Icosapent Ethyl

ICOSAPENT ETHYL- icosapent ethyl capsule
Apotex Corp

1 INDICATIONS AND USAGE

Icosapent ethyl capsules are indicated:

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

Limitations of Use:

The effect of icosapent ethyl capsules on the risk for pancreatitis in patients with severe hypertriglyceridemia has not been determined.

2 DOSAGE AND ADMINISTRATION

2.1 Prior to Initiation of Icosapent Ethyl Capsules

• 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 icosapent ethyl capsules, which should continue during treatment with icosapent ethyl capsules.

2.2 Dosage and Administration

• The daily dose of icosapent ethyl capsules is 4 grams per day taken as:
  • two 1 gram capsules twice daily with food.
• Advise patients to swallow icosapent ethyl capsules whole. Do not break open, crush, dissolve, or chew icosapent ethyl capsules.

3 DOSAGE FORMS AND STRENGTHS

Icosapent ethyl capsules are supplied as:

• 1 gram oblong, natural colored transparent soft gelatin capsules with the logo “A1000” printed in white ink.

4 CONTRAINDICATIONS

Icosapent ethyl capsules are contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to icosapent ethyl or any of its components.

5 WARNINGS AND PRECAUTIONS

5.1 Atrial Fibrillation/Flutter

Icosapent ethyl capsules are associated with an increased risk of atrial fibrillation or atrial flutter requiring hospitalization. In a double-blind, placebo-controlled trial of 8,179 subjects, adjudicated atrial fibrillation or atrial flutter requiring hospitalization for 24 or more hours occurred in 127 (3%) patients treated with icosapent ethyl capsules compared to 84 (2%) patients receiving placebo [HR=1.5 (95% CI 1.14, 1.98)]. The incidence of atrial fibrillation was greater in patients with a previous history of atrial fibrillation or atrial flutter.

5.2 Potential for Allergic Reactions in Patients with Fish Allergy

Icosapent ethyl capsules contain ethyl esters 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 capsules. Inform patients with known hypersensitivity to fish and/or shellfish about the potential for allergic reactions to icosapent ethyl capsules and advise them to discontinue icosapent ethyl capsules and seek medical attention if any reactions occur.

5.3 Bleeding

​Icosapent ethyl capsules are associated with an increased risk of bleeding. In a double-blind, placebo-controlled trial of 8,179 patients, 482 (12%) patients receiving icosapent ethyl capsules experienced a bleeding event compared to 404 (10%) patients receiving placebo. Serious bleeding events occurred in 111 (3%) of patients on icosapent ethyl capsules vs. 85 (2%) of patients receiving placebo. The incidence of bleeding was greater in patients receiving concomitant antithrombotic medications, such as aspirin, clopidogrel, or warfarin.

6 ADVERSE REACTIONS

The following important adverse reactions are described below and elsewhere in the labeling:

• Atrial Fibrillation or Atrial Flutter [see Warnings and Precautions (5.1)]
• Potential for Allergic Reactions in Patients with Fish Allergy [see Warnings and Precautions (5.2)]
• Bleeding [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Common adverse reactions (incidence ≥3% on icosapent ethyl capsules and ≥1% more frequent than placebo) included musculoskeletal pain, peripheral edema, constipation, gout, and atrial fibrillation.

Hypertriglyceridemia Trials

In two randomized, double-blind, placebo-controlled trials in patients with triglyceride levels between 200 and 2000 mg/dL treated for 12 weeks, adverse reactions reported with icosapent ethyl capsules at an incidence ≥1% more frequent than placebo based on pooled data included arthralgia and oropharyngeal pain.

6.2 Postmarketing Experience

Additional adverse reactions have been identified during post-approval use of icosapent ethyl capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Diarrhea
• Blood triglycerides increased
• Abdominal discomfort
• Pain in the extremities

7 DRUG INTERACTIONS

7.1 Increased Bleeding Risk with Anticoagulants and Antiplatelet Agents

Some published studies with omega-3 fatty acids have demonstrated prolongation of bleeding time. The prolongation of bleeding time reported in those studies has not exceeded normal limits and did not produce clinically significant bleeding episodes. Monitor patients receiving icosapent ethyl capsules and concomitant anticoagulants and/or antiplatelet agents for bleeding.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The available data from published case reports and the pharmacovigilance database on the use of icosapent ethyl capsules in pregnant women are insufficient to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies in pregnant rats, non-dose-related imbalances for some minor developmental findings were observed with oral administration of icosapent ethyl during organogenesis at exposures that were equivalent to the clinical exposure at the human dose of 4 g/day, based on body surface area comparisons. In a study in pregnant rabbits orally administered icosapent ethyl during organogenesis, there were no clinically relevant adverse developmental effects at exposures that were 5 times the clinical exposure, based on body surface area comparisons (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

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 non-dose-related imbalances in visceral and skeletal findings, including 13^th 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.

In a multigenerational developmental study in pregnant rats given doses of 0.3, 1, 3 g/kg/day icosapent ethyl by oral gavage from gestation day 7-17, icosapent ethyl did not affect viability in fetuses (F1 or F2). Non-dose-related imbalances in findings of absent optic nerves and unilateral testes atrophy at human exposures based on the maximum dose of 4 g/day and on body surface area comparisons. 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 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 icosapent ethyl from gestation through organogenesis, a decrease in body weight and food consumption was observed at the high dose of 1 g/kg/day (5 times the human exposure at the maximum dose of 4 g/day, based on body surface area comparisons). Slight increases in resorbed and dead fetuses were noted in the 1 g/kg/day group, but these were not significantly different from the control group. There were no differences between the icosapent ethyl groups and control group as to the number of corpora lutea, number of implantations, number of surviving fetuses, sex ratio, body weight of female fetuses or placental weight. There were no treatment-related malformations or skeletal anomalies.

In pregnant rats given icosapent ethyl from gestation day 17 through lactation day 20 at 0.3, 1, 3 g/kg/day no adverse maternal or developmental effects were observed. However, complete litter loss (not dose-related) was noted in 2/23 litters at the low dose and 1/23 mid-dose dams by post-natal day 4 at human exposures at a maximum dose of 4 g/day, based on body surface area comparisons.