Included as part of the PRECAUTIONS section.
Monitoring: Laboratory Tests
In patients with hepatic impairment, alanine
aminotransferase (ALT) and aspartate aminotransferase (AST) levels should be
monitored periodically during therapy with VASCEPA.
VASCEPA 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 VASCEPA. VASCEPA should be used with caution in
patients with known hypersensitivity to fish and/or shellfish.
Patient Counseling Information
Information For Patients
VASCEPA should be used with
caution in patients with known sensallergy to fish and/or shellfish [see
WARNINGS AND PRECAUTIONS]. itivity or Patients should be advised
that use of lipid-regulating agents does not reduce the importance of
appropriate nutritional intake and physical activity [see DOSAGE AND
Patients should be advised not to alter VASCEPA capsules
in any way and to ingest intact capsules only [see DOSAGE AND ADMINISTRATION].
Instruct patients to take VASCEPA as prescribed. 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
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
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
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 Category C: There are
no adequate and well-controlled studies in pregnant women. It is unknown
whether VASCEPA can cause fetal harm when administered to a pregnant woman or
can affect reproductive capacity. VASCEPA should be used during pregnancy only
if the potential benefit to the patient justifies the potential risk to the
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
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.
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 VASCEPA 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.
Safety and effectiveness in pediatric patients have not
Of the total number of subjects in clinical studies of
VASCEPA, 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.