Check the boxes corresponding to any of the exclusion criteria that disqualified the subject from entry.
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Any clinically relevant abnormality identified on the screening history, physical or laboratory examination, or any other medical condition or circumstance making the volunteer unsuitable for participation in the study. (1)
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Subjects who are poor metabolizers of CYP2D6 as determined at screening. (2)
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Treatment with any prescription or non-prescription drugs (including vitamins, herbal and dietary supplements, as well as grapefruit containing products) within 7 days or 5 half-lives (whichever is (3)
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longer) prior to first dose of study medication. Excluded from this list is acetaminophen at doses of <2 grams/day. Hormonal methods of contraception (including oral contraceptives, injectable progesterone, progestin subdermal implants, progesterone-releasing IUDs, postcoital contraception methods) and hormone replacement therapy must be discontinued within thirty days or 5 half-lives (whichever is longer) prior to the first dose of study medication. Depo-Provera must be discontinued at least 6 months prior to the first study period. (4)
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History of regular alcohol consumption exceeding 7 drinks/week for women or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of screening. (4)
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Positive urine drug screen (UDS) including alcohol at screening. (5)
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Treatment with an investigational drug within 30 days or five half-lives, whichever is longer, prior to the (6)
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first dose of study medication (this includes investigational formulations of marketed products). (8)
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Consumption of grapefruit, grapefruit juice within 7 days prior to dosing. (7)
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Pregnant or nursing female subjects; as well as female subjects of childbearing potential who are unwilling or unable to use appropriate forms of contraception (see Section 7 for details) from 14 days prior to dosing in Period 1 until the follow-up visit; or who are unwilling to abstain from sexual activity for the duration of the study. (8)
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For female subjects, a positive serum β-hCG (human chorionic gonadotropin) test at screening or prior to dosing in any of the study periods. (9)
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Resting heart rate of < 45 beats per minute (bpm) at screening (10)
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Any abnormalities on 12-lead ECG during screening (11)
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Documented history of low blood pressure (average SBP < 110 mm Hg and/or DBP < 50 mm Hg) or blood pressure below theses values at time of screening. (12)
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Orthostatic hypotension diagnosed at screening (orthostatic hypotension will be defined as a reduction in systolic blood pressure of 20 mmHg or more and/or a reduction in diastolic blood pressure of 10 mmHg or more for standing vs. supine measurements). (13)
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Blood collection of greater than 500 mL within 56 days prior to study start. (14)
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History of asthma and/or COPD and/or hypersensitivity to β-adrenergic blocking agents (15)
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History of sensitivity to heparin, heparin- induced thrombocytopenia, or sensitivity to any of the study (16)
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medications or components thereof. (19)
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17. b Subjects not willing and able to follow the procedures outlined in the protocol or who are unable to (20)
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provide written informed consent. (21)
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18. b History of sensitivity to carvedilol (or chemically-related drugs), alpha-blockers or beta-blockers. (22)
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Treatment with any PDE5 inhibitors (such as but not limited to vardenafil, sildenafil, tadalafil) two weeks prior to dose and throughout study (follow-up visit). (19)