In a multigenerational developmental study in pregnant rats given oral gavage doses of , 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 ≥ 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.
A variety of infectious agents may be transmitted by transfusion. Definitive evidence of transmission by transfusion requires demonstration of seroconversion or new infection in the recipient and isolation of an agent with genomic identity from both the recipient and the implicated donor. Strong presumptive evidence of transfusion transmission includes recipient seroconversion within an appropriate interval after transfusion, the recognition of appropriate infectious markers in an implicated donor on follow-up investigation, or both. Transfusion transmitted disease should be reported to the Australian Red Cross Blood Service.
In the laboratory classroom clinical trials in children (Studies 1 and 2), both CONCERTA® once daily and methylphenidate three times daily increased resting pulse by an average of 2 to 6 bpm and produced average increases of systolic and diastolic blood pressure of roughly 1 to 4 mm Hg during the day, relative to placebo. In the placebo-controlled adolescent trial (Study 4), mean increases from baseline in resting pulse rate were observed with CONCERTA® and placebo at the end of the double-blind phase (5 and 3 beats/minute, respectively). Mean increases from baseline in blood pressure at the end of the double-blind phase for CONCERTA® and placebo-treated patients were and mm Hg (systolic) and and mm Hg (diastolic), respectively. In one placebo-controlled study in adults (Study 6), dose-dependent mean increases of to bpm from baseline in standing pulse rate were observed with CONCERTA® at the end of the double-blind treatment vs. an increase of beats/minute with placebo. Mean changes from baseline in standing blood pressure at the end of double-blind treatment ranged from to mm Hg (systolic) and to mm Hg (diastolic) for CONCERTA® and was mm Hg (systolic) and - mm Hg (diastolic) for placebo. In a second placebo-controlled study in adults (Study 5), mean changes from baseline in resting pulse rate were observed for CONCERTA® and placebo at the end of the double-blind treatment ( and - beats/minute, respectively). Mean changes from baseline in blood pressure at the end of the double-blind treatment for CONCERTA® and placebo-treated patients were - and - mm Hg (systolic) and and mm Hg (diastolic), respectively [see WARNINGS AND PRECAUTIONS ].