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
Mirapex Side Effects, and Drug Interactions - Pramipexole
Mirapex Side Effects, and Drug Interactions - Pramipexole
SIDE EFFECTS
During the premarketing development
of pramipexole, patients with either early or advanced Parkinson’s
disease were enrolled
in clinical trials.
Apart from the severity and duration
of their disease, the
two populations differed in their use of concomitant
levodopa therapy. Patients
with early disease did not receive concomitant
levodopa therapy
during treatment with
pramipexole; those with advanced Parkinson’s disease
all received concomitant levodopa treatment. Because these two populations
may have differential risks for various adverse events, this section
will, in general, present adverse-event data for these two populations
separately.
Because the controlled trials performed during premarketing development
all used a titration
design, with a resultant confounding of time
and dose, it was impossible to adequately evaluate the effects of
dose on the incidence of
adverse events.
Early Parkinson’s Disease
In the three double-blind, placebo-controlled trials of patients
with early Parkinson’s disease,
the most commonly observed adverse events (> 5%) that were numerically
more frequent in the group
treated with MIRAPEX Tablets were nausea,
dizziness, somnolence,
insomnia, constipation,
asthenia, and hallucinations.
Approximately 12% of 388 patients with early Parkinson’s disease
and treated with MIRAPEX who participated in the double-blind, placebo-controlled
trials discontinued treatment
due to adverse events compared with 11% of 235 patients who received
placebo. The adverse events most commonly causing discontinuation
of treatment were
related to the nervous
system (hallucinations
[3.1% on MIRAPEX vs 0.4% on placebo]; dizziness
[2. 1% on MIRAPEX vs 1% on placebo]; somnolence
[1. 6% on MIRAPEX vs 0% on placebo]; extrapyramidal syndrome [1.
6% on MIRAPEX vs 6.4% on placebo]; headache
and confusion [1. 3% and 1.0%, respectively, on MIRAPEX vs 0% on
placebo]); and gastrointestinal system (nausea [2. 1% on MIRAPEX
vs 0.4% on placebo]).
Adverse-event incidence
in controlled clinical
studies in early Parkinson’s disease: Table 1 lists treatment-emergent
adverse events that occurred in the double-blind, placebo-controlled
studies in early Parkinson’s disease
that were reported by >1% of patients treated with MIRAPEX and
were numerically more frequent than in the placebo
group. In these studies, patients did not receive concomitant
levodopa. Adverse events were usually mild or moderate in intensity.
The prescriber should be aware that these figures cannot be used
to predict the incidence
of adverse events in the course of usual medical
practice where patient
characteristics and other factors differ from those that prevailed
in the clinical studies.
Similarly, the cited frequencies cannot be compared with figures
obtained from other clinical
investigations involving different treatments, uses, and investigators.
However, the cited figures do provide the prescribing physician
with some basis for estimating
the relative contribution of drug and nondrug factors to the adverse-event
incidence rate
in the population studied.
Table 1: Treatment-Emergent Adverse-Event* Incidence in Double-Blind,
Placebo-Controlled Trials in Early Parkinson’s Disease
(Events ³ 1% of Patients
Treated With MIRAPEX and Numerically More Frequent than in the
Placebo Group)
| Body System/ Adverse
Event |
MIRAPEX
(N= 388)
|
Placebo
(N= 235)
|
| Body as a Whole
|
| Asthenia |
14
|
12
|
| General edema
|
5
|
3
|
| Malaise |
2
|
1
|
| Reaction unevaluable
|
2
|
1
|
| Fever |
1
|
0
|
| Digestive System
|
| Nausea |
28
|
18
|
| Constipation |
14
|
6
|
| Anorexia |
4
|
2
|
| Dysphagia |
2
|
0
|
| Metabolic &
Nutritional System |
| Peripheral edema
|
5
|
4
|
| Decreased weight
|
2
|
0
|
| Nervous
System |
| Dizziness |
25
|
24
|
| Somnolence |
22
|
9
|
| Insomnia |
17
|
12
|
| Hallucinations |
9
|
3
|
| Confusion |
4
|
1
|
| Amnesia |
4
|
2
|
| Hypesthesia |
3
|
1
|
| Dystonia |
2
|
1
|
| Akathisia |
2
|
0
|
| Thinking abnormalities |
2
|
0
|
| Decreased libido |
1
|
0
|
| Myoclonus |
1
|
0
|
| Special Senses |
| Vision abnormalities
|
3
|
0
|
| Urogenital System
|
| Impotence |
2
|
1
|
| *Patients may have
reported multiple adverse experiences during the study or
at discontinuation; thus, patients may be included in more
than one category. |
Other events reported by 1 % or more of patients with early Parkinson’s
disease and treated with MIRAPEX but reported equally or more frequently
in the placebo group
were infection, accidental
injury, headache,
pain, tremor, back pain,
syncope, postural
hypotension, hypertonia,
depression, abdominal pain,
anxiety, dyspepsia,
flatulence, diarrhea,
rash, ataxia, dry mouth,
extrapyramidal
syndrome, leg
cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis,
urinary tract
infection, vasodilation,
flu syndrome, increased saliva,
tooth disease,
dyspnea, increased cough,
gait abnormalities, urinary
frequency, vomiting,
allergic reaction,
hypertension, pruritis, hypokinesia,
increased creatine
PK, nervousness, dream
abnormalities, chest pain,
neck pain,
paresthesia, tachycardia,
vertigo, voice alteration,
conjunctivitis, paralysis,
accommodation
abnormalities, tinnitus,
diplopia, and taste perversions.
Advanced Parkinson's Disease
In the four double-blind, placebo-controlled trials of patients
with advanced Parkinson’s disease,
the most commonly observed adverse events (> 5%) that were numerically
more frequent in the group
treated with MIRAPEX and concomitant
levodopa were postural
(orthostatic) hypotension, dyskinesia, extrapyramidal
syndrome, insomnia,
dizziness, hallucinations,
accidental injury, dream
abnormalities, confusion,
constipation ,
asthenia, somnolence, dystonia,
gait abnormality, hypertonia,
dry mouth, amnesia, and
urinary frequency.
Approximately 12% of 260 patients with advanced Parkinson ‘s disease
who received MIRAPEX and concomitant
levodopa in the double-blind,
placebo-controlled trials discontinued treatment
due to adverse events compared with 16% of 264 patients who received
placebo and concomitant
levodopa. The events most commonly causing discontinuation of treatment
were related to the nervous system
(hallucinations 12.7% on MIRAPEX vs 0.4% on placebo]; dyskinesia
[1.9% on MIRAPEX vs 0.8% on placebo]; extrapyramidal
syndrome [1.5% on MIRAPEX
vs 4.9% on placebo]; dizziness
[1.2% on MIRAPEX vs 1.5% on placebo]; confusion [1.2% on MIRAPEX
vs 2.3% on placebo]); and cardiovascular
system (postural [orthostatic] hypotension
[2.3% on MIRAPEX vs 1.1% on placebo]).
Adverse-event incidence
in controlled clinical
studies in advanced Parkinson’s disease: Table 2 lists treatment-emergent
adverse events that occurred in the double-blind, placebo-controlled
studies in advanced Parkinson’s disease
that were reported by ³1% of patients
treated with MIRAPEX and were numerically more frequent than in
the placebo group. In
these studies, MIRAPEX or placebo
was administered to patients who were also receiving concomitant
levodopa. Adverse events were usually mild or moderate in intensity.
The prescriber should be aware that these figures cannot be used
to predict the incidence
of adverse events in the course of usual medical practice where
patient characteristics
and other factors differ from those that prevailed in the clinical
studies. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical
investigations involving different treatments, uses, and investigators.
However, the cited figures do provide the prescribing physician
with some basis for estimating
the relative contribution of drug
and nondrug factors to the adverse-events incidence rate
in the population
studied.
Table 2: Treatment-Emergent Adverse-Event* Incidence in Double-Blind,
Placebo-Controlled Trials in Advanced Parkinson’s Disease (Events
³1% of Patients Treated
with MIRAPEX and Numerically More Frequent than in the Placebo
Group)
|
Body System/
Adverse Event
|
MIRAPEXt
(N= 260)
|
Placebot
(N= 264)
|
| Body as a Whole
|
| Accidental injury
|
17
|
15
|
| Asthenia |
10
|
8
|
| General edema
|
4
|
3
|
| Chest pain
|
3
|
2
|
| Malaise |
3
|
2
|
| Cardiovascular System
|
| Postural hypotension
|
53
|
48
|
| Digestive System
|
|
|
| Constipation |
10
|
9
|
| Dry-mouth |
7
|
3
|
| Metabolic &
Nutritional System |
| Peripheral edema |
2
|
1
|
| Increased creatine
PK |
1
|
0
|
| Musculoskeletal
System |
| Arthritis |
3
|
1
|
| Twitching |
2
|
0
|
| Bursitis |
2
|
0
|
| Myasthenia |
1
|
0
|
| Nervous System |
| Dyskinesia |
47
|
31
|
| Extrapyramidal syndrome |
28
|
26
|
| Insomnia |
27
|
22
|
| Dizziness |
26
|
25
|
| Hallucinations |
17
|
4
|
| Dream abnormalities |
11
|
10
|
| Confusion |
10
|
7
|
| Somnolence |
9
|
6
|
| Dystonia |
8
|
7
|
| Gait abnormalities |
7
|
5
|
| Hypertonia |
7
|
6
|
| Amnesia |
6
|
4
|
| Akathisia |
3
|
2
|
| Thinking abnormalities
|
3
|
2
|
| Paranoid reaction
|
2
|
0
|
| Delusions |
1
|
0
|
| Sleep disorders |
1
|
0
|
| Respiratory System
|
| Dyspnea |
4
|
3
|
| Rhinitis |
3
|
1
|
| Pneumonia |
2
|
0
|
| Skin & Appendages |
| Skin disorders |
2
|
1
|
| Special Senses |
| Accommodation abnormalities |
4
|
2
|
| Vision abnormalities
|
3
|
1
|
| Diplopia |
1
|
0
|
| Urogenital System |
| Urinary frequency
|
6
|
3
|
| Urinary tract
infection |
4
|
3
|
| Urinary incontinence
|
2
|
1
|
| * Patients may have
reported multiple adverse experiences during the study or
at discontinuation; thus, patients may be included in more
than one category. |
| t Patients received
concomitant levodopa. |
Other events reported by 1% or more of patients with advanced Parkinson’s
disease and treated with MIRAPEX but reported equally or more frequently
in the placebo group
were nausea, pain,
infection, headache,
depression, tremor, hypokinesia,
anorexia, back
pain, dyspepsia,
flatulence, ataxia,
flu syndrome, sinusitis,
diarrhea, myalgia,
abdominal pain,
anxiety, rash, paresthesia,
hypertension, increased
saliva, tooth
disorder, apathy, hypotension, sweating, vasodilation,
vomiting, increased
cough, nervousness, pruritus, hypesthesia, neck
pain, syncope,
arthralgia, dysphagia,
palpitations, pharyngitis, vertigo, leg
cramps, conjunctivitis,
and lacrimation
disorders.
Adverse Events
Relationship to Age, Gender, and Race: Among the
treatment-emergent adverse events in patients treated with MIRAPEX,
hallucination
appeared to exhibit a positive
relationship to age. No gender-related
differences were observed. Only a small percentage (4%) of patients
enrolled were non-Caucasian, therefore an evaluation
of adverse events related to race
is not possible.
Other Adverse Events Observed During All Phase 2 and 3 Clinical
Trials: MIRAPEX has been administered to 1408 individuals
during all clinical
trials (Parkinson’s disease
and other patient populations),
648 of whom were in seven double-blind , placebo-controlled Parkinson’s
disease trials. During these trials, all adverse events were recorded
by the clinical investigators
using terminology
of their own choosing. To provide a meaningful estimate of the proportion
of individuals having adverse events, similar types of events were
grouped into a smaller number
of standardized categories using modified COSTART dictionary terminology.
These categories are used in the listing below. The events listed
below occurred in less than 1% of the 1408 individuals exposed to
MIRAPEX and occurred on at least two occasions (on one occasion
if the event was serious). All reported events, except those already
listed above, are included, without regard to determination
of a causal relationship to MIRAPEX.
Events are listed within body-system categories in order
of decreasing frequency.
Body as a whole: enlarged abdomen,
death, fever,
suicide attempt.
Cardiovascular system: peripheral
vascular disease,
myocardial infarction, angina
pectoris, atrial fibrillation,
heart failure, arrhythmia,
atrial arrhythmia,
pulmonary embolism.
Digestive system: thirst.
Musculoskeletal system: joint
disorder, myasthenia.
Nervous system: agitation,
CNS stimulation, hyperkinesia,
psychosis, convulsions.
Respiratory system: pneumonia.
Special senses: cataract, eye
disorder, glaucoma.
Urogenital system: dysuria,
abnormal ejaculation,
prostate cancer, hematuria,
prostate disorder.
DRUG ABUSE AND DEPENDENCE
Pramipexole is not a controlled substance. Pramipexole has not
been systematically studied in animals or humans for its potential
for abuse, tolerance, or physical
dependence. However, in a rat
model on cocaine
self-administration, pramipexole had little or no
effect.
DRUG INTERACTIONS
Carbidopa/Levodopa: Carbidopa/Levodopa does not influence
the pharmacokinetics of pramipexole in healthy
volunteers (N= 10). Pramipexole did not alter the extent of absorption
(AUC) or the elimination
of carbidopa/ levodopa, although it caused an increase in levodopa
Cmax by about 40% and a decrease in Tmax from
2.5 to 0. 5 hours.
Selegiline: In healthy
volunteers (N= 11), selegiline did not influence the pharmacokinetics
of pramipexole.
Amantadine: Population pharmacokinetic analysis
suggests that amantadine is unlikely to alter the oral
clearance of pramipexole
(N= 54).
Cimetidine: Cimetidine, a known inhibitor
of renal tubular
secretion of organic
bases via the cationic transport
system, caused a 50% increase in pramipexole AUC
and a 40% increase in half-life
(N= 12).
Probenecid: Probenecid, a known inhibitor
of renal tubular
secretion of organic
acids via the aruonic transporter,
did not noticeably influence pramipexole pharmacokinetics
(N= 12).
Other drugs eliminated via
renal secretion: Population
pharmacokinetic analysis suggests that coadministration
of drugs that are secreted by the cationic transport
system (e.g., cimetidine,
ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine)
decreases the oral clearance
of pramipexole by about 20%, while those secreted by the anionic
transport system
(e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide,
and chlorpropamide) are likely to have little effect
on the oral clearance
of pramipexole.
CYP interactions: Inhibitors of cytochrome
P450 enzymes would not be expected to affect
pramipexole elimination
because pramipexole is not appreciably metabolized by these enzymes
in vivo or in vitro. Pramipexole does not inhibit CYP
enzymes CYPIA2, CYP2C9, CYP2CI9, CYP2EI, and CYP3A4. Inhibition
of CYP2D6 was observed with an apparent Ki of 30 uM, indicating
that pramipexole will not
inhibit CYP enzymes at plasma concentrations observed following
the highest recommended clinical dose (1.5 mg
tid).
Dopamine antagonists: Since pramipexole is a dopamine agonist,
it is possible that dopamine antagonists, such
as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes)
or metoclopramide, may diminish the effectiveness of MIRAPEX.
Drug/ Laboratory Test Interactions
There are no known interactions
between MIRAPEX and laboratory
tests.
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