicated as an adjunct to diet and exercise to reduce LDL-C in adults with primary (heterozygous familial or non-familial) hypercholesterolaemia in patients with moderate to very high cardiovascular risk:
in combination with a statin, or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with maximum tolerated dose of a statin;
alone or in combination with other lipid lowering therapies in patients who are statin intolerant or for whom a statin is contraindicated who are unable to reach LDL-C goals.

Prevention of cardiovascular events.

Praluent is indicated to reduce the risk of cardiovascular events (myocardial infarction, stroke, unstable angina requiring hospitalisation) in adults with established cardiovascular disease, in combination with optimally dosed statins and/or other lipid-lowering therapies (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

The recommended starting dose of Praluent is 75 mg once every 2 weeks or 300 mg once every 4 weeks (monthly), administered subcutaneously.
The dose of Praluent can be individualised based on patient characteristics such as baseline LDL-C level, goal of therapy and response. Lipid levels may be measured from 4 - 8 weeks of initiating or titrating Praluent, to assess the response and adjust the dose, if needed. If additional LDL-C reduction is needed in patients treated with 75 mg once every 2 weeks or 300 mg once every 4 weeks (monthly), the dosage may be adjusted to the maximum dosage of 150 mg once every 2 weeks.
If a dose is missed, instruct the patient to administer the injection within 7 days from the missed dose and then resume the patient's original schedule. If an every-2-week dose is not administered within 7 days, instruct the patient to wait until the next dose on the original schedule. If an every-4-week dose is not administered within 7 days, instruct the patient to administer the dose, starting a new schedule based on this date.
No dose adjustments are needed for elderly patients or patients based on weight. No dose adjustments are needed for patients with mild or moderate renal or hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Praluent is injected as a subcutaneous injection into the thigh, abdomen or upper arm.
To administer the 300 mg dose, give either one 300 mg injection or two 150 mg injections consecutively at two different injection sites.
It is recommended to rotate the injection site with each injection.
Praluent should not be injected into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections.
The patient may either self-inject Praluent or a caregiver may administer Praluent, after guidance has been provided by a healthcare professional on proper subcutaneous injection technique.
Praluent must not be co-administered with other injectable medicinal products at the same injection site.
Praluent is a sterile product and contains no antimicrobial preservatives. Product is for single use in one patient only. Discard any residue.
Before administration, Praluent should be inspected visually for particulate matter and discolouration. If the solution is discoloured or contains particulate matter, the solution should not be used.
To avoid discomfort, Praluent should be allowed to warm to room temperature (up to 25°C) for 30 to 40 minutes prior to use. Do not heat, let it warm up on its own. Praluent should be used as soon as possible after it has warmed up. Time out of refrigeration should not exceed a maximum of 30 days at temperatures below 25°C.
After use, place the Praluent pre-filled pen or pre-filled syringe into a puncture resistant container and discard in accordance with local requirements.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1.

4.4 Special Warnings and Precautions for Use

General allergic reactions, including pruritus, as well as rare and sometimes serious allergic reactions such as hypersensitivity, nummular eczema, urticaria, and hypersensitivity vasculitis have been reported in clinical studies. Angioedema has been reported in the post-marketing setting (see Section 4.8 Adverse Effects (Undesirable Effects)). If signs or symptoms of serious allergic reactions occur, treatment with Praluent must be discontinued and appropriate symptomatic treatment initiated.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity. In the ODYSSEY OUTCOMES trial, 5.5% of patients treated with alirocumab 75 mg and/or 150 mg every 2 weeks (Q2W) had anti-drug antibodies (ADA) detected after initiating treatment compared with 1.6% of patients treated with placebo. Most of these were transient responses. Persistent ADA responses were observed in 0.7% of patients treated with alirocumab and 0.4% of patients treated with placebo. Neutralising antibody (NAb) responses were observed in 0.5% of patients treated with alirocumab and in < 0.1% of patients treated with placebo in the OUTCOMES trial. Only 1.2% of patients exhibited neutralising antibodies (NAb) in the ten pooled phase 3 studies in the hypercholesterolemia program, all of them in the alirocumab group.
Anti-drug antibody responses, including NAb, were low titre and did not appear to have a clinically meaningful impact on the efficacy or safety of alirocumab for most patients. Patients with treatment emergent ADA experienced a higher rate of injection site reactions compared to patients who were ADA negative (7.5% vs 3.6%).
The long-term consequences of continuing alirocumab treatment in the presence of ADA are unknown.
In a pool of ten placebo-controlled and active-controlled trials of patients treated with alirocumab 75 mg and/or 150 mg Q2W as well as in a separate clinical study of patients treated with alirocumab 75 mg Q2W or 300 mg every 4 weeks (including some patients with dose adjustment to 150 mg Q2W), the incidence of detecting ADA and NAb was similar to the results from the ODYSSEY OUTCOMES trial described above.
Immunogenicity data are highly dependent on the sensitivity and specificity of the ADA assay.

Low LDL-C.

Although adverse consequences of very low LDL-C were not identified in the clinical trials, the long-term effects of very low levels of LDL-C are unknown.

Use in hepatic impairment.

Patients with severe hepatic impairment (Child-Pugh C) have not been studied. Praluent should be used with caution in patients with severe hepatic impairment.

Use in renal impairment.

In clinical studies, there was limited representation of patients with severe renal impairment (defined as eGFR < 30 mL/min/1.73 m2). Praluent should be used with caution in patients with severe renal impairment.

Use in the elderly.

In the phase 3 primary hypercholesterolemia controlled studies, 1158 patients (34.7%) treated with Praluent were ≥ 65 years of age and 241 patients (7.2%) treated with Praluent were ≥ 75 years of age. In the cardiovascular outcomes controlled study, 2505 patients (26.5%) treated with Praluent were ≥ 65 years of age and 493 patients (5.2%) treated with Praluent were ≥ 75 years of age. There were no significant differences observed in safety and efficacy with increasing age.

Paediatric use.

The safety and efficacy of Praluent in patients below the age of 18 have not been established.

Effects on laboratory tests.

No interactions with laboratory tests have been identified.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of alirocumab on other medicinal products.

Since alirocumab is a biologic, no pharmacokinetic effects of alirocumab on other medicinal products are anticipated. In clinical studies where alirocumab was administered in combination with atorvastatin or rosuvastatin, no relevant changes in statin concentrations were observed in the presence of repeated administration of alirocumab, indicating that cytochrome P450 enzymes (mainly CYP3A4 and CYP2C9) and transporter proteins such as P-gp and OATP were not affected by alirocumab.

Effects of other medicinal products on alirocumab.

Statins and other lipid-modifying therapy are known to increase production of PCSK9, the protein targeted by alirocumab. Because a component of the clearance of alirocumab is target-mediated, an elevation in target could lead to lower alirocumab exposure. However, this effect does not impact the duration of efficacy when alirocumab is administered every two weeks.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no adverse effects of alirocumab on surrogate markers of fertility (e.g. oestrous cycling, testicular volume, ejaculate volume, sperm motility, sperm concentration and total sperm count per ejaculate) in a 26-week toxicity study in sexually-mature monkeys. The highest dose in this study resulted in a serum AUC that was about 100 times that expected in patients at the maximum recommended dose. In addition, there were no alirocumab-related macroscopic or microscopic findings in reproductive organs in any rat or monkey toxicity study.
(Category B1)
The use of Praluent is not recommended during pregnancy.
There are no data from the use of Praluent in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive and developmental toxicity.
When pregnant female animals were exposed to alirocumab, measurable alirocumab concentrations in serum were observed in foetal rats (and also infant monkeys), indicating that alirocumab, like other IgG antibodies, crosses the placenta.
There were no effects on foetal growth or development in the rat embryofoetal development study conducted at doses up to 75 mg/kg/dose administered on gestation days 6 and 12. At this dose, serum AUC was about 20 times the AUC expected in patients at the maximum recommended dose.
There was a slight attenuation of secondary anti-KLH IgG antibody response in infant offspring of cynomolgus monkeys dosed with alirocumab during organogenesis to parturition at maternal exposure of 13-fold the exposure at the maximum recommended human dose of 150 mg every two weeks. Alirocumab given at subcutaneous doses of up to 75 mg/kg/week to pregnant monkeys from gestation day 20 until parturition, had no adverse effects on the growth and development of offspring up to 6 months post-birth. At this dose, serum AUC was about 80-fold the AUC expected in patients at the maximum recommended dose.
Animal studies are not always predictive of human response. Therefore, it is not known whether Praluent can cause foetal harm when administered to a pregnant woman and Praluent should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

For use in combination therapy with a statin.

Statins are contraindicated in pregnant women. Please refer to the current respective product information.
 It is not known whether alirocumab is excreted in human milk. Because many drugs and immunoglobulins are excreted in human milk, the use of Praluent is not recommended in breast-feeding women. A decision should be made whether to discontinue nursing or to discontinue Praluent.

For use in combination therapy with a statin.

Statins are contraindicated in breast-feeding women. Please refer to the current respective product information.

4.7 Effects on Ability to Drive and Use Machines

Praluent has no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

The safety data are based on pooled results from nine placebo-controlled studies (four phase 2 and five phase 3 studies, all in patients on background statin), and five ezetimibe-controlled phase 3 studies (with three studies in patients on background statin). This reflects exposure to alirocumab in 3340 patients (3451 patient-years of exposure), the majority with high or very high cardiovascular risk, treated with alirocumab at a dose of 75 and/or 150 mg, administered subcutaneously once every 2 weeks, for a treatment duration of up to 18 months (including 2408 patients exposed to alirocumab for at least 52 weeks, and 639 patients exposed to alirocumab for at least 76 weeks).
In ten phase 3 controlled trials, involving patients with primary hypercholesterolemia, the most common adverse reactions (≥ 1% of patients treated with Praluent) were local injection site reactions, upper respiratory tract signs and symptoms and pruritus. Most common adverse reactions leading to treatment discontinuation in patients treated with Praluent were local injection site reactions.
The safety profile in ODYSSEY OUTCOMES (a long-term cardiovascular outcome trial) was consistent with the overall safety profile described in the phase 3 controlled trials. A total of 9451 patients were exposed to Praluent for a median of 31 months and 9443 patients were exposed to placebo for a median of 32 months.
No difference in the safety profile was observed between the two doses (75 mg once every 2 weeks and 150 mg once every 2 weeks) used in the phase 3 program.
In controlled studies, 1158 patients (34.7%) treated with Praluent were ≥ 65 years of age and 241 patients (7.2%) treated with Praluent were ≥ 75 years of age. There were no significant differences observed in safety and efficacy with increasing age.
Table 1 shows the adverse reactions reported in patients treated with alirocumab in pooled phase 3 controlled studies and the ODYSSEY OUTCOMES trial. Frequencies for all events have been calculated based on their incidence in pooled phase 3 clinical trials.
The frequency categories are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (cannot be estimated from the available data).
Table 2 shows the adverse events reported in ≥ 1% of patients treated with alirocumab and more frequently than with placebo in pooled placebo-controlled studies.
Table 3 shows the adverse events reported in ≥ 1% of patients treated with alirocumab and more frequently than with ezetimibe in pooled ezetimibe-controlled studies.
Table 4 shows the adverse events reported in ≥ 2% of patients treated with alirocumab 300 mg monthly dose as compared to placebo and alirocumab fortnightly dose, irrespective of concomitant statin therapy.

Adverse reactions in the cardiovascular outcomes trial.

In a double-blind, randomised, placebo-controlled cardiovascular outcomes trial (Study 1: ODYSSEY OUTCOMES, NCT01663402), 18,924 patients received at least one dose of Praluent or placebo [see clinical studies (14.1)]. The mean age was 58 years (range: 39 to 92 years), 25.2% women, 79.4% Caucasian, 2.5% Black, 13.2% Asian, and 16.6% Hispanic/Latino. Patients were exposed to Praluent for a median of 31 months; 87% of patients were exposed for ≥ 12 months, 78% were exposed for ≥ 24 months, 33% were exposed for ≥ 36 months, and 6% were exposed for ≥ 48 months.
The safety profile of Praluent in this trial was consistent with the safety profile described above in the placebo-controlled trials involving patients with primary hyperlipidemia and mixed dyslipidemia. Serious adverse events occurred in 23.3% of Praluent treated patients and 24.9% of placebo-treated patients. Adverse events led to discontinuation of study treatment in 3.8% of patients treated with Praluent and 3.7% treated with placebo. The only adverse reaction reported in at least 2% of Praluent treated patients, and occurring more frequently than in placebo-treated patients, was local injection site reactions (3.8% Praluent, 2.1% placebo). General allergic reactions were similar in Praluent treated patients and placebo-treated patients (7.9% Praluent, 7.8% placebo). No difference was seen in the incidence of pruritus.
Table 5 shows the adverse events reported in > 1% of patients treated with Praluent and more frequently than with placebo in the ODYSSEY OUTCOMES study.

Local injection site reactions.

Local injection site reactions, including erythema/redness, swelling, and pain/tenderness were reported in 6.1% of patients treated with alirocumab versus 4.1% in the control group with Q2W dosing and in 16.6% of patients treated with alirocumab compared to 7.9% in the placebo arm in the Q4W dose regimen. Patients in the alirocumab 300 mg every 4 weeks treatment group received alternating placebo injections to maintain blinding in regard to injection frequency. Excluding injection site reactions (ISRs) that occurred after these placebo injections, the frequency of ISRs was 11.8% in the alirocumab group. Most injection site reactions were transient and of mild intensity. The discontinuation rate due to local injection site reactions was comparable between the two groups (0.2% in the alirocumab group versus 0.3% in the control group) with the Q2W dose regimen, and 0.7% in the alirocumab group versus 0% in the placebo group with the Q4W dose regimen. In the cardiovascular outcomes study (ODYSSEY OUTCOMES), injection site reactions also occurred more frequently in alirocumab treated patients than in placebo-treated patients (3.8% alirocumab 2.1% placebo).

General allergic reactions.

General allergic reactions were reported more frequently in the alirocumab group than in the control group, mainly due to a difference in the incidence of pruritus. The observed cases of pruritus were typically mild and transient. In addition, rare and sometimes serious allergic reactions such as hypersensitivity, nummular eczema, urticaria, and hypersensitivity vasculitis have been reported in controlled clinical studies (see Section 4.4 Special Warnings and Precautions for Use). In the cardiovascular outcomes study (ODYSSEY OUTCOMES), general allergic reactions were similar in alirocumab-treated patients and placebo-treated patients (7.9% alirocumab 7.8% placebo). No difference was seen in the incidence of pruritus.

Low LDL-C values.

LDL-C values < 0.65 mmol/L.

In all clinical studies background lipid lowering therapies could not be adjusted by trial design. The percentage of patients who reached LDL-C values < 25 mg/dL (< 0.65 mmol/L) depended both on the baseline LDL-C and the dose of alirocumab.
In a pool of controlled studies using a 75 mg every 2 week (Q2W) starting dose and in which the dose was increased to 150 mg Q2W if the patient's LDL-C was not < 70 mg/dL or < 100 mg/dL (1.81 mmol/L or 2.59 mmol/L), 29.3% of patients with baseline LDL-C < 100 mg/dL and 5.0% of patients with baseline LDL-C ≥ 100 mg/dL treated with alirocumab had two consecutive values of LDL-C < 25 mg/dL (< 0.65 mmol/L). In the ODYSSEY OUTCOMES study, in which the starting alirocumab dose was 75 mg Q2W and the dose was increased to 150 mg Q2W if the patient's LDL-C was not < 50 mg/dL (1.29 mmol/L), 54.8% of patients with baseline LDL-C < 100 mg/dL and 24.2% of patients with baseline LDL-C ≥ 100 mg/dL treated with alirocumab had two consecutive values of LDL-C < 25 mg/dL (< 0.65 mmol/L).
Although adverse consequences of very low LDL-C were not identified in alirocumab trials, the long-term effects of very low levels of LDL-C are unknown. In published genetic studies as well as clinical and observational trials with lipid lowering therapies an increased risk of new onset of diabetes has been associated with lower levels of LDL-C.

Cardiovascular (CV) events.

In pre-specified analysis of the ten pooled phase 3 studies in the hypercholesterolemia program, treatment-emergent CV events confirmed by adjudication, consisting of coronary heart disease (CHD) death, myocardial infarction, ischemic stroke, unstable angina requiring hospitalization, congestive heart failure hospitalization, and revascularization, were reported in 129 (4.1%) patients in the alirocumab group and 63 (3.5%) patients in the control group (placebo or active control) with HR = 1.06 (95% CI: 0.79 to 1.44). MACE confirmed by adjudication were reported in 65 of 3182 (2.0%) patients in the alirocumab group and 39 of 1792 (2.2%) patients in the control group (placebo or active control); HR = 0.85 (95% CI: 0.57 to 1.27).
In pre-specified final analyses of the LONG TERM study, treatment-emergent CV events confirmed by adjudication occurred in 72 of 1550 (4.6%) patients in the alirocumab group and in 40 of 788 (5.1%) patients in the placebo group; MACE confirmed by adjudication were reported in 27 of 1550 (1.7%) patients in the alirocumab group and 26 of 788 (3.3%) patients in the placebo group. Hazard ratios were calculated post-hoc; for all CV events, HR = 0.91 (95% CI: 0.62 to 1.34); for MACE, HR = 0.52 (95% CI: 0.31 to 0.90).

All-cause mortality.

All-cause mortality in the ten pooled phase 3 studies in the hypercholesterolemia program was 0.8% (26 of 3182 patients) in the alirocumab group and 1.1% (20 of 1792 patients) in the control group. The primary cause of death in the majority of these patients was CV events.

Neurocognitive events.

Neurocognitive events were reported in 1.3% of patients treated with alirocumab and 1.7% of patients treated with placebo. Confusion or memory impairment were each reported in 0.2% of patients treated with alirocumab and in < 0.1% (for each) in the placebo group patients. The majority of neurocognitive events were non-serious. The causal relationship between these events and alirocumab has not been established.

Postmarketing experience.

The following adverse reactions have been reported during post-approval use of Praluent. The adverse reactions are derived from spontaneous reports and therefore, the frequency is "not known" (cannot be estimated from the available data).

General disorders and administration site conditions.

Flu-like illness.

Skin and subcutaneous tissue disorders.

Angioedema.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

In controlled clinical studies, no safety issues were identified with more frequent dosing than the recommended once every 2 weeks dosing schedule.
For general advice on management of overdose, contact the Poisons Information Centre, telephone number 13 11 26 (Australia) or the National Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other lipid modifying agents, ATC code: C10AX14.
Alirocumab inhibits PCSK9 activity in both in vitro assays and in vivo model systems. Many studies in animals and humans have demonstrated the central role that elevated levels of LDL-C play in the initiation and progression of atherosclerosis.

Mechanism of action.

Alirocumab binds with high affinity and specificity to PCSK9 which binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote their degradation. LDLR is the primary receptor that clears circulating low-density lipoprotein (LDL), therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of low-density lipoprotein cholesterol (LDL-C). By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.
In genetic studies in humans, PCSK9 variants with either loss-of-function or gain-of-function mutations have been identified. Individuals with single allele PCSK9 loss-of-function mutation have lower levels of LDL-C, which correlated with a significantly lower incidence of coronary heart disease. A few individuals have been reported, who carry PCSK9 loss-of-function mutations in two alleles and have profoundly low LDL-C levels, with HDL-C and triglyceride (TG) levels in the normal range. Conversely, gain-of-function mutations in the PCSK9 gene have been identified in patients with increased LDL-C levels and a clinical diagnosis of familial hypercholesterolaemia (FH).
Observational analyses have demonstrated that the untreated LDL-C levels in patients with gain-of-function mutations in the PCSK9 gene are in a similar range to those observed in patients with the more traditional mutations that cause heterozygous FH (heFH) (such as in the LDLR gene) demonstrating a central role for PCSK9 in LDL-C metabolism and levels. In a multicentre, double-blind, placebo-controlled, 14 week study, 13 patients with heFH due to gain-of-function mutations in the PCSK9 gene were randomised to receive either alirocumab 150 mg once every 2 weeks or placebo. Mean baseline LDL-C was 3.92 mmol/L. At week 2, the mean reduction from baseline in LDL-C was 62.5% in the alirocumab-treated patients as compared to 8.8% in the placebo patients. At week 8, the mean reduction in LDL-C from baseline with all patients treated with alirocumab was 72.4%.

Pharmacodynamic effects.

In in vitro assays, alirocumab did not induce Fc-mediated effector function activity (antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity) either in the presence or absence of PCSK9 and no soluble immune complexes capable of binding complement proteins were observed for alirocumab when bound to PCSK9.
The pharmacodynamic effect of alirocumab in lowering LDL-C is indirect, and mediated through the binding to PCSK9. A concentration-dependent reduction in free PCSK9 and LDL-C is observed until target saturation is achieved. Upon saturation of PCSK9 binding, further increases in alirocumab concentrations do not result in a further LDL-C reduction, however an extended duration of the LDL-C lowering effect is observed.

Clinical trials.

Every 2 weeks (Q2W) dosing regimen.

The efficacy of Praluent was investigated in ten phase 3 trials (five placebo-controlled and five ezetimibe-controlled studies), involving 5,296 randomised patients with 3188 patients randomised to Praluent. The five placebo-controlled trials involved 3499 patients of which 36% were patients with heterozygous familial hypercholesterolemia (heFH) and 54% were non-FH patients who had clinical atherosclerotic cardiovascular disease. Three of the ten studies were conducted exclusively in patients with (heFH). The majority of patients in the phase 3 program were taking background lipid-modifying therapy (LMT) consisting of a maximally tolerated dose of statin, with or without other LMTs, and were at high or very high cardiovascular (CV) risk.
Two studies were conducted in patients who were not concomitantly treated with a statin, including one study in patients with documented statin intolerance. Alirocumab has not been studied in patients with homozygous familial hypercholesterolaemia.
Eight studies were performed with a dose of 75 mg once every 2 weeks, and criteria-based up-titration to 150 mg once every 2 weeks at week 12 in patients who did not achieve their pre-defined target LDL-C based on their level of CV risk at week 8. Two studies (LONG TERM and HIGH FH), involving a total of 2,416 patients, were performed with a 150 mg once every 2 weeks dose only. Baseline demographic characteristics were well matched between the Praluent and control groups. The age of the patients ranged from 18 to 89 years across studies (mean age 60 years); 38% were women; the majority of patients were Caucasian (90%), 5% were Black, 2% were Asian; the mean body mass index (BMI) was 30 kg/m2. In the phase 3 studies, 31% of patients had type 2 diabetes mellitus, and 64% of patients had a history of coronary heart disease.
The primary efficacy endpoint in all of the phase 3 studies was the mean percent reduction from baseline in LDL-C at week 24 as compared to placebo or ezetimibe. All of the studies met their primary endpoint.
In general, administration of Praluent also resulted in a statistically significant greater percent reduction in Total-C, non-HDL-C, Apo B, and Lp(a) as compared to placebo/ ezetimibe, whether or not patients were concomitantly being treated with a statin. Praluent also reduced triglycerides, and increased HDL-C and Apo A-1 as compared to placebo.
Reduction in LDL-C was seen across age, gender, body mass index (BMI), race and baseline LDL-C levels. LDL-C reduction was consistent regardless of concomitantly used statins and doses. A significantly higher proportion of patients achieved an LDL-C of < 1.81 mmol/L in the Praluent group as compared to placebo or ezetimibe at week 12 and week 24. In studies using the criteria-based up-titration regimen, a majority of patients achieved the pre-defined target LDL-C (based on their level of CV risk) on the 75 mg once every 2 weeks dose, and a majority of patients maintained treatment on the 75 mg once every 2 week dose.
The lipid-lowering effect of Praluent was observed within 15 days of the first dose reaching maximum effect at approximately 4 weeks. Efficacy was sustained over the duration of study treatment (up to 2 years). Following discontinuation of Praluent, no rebound in LDL-C was observed, and LDL-C levels gradually returned to baseline levels.
Table 6 summarises the mean percent change from baseline in LDL-C with Praluent at week 12 (before up-titration) and at week 24 (primary endpoint) based on analyses across pooled phase 3 studies.
In analyses of pooled phase 3 studies that allowed up-titration, among the subgroup of patients up-titrated, an increase from 75 mg once every 2 weeks to 150 mg once every 2 weeks Praluent at week 12 resulted in an additional 14% mean reduction in LDL-C in patients on a background statin. In patients not on a background statin, up-titration of Praluent resulted in an additional 3% mean reduction in LDL-C, with the majority of the effect seen in approximately 25% of patients who achieved at least an additional 10% LDL-C lowering after up-titration. Patients up-titrated to 150 mg once every 2 weeks had a higher mean baseline LDL-C.
Figure 1 summarises the mean reduction from baseline in LDL-C with Praluent at week 12 (before up-titration) across phase 3 studies. This figure shows the efficacy of the 75 mg once every 2 week and 150 mg once every 2 week doses. Week 24 results are provided in the description of the individual studies.

Combination therapy with a statin.

Placebo-controlled phase 3 studies.

FH I and FH II studies.

Two multicentre, placebo-controlled, double-blind 18-month studies included 732 patients (488 in the Praluent group and 244 patients in the placebo group, with a majority of patients treated for a minimum of 52 weeks) with heFH receiving a maximally tolerated dose of statin, with or without other lipid-modifying therapy. Patients received either Praluent 75 mg once every 2 weeks or placebo in addition to their existing lipid modifying therapy. Dose up-titration of Praluent to 150 mg once every 2 weeks occurred at week 12 in patients with LDL-C ≥ 1.81 mmol/L. At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was -55.8% (95% CI: -60.0%, -51.6%; p-value: < 0.0001). At week 12 (before up-titration), 50.2% of patients reached an LDL-C of < 1.81 mmol/L as compared to 0.6% in the placebo group. Among the subgroup of patients up-titrated at week 12, an additional 15.7% mean reduction in LDL-C was achieved at week 24. See Table 7 and Figure 2 for details.

HIGH FH study.

A third multicentre, double-blind, placebo-controlled 18-month study included 106 heFH patients (71 patients in the Praluent group and 35 patients in the placebo group with a majority of patients treated for a minimum of 52 weeks) on a maximally tolerated dose of statin, with or without other lipid-modifying therapies, and a baseline LDL-C ≥ 4.14 mmol/L. Patients received either Praluent at a dose of 150 mg once every 2 weeks or placebo in addition to their existing lipid-modifying therapy. Mean baseline LDL-C was 5.08 mmol/L in the Praluent group and 5.20 mmol/L in the placebo group. The mean percent change from baseline with Praluent in LDL-C (ITT analysis) was -46.9% at week 12 and -45.7% at week 24 compared to -6.6% at week 12 and -6.6% at week 24 for placebo. This corresponded to a mean absolute change from baseline at week 24 of -2.35 mmol/L. At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was -39.1% (95% CI: -51.1%, -27.1%; p-value: < 0.0001). Mean changes for all other lipids/ lipoproteins were similar to the FH I and FH II studies, however statistical significance was not reached for TG, HDL-C and Apo A-1. See Table 7 for details.

COMBO I study.

A multicentre, double-blind, placebo-controlled, 52 week study included 311 patients (205 in the Praluent group and 106 in placebo group) categorised as very high CV risk and not at their pre-defined target LDL-C on a maximally tolerated dose of statin, with or without other lipid-modifying therapy. Patients received either 75 mg Praluent once every 2 weeks or placebo in addition to their existing lipid-modifying therapy. Dose up-titration of Praluent to 150 mg once every 2 weeks occurred at week 12 in patients with LDL-C ≥ 1.81 mmol/L. Mean baseline LDL-C was 2.60 mmol/L in the Praluent group and 2.71 mmol/L in the placebo group. The mean percent change from baseline with Praluent in LDL-C (ITT analysis) was -46.3% at week 12 and -48.2% at week 24 compared to 1.1% at week 12 and -2.3% at week 24 for placebo. This corresponded to a mean absolute change from baseline at week 24 of -1.30 mmol/L. At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was -45.9% (95% CI: -52.5%, -39.3%; p-value: < 0.0001). At week 12 (before up-titration), 76.0% of patients in the Praluent group reached an LDL-C of < 1.81 mmol/L as compared to 11.3% in the placebo group. The dose was up-titrated to 150 mg once every 2 weeks in 32 (16.8%) patients treated beyond 12 weeks. Among the subgroup of patients up-titrated at week 12, an additional 22.8% mean reduction in LDL-C was achieved at week 24. The difference versus placebo was statistically significant at week 24 for all lipids/ lipoproteins except TG and Apo A-1. See Table 7 for details.
Ezetimibe-controlled phase 3 study (on background statin).

COMBO II study.

A multicentre, double-blind, ezetimibe-controlled 2 year study included 707 patients (467 patients in the Praluent group and 240 patients in the ezetimibe group, with a majority of patients treated for a minimum of 52 weeks) categorised as very high CV risk and not at their pre-defined target LDL-C on a maximally tolerated dose of statin. Patients received either Praluent 75 mg once every 2 weeks or ezetimibe 10 mg once daily in addition to their existing statin therapy. Dose up-titration of Praluent to 150 mg once every 2 weeks occurred at week 12 in patients with LDL-C ≥ 1.81 mmol/L. At week 24, the mean treatment difference from ezetimibe in LDL-C percent change from baseline was -29.8% (95% CI: -34.4%, -25.3%; p-value: < 0.0001). At week 12 (before up-titration), 77.2% of patients reached an LDL-C of < 1.81 mmol/L as compared to 46.2% in the ezetimibe group. Among the subgroup of patients up-titrated at week 12, an additional 10.5% mean reduction in LDL-C was achieved at week 24. See Table 7 for details.

Statin intolerant therapy (add-on to non-statin lipid modifying therapy).

ALTERNATIVE study.

A multicentre, double-blind, ezetimibe-controlled, 24 week study included 248 patients (126 patients in the Praluent group and 122 in the ezetimibe group) with documented statin intolerance due to skeletal muscle-related symptoms. Patients received either Praluent 75 mg once every 2 weeks or ezetimibe 10 mg once daily, or atorvastatin 20 mg once daily (as a re-challenge arm). Dose up-titration of Praluent to 150 mg once every 2 weeks occurred at week 12 in patients with LDL-C ≥ 1.81 mmol/L or ≥ 2.59 mmol/L, depending on their level of CV risk. At week 24, the mean treatment difference from ezetimibe in LDL-C percent change from baseline was -30.4% (95% CI: -36.6%, -24.2%; p-value: < 0.0001). At week 12 (before up-titration), 34.9% of patients achieved an LDL-C of < 1.81 mmol/L as compared to 0% in the ezetimibe group. Among the subgroup of patients up-titrated at week 12, an additional 3.6% mean reduction in LDL-C was achieved at week 24.
This trial evaluated patients who did not tolerate at least two statins (at least one at the lowest approved dose), and enrolled only patients willing to be re-challenged with a statin. The statin re-challenge arm was included to further validate the diagnosis of statin intolerance in a blinded manner. In these patients with a history of statin intolerance, musculoskeletal adverse events occurred at a lower rate in the Praluent group (32.5%) as compared to the atorvastatin group (46.0%) (HR = 0.61 [95% CI: 0.38 to 0.99]), and a lower percentage of patients in the Praluent group (15.9%) discontinued study treatment due to musculoskeletal adverse events as compared to the atorvastatin group (22.2%). These discontinuation rates due to musculoskeletal adverse events in the ALTERNATIVE study were higher than in other phase 3 studies. In the five placebo-controlled trials in patients on a maximally tolerated dose of statin (n = 3752), the discontinuation rate due to musculoskeletal adverse events was 0.4% in the Praluent group and 0.5% in the placebo group. See Table 7 for details.

Long-term efficacy in primary hypercholesterolaemia.

LONG TERM study.

This multicentre, double-blind, placebo-controlled, 18-month study included 2,310 patients (1,530 patients in the Praluent group and 780 patients in the placebo group) with primary hypercholesterolaemia at high or very high CV risk and on a maximally tolerated dose of statin, with or without other lipid-modifying therapy. Patients received either Praluent at a dose of 150 mg once every 2 weeks or placebo in addition to their existing lipid-modifying therapy. The LONG TERM study included 17.7% heFH patients, 34.6% with type 2 diabetes mellitus, and 68.6% with a history of coronary heart disease. Mean treatment duration was 64.6 weeks, with a majority of patients treated for a minimum of 52 weeks, and 607 patients with 18-month data analysed. At week 24, the mean treatment difference from placebo in LDL-C percent change from baseline was -61.9% (95% CI: -64.3%, -59.4%; p-value: < 0.0001). For detailed results see Table 7. At week 12, 82.1% of patients in the Praluent group reached an LDL-C < 1.81 mmol/L compared to 7.2% of patients in the placebo group. Reduction in LDL-C was seen across age, gender, body mass index (BMI), race, and baseline LDL-C levels. Efficacy results were consistent in patients with heFH and non-heFH, patients with mixed dyslipidaemia, and diabetic patients. LDL-C reduction was consistent regardless of concomitantly used statins and doses.

Other studies.

OPTIONS I and OPTIONS II studies.

Two additional multicentre, double-blind, active-controlled 24 week studies were performed in 643 patients (combined) with primary hypercholesterolaemia at high or very high CV risk not adequately controlled on a moderate dose of atorvastatin (20 mg or 40 mg, OPTIONS I) or rosuvastatin (10 mg or 20 mg, OPTIONS II). Dose up-titration of Praluent from 75 mg once every 2 weeks to 150 mg once every 2 weeks occurred at week 12 in patients with LDL-C ≥ 1.81 mmol/L or 2.59 mmol/L, depending on their level of CV risk. Mean baseline LDL-C levels ranged from 2.72 mmol/L (OPTIONS I) to 2.88 mmol/L (OPTIONS II). At week 24, the mean percent change in LDL-C from baseline with Praluent added to moderate doses of atorvastatin was -48.5% in OPTIONS I, and -42.7% when added to a moderate dose of rosuvastatin in OPTIONS II.

MONO study.

A multicentre, double-blind, ezetimibe-controlled, 24-week study included 103 patients with a moderate CV risk, not taking statins or other lipid-modifying therapies, and a baseline LDL-C between 100 mg/dL (2.59 mmol/L) to 190 mg/dL (4.91 mmol/L). Patients received either alirocumab 75 mg Q2W or ezetimibe 10 mg once daily. Dose up-titration of alirocumab to 150 mg Q2W occurred at week 12 in patients with LDL-C ≥ 70 mg/dL (≥ 1.81 mmol/L). At week 24, the mean treatment difference from ezetimibe in LDL-C percent change from baseline was -31.6% (95% CI: -40.2%, -23.0%; p-value: ˂ 0.0001). At week 12 (before up-titration), 57.7% of patients reached an LDL-C of ˂ 70 mg/dL (< 1.81 mmol/L) as compared to 0% in the ezetimibe group. The dose was up-titrated to 150 mg Q2W in 14 (30.4%) patients treated beyond 12 weeks. Among the subgroup of patients up-titrated at week 12, an additional 1.4% mean reduction in LDL-C was achieved at week 24. The difference versus ezetimibe was statistically significant at week 24 for LDL-C, Total-C, Non-HDL-C and Apo B.

Every 4 week (Q4W) dosing regimen.

Choice I study.

A multicentre, double-blind, placebo-controlled, 48 week study included 540 patients on a maximally tolerated dose of a statin, with or without other lipid-modifying therapy (308 in the Praluent 300 mg Q4W group, 76 in the Praluent 75 mg Q2W group, and 156 in the placebo group), and 252 patients not treated with a statin (144 in the Praluent 300 mg Q4W group, 37 in the Praluent 75 mg Q2W group, and 71 in the placebo group). Patients received either Praluent 300 mg Q4W, Praluent 75 mg Q2W, or placebo in addition to their existing lipid-modifying therapy (statin, non-statin therapy or diet alone). Overall, 71.6% of patients were categorized at high or very high CV risk and not at their LDL-C target. Dose adjustment in the Praluent arms to 150 mg Q2W occurred at week 12 in patients with LDL-C ≥ 70 mg/dL (≥ 1.81 mmol/L) or ≥ 100 mg/dL (≥ 2.59 mmol/L), depending on their level of CV risk, or in patients who did not have at least a 30% reduction of LDL-C from baseline.
In the cohort of patients on background statin, the mean baseline LDL-C was 112.7 mg/dL (2.91 mmol/L). At week 12, the mean percent change from baseline with Praluent 300 mg Q4W in LDL-C (ITT analysis) was -55.3% compared to +1.1% for placebo. At week 12 (before dose adjustment), 77.3% of patients treated with Praluent 300 mg Q4W reached an LDL-C of < 70 mg/dL (< 1.81 mmol/L) as compared to 9.3% in the placebo group. At week 24, the mean percent change from baseline with Praluent 300 mg Q4W/150 mg Q2W in LDL-C (ITT analysis) was -58.8% compared to -0.1% for placebo. At week 24, the mean treatment difference for Praluent 300 mg Q4W/150 mg Q2W from placebo in LDL-C percent change from baseline was -58.7.% (97.5% CI: -65.0%, -52.4%; p-value: < 0.0001). In patients treated beyond 12 weeks, the dose was adjusted to 150 mg Q2W in 56 (19.3%) of 290 patients in the Praluent 300 mg Q4W arm. Among the subgroup of patients dose adjusted to 150 mg Q2W at week 12, an additional 25.4% reduction in LDL-C was achieved at week 24.
In the cohort of patients not treated with a concomitant statin, the mean baseline LDL-C was 142.1 mg/dL (3.67 mmol/L). At week 12, the mean percent change from baseline with Praluent 300 mg Q4W in LDL-C (ITT analysis) was -58.4% compared to +0.3% for placebo. At week 12 (before dose adjustment), 65.2% of patients treated with Praluent 300 mg Q4W reached an LDL-C of < 70 mg/dL (< 1.81 mmol/L) as compared to 2.8% in the placebo group. At week 24, the mean percent change from baseline with Praluent 300 mg Q4W/150 mg Q2W in LDL-C (ITT analysis) was -52.7% compared to -0.3% for placebo. At week 24, the mean treatment difference for Praluent 300 mg Q4W/150 mg Q2W from placebo in LDL-C percent change from baseline was -52.4% (97.5% CI: -59.8%, -45.0%; p-value: < 0.0001). In patients treated beyond 12 weeks, the dose was adjusted to 150 mg Q2W in 19 (14.7%) of 129 patients in the Praluent 300 mg Q4W arm. Among the subgroup of patients dose adjusted to 150 mg Q2W at week 12, an additional 7.3% mean reduction in LDL-C was achieved at week 24.
In both cohorts, the difference vs placebo was statistically significant at week 24 for all lipid parameters, except for Apo A-1 in the subgroup of patients on background statin.

Clinical efficacy and safety in prevention of cardiovascular events.

ODYSSEY OUTCOMES study.

A multicentre, double-blind, placebo-controlled trial in 18,924 adult patients (9462 alirocumab; 9462 placebo) followed for up to 5 years. Patients had experienced an acute coronary syndrome (ACS) event 4 to 52 weeks prior to randomisation and were treated with a lipid-modifying-therapy (LMT) regimen that was statin-intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) or at maximally tolerated dose of those statins, with or without other LMT. All patients were randomised 1:1 to receive either alirocumab 75 mg once every two weeks (Q2W) or placebo Q2W. At month 2, if additional LDL-C lowering was required based on pre-specified LDL-C criteria (LDL-C ≥ 50 mg/dL or 1.29 mmol/dL), alirocumab was adjusted to 150 mg Q2W. For patients who had their dose adjusted to 150 mg Q2W and who had two consecutive LDL-C values below 25 mg/dL (0.65 mmol/L), down-titration from 150 mg Q2W to 75 mg Q2W was performed. Patients on 75 mg Q2W who had two consecutive LDL-C values below 15 mg/dL (0.39 mmol/L) were switched to placebo in a blinded fashion. Approximately 2615 (27.7%) of 9451 patients treated with alirocumab required dose adjustment to 150 mg Q2W. Of these 2615 patients, 805 (30.8%) were down-titrated to 75 mg Q2W. Overall, 730 (7.7%) of 9451 patients switched to placebo. A total of 99.5% of patients were followed for survival until the end of the trial. The median follow-up duration was 33 months.
The index ACS event was a myocardial infarction in 83.2% of patients (34.6% STEMI, 48.6% NSTEMI) and an episode of unstable angina in 16.8% of patients. Prior to the index ACS event, 19.2% had a myocardial infarction and 22.7% had coronary revascularization procedures (CABG/PCI). Most patients (88.8%) were receiving high intensity statin therapy with or without other LMT at randomisation. The mean LDL-C value at baseline was 92.4 mg/dL (2.39 mmol/L).
Alirocumab significantly reduced the risk for the primary composite endpoint of the time to first occurrence of Major Adverse Cardiovascular Events (MACE) consisting of coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), fatal and non-fatal ischemic stroke, or unstable angina (UA) requiring hospitalization (HR 0.85, 95% CI: 0.78, 0.93; p-value = 0.0003). Alirocumab also significantly reduced the following composite endpoints: risk of CHD event; major CHD event; cardiovascular event; and the composite of all-cause mortality, non-fatal MI, and non-fatal ischemic stroke. The results are presented in Table 8. In the subgroup of high risk patients with baseline LDL-C ≥ 100 mg/dL (2.59 mmol/L), primary and all secondary endpoints were improved with alirocumab treatment including CHD death (HR 0.72, 95% CI: 0.53, 0.98), CV death (HR 0.69, 95% CI:0.52, 0.92) and all-cause mortality (HR 0.71, 95% CI:0.56, 0.90).
The Kaplan-Meier estimates of the cumulative incidence of the primary endpoint and all-cause mortality endpoint for the overall patient population over time are presented in Figure 3 and Figure 4.

Neurocognitive function.

A 96 week, randomized, double-blinded, placebo‑controlled trial evaluated the effect of alirocumab on neurocognitive function after 96 weeks of treatment (~2 years) in patients with heterozygous familial hypercholesterolemia (HeFH) or non-familial hypercholesterolemia, at high or very high cardiovascular risk. Neurocognitive function was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). A total of 2171 patients were randomized; 1087 patients were treated with alirocumab 75 mg and/or 150 mg every 2 weeks and 1084 patients were treated with placebo. A majority (> 80%) of patients in each group completed the 96-week, double-blind treatment period. Over the 96 weeks of treatment, alirocumab showed no additional effect on neurocognitive function. The percentage of patients who experienced neurocognitive disorders was low in the alirocumab (1.3%) treatment groups and comparable to placebo (1.7%).

5.2 Pharmacokinetic Properties

Absorption.

After subcutaneous administration of 50 mg to 300 mg alirocumab, median times to maximum serum concentration (tmax) were 3-7 days. The pharmacokinetics of alirocumab after single subcutaneous administration of 75 mg into the abdomen, upper arm or thigh were similar. The absolute bioavailability of alirocumab after subcutaneous administration was 85% as determined by population pharmacokinetic analysis. A slightly greater than dose proportional increase was observed, with a 2.1- to 2.7-fold increase in total alirocumab concentrations for a 2-fold increase in dose. Steady state was reached after 2 to 3 doses with an accumulation ratio of up to a maximum of about 2-fold.

Distribution.

Following intravenous administration, the volume of distribution was about 0.04 to 0.05 L/kg indicating that alirocumab is distributed primarily in the circulatory system.

Metabolism.

Specific metabolism studies were not conducted, because alirocumab is a protein. Alirocumab is expected to degrade to small peptides and individual amino acids.

Excretion.

Two elimination phases were observed for alirocumab. At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of alirocumab is largely through a non-saturable proteolytic pathway.
Based on a population pharmacokinetic analysis, the median apparent half-life of alirocumab at steady state was 17 to 20 days in patients receiving alirocumab as monotherapy at subcutaneous doses of either 75 mg once every 2 weeks or 150 mg once every 2 weeks. When co-administered with a statin, the median apparent half-life of alirocumab was 12 days.

Special populations.

Gender.

Based on a population pharmacokinetic analysis, gender has no impact on alirocumab pharmacokinetics.

Elderly.

In the phase 3 primary hypercholesterolemia controlled studies, 1158 patients (34.7%) treated with Praluent were ≥ 65 years of age and 241 patients (7.2%) were ≥ 75 years of age. In the cardiovascular outcomes controlled study, 2505 patients (26.5%) treated with Praluent were ≥ 65 years of age and 493 patients (5.2%) treated with Praluent were ≥ 75 years of age. Based on a population pharmacokinetic analysis, age was associated with a small difference in alirocumab exposure at steady state, with no impact on efficacy or safety.

Paediatric.

The pharmacokinetic effects of alirocumab administration in paediatric patients have not been studied.

Race.

Based on a population pharmacokinetic analysis, race had no impact on alirocumab pharmacokinetics. Following single-dose subcutaneous administration of 100 mg to 300 mg alirocumab, there was no meaningful difference in exposure between Japanese and Caucasian healthy subjects.

Body weight.

Based on a population pharmacokinetic analysis, body weight had a small impact on alirocumab exposure, with no effect on efficacy or safety.

Hepatic impairment.

In a phase 1 study, after administration of a single 75 mg subcutaneous dose, alirocumab pharmacokinetic profiles in subjects with mild and moderate hepatic impairment were similar as compared to subjects with normal hepatic function. No data are available in patients with severe hepatic impairment.

Renal impairment.

Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of alirocumab. Population pharmacokinetic analyses showed that mild and moderate renal impairment did not have a meaningful impact on alirocumab pharmacokinetics. No data are available in patients with severe renal impairment (defined as eGFR < 30 mL/min/1.73 m2).

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been conducted with alirocumab. As alirocumab is a monoclonal antibody it would not be expected to have genotoxic potential.

Carcinogenicity.

Carcinogenicity studies have not been conducted with alirocumab.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each pre-filled pen or pre-filled syringe contains the following excipients: histidine, sucrose, polysorbate 20 and water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze). Do not expose to extreme heat. Time out of refrigeration should not exceed a maximum of 30 days at temperatures below 25°C. Keep in the outer carton in order to protect from light.

6.5 Nature and Contents of Container

Praluent 75 mg/mL and 150 mg/mL solution for injection is supplied in a siliconised 1 mL or 2 mL Type 1 clear glass syringe, equipped with a stainless steel needle, a styrene-butadiene rubber soft needle shield (does not contain natural latex), and a coated bromobutyl rubber plunger stopper.

Pre-filled pen.

75 mg/mL pre-filled syringe components are assembled into a pen with a blue cap and a light green activation button. Available in pack sizes of 1, 2 or 6 per carton.
150 mg/mL pre-filled syringe components are assembled into a pen with a blue cap and a dark grey activation button. Available in pack sizes of 1, 2 or 6 per carton.
300 mg/2 mL pre-filled syringe components are assembled into a pen with a blue cap and no activation button. Available in pack sizes of 1 or 3 per carton.

Pre-filled syringe*.

75 mg/mL pre-filled syringe is equipped with a light green polypropylene plunger rod. Available in pack sizes of 1, 2 or 6 per carton.
150 mg/mL pre-filled syringe is equipped with a dark grey polypropylene plunger rod. Available in pack sizes of 1, 2 or 6 per carton.
* Presentations currently not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Alirocumab consists of two disulfide-linked human heavy chains, each covalently linked through a disulfide bond to a fully human kappa light chain. A single N-linked glycosylation site is located in each heavy chain within the CH2 domain of the Fc constant region of the molecule. The variable domains of the heavy and light chains combine to form the proprotein convertase subtilisin kexin type 9 (PCSK9) binding site within the antibody. Alirocumab has an approximate molecular weight of 146 kDa.

Chemical structure.


CAS number.

1245916-14-6.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes