VAZKEPA 998mg soft capsules medication leaflet

Vazkepa 998 mg soft capsules

Each capsule contains 998 mg icosapent ethyl.

Each capsule contains 30 mg maltitol (E965 ii), 83 mg sorbitol (E420 ii) and soya lecithin.

For the full list of excipients, see section 6.1.

Soft capsule (capsule)

Oblong soft capsule, 25 x 10 mm, printed with “IPE” in white ink, with a light yellow to amber shellcontaining a colourless to pale yellow liquid.

Vazkepa is indicated to reduce the risk of cardiovascular events in adult statin-treated patients at highcardiovascular risk with elevated triglycerides (≥ 150 mg/dL [≥ 1.7 mmol/L]) and

* established cardiovascular disease, or

* diabetes, and at least one other cardiovascular risk factor.

For trial details including cardiovascular risk factors and results with respect to effects oncardiovascular events see section 5.1.

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 ismissed, the next dose should not be doubled.

No dose adjustment is necessary in elderly patients (≥ 65 years of age) (see section 5.2).

No dose reduction is recommended (see section 5.2).

No dose reduction is recommended (see sections 4.4 and 5.2).

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

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 wholeand not to break, crush, dissolve, or chew them.

Hypersensitivity to the active substance, soya or to any of the excipients listed in section 6.1.

Allergies to fish and/or shellfish

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

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 atappropriate intervals during treatment (see sections 4.2 and 5.2).

Atrial fibrillation or flutter

Icosapent ethyl was associated with an increased risk of atrial fibrillation or flutter requiringhospitalisation in a double-blind placebo-controlled trial. The incidence of atrial fibrillation wasgreater in patients with a previous history of atrial fibrillation or flutter (see section 4.8). Patients,particularly those with a relevant medical history, should be monitored for clinical evidence of atrialfibrillation or atrial flutter (e.g. dyspnoea, palpitations, syncope/dizziness, chest discomfort, change inblood pressure, or irregular pulse). Electrocardiographic evaluation should be performed whenclinically indicated.

Treatment with icosapent ethyl has been associated with an increased incidence of bleeding. Whenicosapent ethyl is administered concomitantly with antithrombotic agents, appropriate laboratoryinvestigations may be considered, whenever clinical signs suggestive of hemorrhage - such ascontusion, epistaxis, hematuria, or gastrointestinal bleeding - occur during treatment.

Patients should be advised to promptly report any signs or symptoms of bleeding to their physician(see section 4.8).

Maltitol (E965 ii)

This medicinal product contains 30 mg maltitol in each capsule.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Sorbitol (E420 ii)

This medicinal product contains 83 mg sorbitol in each capsule. The additive effect of concomitantlyadministered 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 othermedicinal products for oral use administered concomitantly.

Patients with hereditary fructose intolerance (HFI) should not take this medicinal product.

Soya lecithin

This medicinal product contains soya lecithin. Patients who are allergic to soya or peanut must not usethis medicinal product.

Icosapent ethyl was studied at the dose level of four 998 mg capsules/day with the following medicinalproducts which are typical substrates of cytochrome P450 enzymes: omeprazole, rosiglitazone,warfarin and atorvastatin. No interactions were observed.

Patients taking icosapent ethyl along with antithrombotic agents, i.e. antiplatelet agents, includingacetylsalicylic acid, and/or anticoagulants, may be at increased risk of bleeding and should bemonitored periodically.

There are a limited amount of data from the use of icosapent ethyl in pregnant women. Animal studiesdo not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of Vazkepa during pregnancy unless thebenefit of use outweighs the potential risk to the foetus.

It is unknown whether icosapent ethyl is excreted in human milk. Studies from the literature haveshown that the active metabolite eicosapentaenoic acid (EPA) is excreted in human milk at levelswhich correlated to maternal diet. Available toxicological data in rats have shown excretion oficosapent ethyl in milk (see section 5.3).

A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Vazkepa therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

There are no data on fertility in humans from the use of icosapent ethyl. Animal studies do not indicatedirect or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

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

The most frequently reported adverse reactions associated with icosapent ethyl are 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 %).

Adverse reactions are listed below and classified according to frequency and MedDRA system organclass based on all available interventional and non-interventional clinical trials and spontaneousreporting. 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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions

MedDRA System organ class Adverse reaction Frequency

Immune system disorders Hypersensitivity Uncommon

Pharyngeal swelling Not known

Metabolism and nutrition disorders Gout Common

Nervous system disorders Dysgeusia1 Uncommon

Cardiac disorders Atrial fibrillation or Commonflutter2

Vascular disorders Bleeding2 Very common

Gastrointestinal disorders Constipation2 Common

Eructation Common

Skin and subcutaneous tissue disorders Rash Common

Musculoskeletal and connective tissue disorders Musculoskeletal pain Common

General disorders and administration site Peripheral oedema Commonconditions1 Dysguesia describes the ‘verbatim’ term: Fishy taste2 See ‘Description of selected adverse reactions’

Bleeding occurred in 11.8 % of subjects receiving icosapent ethyl in a placebo-controlledcardiovascular outcomes trial compared with 9.9 % in subjects receiving placebo. Serious bleedingevents were reported more frequently in subjects receiving icosapent ethyl than in those receivingplacebo 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 concomitantanticoagulant/antiplatelet medication (see section 4.4).

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. Atrialfibrillation or atrial flutter requiring hospitalisation for 24 hours or more occurred in 3 % of subjectstreated with icosapent ethyl compared with 2 % in subjects receiving placebo. Atrial fibrillation andatrial flutter were reported more frequently in subjects with a previous history of atrial fibrillation oratrial flutter receiving icosapent ethyl than in those receiving placebo (12.5 % vs. 6.3 %) (seesection 4.4).

Constipation occurred in 5.4 % of subjects receiving icosapent ethyl in a placebo-controlledcardiovascular outcomes trial compared with 3.6 % of subjects receiving placebo. Serious constipationwas less common for icosapent ethyl (0.1 %) and placebo (0.2 %). The relative incidence ofconstipation in this trial may have been confounded by a residual laxative effect for placebo, whichcomprised a subtherapeutic dose of light mineral oil (4 mL).

The following adverse reactions have been identified from global post-marketing use of icosapentethyl. Because these reactions are reported voluntarily from a population of uncertain size, it isgenerally not possible to reliably estimate their frequency or establish causal relationship to drugexposure: blood triglycerides increased, arthralgia, diarrhoea, abdominal discomfort, and pain in theextremities.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific treatment for icosapent ethyl overdose. In the event of an overdose, the patientshould be treated symptomatically, and supportive measures instituted as required.

Pharmacotherapeutic group: Lipid modifying agents, other lipid modifying agents, ATC code:

C10AX06

Icosapent ethyl is a stable ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA). Themechanisms of action contributing to reduction of cardiovascular events with icosapent ethyl are notcompletely understood. The mechanisms are likely multi-factorial including improved lipoproteinprofile with reduction of triglyceride-rich lipoproteins, anti-inflammatory, and antioxidant effects,reduction of macrophage accumulation, improved endothelial function, increased fibrous capthickness/stability, and antiplatelet effects. Each of these mechanisms can beneficially alter thedevelopment, progression, and stabilisation of atherosclerotic plaque, as well as the implications ofplaque rupture, and preclinical and clinical studies support such benefits with EPA. Systemic andlocalised anti-inflammatory effects of EPA may result from displacement of pro-inflammatoryarachidonic acid (AA), directing catabolism away from eicosanoids (2-series prostaglandins andthromboxanes, and 4-series leukotrienes) to non- or anti-inflammatory mediators. However, the directclinical meaning of individual findings is not clear.

Icosapent ethyl improves the lipoprotein profile by suppressing cholesterol-, fatty acid- andtriglyceride (TG)-synthesising enzymes, increasing fatty acid β-oxidation, and reducing microsomaltriglyceride transfer (MTP) protein, resulting in decreased hepatic TG and very low-densitylipoprotein (VLDL) synthesis and release. Icosapent ethyl also increases expression of lipoproteinlipase leading to increased TG removal from circulating VLDL and chylomicron particles. In patientswith elevated TG levels, icosapent ethyl lowers TG, VLDL, remnant lipoprotein cholesterol, andlevels of inflammatory markers such as C-reactive protein. However, TG reduction appears to provideonly a minor contribution to the reduction in risk of cardiovascular events with icosapent ethyl.

REDUCE-IT was a multinational, double-blind, randomised, placebo-controlled, event-driven trial in8 179 (4 089 icosapent ethyl, 4 090 placebo) statin-treated adult patients enrolled with low-densitylipoprotein cholesterol (LDL-C) > 1.03 mmol/L (40 mg/dL) and ≤ 2.59 mmol/L (100 mg/dL) andmoderately 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 eitherestablished cardiovascular disease (70.7 %) or diabetes and other risk factors for cardiovasculardisease (29.3 %). Patients with established cardiovascular disease were defined as being at least45 years of age and having a documented history of coronary artery disease, cerebrovascular or carotiddisease, or peripheral artery disease. Patients in the other risk group were defined as being at least50 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 least65 years (women); low high-density lipoprotein cholesterol levels; smoking; raised high-sensitivity C-reactive protein levels; renal impairment; micro or macroalbuminuria; retinopathy; or reduced anklebrachial index. Patients were randomly assigned 1:1 to receive either icosapent ethyl or placebo (as4 capsules daily). The median follow-up duration was 4.9 years. Overall, 99.8 % of patients werefollowed 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 trialpopulation 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 transientischemic 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 %), congestiveheart failure (17.7 %), and current daily cigarette smoking (15.2 %). Most patients were takingmoderate-intensity (63 %) or high-intensity (31 %) statin therapy at baseline. Most patients at baselinewere taking at least one other cardiovascular medicinal product including antiplatelet and/orantithrombotic agents (85.5 %), beta blockers (70.7 %), antihypertensives (95.2 %), angiotensinconverting 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 PCSK9inhibitors. On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was1.9 [1.6, 2.3] mmol/L (75 [62, 89] mg/dL); the mean (SD) was 2 (0.5) mmol/L (76.2 [20.3] mg/dL).

On stable background lipid-lowering therapy, the median [Q1, Q3] fasting TG was2.4 [2, 3.1] mmol/L (216 [176, 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 firstoccurrence of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, orhospitalisation for unstable angina; p < 0.0001) and the key secondary composite endpoint (time tofirst occurrence of cardiovascular death, myocardial infarction, or stroke; p < 0.0001). The results ofthe primary and secondary efficacy endpoints are shown in Table 2. The Kaplan-Meier estimates ofthe cumulative incidence of the key secondary composite endpoint over time are shown in Figure 1.

Table 2 Effect of icosapent ethyl on time to first occurrence of cardiovascular events in patientswith elevated triglyceride levels and cardiovascular disease or diabetes and other risk factors in

REDUCE-IT

Icosapent ethyl Placebo Icosapent ethylvs Placebo

N = 4 089 N = 4 090 Hazard ration (%) n (%) (95 % CI)

Primary composite endpoint

Cardiovascular death, myocardialinfarction, stroke, coronary 705 901 0.75revascularisation, hospitalisation for (17.2) (22) (0.68, 0.83)unstable angina (5-point MACE)

Key secondary composite endpoint

Cardiovascular death, myocardial 459 606 0.74infarction, stroke (3-point MACE) (11.2) (14.8) (0.65, 0.83)

Other secondary endpoints

Cardiovascular death[1] 174 213 0.80(4.3) (5.2) (0.66, 0.98)

Death by any cause[2] 274 310 0.87(6.7) (7.6) (0.74, 1.02)

Fatal or non-fatal myocardial infarction 250 355 0.69(6.1) (8.7) (0.58, 0.81)

Fatal or non-fatal stroke 98 134 0.72(2.4) (3.3) (0.55, 0.93)

Emergent or urgent coronary 216 321 0.65revascularisation (5.3) (7.8) (0.55, 0.78)

Coronary revascularisation[3] 376 544 0.66(9.2) (13.3) (0.58, 0.76)

Hospitalisation for unstable angina[4] 108 157 0.68(2.6) (3.8) (0.53, 0.87)[1] Cardiovascular death includes adjudicated cardiovascular deaths and deaths of undeterminedcausality.[2] Death by any cause, or total mortality, is not a component of either the primary compositeendpoint or key secondary composite endpoint.[3] The predefined composite secondary endpoint included emergent or urgent revascularisation(p < 0.0001); coronary revascularisations is the composite of all revascularisation and waspredefined as a tertiary endpoint.[4] Determined to be caused by myocardial ischemia by invasive/non-invasive testing and requiringemergent hospitalisation.

Figure 1 Kaplan-Meier estimated incidence of key secondary composite endpoint in

REDUCE-IT20 Hazard Ratio, 0.74(95% CI, 0.65-0.83)p<0.0001

Placebo

Vazkepa0 1 2 3 4 5

Years since Randomization

No. at Risk

Placebo 4090 3837 3500 3002 2542 1487

Vazkepa 4089 3861 3565 3115 2681 1562

Key secondary composite endpoint consisted of cardiovascular death, myocardial infarction, or stroke(3-point MACE)

Abbreviation: CI confidence interval

The median TG and LDL-C baseline values were similar between the icosapent ethyl group andplacebo 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 medianchange in LDL-C from baseline to Year 1 was 0.1 mmol/L (2 mg/dL, 3 %) in the icosapent ethylgroup and 0.2 mmol/L (7 mg/dL, 10 %) in the placebo group. Prespecified analyses of the effect oficosapent ethyl on cardiovascular outcomes in the REDUCE-IT trial showed little to no correlationbetween either TG or LDL-C response and cardiovascular effect based on baseline or on-studyachieved TG or LDL-C levels. See section 5.1 mechanism of action for more information.

The European Medicines Agency has waived the obligation to submit the results of studies withicosapent ethyl in all subsets of the paediatric population for the treatment of hypertriglyceridemia andto reduce the risk of cardiovascular events (see section 4.2 for information on paediatric use).

After oral administration, icosapent ethyl is de-esterified during the absorption process and the activemetabolite EPA is absorbed in the small intestine and enters the systemic circulation mainly via thethoracic duct lymphatic system. Peak plasma concentrations of EPA were reached approximately5 hours following oral doses of icosapent ethyl.

Icosapent ethyl was administered with or following a meal in all clinical studies; no food effect studieswere performed (see section 4.2).

Patients with an Event (%)

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 toplasma proteins.

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

Krebs cycle. 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.

Triglycerides level/reduction in hypertriglyceridemia

A linear relationship between EPA levels in plasma or red blood cells (RBCs) and TG reduction wasobserved 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 reductionobserved in REDUCE-IT. Baseline serum EPA level was 26 μg/mL; compared to patients with an on-treatment steady-state serum EPA level below 100 μg/mL, patients with on-treatment EPA levels≥ 175 μg/mL had a > 50 % reduced risk of a cardiovascular event.

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

The pharmacokinetics of icosapent ethyl has not been studied in elderly patients (≥ 65 years of age).

Elderly patients did not require routine dose adjustment in well-controlled clinical studies of icosapentethyl.

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

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dosetoxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.

At the highest dose levels in reproductive and developmental studies, no adverse reactions wereobserved in rats or rabbits at approximately 6 to 8 times the human equivalent dose based on bodysurface area comparison. In a rat embryo-foetal trial, no adverse reactions were observed at exposures6.9-fold higher than the clinical exposure (based on AUC).

Animal studies indicate that icosapent ethyl crosses the placenta and is found in foetal plasma.

Animal studies indicate that icosapent ethyl is excreted in milk.

Capsule fill

All-rac-alpha-tocopherol

Gelatin

Glycerol

Liquid maltitol (E965 ii)

Liquid sorbitol (non-crystallising) (E420 ii)

Purified water

Soya lecithin

Titanium dioxide

Hypromellose

Not applicable.

5 years

Store below 30 °C.

Keep the bottle tightly closed in order to protect from moisture.

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

High density polyethylene (HDPE) bottles with a child-resistant polypropylene heat induction sealedclosure containing 120 soft capsules.

Pack size of one bottle or three bottles per carton.

PVC/PCTFE/Al perforated unit dose blisters containing 4x2 soft capsules.

Not all pack sizes may be marketed.

How to open the bottle

Push down the screw cap and turn it anticlockwise.

No special requirements for disposal.

Amarin Pharmaceuticals Ireland Limited88 Harcourt Street

Dublin 2, D02DK18

Ireland

EU/1/20/1524/001

EU/1/20/1524/002

EU/1/20/1524/003

Date of first authorisation: 26 March 2021

Date of latest renewal:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.