Eicosapentaenoic acid Other names: Timnodonic acid Icosapent

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.

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.

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.

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. 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 foetus.

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. 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.

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.

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.

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. 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).

The following table lists adverse reactions.

Adverse reactions:

¹ Dysguesia describes the “verbatim” term: Fishy taste
² See section Description of selected adverse reactions

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.

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 placebocontrolled 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%).

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.