Vascepa is an ethyl ester of eicosapentaenoic acid (EPA) indicated:

·   To reduce the risk of cardiovascular events as an adjunct to statin therapy in adult patients with elevated triglycerides (≥150 mg/dL), who are at high risk of cardiovascular events due to:

o   established cardiovascular disease, or

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

For study details and results with respect to effects on cardiovascular events see section 5.1.

·        as an adjunct to diet to reduce TG levels in adult patients with severe (≥ 500 mg/dL) hypertriglyceridemia.

The effect of Vascepa on the risk of pancreatitis in patients with severe hypertriglyceridemia has not been determined.

Posology

Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high triglyceride levels and manage as appropriate.

Patients should engage in appropriate nutritional intake and physical activity before receiving Vascepa, which should continue during treatment with Vascepa.

The recommended daily oral dose is 4 g taken as two 1 g capsules twice daily.

If a dose is missed, patients should take it as soon as they remember. However, if they miss one day of Vascepa, they should not double the dose when they take it.

Elderly (≥ 65 years)

In well-controlled clinical studies of Vascepa, no overall differences in safety or effectiveness were observed between elderly and younger patients. No dose adjustment is necessary based on age (see section 5.2).

Renal impairment

No dose reduction is recommended (see also section 5.2).

Hepatic impairment

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

Paediatric population

There is no relevant use of icosapent ethyl in children aged <18 years of age in reducing the risk of cardiovascular events as an adjunct to statin therapy in patients with elevated triglycerides, who are at high risk of cardiovascular events.

Method of administration

Oral use.

Take Vascepa with or following a meal.

To ensure the full intended dose is received, patients should be advised to swallow Vascepa capsules whole. Do not break, crush, dissolve, or chew Vascepa.

Allergies to fish and/or shellfish

Vascepa contains icosapent ethyl, an ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA), 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. Vascepa should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

Hepatic impairment

In patients with hepatic impairment, periodically monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels according to standard medical practice during therapy with Vascepa.

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 . 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 Vascepa has been associated with an increased incidence of bleeding. Patients taking Vascepa 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).

Excipients content

Each capsule contains up to 83 mg of sorbitol liquid, non-crystallising, and up to 30 mg of maltitol liquid. Vascepa should be used with caution in patients with rare hereditary problems of fructose intolerance.

Icosapent ethyl was studied at the 4 g/day dose level with the following medicinal products which are typical substrates of cytochrome P450 enzymes, and no interactions were observed:

·   Omeprazole: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUC_τ or C_max of omeprazole when co-administered at 40 mg/day to steady-state.

·   Rosiglitazone: In a drug-drug interaction study with 28 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or C_max of rosiglitazone at 8 mg.

·   Warfarin: In a drug-drug interaction study with 25 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the single dose AUC or C_max of R- and S- warfarin or the anticoagulation pharmacodynamics of warfarin when co-administered as racemic warfarin at 25 mg.

·   Atorvastatin: In a drug-drug interaction study of 26 healthy adult subjects, icosapent ethyl 4 g/day at steady-state did not significantly change the steady-state AUC_τ or C_max of atorvastatin, 2-hydroxyatorvastatin, or 4-hydroxyatorvastatin when co-administered with atorvastatin 80 mg/day to steady-state.

Pregnancy

There are 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 section 5.3). As a precautionary measure, it is preferable to avoid the use of Vascepa during pregnancy unless the benefit of use outweighs the potential risk to the foetus.

Breastfeeding

It is not known whether icosapent ethyl is excreted in human milk. Studies from the literature have shown that the active metabolite EPA is excreted in human milk at levels which correlated to maternal diet. Available toxicological data in rats have shown excretion of icosapent ethyl in milk (see section 5.3).

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from Vascepa therapy considering the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

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

On the basis of its pharmacodynamic profile and clinical trial adverse event data, Vascepa is expected to have no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

Adverse reactions below were identified from three well-controlled clinical studies with Vascepa: the MARINE, ANCHOR, and REDUCE-IT studies.  MARINE was a 12-week lipid study in patients with severe hypertriglyceridemia, with or without background statin therapy.  ANCHOR was a 12-week lipid study in patients with hypertriglyceridemia in which all patients received background statin therapy.  REDUCE-IT was a long-term cardiovascular outcomes trial with a median follow-up duration of 4.9 years in patients at high risk for cardiovascular disease. All patients in the REDUCE-IT were receiving statin therapy in addition to other cardiovascular medicinal products including antiplatelet agents (79.4%), 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. Placebo rates for identified adverse reactions were high and generally similar to treatment with Vascepa.

A very common adverse reaction of bleeding (11.8%) is associated with icosapent ethyl (see section 4.4). Common adverse reactions are peripheral oedema (7.8%), constipation (5.4%), atrial fibrillation (5.8%), musculoskeletal pain (4.3%), gout (4.3%), rash (3.0%), arthralgia (2.3%), oropharyngeal pain (1.1%), and eructation (1.1%). Uncommon adverse reactions include hypersensitivity (0.4%) and dysgeusia (0.3%).

Tabulated list of adverse reactions

Adverse reactions are classified according to frequency and system organ class. 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) and very rare (<1/10,000).

Table 1 lists adverse reactions identified in clinical study REDUCE-IT.

Table 1 Adverse Reactions

1 Includes the synonym Preferred term: Drug sensitivity

2 Includes the synonym Preferred terms: Gouty tophus and gouty arthritis

3 Dysguesia describes the “verbatim” term: Fishy taste

4 Includes the synonym Preferred term: Atrial flutter

5 See section Description of selected adverse reactions

6 See section Description of selected adverse reactions

7 Includes the synonym Preferred term: Rash generalised

8 Includes the synonym Preferred term: Peripheral swelling

Description of selected adverse reactions

Bleeding at 11.8% was identified as very common in a placebo-controlled cardiovascular outcomes trial for patients receiving icosapent ethyl but was observed similarly in patients receiving placebo at 9.9%. Serious bleeding events were less common at 3% for icosapent ethyl and 2% for placebo. Bleeding includes Preferred terms in the following Standardised MedDRA Queries (SMQs): Gastrointestinal haemorrhage SMQ, Central Nervous System haemorrhages and cerebrovascular conditions SMQ, Haemorrhage terms (excluding laboratory terms) SMQ.

Atrial fibrillation or atrial flutter at 5.8% was identified as common in a placebo-controlled cardiovascular outcomes trial for patients receiving icospanet ethyl but was observed similarly in patients receiving placebo at 4.5%. Adjudicated atrial fibrillation or atrial flutter requiring hospitalisation for 24 or more hours occurred in 3% patients treated with icosapent ethyl compared to 2% patients receiving placebo. The incidence of atrial fibrillation was greater in patients with a previous history of atrial fibrillation or atrial flutter.

The following adverse reactions have been identified from global post-marketing use of Vascepa. 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, diarrhoea, abdominal discomfort, and pain in the extremities.

- Please report adverse drug events to:

Saudi Arabia:

The National Pharmacovigilance Centre (NPC)

• SFDA Call Center: 19999

• E-mail: npc.drug@sfda.gov.sa

• Website: https://ade.sfda.gov.sa

United Arab Emirates:

Pharmacovigilance and Medical device section

Drug Department

Ministry of Health and Prevention

P.O. Box: 1853 Dubai

United Arab Emirates

• Hotline: 80011111

• Email: pv@mohap.gov.ae

Oman:

Department of Pharmacovigilance & Drug Information

Directorate General of Pharmaceutical Affairs & Drug Control

Ministry of Health, Sultanate of Oman

Tel: +968 22357687 / +968 22357686

Fax: +968 22358489

Email: pharma-vigil@moh.gov.om

Website: www.moh.gov.om

Kuwait:

Drug & Food Control, Ministry of Health, Kuwait

Tel.: +965-24811532

Fax: +965-24811507

E-mail: Adr_reporting@moh.gov.kw

Other GCC States:

Please contact the relevant competent authority.

There is no specific treatment for Vascepa overdose. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

Pharmacotherapeutic group: Other lipid modifying agents, ATC code: C10AX06

Mechanism of action

Icosapent ethyl is an ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid (EPA). The mechanisms of action contributing to reduction of cardiovascular events with Vascepa are not completely understood. The mechanisms are likely multi-factorial including improved lipoprotein profile with reduction of triglyceride-rich lipoproteins, anti-inflammatory, antioxidant, and membrane stabilising 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.

Studies suggest that EPA reduces hepatic very low-density lipoprotein triglycerides (VLDL-TG) synthesis and/or secretion and enhances TG clearance from circulating VLDL particles.  Potential mechanisms of action include increased β-oxidation; inhibition of acyl‑CoA:1,2-diacylglycerol acyltransferase (DGAT); decreased lipogenesis in the liver; and increased plasma lipoprotein lipase activity.

Pharmacodynamics

Vascepa 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. Vascepa also increases expression of lipoprotein lipase leading to increased TG removal from circulating VLDL and chylomicron particles. In patients with elevated TG levels, Vascepa 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 Vascepa.

Clinical efficacy and safety

Prevention of Cardiovascular Events

REDUCE-IT was a multinational, double-blind, randomised, placebo-controlled, event-driven trial in 8,179 (4,089 Vascepa, 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 with other risk factors for cardiovascular disease were defined as being at least 50 years of age with diabetes requiring medical treatment and at least one additional risk factor (including risk factors such as hypertension and low high-density lipoprotein cholesterol levels). Patients were randomly assigned 1:1 to receive either Vascepa (4 grams daily) or placebo. 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 agents (79.4%), 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. 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).

Vascepa 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 2. The Kaplan-Meier estimates of the cumulative incidence of the primary composite endpoint over time are shown in Figure 1. Additionally, the Kaplan-Meier estimates of the cumulative incidence of the key secondary composite endpoint over time are shown in Figure 2.

Table 2. Effect of VASCEPA on Time to First Occurrence of Cardiovascular Events in Patients with Elevated Triglyceride Levels and Other Risk Factors for Cardiovascular Disease in REDUCE-IT

Figure 1. Kaplan-Meier Estimated Cumulative Incidence of Primary Composite Endpoint in REDUCE-IT

Key primary composite endpoint consisted of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or hospitalisation for unstable angina (5-point MACE)

CI=confidence interval; RRR = relative risk reduction; ARR= absolute risk reduction; NNT= number needed to treat

Figure 2.  Kaplan-Meier Estimated Incidence of Key Secondary Composite Endpoint in

REDUCE-IT

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

Abbreviations: CI confidence interval; RRR relative risk reduction; ARR absolute risk reduction; NNT number needed to treat

Vascepa significantly reduced the risks for total (first and subsequent) 5-point MACE events by 30% and 3-point MACE events by 28%. It is estimated that for every 1,000 patients with high risk of cardiovascular events treated with Vascepa for 5 years the following numbers of 5-point MACE could be prevented: 12 cardiovascular deaths, 42 myocardial infarctions, 14 strokes, 76 coronary revascularisations, and 16 episodes of hospitalisation for unstable angina.

The median TG and LDL-C baseline values were similar between the Vascepa 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 Vascepa 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 Vascepa group and 0.2 mmol/L (7 mg/dL, 10%) in the placebo group. Prespecified analyses of the effect of Vascepa 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 mechanism of action for more information.

Severe Hypertriglyceridemia

The effects of Vascepa 4 grams per day were assessed in a randomized, placebo-controlled, double-blind, parallel-group study of adult patients (76 on Vascepa, 75 on placebo) with severe hypertriglyceridemia. Patients whose baseline TG levels were between 500 and 2,000 mg/dL were enrolled in this study for 12 weeks. The median baseline TG and LDL-C levels in these patients were 684 mg/dL and 86 mg/dL, respectively.  Median baseline HDL-C level was 27 mg/dL. The randomized population in this study was mostly Caucasian (88%) and male (76%). The mean age was 53 years and the mean body mass index was 31 kg/m².  Twenty-five percent of patients were on concomitant statin therapy, 28% were diabetics, and 39% of the patients had TG levels >750 mg/dL.

The changes in the major lipoprotein lipid parameters for the groups receiving Vascepa or placebo are shown in Table 2. 

Table 2. Median Baseline and Percent Change from Baseline in Lipid Parameters in Patients with Severe Hypertriglyceridemia (≥500 mg/dL)

% Change= Median Percent Change from Baseline

Difference= Median of [Vascepa % Change – Placebo % Change] (Hodges-Lehmann Estimate)

p-values from Wilcoxon rank-sum test

^*p-value < 0.001 (primary efficacy endpoint)

^**p-value < 0.05 (key secondary efficacy endpoints determined to be statistically significant according to the pre-specified multiple comparison procedure)

Vascepa 4 grams per day reduced median TG, VLDL-C, and Apo B levels from baseline relative to placebo.  The reduction in TG observed with Vascepa was not associated with elevations in LDL-C levels relative to placebo.

For clinical safety, see Section 4.8

Paediatric population

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

Additionally, the U.S. Food and Drug Administration waived the obligation to submit the results of studies with Vascepa in all subsets of the paediatric population for the treatment of hypertriglyceridemia and to reduce the risk cardiovascular events.

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 Vascepa.

Vascepa was administered with or following a meal in all clinical studies; no food effect studies were performed (see section 4.2 for information on dosage and 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.

Biotransformation and elimination

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. 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 (t_1/2) of EPA is approximately 89 hours. Icosapent ethyl does not undergo renal excretion.

Linearity/non-linearity

Oral doses of 2 g/day and 4 g/day of Vascepa resulted in maximum plasma concentrations of total EPA approximately 5 hours after dosing. The mean terminal half-life of total EPA in plasma was long, ranging between 75 and 89 hours based on baseline-adjusted concentrations (baseline subtracted), and between 113 and 152 hours based on baseline-unadjusted concentrations. Total plasma EPA concentrations returned to baseline by 8 to 13 days after the final dose following a 28-day dosing regimen of 2 g/day and 4 g/day Vascepa. Accumulation of EPA was observed with BID dosing, with quantifiable trough concentrations of total and unesterified EPA in plasma. Steady state was reached by Day 14. Dose-normalized exposures of 2 g/day or 4 g/day Vascepa were comparable, indicating linear PK in this dose range. Dose-linearity was demonstrated based on comparisons of EPA Cmax and AUC measured via LC/MS-MS assay of EPA concentrations in plasma. Incorporation in RBCs was also evaluated.  Within the 28 day dosing period, RBC concentrations of EPA increased in a dose-dependent manner, but had not reached steady-state and consequently linearity across dosages could not be confirmed within that matrix.

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 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.

Renal and hepatic impairment

The pharmacokinetics of Vascepa 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 Vascepa.

Other special populations

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

The pharmacokinetics of Vascepa has not been studied in paediatric subjects.

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year rat carcinogenicity study with oral gavage doses of 0.09, 0.27, and 0.91 g/kg/day icosapent ethyl, respectively, males did not exhibit drug-related neoplasms.  Hemangiomas and hemangiosarcomas of the mesenteric lymph node, the site of drug absorption, were observed in females at clinically relevant exposures based on body surface area comparisons across species relative to the maximum clinical dose of 4 g/day.  Overall incidence of hemangiomas and hemangiosarcomas 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 0.5, 1, 2, and 4.6 g/kg/day icosapent ethyl, drug-related incidences of benign squamous cell papilloma in the skin and subcutis of the tail was observed in high dose male mice.  The papillomas were considered to develop secondary to chronic irritation of the proximal tail associated with fecal excretion of oil and therefore not clinically relevant.  Drug-related neoplasms were not observed in female mice.

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.

In pregnant rats given oral gavage doses of 0.3, 1 and 2 g/kg/day icosapent ethyl from gestation through organogenesis all drug treated groups had visceral or skeletal abnormalities including: 13th reduced ribs, additional liver lobes, testes medially displaced and/or not descended at human systemic exposures following a maximum oral dose of 4 g/day based on body surface comparisons.  Variations including incomplete or abnormal ossification of various skeletal bones were observed in the 2 g/kg/day group at 5 times human systemic exposure following an oral dose of 4 g/day based on body surface area comparison.
 

In a multigenerational developmental study in pregnant rats given oral gavage doses of 0.3, 1, 3 g/kg/day ethyl-EPA from gestation day 7-17, an increased incidence of absent optic nerves and unilateral testes atrophy were observed at ≥0.3 g/kg/day at human systemic exposure following an oral dose of 4 g/day based on body surface area comparisons across species.  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 multigenerational effects of ethyl-EPA at 7 times human systemic exposure following 4 g/day dose based on body surface area comparisons across species.
 

In pregnant rabbits given oral gavage doses of 0.1, 0.3, and 1 g/kg/day from gestation through organogenesis there were increased dead fetuses at 1 g/kg/day secondary to maternal toxicity (significantly decreased food consumption and body weight loss).
 

In pregnant rats given ethyl-EPA from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day complete litter loss was observed in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human exposures based on a maximum dose of 4 g/day comparing body surface areas across species. 

An animal study in lactating rats given oral gavage ¹⁴C-ethyl EPA demonstrated that drug levels were 6 to 14 times higher in milk than in plasma.

In an oral gavage rat fertility study, ethyl-EPA, administered at doses of 0.3, 1, and 3 g/kg/day to male rats for 9 weeks before mating and to female rats for 14 days before mating through day 7 of gestation, increased anogenital distance in female pups and increased cervical ribs were observed at 3 g/kg/day (7 times human systemic exposure with 4 g/day clinical dose based on a body surface area comparison).

Environmental Risk Assessment (ERA)

The active moiety for the drug product is icosapent ethyl, which is the ethyl ester of eicosapentaenoic acid (EPA), one of the omega-3 fatty acids present in fish oil.  As this is a naturally occurring substance, no extraordinary circumstances exist that may affect the quality of the human environment.  Further, medical use of the drug product will not significantly alter the concentration or distribution of the substance, its metabolites, or degradation products in the environment.

Capsule fill

all-rac-alpha-tocopherol

Capsule shell

Gelatin

Glycerol

Maltitol liquid (E965 ii)

Sorbitol liquid, non-crystallising (E420 ii)

Purified water

Lecithin

Printing ink

Titanium dioxide

Propylene glycol

Hypromellose

Not Applicable

Do not store above 30^oC. 

Keep out of reach of children.

Bottle: keep the bottle tightly closed in order to protect from moisture.

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

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.