Hypotension, Syncope, and CNS Depression
in Studies of Healthy Subjects
Hypotension,
Syncope, and CNS Depression with Alcohol
Alcohol
and ADDYI Administration at the Same Time
Additions
and/or revisions underlined:
The first alcohol
interaction study was conducted in 25 healthy subjects (23 men and 2
premenopausal women). The study excluded subjects who drank fewer than five
alcoholic drinks per week and those with a history of orthostatic hypotension,
or syncope. A single dose of 100 mg ADDYI was administered concurrently with
0.4 g/kg or 0.8 g/kg alcohol in the morning; alcohol was consumed over
10 minutes.
Hypotension or syncope requiring
therapeutic intervention (ammonia salts and/or placement in supine or
Trendelenburg position) occurred in 4 (17%) of the 23 subjects co-administered
100 mg ADDYI and 0.4 g/kg alcohol (equivalent to two 12-ounce cans of beer
containing 5% alcohol content, two 5-ounce glasses of wine containing 12%
alcohol content, or two 1.5-ounce shots of 80-proof spirit in a 70 kg
person). In these four subjects, all of
whom were men, the magnitude of the systolic blood pressure reductions ranged
from 28 to 54 mmHg and the magnitude of the diastolic blood pressure reductions
ranged from 24 to 46 mmHg. In addition, 6 (25%) of the 24 subjects
co-administered 100 mg ADDYI and 0.8 g/kg alcohol (equivalent to four 12-ounce
cans of beer containing 5% alcohol content, four 5-ounce glasses of wine
containing 12% alcohol content, or four 1.5-ounce shots of 80-proof spirit in a
70 kg person) experienced orthostatic hypotension when standing from a sitting
position. The magnitude of the systolic blood pressure reduction in these 6
subjects ranged from 22 to 48 mmHg, and the diastolic blood pressure reductions
ranged from 0 to 27 mmHg. One of these
subjects required therapeutic intervention (ammonia salts and placement supine
with the foot of the bed elevated). There were no events requiring therapeutic
interventions when ADDYI or alcohol were administered alone.
In this study, somnolence was
reported in 67%, 74%, and 92% of subjects who received ADDYI alone, ADDYI in
combination with 0.4 g/kg alcohol, and ADDYI in combination with 0.8 g/kg
alcohol, respectively.
In the second alcohol interaction study,
96 healthy premenopausal women received a single dose of 100 mg ADDYI
concurrently with 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg alcohol (equivalent to one,
two or three alcoholic drinks in a 70 kg person, respectively) in the morning.
The study excluded subjects with a history of syncope, orthostatic hypotension,
hypotensive events, and dizziness, and those with a resting systolic blood
pressure less than 110 mmHg or diastolic blood pressure less than 60 mmHg.
In this study, no subjects experienced
syncope or hypotension requiring therapeutic intervention. However, subjects
who were already hypotensive (blood pressure below 90/60 mmHg) or symptomatic
(e.g., dizzy) while in the semi-recumbent position were not permitted to stand
for orthostatic measurements, and those with blood pressures below 90/40 mmHg
while in the semi-recumbent position had blood pressures repeated until it was
deemed safe for them to change position. More subjects had missing or delayed
orthostatic measurements (in general, due to hypotension or dizziness) when receiving ADDYI and
alcohol, compared to those who received alcohol alone or ADDYI alone. This
pattern of missing or delayed orthostatic measurements is concerning for a risk
of hypotension and syncope if those subjects had been allowed to stand.
In this study, somnolence was reported in
81-89% of subjects administered ADDYI with alcohol, compared to 25-41% of
subjects administered alcohol alone and 84% of subjects taking ADDYI
alone. Dizziness was reported in 27-40%
of subjects administered ADDYI with alcohol, compared to 6-20% of subjects
administered alcohol alone and 31% of subjects taking ADDYI alone.
Alcohol
Use at Various Time Intervals Before ADDYI Administration
In a third alcohol interaction study, 64
healthy premenopausal women consumed 0.4 g/kg alcohol (equivalent to 2
alcoholic drinks in a 70 kg person) two, four or six hours prior to receiving ADDYI
100 mg or placebo in the afternoon. The study excluded subjects with a history
or presence of orthostatic hypotension, history of
hypotension, syncope, or dizziness. Prior
to receiving alcohol, the subjects in the ADDYI arm had taken ADDYI for three
days to achieve steady state. Syncope occurred in one subject who received
alcohol alone. The incidences of orthostatic hypotension and hypotension (blood
pressure below 90/60 mmHg) at all time points were similar among subjects
administered alcohol before ADDYI, subjects administered alcohol alone, and
subjects administered ADDYI alone. Three
subjects were unable to stand due to feeling dizzy or hypotension; two
following alcohol and ADDYI separated by 2 and 6 hours, and one subject who
received ADDYI alone.
In this study, somnolence was reported in
35-53% of subjects administered ADDYI and alcohol, compared to 5-8% of subjects
taking alcohol alone and 50% of subjects taking ADDYI alone. Dizziness was
reported in 5-13% of subjects administered ADDYI and alcohol, compared to 0-3%
of subjects taking alcohol alone and 12% of subjects taking ADDYI alone.
Alcohol
Use in the Evening Before Bedtime ADDYI Administration
In another alcohol interaction study, 24
premenopausal women consumed 0.4 g/kg alcohol (equivalent to 2 alcoholic drinks
in a 70 kg person) during the evening meal two and a half to four hours prior
to taking ADDYI 100 mg at bedtime. There were no cases of syncope. Upon rising
the following morning, the incidence of hypotension was 23% among subjects
administered ADDYI after alcohol, 23% among subjects administered alcohol alone
and 36% with ADDYI alone. No cases of somnolence or dizziness were reported in
this study. Conclusions are limited because blood pressure and orthostatic
measurements were not taken after ADDYI administration until the following
morning.
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