A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Reminyl Side Effects, and Drug Interactions - Galantamine Hydrobromide
Reminyl Side Effects, and Drug Interactions - Galantamine Hydrobromide
SIDE EFFECTS
Adverse Events Leading to Discontinuation: In two large
scale, placebo-controlled trials of 6 months duration, in which patients were
titrated weekly from 8 to 16 to 24, and to 32 mg/day, the risk of discontinuation
because of an adverse event in the galantamine group exceeded that in the placebo
group by about threefold.In contrast, in a 5-month trial with escalation of
the dose by 8 mg/day every 4 weeks, the overall risk of discontinuation because
of an adverse event was 7%, 7%, and 10% for the placebo, galantamine 16 mg/day,
and galantamine 24 mg/day groups, respectively, with gastrointestinal adverse
effects the principle reason for discontinuing galantamine.Table 1 shows the
most frequent adverse events leading to discontinuation in this study.
Table 1:Most Frequent Adverse Events Leading to Discontinuation
in a Placebo-controlled, Double-blindTrialwitha 4-Week Dose Escalation Schedule
|
4-week Escalation
|
| |
Placebo
|
16 mg/day
|
24 mg/day
|
|
Adverse Event
|
N=286
|
N=279
|
N=273
|
|
Nausea
|
<1%
|
2%
|
4%
|
|
Vomiting
|
0%
|
1%
|
3%
|
|
Anorexia
|
<1%
|
1%
|
<1%
|
|
Dizziness
|
<1%
|
2%
|
1%
|
|
Syncope
|
0%
|
0%
|
1%
|
Adverse Events Reported in Controlled Trials: The reported
adverse events in REMINYL® (galantamine hydrobromide) trials
reflect experience gained under closely monitored conditions in a highly selected
patient population. In actual practice or in other clinical trials, these frequency
estimates may not apply, as the conditions of use, reporting behavior and the
types of patients treated may differ.
The majority of these adverse events occurred during the dose-escalation
period. In those patients who experienced the most frequent adverse event, nausea,
the median duration of the nausea was 5-7 days.
Administration of REMINYL® with food, the use
of anti-emetic medication, and ensuring adequate fluid intake may reduce the
impact of these events. The most frequent adverse events, defined as those occurring
at a frequency of at least 5% and at least twice the rate on placebo with the
recommended maintenance dose of either 16 or 24 mg/day of REMINYL®
under conditions of every 4 week dose-escalation for each dose increment
of 8 mg/day, are shown in Table 2. These events were primarily gastrointestinal
and tended to be less frequent with the 16 mg/day recommended initial maintenance
dose.
Table 2:The Most Frequent Adverse Events in the Placebo-controlled
Trial with Dose Escalation Every 4 Weeks Occurring in at Least 5% of Patients
Receiving REMINYL® and at Least Twice the Rate on Placebo.
|
|
Placebo
|
REMINYL®
16mg/day
|
REMINYL®
24mg/day
|
|
Adverse Event
|
N=286
|
N=279
|
N=273
|
|
Nausea
|
5%
|
13%
|
17%
|
|
Vomiting
|
1%
|
6%
|
10%
|
|
Diarrhea
|
6%
|
12%
|
6%
|
|
Anorexia
|
3%
|
7%
|
9%
|
|
Weight decrease
|
1%
|
5%
|
5%
|
Table 3:The most common adverse events (adverse events occurring
with an incidence of at least 2% with REMINYL® treatment and
in which the incidence was greater than with placebo treatment) are listed in
Table 3 for four placebo-controlled trials for patients treated with 16 or 24
mg/day of REMINYL®.
Table 3:Adverse Events Reported in at Least 2% of Patients
with Alzheimer’s Disease Administered REMINYL® and at a Frequency
Greater than with Placebo
|
Body System
Adverse Event
|
Placebo
(N=801)
|
REMINYL®a
(N=1040)
|
|
Body as a whole - general disorders
|
|
Fatigue
|
3%
|
5%
|
|
Syncope
|
1%
|
2%
|
|
Central & peripheral nervous system disorders
|
|
|
|
Dizziness
|
6%
|
9%
|
|
Headache
|
5%
|
8%
|
|
Tremor
|
2%
|
3%
|
|
Gastrointestinal system disorders
|
|
Nausea
|
9%
|
24%
|
|
Vomiting
|
4%
|
13%
|
|
Diarrhea
|
7%
|
9%
|
|
Abdominal pain
|
4%
|
5%
|
|
Dyspepsia
|
2%
|
5%
|
|
Heart rate and rhythm disorders
|
|
|
|
Bradycardia
|
1%
|
2%
|
|
Metabolic and nutritional disorders
|
|
Weight decrease
|
2%
|
7%
|
|
Psychiatric disorders
|
|
Anorexia
|
3%
|
9%
|
|
Depression
|
5%
|
7%
|
|
Insomnia
|
4%
|
5%
|
|
Somnolence
|
3%
|
4%
|
|
Red blood cell disorders
|
|
Anemia
|
2%
|
3%
|
|
Respiratory system disorders
|
|
Rhinitis
|
3%
|
4%
|
|
Urinary system disorders
|
|
Urinary tract infection
|
7%
|
8%
|
|
Hematuria
|
2%
|
3%
|
a: Adverse events in patients treated with 16 or
24 mg/day of REMINYL® in four placebo-controlled trialsare
included.
Adverse events occurring with an incidence of at least 2% in
placebo-treated patients that was either equal to or greater than with REMINYL®
treatment were constipation, agitation, confusion, anxiety, hallucination,
injury, back pain, peripheral edema, asthenia, chest pain, urinary incontinence,
upper respiratory tract infection, bronchitis, coughing, hypertension, fall,
and purpura.
There were no important differences in adverse event rate related
to dose or sex. There were too few non-Caucasian patients to assess the effects
of race on adverse event rates.
No clinically relevant abnormalities in laboratory values were
observed.
Other Adverse Events Observed During Clinical Trials
REMINYL® was administered to 3055 patients with
Alzheimer's disease. A total of 2357 patients received galantamine in placebo-controlled
trials and 761 patients with Alzheimer's disease received galantamine 24 mg/day,
the maximum recommended maintenance dose. About 1000 patients received galantamine
for at least one year and approximately 200 patients received galantamine for
two years.
To establish the rate of adverse events, data from all patients
receiving any dose of galantamine in 8 placebo-controlled trials and 6 open-label
extension trials were pooled. The methodology to gather and codify these adverse
events was standardized across trials, using WHO terminology. All adverse events
occurring in approximately 0.1% are included, except for those already listed
elsewhere in labeling, WHO terms too general to be informative, or events unlikely
to be drug caused. Events are classified by body system and listed using the
following definitions: frequent adverse events - those occurring in at least
1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000
patients; rare adverse events - those occurring in fewer than 1/1000 patients.
These adverse events are not necessarily related to REMINYL® treatment
and in most cases were observed at a similar frequency in placebo-treated patients
in the controlled studies.
Body As a Whole – General Disorders: Frequent: chest
pain
Cardiovascular System Disorders: Infrequent: postural
hypotension, hypotension, dependent edema, cardiac failure
Central & Peripheral Nervous System Disorders: Infrequent:
vertigo, hypertonia, convulsions, involuntary muscle contractions, paresthesia,
ataxia, hypokinesia, hyperkinesia, apraxia, aphasia
Gastrointestinal System Disorders: Frequent: flatulence;
Infrequent: gastritis, melena, dysphagia, rectal hemorrhage, dry mouth, saliva
increased, diverticulitis, gastroenteritis, hiccup; rare: esophageal perforation
Heart Rate & Rhythm Disorders: Infrequent: AV block,
palpitation, atrial fibrillation, QT prolonged, bundle branch block, supraventricular
tachycardia, T-wave inversion, ventricular tachycardia
Metabolic & Nutritional Disorders: Infrequent: hyperglycemia,
alkaline phosphatase increased
Platelet, Bleeding & Clotting Disorders: Infrequent:
purpura, epistaxis, thrombocytopenia Psychiatric Disorders: Infrequent:
apathy, paroniria, paranoid reaction, libido increased, delirium
Urinary System Disorders: Frequent: incontinence; Infrequent:
hematuria, micturition frequency, cystitis, urinary retention, nocturia, renal
calculi
Drug-Drug Interactions
Multiple metabolic pathways and renal excretion are involved
in the elimination of galantamine so no single pathway appears predominant.
Based on in vitro studies, CYP2D6 and CYP3A4 were the major enzymes involved
in the metabolism of galantamine. CYP2D6 was involved in the formation of O-desmethyl-galantamine,
whereas CYP3A4 mediated the formation of galantamine-N-oxide. Galantamine is
also glucuronidated and excreted unchanged in urine.
(A) Effect of other drugs on the metabolism of REMINYL®:
Drugs that are potent inhibitors for CYP2D6 or CYP3A4 may increase the AUC
of galantamine. Multiple dose pharmacokinetic studies demonstrated that the
AUC of galantamine increased 30% and 40%, respectively, during coadministration
of ketoconazole and paroxetine. As coadministered with erythromycin, another
CYP3A4 inhibitor, the galantamine AUC increased only 10%. Population PK analysis
with a database of 852 patients with Alzheimer’s disease showed that the clearance
of galantamine was decreased about 25-33% by concurrent administration of amitriptyline
(n = 17), fluoxetine (n = 48), fluvoxamine (n = 14), and quinidine (n = 7),
known inhibitors of CYP2D6.
Concurrent administration of H2-antagonists demonstrated
that ranitidine did not affect the pharmacokinetics of galantamine, and cimetidine
increased the galantamine AUC by approximately 16%.
(B) Effect of REMINYL® on the metabolism
of other drugs: In vitro studies show that galantamine did not inhibit the
metabolic pathways catalyzed by CYP1A2, CYP2A6, CYP3A4, CYP4A, CYP2C, CYP2D6
and CYP2E1.This indicated that the inhibitory potential of galantamine towards
the major forms of cytochrome P450 is very low. Multiple doses of galantamine
(24 mg/day) had no effect on the pharmacokinetics of digoxin and warfarin (R-and-S-
forms). Galantamine had no effect on the increased prothrombin time induced
by warfarin.
top
