Melbural

Melbural® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe ( ≥ 500 mg/dL) hypertriglyceridemia.

Usage Considerations

Patients should be placed on an appropriate lipid-lowering diet and exercise regimen before receiving Melbural and should continue this diet and exercise regimen with Melbural.

Attempts should be made to control any medical problems such as diabetes mellitus, hypothyroidism, and alcohol intake that may contribute to lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (such as beta blockers, thiazides, estrogens) should be discontinued or changed, if possible, prior to consideration of TG-lowering drug therapy.

Limitations Of Use

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

The effect of Melbural on cardiovascular mortality and morbidity in patients with severe hypertriglyceridemia has not been determined.

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 Melbural, which should continue during treatment with Melbural.

The daily dose of Melbural is 4 grams per day taken as either:

• four 0.5-gram capsules twice daily with food; or as
• two 1-gram capsules twice daily with food

Patients should be advised to swallow Melbural capsules whole. Do not break open, crush, dissolve, or chew Melbural.

Melbural is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to Melbural or any of its components.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Monitoring: Laboratory Tests

In patients with hepatic impairment, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be monitored periodically during therapy with Melbural.

Fish Allergy

Melbural contains 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 Melbural. Melbural should be used with caution in patients with known hypersensitivity to fish and/or shellfish.

Patient Counseling Information

Information For Patients

Melbural should be used with caution in patients with known sensallergy to fish and/or shellfish. itivity or Patients should be advised that use of lipid-regulating agents does not reduce the importance of appropriate nutritional intake and physical activity.

Patients should be advised not to alter Melbural capsules in any way and to ingest intact capsules only.

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

Nonclinical Toxicology

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 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).

Use In Specific Populations

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. It is unknown whether Melbural can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Melbural should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

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 Page 3 of 8 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.

Nursing Mothers

Studies with omega-3-acid ethyl esters have demonstrated excretion in human milk. The effect of this excretion on the infant of a nursing mother is unknown; caution should be exercised when Melbural is administered to a nursing mother. 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of subjects in clinical studies of Melbural, 33% were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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.

Adverse reactions reported in at least 2% and at a greater rate than placebo for patients treated with Melbural based on pooled data across two clinical studies are listed in Table 1.

Table 1: Adverse Reactions Occurring at Incidence > 2% and Greater than Placebo in Double-Blind, Placebo-Controlled Trials*

An additional adverse reaction from clinical studies was oropharyngeal pain.

No information provided.

Absorption

After oral administration, Melbural 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 Melbural.

Melbural was administered with or following a meal in all clinical studies; no food effect studies were performed. Take Melbural with or following a meal.

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 And Excretion

EPA is mainly metabolized 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 (t½) of EPA is approximately 89 hours. Melbural does not undergo renal excretion.