Consumer medicine information

Vazkepa

Icosapent ethyl

BRAND INFORMATION

Brand name

Vazkepa

Active ingredient

Icosapent ethyl

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vazkepa.

SUMMARY CMI

VAZKEPA®

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.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using VAZKEPA®?

VAZKEPA® contains the active ingredient icosapent ethyl. VAZKEPA® is used with a statin medicine to prevent conditions that affect the heart and blood vessels.

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

2. What should I know before I use VAZKEPA®?

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

Talk to your doctor if you are allergic to fish or to shellfish, 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 VAZKEPA®? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VAZKEPA® 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 take VAZKEPA®?

  • The recommended dose is two capsules by mouth, twice a day, with or after a meal.
  • Swallow the capsules whole; do not break, crush, dissolve or chew the capsules.

More instructions can be found in Section 4. How do I take VAZKEPA®? in the full CMI.

5. What should I know while using VAZKEPA®?

Things you should do
  • Attend your scheduled appointments so that your doctor can carry out blood tests to check for any problems and discuss appropriate precautions with you.
  • Remind any doctor, dentist or pharmacist you visit that you are using VAZKEPA®.
Things you should not do
  • Do not stop taking this medicine until you have discussed with your doctor.
Looking after your medicine
  • Follow the instructions in the carton or product label on how to take care of your medicine properly.
  • Store below 30°C.

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

6. Are there any side effects?

The most common side effects of VAZKEPA® are bleeding, swelling of your hands, arms, legs and feet; heart palpitations or irregular heartbeat; constipation; pain in muscles, bones or joints; gout and rash.

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.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

VAZKEPA®

Active ingredient: icosapent ethyl

Consumer Medicine Information (CMI)

This leaflet provides important information about using VAZKEPA®. 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 VAZKEPA®.

Where to find information in this leaflet:

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

1. Why am I using VAZKEPA®?

VAZKEPA® contains the active ingredient icosapent ethyl, a highly purified omega-3 fatty acid obtained from the oil of fish. VAZKEPA® is used with a statin medicine to prevent cardiovascular events, such as:

  • Heart attack
  • Stroke
  • Death from heart or vascular disease

VAZKEPA® is a prescription medicine and is used in adults with high blood triglycerides who already have heart disease or have diabetes and other conditions that put them at a higher risk of cardiovascular events.

2. What should I know before I use VAZKEPA®?

Warnings

Do not use VAZKEPA® if:

  • you are allergic to icosapent ethyl, soya or peanut or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • are allergic to fish or shellfish. The active ingredient icosapent ethyl is derived from the oil of fish.
  • have problems with your liver.
  • have problems with irregular heartbeat (atrial fibrillation or flutter).
  • take an anticoagulant medicine (which prevents blood from clotting), medicines that inhibit platelets in the blood or are at risk of bleeding.
  • have an intolerance to some sugars or have been diagnosed with hereditary fructose intolerance (HFI). VAZKEPA contains maltitol and sorbitol.

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. VAZKEPA® is not recommended for use during pregnancy unless your doctor advises you to take it.

Talk to your doctor if you are breastfeeding or intend to breastfeed. VAZKEPA® is not recommended for use while breast-feeding as the effect on your baby is not known.

Use in children and adolescents

VAZKEPA® should not be used in children and adolescents under the age of 18 years because it has not been studied in this age group.

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.

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

4. How do I take VAZKEPA®?

How much to take

  • The recommended dose is two capsules by mouth, twice a day, with or after a meal.
  • Swallow the capsules whole; do not break, crush, dissolve or chew the capsules.

If you forget to take VAZKEPA®

If you miss your dose at the usual time, take it as soon as you remember.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

If you use too much VAZKEPA®

If you think that you have taken too much VAZKEPA®, you may need urgent medical attention.

You should immediately:

  • Phone the Poisons Information Centre (in Australia telephone 13 11 26. In New Zealand telephone 0800 POISON or 0800 764 766), 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.

5. What should I know while using VAZKEPA®?

Things you should do

  • Attend your scheduled appointments so that your doctor can check on your progress.
    Blood tests: During your treatment your doctor may carry out blood tests to check for any problems with your liver and to check how your blood is clotting.

Call your doctor straight away if you:

  • get heart palpitations or irregular heartbeat. These could be symptoms of a serious condition known as atrial fibrillation.
  • bruise easily or cannot stop bleeding. Your risk of bleeding may increase if you are also taking an anticoagulant medicine.

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

Things you should not do

  • Do not stop taking this medicine until you have spoken with your doctor.

Driving or using machines

This medicine is unlikely to affect your ability to drive or use tools or machines.

Looking after your medicine

Store below 30°C.

  • Bottle: keep the bottle tightly closed in order to protect from moisture.
  • Blister pack: store in the original package in order to protect from moisture.

Store it in a cool dry place away from moisture, 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.

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
Metabolism/ nutrition related:
  • Gout (painful swelling in the joints because of a build-up of uric acid)
Gastrointestinal related:
  • Constipation
  • Burping
Skin related:
  • Rash
Muscle and joints related:
  • Pain in muscles, bones or joints.
Other:
  • Swelling of your hands, arms, legs and feet.
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
Hypersensitivity/allergy related:
  • shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
Bleeding related:
  • Tendency to bruise easily or can't stop bleeding (especially if you are also taking an anticoagulant medicine).
Heart related:
  • Heart palpitations or irregular heart beats (atrial fibrillation)
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 VAZKEPA® contains

Active ingredient
(main ingredient)		Icosapent ethyl 998 mg
Other ingredients
(inactive ingredients)		Capsule fill: dl-alpha-tocopherol
Capsule shell: Gelatin, glycerol, maltitol solution, sorbitol solution (70 per cent) (non-crystallising), purified water, medium chain triglycerides, lecithin
Printing ink: Titanium dioxide, propylene glycol, hypromellose
AllergensSoya bean products and fish products.

Do not take this medicine if you are allergic to icosapent ethyl, soya or peanut or any of the ingredients listed above. Icosapent ethyl is obtained from the oil of fish. Check with your doctor if you are allergic to fish or to shellfish see ‘Section 2. What should I know before I use VAZKEPA®?’.

What VAZKEPA® looks like

VAZKEPA® is an oblong soft capsule, printed with “IPE” in white ink, with a light yellow to amber shell containing a colourless to pale yellow liquid.

VAZKEPA® is supplied in HDPE bottles with child-resistant polypropylene heat induction sealed closure containing 120 soft capsules and in PVC/PCTFE/Al perforated unit dose blisters containing 4x2 soft capsules.

Not all pack sizes may be available.

Who distributes VAZKEPA®

Seqirus Pty Ltd
ABN: 26 160 735 035
63 Poplar Road
Parkville VIC 3052
Australia
Telephone: 1800 642 865
www.cslseqirus.com.au

This leaflet was prepared in Feb 2024.

Vazkepa is a registered trademark of Amarin Pharmaceuticals Ireland Ltd.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Vazkepa

Active ingredient

Icosapent ethyl

Schedule

S4

 

1 Name of Medicine

Icosapent ethyl.

2 Qualitative and Quantitative Composition

Each soft capsule contains 998 mg of icosapent ethyl.

Excipients with known effect.

Maltitol, sorbitol and soya bean products (see Section 4.4 Special Warnings and Precautions for Use).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Soft capsule.
Oblong soft capsule, 25 x 10 mm, printed with "IPE" in white ink, with a light yellow to amber shell containing a colourless to pale yellow liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Vazkepa is indicated to reduce the risk of cardiovascular events in adult statin-treated patients at high cardiovascular risk with elevated triglycerides (≥ 1.7 mmol/L) and established cardiovascular disease, or diabetes, and at least one other cardiovascular risk factor.

4.2 Dose and Method of Administration

The recommended daily oral dose is 4 capsules taken as two 998 mg capsules twice daily.
If a dose is missed, patients should take it as soon as they remember. However, if one daily dose is missed, the next dose should not be doubled.

Method of administration.

Oral use.
Vazkepa should be taken with or following a meal.
To ensure the full intended dose is received, patients should be advised to swallow the capsules whole and not to break, crush, dissolve, or chew them.

Dosage adjustment.

Renal impairment.

No dose reduction is recommended (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

No dose reduction is recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Elderly.

No dose adjustment is necessary based on age (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Hypersensitivity to the active substance, soya or to any of the excipients listed, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Allergies to fish and/or shellfish.

Icosapent ethyl is obtained from the oil of fish. It is not known whether patients with allergies to fish and/or shellfish are at increased risk of an allergic reaction to icosapent ethyl. Icosapent ethyl should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

Atrial fibrillation or flutter.

Icosapent ethyl was associated with an increased risk of atrial fibrillation or flutter requiring hospitalisation in a double-blind placebo-controlled trial. The incidence of atrial fibrillation was greater in patients with a previous history of atrial fibrillation or flutter (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients, particularly those with a relevant medical history, should be monitored for clinical evidence of atrial fibrillation or atrial flutter (e.g. dyspnoea, palpitations, syncope/ dizziness, chest discomfort, change in blood pressure, or irregular pulse). Electrocardiographic evaluation should be performed when clinically indicated.

Bleeding.

Treatment with icosapent ethyl has been associated with an increased incidence of bleeding. Patients taking icosapent ethyl along with antithrombotic agents, i.e. antiplatelet agents, including acetylsalicylic acid, and/or anticoagulants, may be at increased risk of bleeding and should be monitored periodically (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in hepatic impairment.

In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations should be monitored as clinically indicated before the start of treatment and at appropriate intervals during treatment.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

There is no relevant use of icosapent ethyl in children aged < 18 years of age in reducing the risk of cardiovascular events in statin-treated patients at high cardiovascular risk with elevated triglycerides and other risk factors for cardiovascular disease.

Excipients content.

Sorbitol.

This medicinal product contains 83 mg of sorbitol in each capsule. The additive effect of concomitantly administered medicinal products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.
The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.
Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Maltitol.

This medicinal product contains 30 mg of maltitol in each capsule.
Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

Soya lecithin.

This medicinal product contains soya lecithin. Patients who are allergic to soya or peanut should not use this medicinal product.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Icosapent ethyl was studied at the dose level of four 998 mg capsules/day with the following medicinal products which are typical substrates of cytochrome P450 enzymes: omeprazole, rosiglitazone, warfarin and atorvastatin. No interactions were observed.
In vitro studies show that the free acid form of icosapent ethyl, eicosapentaenoic acid (EPA), is a weak inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A. In a separate in vitro study, EPA was found not to induce CYP isoforms CYP3A, CYP2C9, and CYP1A2. Additional in vitro studies showed that EPA at a concentration of 1 microM did not significantly inhibit P-gp, BCRP, OAT1, OCT2, OATP1B1 and OATP1B3, but did mildly inhibit the transport of OAT3.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on fertility in humans from the use of icosapent ethyl. A rat fertility study at doses up to 3000 mg/kg/day indicated no effect on female or male fertility in up to 3000 mg/kg/day (approximately 8-fold the clinical AUC at the MRHD).
(Category B1)1
There is a limited amount of data from the use of icosapent ethyl in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Effects on fertility). As a precautionary measure, it is preferable to avoid the use of icosapent ethyl during pregnancy unless the benefit of use outweighs the potential risk to the fetus.
Animal studies indicate that icosapent ethyl crosses the placenta and is found in fetal plasma.
In pregnant rats (up to 2000 mg/kg/day) or rabbits (up to 1000 mg/kg/day) orally administered icosapent ethyl from gestation through organogenesis revealed no adverse visceral and skeletal findings up to 8- or 7-fold the clinical dose (relative to clinical exposures based on AUC and BSA, respectively) respectively. While reduced 13th rib, additional liver lobes, and medially displaced testes were reported in rat embryos no dose correlation was noted.
In a multigenerational developmental study in pregnant rats given doses up to 3000 mg/kg/day orally from gestation day 7-17, icosapent ethyl did not affect viability in fetuses (F1 or F2) at approximately 8-fold the clinical dose (based on exposures of comparative studies). Non-dose-related findings included absent optic nerves and unilateral testes atrophy. Additional variations consisting of early incisor eruption and increased percent cervical ribs were observed at the same exposures. Pups from high dose treated dams exhibited decreased copulation rates, delayed estrus, decreased implantations and decreased surviving fetuses (F2) suggesting potential multigenerational effects of icosapent ethyl at 8-times human systemic exposure.
1Australian Pregnancy Category B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
 It is not known whether icosapent ethyl is excreted in human milk. Studies from the literature have shown that the active metabolite eicosapentaenoic acid (EPA) is excreted in human milk at levels which correlated to maternal diet. Animal studies indicate that icosapent ethyl is excreted in milk. Available toxicological data in rats have shown excretion of icosapent ethyl in milk.
A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from icosapent ethyl therapy considering the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7 Effects on Ability to Drive and Use Machines

On the basis of its pharmacodynamic profile and clinical study adverse reaction data, icosapent ethyl is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Adverse events in the REDUCE-IT trial.

In the pivotal Phase 3 study, REDUCE-IT, 81.8% (3343/4089) and 81.3% (3326/4090) of patients in the Vazkepa and placebo groups, respectively, experienced at least one treatment-emergent adverse event (TEAE). The proportions of patients who experienced TEAEs, treatment-related TEAEs, serious adverse events (SAEs), or discontinuations due to TEAEs were similar between the Vazkepa and placebo groups. The most frequent TEAE in both treatment groups was diarrhoea, with a lower incidence in the Vazkepa group than in the placebo group (9.0% [367/4089] versus 11.1% [453/4090], respectively). Other frequently reported TEAEs included back pain, hypertension, nasopharyngitis and arthralgia where similar incidence was seen in the Vazkepa and placebo groups. Common adverse events with a higher incidence (> 1%) in the Vazkepa group versus placebo are provided in Table 1.

Summary of the safety profile.

The most frequently reported adverse reactions associated with icosapent ethyl were bleeding (11.8%), peripheral oedema (7.8%), atrial fibrillation (5.8%), constipation (5.4%), musculoskeletal pain (4.3%), gout (4.3%) and rash (3.0%).

Tabulated list of adverse reactions.

Adverse reactions are classified according to frequency and system organ class. Reporting frequencies for adverse reactions have been estimated from a long-term cardiovascular outcomes study in which subjects were observed for a median follow-up duration of 4.9 years (Table 2). Frequency categories are defined according to the following conventions: 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).

Description of selected adverse reactions.

Bleeding.

Bleeding occurred in 11.8% of subjects receiving icosapent ethyl in a placebo-controlled cardiovascular outcomes trial compared with 9.9% in subjects receiving placebo. Serious bleeding events were reported more frequently in subjects receiving icosapent ethyl than in those receiving placebo when administered in combination with concomitant antithrombotic medication (3.4% vs. 2.6%), but occurred at the same rate (0.2%) in subjects not taking concomitant anticoagulant/antiplatelet medication (see Section 4.4 Special Warnings and Precautions for Use).
The bleeding events most frequently observed with icosapent ethyl were gastrointestinal bleeding (3.1%), contusion (2.5%), haematuria (1.9%), and epistaxis (1.5%).

Atrial fibrillation/ flutter.

Atrial fibrillation or atrial flutter occurred in 5.8% of subjects receiving icosapent ethyl in a placebo-controlled cardiovascular outcomes trial compared with 4.5% in subjects receiving placebo. Atrial fibrillation or atrial flutter requiring hospitalisation for 24 hours or more occurred in 3% of subjects treated with icosapent ethyl compared with 2% in subjects receiving placebo. Atrial fibrillation and atrial flutter were reported more frequently in subjects with a previous history of atrial fibrillation or atrial flutter receiving icosapent ethyl than in those receiving placebo (12.5% vs. 6.3%) (see Section 4.4 Special Warnings and Precautions for Use).

Constipation.

Constipation occurred in 5.4% of subjects receiving icosapent ethyl in a placebo-controlled cardiovascular outcomes trial compared with 3.6% of subjects receiving placebo. Serious constipation was less common for icosapent ethyl (0.1%) and placebo (0.2%). The relative incidence of constipation in this study may have been confounded by a residual laxative effect for placebo, which comprised a subtherapeutic dose of light mineral oil (4 mL).
The following adverse reactions have been identified from global post-marketing use of icosapent ethyl. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure: blood triglycerides increased, arthralgia, diarrhoea, abdominal discomfort, and pain in the extremities.

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.

4.9 Overdose

There is no specific treatment for icosapent ethyl overdose. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Icosapent ethyl is a stable ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA). The mechanisms of action contributing to reduction of cardiovascular events with icosapent ethyl are not completely understood. The mechanisms are likely multi-factorial including improved lipoprotein profile with reduction of triglyceride-rich lipoproteins, anti-inflammatory, and antioxidant effects, reduction of macrophage accumulation, improved endothelial function, increased fibrous cap thickness/stability, and antiplatelet effects. Each of these mechanisms can beneficially alter the development, progression, and stabilisation of atherosclerotic plaque, as well as the implications of plaque rupture, and preclinical and clinical studies support such benefits with EPA. Systemic and localised anti-inflammatory effects of EPA may result from displacement of pro-inflammatory arachidonic acid (AA), directing catabolism away from eicosanoids (2-series prostaglandins and thromboxanes, and 4-series leukotrienes) to non- or anti-inflammatory mediators. However, the direct clinical meaning of individual findings is not clear.
Icosapent ethyl improves the lipoprotein profile by suppressing cholesterol-, fatty acid- and triglyceride (TG)-synthesising enzymes, increasing fatty acid β-oxidation, and reducing microsomal triglyceride transfer (MTP) protein, resulting in decreased hepatic TG and very low-density lipoprotein (VLDL) synthesis and release. Icosapent ethyl also increases expression of lipoprotein lipase leading to increased TG removal from circulating VLDL and chylomicron particles. In patients with elevated TG levels, icosapent ethyl lowers TG, VLDL, remnant lipoprotein cholesterol, and levels of inflammatory markers such as C-reactive protein. However, TG reduction appears to provide only a minor contribution to the reduction in risk of cardiovascular events with icosapent ethyl.

Clinical trials.

REDUCE-IT was a multinational, double-blind, randomised, placebo-controlled, event-driven trial in 8,179 (4,089 icosapent ethyl, 4,090 placebo) statin-treated adult patients enrolled with low-density lipoprotein cholesterol (LDL-C) > 1.03 mmol/L (40 mg/dL) and ≤ 2.59 mmol/L (100 mg/dL) and moderately elevated triglyceride (TG) levels (≥ 1.53 mmol/L and < 5.64 mmol/L [≥ 135 mg/dL and < 500 mg/dL] as measured during patient screening, i.e. qualifying visits pre-enrolment) and either established cardiovascular disease (70.7%) or diabetes and other risk factors for cardiovascular disease (29.3%). Patients with established cardiovascular disease were defined as being at least 45 years of age and having a documented history of coronary artery disease, cerebrovascular or carotid disease, or peripheral artery disease. Patients in the other risk group were defined as being at least 50 years of age with diabetes requiring medical treatment and at least one additional risk factor i.e. hypertension or on an antihypertensive medicinal product; age at least 55 years (men) or at least 65 years (women); low high-density lipoprotein cholesterol levels; smoking; raised high-sensitivity C-reactive protein levels; renal impairment; micro or macroalbuminuria; retinopathy; or reduced ankle brachial index. Patients were randomly assigned 1:1 to receive either icosapent ethyl or placebo (as 4 capsules daily). The median follow-up duration was 4.9 years. Overall, 99.8% of patients were followed for vital status until the end of the trial or death.
The baseline characteristics were balanced between the groups, median age at baseline was 64 years (range: 44 years to 92 years), with 46% being at least 65 years old; 28.8% were women. The trial population was 90.2% White, 5.5% Asian, 4.2% identified as Hispanic ethnicity, and 1.9% were Black. Regarding prior diagnoses of cardiovascular disease, 46.7% had prior myocardial infarction, 9.2% had symptomatic peripheral arterial disease, and 6.1% prior unknown stroke or transient ischemic attack (TIA). Selected additional baseline risk factors included hypertension (86.6%), diabetes mellitus (0.7% type 1; 57.8% type 2), eGFR < 60 mL/min per 1.73 m2 (22.2%), congestive heart failure (17.7%), and current daily cigarette smoking (15.2%). Most patients were taking moderate-intensity (63%) or high-intensity (31%) statin therapy at baseline. Most patients at baseline were taking at least one other cardiovascular medicinal product including antiplatelet and/or antithrombotic agents (85.5%), beta blockers (70.7%), antihypertensives (95.2%), angiotensin converting enzyme (ACE) inhibitors (51.9%), or angiotensin receptor blockers (ARB; 26.9%); 77.5% were taking an ACE inhibitor or ARB. The protocol excluded patients taking PCSK9 inhibitors. On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 1.9 [1.6, 2.3] mmol/L (75.0 [62.0, 89.0] mg/dL); the mean (SD) was 2.0 (0.5) mmol/L (76.2 [20.3] mg/dL). On stable background lipid-lowering therapy, the median [Q1, Q3] fasting TG was 2.4 [2.0, 3.1] mmol/L (216.0 [176.0, 272.5] mg/dL); the mean (SD) was 2.6 (0.9) mmol/L (233.2 [80.1] mg/dL).
Icosapent ethyl significantly reduced the risk for the primary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or hospitalisation for unstable angina; p < 0.0001) and the key secondary composite endpoint (time to first occurrence of cardiovascular death, myocardial infarction, or stroke; p < 0.0001). The results of the primary and secondary efficacy endpoints are shown in Table 3. The Kaplan-Meier estimates of the cumulative incidence of the key secondary composite endpoint over time are shown in Figure 1.
The median TG and LDL-C baseline values were similar between the icosapent ethyl group and placebo group. The median change in TG from baseline to Year 1 was -0.4 mmol/L (-39 mg/dL, -18%) in the icosapent ethyl group and 0.1 mmol/L (5 mg/dL, 2%) in the placebo group. The median change in LDL-C from baseline to Year 1 was 0.1 mmol/L (2 mg/dL, 3%) in the icosapent ethyl group and 0.2 mmol/L (7 mg/dL, 10%) in the placebo group. Prespecified analyses of the effect of icosapent ethyl on cardiovascular outcomes in the REDUCE-IT trial showed little to no correlation between either TG or LDL-C response and cardiovascular effect based on baseline or on-study achieved TG or LDL-C levels. See Section 5.1 Pharmacodynamic Properties, Mechanism of action for more information.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, icosapent ethyl is de-esterified during the absorption process and the active metabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via the thoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately 5 hours following oral doses of icosapent ethyl.
Icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studies were performed (see Section 4.2 Dose and Method of Administration).

Distribution.

The mean volume of distribution at steady-state of EPA is approximately 88 liters. The majority of EPA circulating in plasma is incorporated in phospholipids, triglycerides and cholesteryl esters, and < 1% is present as the unesterified fatty acid. Greater than 99% of unesterified EPA is bound to plasma proteins.

Metabolism.

EPA is mainly metabolised by the liver via beta-oxidation similar to dietary fatty acids. Beta oxidation splits the long carbon chain of EPA into acetyl coenzyme A, which is converted into energy via the Krebs cycle.

Excretion.

Cytochrome P450-mediated metabolism is a minor pathway of elimination of EPA. The total plasma clearance of EPA at steady-state is 684 mL/hr. The plasma elimination half-life (t1/2) of EPA is approximately 89 hours. Icosapent ethyl does not undergo renal excretion.

Pharmacokinetic/ pharmacodynamic relationship(s).

Triglycerides level/ reduction in hypertriglyceridemia.

A linear relationship between EPA levels in plasma or red blood cells (RBCs) and TG reduction was observed in two Phase III studies.

Cardiovascular risk reduction.

Analyses of the primary (5-point) and key secondary (3-point) MACE endpoints suggest that on-treatment lipoprotein changes had limited influence on cardiovascular risk reductions, while on-treatment steady-state serum EPA levels accounted for the majority of the relative risk reduction observed in REDUCE-IT. Baseline serum EPA level was 26 microgram/mL; compared to patients with an on-treatment steady-state serum EPA level below 100 microgram/mL, patients with on-treatment EPA levels ≥ 175 microgram/mL had a > 50% reduced risk of a cardiovascular event.

Renal and hepatic impairment.

The pharmacokinetics of icosapent ethyl has not been studied in patients with renal or hepatic impairment. Patients did not require routine dose adjustment due to hepatic or renal impairment in a well-controlled cardiovascular outcomes study of icosapent ethyl.

Elderly (≥ 65 years).

The pharmacokinetics of icosapent ethyl has not been studied in elderly patients. Elderly patients did not require routine dose adjustment in well-controlled clinical studies of icosapent ethyl.

Paediatric population.

The pharmacokinetics of icosapent ethyl has not been studied in paediatric subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Nonclinical data reveal no special hazard for humans based on conventional genotoxicity studies.
Icosapent ethyl was not mutagenic with or without metabolic activation in the bacterial mutagenesis (Ames) assay or in the in vivo mouse micronucleus assay. A chromosomal aberration assay in Chinese hamster ovary (CHO) cells was positive for clastogenicity with and without metabolic activation, which appeared to be a class effect.

Carcinogenicity.

Nonclinical data reveal no special hazard for humans based on conventional studies of carcinogenic potential.
In a 2-year rat carcinogenicity study with oral gavage doses of 90, 270 and 910 mg/kg/day icosapent ethyl, respectively, did not result in drug-related neoplasms (up to ~7-fold the clinical exposure based on AUC). While haemangiomas and haemangiosarcomas of the mesenteric lymph node were noted, overall incidence in all vascular tissues did not increase with treatment.
In a 6-month carcinogenicity study in Tg.rasH2 transgenic mice with oral gavage doses of 500, 1000, 2000 and 4600 mg/kg/day icosapent ethyl did not result in test-article related neoplasms (up to 4-fold the clinical exposure based on AUC). However, benign squamous cell papilloma in the skin and subcutis of the proximal tail were observed at the highest dose which appeared to be secondary to chronic irritation of the proximal tail associated with faecal excretion of oil.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule fill.

dl-alpha-tocopherol.

Capsule shell.

Gelatin, glycerol, maltitol solution, sorbitol solution (70 per cent) (non-crystallising), purified water, medium chain triglycerides, lecithin.

Printing ink.

Titanium dioxide, propylene glycol, hypromellose.

6.2 Incompatibilities

Not applicable.

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 below 30°C.

Bottles.

Keep bottle tightly close in order to protect from moisture.

Blisters.

Store in the original package in order to protect from moisture.

6.5 Nature and Contents of Container

High density polyethylene (HDPE) bottle with child-resistant polypropylene heat induction sealed closure containing 120 soft capsules.
PVC/PCTFE/Al perforated unit dose blisters containing 4 x 2 soft capsules (sample only).
Not all pack sizes may be 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

Chemical structure.


CAS number.

73310-10-8.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes