SIDE EFFECTS
Adverse Events leading to Discontinuation
The rates of discontinuation from controlled clinical
trials of ARICEPT™ due to adverse events for the
ARICEPT™ 5 mg/day treatment groups were comparable
to those of placebo-treatment groups at approximately
5%. The rate of discontinuation of patients who received
7-day escalations from 5 mg/day to 10 mg/day was higher
at 13%.
The most common adverse events leading to discontinuation,
defined as those occurring in at least 2% of patients
and at twice the incidence seen in placebo patients are
shown in Table 1.
|
Most Frequent Adverse Events Leading to Withdrawal From
Controlled Clinical Trials by Dose Group
|
|
Dose Group
|
Placebo
|
5 mg/day ARICEPT Ô
|
10 mg/day ARICEPT Ô
|
| Patients
Randomized |
355
|
350
|
315
|
| Event
% Discontinuing |
| Nausea
|
1%
|
1%
|
3%
|
| Diarrhea
|
0%
|
<1%
|
3%
|
| Vomiting
|
<1%
|
<1%
|
7%
|
Most Frequent Adverse Clinical Events Seen in Association
with the Use of ARICEPT™
The most common adverse events, defined as those
occurring at a frequency of at least 5% in patients receiving
10 mg/day and twice the placebo rate, are largely predicted
by ARICEPT™’s cholinomimetic effects. These
include nausea, diarrhea, insomnia, vomiting, muscle cramp,
fatigue and anorexia. These adverse events were often of
mild intensity and transient, resolving during continued
ARICEPT™ treatment without the need for dose modification.
There is evidence to suggest that the frequency of these
common adverse events may be affected by the rate of titration.
An open-label study was conducted with 269 patients who
received placebo in the 15 and 30-week studies. These patients
were titrated to a dose of 10 mg/day over a 6-week period.
The rates of common adverse events were lower than those
seen in patients titrated to 10 mg/day over one week in
the controlled clinical trials and were comparable to those
seen in patients on 5 mg/day.
See Table 2 for a comparison of the most common adverse
events following one and six week titration regimens.
Table 2.
Table 2.
|
Comparison of rates of adverse events in patients
titrated to 10 mg/day over 1 and 6 weeks |
| Adverse
Event |
No titration |
One week Titration
|
Six week titration
|
|
Placebo |
5mg/day |
10m /day |
10 mg/day |
|
(n=315) |
(n=311) |
(n=315) |
(n=269) |
| Nausea |
6%
|
5%
|
19%
|
6%
|
| Diarrhea
|
5%
|
8%
|
15%
|
9%
|
| Insomnia
|
6%
|
6%
|
14%
|
6%
|
| Fatigue |
3%
|
4%
|
8%
|
3%
|
| Vomiting
|
3%
|
3%
|
8%
|
5%
|
| Muscle Cramps
|
2%
|
6%
|
8%
|
3%
|
| Anorexia
|
2%
|
3%
|
7%
|
3%
|
Adverse Events Reported In Controlled Trials
The events cited reflect experience gained under
closely monitored conditions of clinical trials in a highly
selected patient population. In actual clinical practice
or in other clinical trials, these frequency estimates may
not apply, as the conditions of use, reporting behavior;
and the kinds of patients treated may differ. Table 3 lists
treatment emergent signs and symptoms that were reported
in at least 2% of patients in placebo-controlled trials
who received ARICEPT™ and for which the rate of occurrence
was greater for ARICEPT™ assigned than placebo assigned
patients. In general, adverse events occurred more frequently
in female patients and with advancing age.
Table 3.
|
Adverse Events Reported in Controlled Clinical Trials
in at Least 2% of Patients Receiving ARICEPT
Ô and at a Higher Frequency than Placebo-treated
Patients
|
|
Body System/Adverse Events
|
Placebo
|
ARICEPT Ô
|
|
(n=355)
|
(n=747)
|
| Percent
of Patients with any Adverse Event |
72
|
74
|
| Body
as a Whole |
| •
Headache |
9
|
10
|
| •
Pain, various locations |
8
|
9
|
| •
Accident |
6
|
7
|
| •
Fatigue |
3
|
5
|
| Cardiovascular
System |
| •
Syncope |
1
|
2
|
| Digestive
System |
| •
Nausea |
6
|
11
|
| •
diarrhea |
5
|
10
|
| •
vomiting |
3
|
5
|
| •
Anorexia |
2
|
4
|
| Hemic
and Lymphatic System |
| •
Ecchymosis |
3
|
4
|
| Metabolic
and Nutritional Systems |
| •
Weight Decrease |
1
|
3
|
| Musculoskeletal
|
| •
Muscle Cramps |
2
|
6
|
| •
Arthritis |
1
|
2
|
| Nervous
System |
| •
Insomnia |
6
|
9
|
| •
Dizziness |
6
|
8
|
| •
Depression |
<1
|
3
|
| •
Abnormal Dreams |
0
|
3
|
| •
Somnolence |
<1
|
2
|
| Urogenital
System |
| •
Frequent Urination |
1
|
2
|
Other Adverse Events Observed During Clinical Trials
ARICEPT™ has been administered to over 1700 individuals
during clinical trials worldwide. Approximately 1200 of
these patients have been treated for at least 3 months and
more than 1000 patients have been treated for at least 6
months. Controlled and uncontrolled trials in the United
States included approximately 900 patients. In regards to
the highest dose of 10 mg/day, this population includes
650 patients treated for 3 months, 475 patients treated
for 6 months and 116 patients treated for over 1 year. The
range of patient exposure is from 1 to 1214 days.
Treatment emergent signs and symptoms that occurred during
3 controlled clinical trials and two open-label trials in
the United States were recorded as adverse events by the
clinical investigators using terminology of their own choosing.
To provide an overall estimate of the proportion of individuals
having similar types of events, the events were grouped
into a smaller number of standardized categories using a
modified COSTART dictionary and event frequencies were calculated
across all studies. These categories are used in the listing
below. The frequencies represent the proportion of 900 patients
from these trials who experienced that event while receiving
ARICEPT™. All adverse events occurring at least twice
are included, except for those already listed in Tables
2 or 3. COSTART terms too general to be informative, or
events less likely to be drug caused. Events are classified
,by body system and listed using the following definitions:
frequent adverse events-those occurring in at least l/100
patients: infrequent adverse events-those occurring in 1/l00
to l/l000 patients. These adverse events are not necessarily
related to ARICEPT™ treatment and in most cases were
observed at a similar frequency in placebo-treated patients
in the controlled studies. No important additional adverse
events were seen in studies conducted outside the United
States.
Body as a Whole: Frequent: influenza, chest
pain, toothache; Infrequent: fever, edema face, periorbital
edema, hernia hiatal, abscess, cellulitis, chills, generalized
coldness, head fullness, listlessness.
Cardiovascular System: Frequent: hypertension,
vasodilation. atrial fibrillation, hot flashes, hypotension;
Infrequent: angina pectoris, postural hypotension, myocardial
infarction, AV block (first degree), congestive heart failure,
arteritis, bradycardia, peripheral vascular disease, supraventricular
tachycardia, deep vein thrombosis.
Digestive System: Frequent: fecal incontinence,
gastrointestinal bleeding, bloating, epigastric pain; Infrequent:
eructation, gingivitis, increased appetite, flatulence,
periodontal abscess, cholelithiasis, diverticulitis, drooling,
dry mouth, fever sore, gastritis, irritable colon, tongue
edema, epigastric distress, gastroenteritis, increased transaminases,
hemorrhoids, ileus, increased thirst, jaundice, melena,
polydypsia, duodenal ulcer; stomach ulcer,
Endocrine System: Infrequent: diabetes
mellitus, goiter,
Hemic and Lymphatic System: Infrequent:
anemia, thrombocythemia, thrombocytopenia, eosinophilia,
erythrocytopenia.
Metabolic and Nutritional Disorders: Frequent:
dehydration; infrequent: gout, hypokalemia, increased creatine
kinase, hyperglycemia, weight increase, increased lactate
dehydrogenase.
Musculoskeletal System: Frequent: bone
fracture: Infrequent: muscle weakness, muscle fasciculation.
Nervous System: Frequent: delusions, tremor,
irritability paresthesia, aggression, vertigo, ataxia, increased
libido, restlessness, abnormal crying, nervousness, aphasia;
Infrequent: cerebrovascular accident, intracranial hemorrhage,
transient ischemic attack, emotional lability, neuralgia,
coldness (localized), muscle spasm, dysphoria, gait abnormality,
hypertonia, hypokinesia, neurodermatitis, numbness (localized),
paranoia, dysarthria, dysphasia, hostility, decreased libido,
melancholia, emotional withdrawal, nystagmus, pacing.
Respiratory System: Frequent: dyspnea,
sore throat, bronchitis; Infrequent: epistaxis, post nasal
drip, pneumonia, hyperventilation, pulmonary congestion,
wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse,
sleep apnea, snoring.
Skin and Appendages: Frequent: pruritus,
diaphoresis, urticaria; Infrequent: dermatitis, erythema,
skin discoloration, hyperkeratosis, alopecia, tungal dermatitis,
herpes zoster, hirsutism, skin striae, night sweats, skin
ulcer.
Special Senses: Frequent: cataract, eye
irritation, vision blurred; Infrequent: dry eyes, glaucoma,
earache, tinnitus, blepharitis, decreased hearing, retinal
hemorrhage, otitis externa, otitis media, bad taste, conjunctival
hemorrhage, ear buzzing, motion sickness, spots before eyes.
Urogenital System: Frequent: urinary incontinence,
nocturia; Infrequent: dysuria, hematuria, urinary urgency,
metrorrhagia, cystitis, enuresis, prostate hypertrophy,
pyelonephritis, inability to empty bladder, breast fibroadenosis,
tibrocystic breast, mastitis, pyuria, renal failure, vaginitis.
DRUG INTERACTIONS
Drugs Highly Bound to Plasma Proteins: Drug displacement
studies have been performed in vitro between this highly
bound drug (96%) and other drugs such as furosemide, digoxin,
and warfarin. ARICEPT™ at concentrations of 0.3-10
mcg/mL did not affect the binding of furosemide (5 mcg/mL),
digoxin (2 mg/mL), and warfarin (3 mc/mL) to human albumin.
Similarly, the binding of ARICEPT™ to human albumin
was not affected by furosemide, digoxin and warfarin.
Effect of ARICEPT™ on the Metabolism of Other Drugs:
No in vivo clinical trials have investigated the effect
of ARICEPT™ on the clearance of drugs metabolized
by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g.
imipramine). However, in vitro studies show a low rate of
binding to these enzymes (mean K, about 50130 mcM), that,
given the therapeutic plasma concentrations of donepezil
(l64 nM), indicates little likelihood of interference.
Whether ARICEPT™ has any potential for enzyme induction
is not known.
Formal pharmacokinetic studies evaluated the potential of
ARICEPT™ for interaction with theophylline, cimetidine,
warfarin and digoxin. No significant effects on the pharmacokinetics
of these drugs were observed.
Effect of Other Drugs on the Metabolism of ARICEPT™:
Ketoconazole and quinidine, inhibitors of CYP450,3A4 and
2D6, respectively, inhibit donepezil metabolism in vitro.
Whether there is a clinical effect of these inhibitors is
not known. Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin,
carbamazepine, dexamethasone, rifampin, and phenobarbital)
could increase the rate of elimination of ARICEPT™.
Formal pharmacokinetic studies demonstrated that the metabolism
of ARICEPT™ is not significantly affected by concurrent
administration of digoxin or cimetidine.
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