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
Risperdal Side Effects, and Drug Interactions - Risperidone
Risperdal Side Effects, and Drug Interactions - Risperidone
SIDE EFFECTS
The following findings are based on the short-term, placebo-controlled,
North American, premarketing trials for schizophrenia and acute bipolar mania.
In patients with Bipolar I Disorder, treatment-emergent adverse events are presented
separately for risperidone as monotherapy and as adjunctive therapy to mood
stabilizers.
Certain portions of the discussion below relating to objective
or numeric safety parameters, namely dose-dependent adverse events, vital sign
changes, weight gain, laboratory changes, and ECG changes are derived from studies
in patients with schizophrenia. However, this information is also generally
applicable to bipolar mania.
Associated With Discontinuation of Treatment
Schizophrenia
Approximately 9% (244/2607) of RISPERDAL® (risperidone)-treated
patients in Phase 2 and 3 studies discontinued treatment due to an adverse event,
compared with about 7% on placebo and 10% on active control drugs. The more
common events (³0.3%) associated with discontinuation
and considered to be possibly or probably drug-related included:
|
Adverse Event
|
RISPERDAL®
|
Placebo
|
|
Extrapyramidal symptoms
|
2.1%
|
0%
|
|
Dizziness
|
0.7%
|
0%
|
|
Hyperkinesia
|
0.6%
|
0%
|
|
Somnolence
|
0.5%
|
0%
|
|
Nausea
|
0.3%
|
0%
|
Suicide attempt was associated with discontinuation in 1.2%
of RISPERDAL®-treated patients compared to 0.6% of placebo patients,
but, given the almost 40-fold greater exposure time in RISPERDAL® compared
to placebo patients, it is unlikely that suicide attempt is a RISPERDAL®-related
adverse event (see PRECAUTIONS). Discontinuation
for extrapyramidal symptoms was 0% in placebo patients, but 3.8% in active-control
patients in the Phase 2 and 3 trials.
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy,
approximately 8% (10/134) of RISPERDAL®-treated patients discontinued
treatment due to an adverse event, compared with approximately 6% (7/125) of
placebo-treated patients. The adverse events associated with discontinuation
and considered to be possibly, probably, or very likely drug-related included
paroniria, somnolence, dizziness, extrapyramidal disorder, and muscle contractions
involuntary. Each of these events occurred in one RISPERDAL®-treated
patient (0.7%) and in no placebo-treated patients (0%).
In the US placebo-controlled trial with risperidone as adjunctive
therapy to mood stabilizers, there was no overall difference in the incidence
of discontinuation due to adverse events (4% for RISPERDAL® vs.
4% for placebo).
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
Schizophrenia
In two 6- to 8-week placebo-controlled trials, spontaneously-reported,
treatment-emergent adverse events with an incidence of 5% or greater in at least
one of the RISPERDAL® groups and at least twice that of placebo
were anxiety, somnolence, extra-pyramidal symptoms, dizziness, constipation,
nausea, dyspepsia, rhinitis, rash, and tachycardia.
Adverse events were also elicited in one of these two trials
(i.e., in the fixed-dose trial comparing RISPERDAL® atdoses of
2, 6, 10, and 16 mg/day with placebo) utilizing a checklist for detecting adverse
events, a method that is more sensitive than spontaneous reporting. By this
method, the following additional common and drug-related adverse events occurred
at an incidence of at least 5% and twice the rate of placebo: increased dream
activity, increased duration of sleep, accommodation disturbances, reduced salivation,
micturition disturbances, diarrhea, weight gain, menorrhagia, diminished sexual
desire, erectile dysfunction, ejaculatory dysfunction, and orgastic dysfunction.
Bipolar Mania
In the US placebo-controlled trial with risperidone as monotherapy,
the most commonly observed adverse events associated with the use of RISPERDAL®
(incidence of 5% or greater and at least twice that of placebo) were somnolence,
dystonia, akathisia, dyspepsia, nausea, parkinsonism, vision abnormal, and saliva
increased. In the US placebo-controlled trial with risperidone as adjunctive
therapy to mood stabilizers, the most commonly observed adverse events associated
with the use of RISPERDAL® were somnolence, dizziness, parkinsonism,
saliva increased, akathisia, abdominal pain, and urinary incontinence.
Adverse Events Occurring at an Incidence of 1% or More Among
RISPERDAL®-Treated Patients - Schizophrenia
The table that follows enumerates adverse events that occurred
at an incidence of 1% or more, and were more frequent among RISPERDAL®-treated
patients treated at doses of £10 mg/day than among
placebo-treated patients in the pooled results of two 6- to 8-week controlled
trials. Patients received RISPERDAL® doses of 2, 6, 10, or 16 mg/day in
the dose comparison trial, or up to a maximum dose of 10 mg/day in the titration
study. This table shows the percentage of patients in each dose group (£10
mg/day or 16 mg/day) who spontaneously reported at least one episode of an event
at some time during their treatment. Patients given doses of 2, 6, or 10mg did
not differ materially in these rates. Reported adverse events were classified
using the World Health Organization preferred terms.
The prescriber should be aware that these figures cannot be
used to predict the incidence of side effects in the course of usual medical
practice where patient characteristics and other factors differ from those which
prevailed in this clinical trial. Similarly, the cited frequencies cannot be
compared with figures obtained from other clinical investigations involving
different treatments, uses, and investigators. The cited figures, however, do
provide the prescribing physician with some basis for estimating the relative
contribution of drug and non-drug factors to the side effect incidence rate
in the population studied.
|
Table 1. Incidence of Treatment-Emergent Adverse Events
in 6- to 8-Week Controlled Clinical Trials1
|
|
Body System/ Preferred Term
|
RISPERDAL®
|
Placebo
(N=142)
|
|
£10 mg/day
(N=324)
|
16 mg/day
(N=77)
|
|
Psychiatric
|
|
Insomnia
|
26%
|
23%
|
19%
|
|
Agitation
|
22%
|
26%
|
20%
|
|
Anxiety
|
12%
|
20%
|
9%
|
|
Somnolence
|
3%
|
8%
|
1%
|
|
Aggressive reaction
|
1%
|
3%
|
1%
|
|
Central & peripheral nervous system
|
|
Extrapyramidal symptoms2
|
17%
|
34%
|
16%
|
|
Headache
|
14%
|
12%
|
12%
|
|
Dizziness
|
4%
|
7%
|
1%
|
|
Gastrointestinal
|
|
Constipation
|
7%
|
13%
|
3%
|
|
Nausea
|
6%
|
4%
|
3%
|
|
Dyspepsia
|
5%
|
10%
|
4%
|
|
Vomiting
|
5%
|
7%
|
4%
|
|
Abdominal pain
|
4%
|
1%
|
0%
|
|
Saliva increased
|
2%
|
0%
|
1%
|
|
Toothache
|
2%
|
0%
|
0%
|
|
Respiratory system
|
|
Rhinitis
|
10%
|
8%
|
4%
|
|
Coughing
|
3%
|
3%
|
1%
|
|
Sinusitis
|
2%
|
1%
|
1%
|
|
Pharyngitis
|
2%
|
3%
|
0%
|
|
Dyspnea
|
1%
|
0%
|
0%
|
|
Body as a whole - general
|
|
Back pain
|
2%
|
0%
|
1%
|
|
Chest pain
|
2%
|
3%
|
1%
|
|
Fever
|
2%
|
3%
|
0%
|
|
Dermatological
|
|
Rash
|
2%
|
5%
|
1%
|
|
Dry skin
|
2%
|
4%
|
0%
|
|
Seborrhea
|
1%
|
0%
|
0%
|
|
Infections
|
|
Upper respiratory
|
3%
|
3%
|
1%
|
|
Visual
|
|
Abnormal vision
|
2%
|
1%
|
1%
|
|
Musculo-Skeletal
|
|
Arthralgia
|
2%
|
3%
|
0%
|
|
Cardiovascular
|
|
Tachycardia
|
3%
|
5%
|
0%
|
|
1 Events reported by at least 1% of patients
treated with RISPERDAL® £10 mg/day
are included, and are rounded to the nearest %. Comparative
rates for RISPERDAL® 16 mg/day and placebo are provided
as well. Events for which the RISPERDAL® incidence (in
both dose groups) was equal to or less than placebo are not listed in
the table, but included the following: nervousness, injury, and fungal
infection.
|
|
2 Includes tremor, dystonia, hypokinesia,
hypertonia, hyperkinesia, oculogyric crisis, ataxia, abnormal gait, involuntary
muscle contractions, hyporeflexia, akathisia, and extrapyramidal disorders.
Although the incidence of 'extrapyramidal symptoms' does not appear to
differ for the '10 mg/day' group and placebo, the data forindividual dose
groups in fixed dose trials do suggest a dose/response relationship (see
ADVERSE REACTIONS – Dose Dependency
of Adverse Events).
|
Adverse Events Occurring at an Incidence of 2% or More Among
RISPERDAL®-Treated Patients - Bipolar Mania
Tables 2 and 3 display adverse events that occurred at an incidence
of 2% or more, and were more frequent among patients treated with flexible doses
of RISPERDAL® (1-6 mg daily as monotherapy and as adjunctive
therapy to mood stabilizers, respectively) than among patients treated with
placebo. Reported adverse events were classified using the World Health Organization
preferred terms.
|
Table 2. Incidence of Treatment-Emergent Adverse Events
in a 3-Week, Placebo-Controlled Trial - Monotherapy in Bipolar Mania1
|
|
Body System/ Preferred Term
|
RISPERDAL®
(N=134)
|
Placebo
(N=125)
|
|
Central & peripheral nervous system
|
|
Dystonia
|
18%
|
6%
|
|
Akathisia
|
16%
|
6%
|
|
Dizziness
|
11%
|
9%
|
|
Parkinsonism
|
6%
|
3%
|
|
Hypoaesthesia
|
2%
|
1%
|
|
Psychiatric
|
|
Somnolence
|
28%
|
7%
|
|
Agitation
|
8%
|
6%
|
|
Manic reaction
|
8%
|
6%
|
|
Anxiety
|
4%
|
2%
|
|
Concentration impaired
|
2%
|
1%
|
|
Gastrointestinal system
|
|
Dyspepsia
|
11%
|
6%
|
|
Nausea
|
11%
|
2%
|
|
Saliva increased
|
5%
|
1%
|
|
Mouth dry
|
3%
|
2%
|
|
Body as a whole - general
|
|
Pain
|
5%
|
3%
|
|
Fatigue
|
4%
|
2%
|
|
Injury
|
2%
|
0%
|
|
Respiratory system
|
|
Sinusitis
|
4%
|
1%
|
|
Rhinitis
|
3%
|
2%
|
|
Coughing
|
2%
|
2%
|
|
Skin and appendage
|
|
Acne
|
2%
|
0%
|
|
Pruritus
|
2%
|
1%
|
|
Musculo-Skeletal
|
|
Myalgia
|
5%
|
2%
|
|
Skeletal pain
|
2%
|
1%
|
|
Metabolic and nutritional
|
|
Weight increase
|
2%
|
0%
|
|
Vision disorders
|
|
Vision abnormal
|
6%
|
2%
|
|
Cardiovascular, general
|
|
Hypertension
|
3%
|
1%
|
|
Hypotension
|
2%
|
0%
|
|
Heart rate and rhythm
|
|
Tachycardia
|
3%
|
2%
|
|
1 Events reported by at least 2% of patients
treated with RISPERDAL® are included and are rounded to
the nearest %. Events reported by at least 2% of patients treated with
RISPERDAL® that were less than the incidence reported by
patients treated with placebo are not listed in the table, but included
the following: headache, tremor, insomnia, constipation, back pain, upper
respiratory tract infection, pharyngitis, and arthralgia.
|
|
Table 3. Incidence of Treatment-Emergent Adverse Events
in a 3-Week, Placebo-Controlled Trial - Adjunctive Therapy in Bipolar
Mania1
|
|
Body System/ Preferred Term
|
RISPERDAL® + Mood Stabilizer (N=52)
|
Placebo + Mood Stabilizer (N=51)
|
|
Gastrointestinal system
|
|
Saliva increased
|
10%
|
0%
|
|
Diarrhea
|
8%
|
4%
|
|
Abdominal pain
|
6%
|
0%
|
|
Constipation
|
6%
|
4%
|
|
Mouth dry
|
6%
|
4%
|
|
Tooth ache
|
4%
|
0%
|
|
Tooth disorder
|
4%
|
0%
|
|
Central & peripheral nervous system
|
|
Dizziness
|
14%
|
2%
|
|
Parkinsonism
|
14%
|
4%
|
|
Akathisia
|
8%
|
0%
|
|
Dystonia
|
6%
|
4%
|
|
Psychiatric
|
|
Somnolence
|
25%
|
12%
|
|
Anxiety
|
6%
|
4%
|
|
Confusion
|
4%
|
0%
|
|
Respiratory system
|
|
Rhinitis
|
8%
|
4%
|
|
Pharyngitis
|
6%
|
4%
|
|
Coughing
|
4%
|
0%
|
|
Body as a whole - general
|
|
Asthenia
|
4%
|
2%
|
|
Urinary system
|
|
Urinary incontinence
|
6%
|
2%
|
|
Heart rate and rhythm
|
|
Tachycardia
|
4%
|
2%
|
|
Metabolic and nutritional
|
|
Weight increase
|
4%
|
2%
|
|
Skin and appendages
|
|
Rash
|
4%
|
2%
|
|
1 Events reported by at least 2% of patients
treated with RISPERDAL® are included and are rounded to
the nearest %. Events reported by at least 2% of patients treated with
RISPERDAL® that were less than the incidence reported by
patients treated with placebo are not listed in the table, but included
the following: dyspepsia, nausea, vomiting, headache, tremor, insomnia,
chest pain, fatigue, pain, skeletal pain, hypertension, and vision abnormal.
|
Dose Dependency of Adverse Events
Extrapyramidal Symptoms
Data from two fixed-dose trials provided evidence of dose-relatedness
for extrapyramidal symptoms associated with risperidone treatment. Two methods
were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing
4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a parkinsonism
score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale,
and (2)incidence of spontaneous complaints of EPS:
|
Dose Groups
|
Placebo
|
Ris 2
|
Ris 6
|
Ris 10
|
Ris 16
|
|
Parkinsonism
|
1.2
|
0.9
|
1.8
|
2.4
|
2.6
|
|
EPS Incidence
|
13%
|
13%
|
16%
|
20%
|
31%
|
Similar methods were used to measure extrapyramidal symptoms
(EPS) in an 8-week trial comparing5 fixed doses of risperidone (1, 4, 8, 12,
and 16 mg/day):
|
Dose Groups
|
Ris 1
|
Ris 4
|
Ris 8
|
Ris 12
|
Ris 16
|
|
Parkinsonism
|
0.6
|
1.7
|
2.4
|
2.9
|
4.1
|
|
EPS Incidence
|
7%
|
12%
|
18%
|
18%
|
21%
|
Other Adverse Events
Adverse event data elicited by a checklist for side effects
from a large study comparing 5fixed doses of RISPERDAL® (1, 4,
8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events.
A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05)
for the following adverse events: sleepiness, increased duration of sleep, accommodation
disturbances, orthostatic dizziness, palpitations, weight gain, erectile dysfunction,
ejaculatory dysfunction, orgastic dysfunction, asthenia/ lassitude/ increased
fatigability, and increased pigmentation.
Vital Sign Changes
RISPERDAL® is associated with orthostatic hypotension
and tachycardia (see PRECAUTIONS).
Weight Changes
The proportions of RISPERDAL® and placebo-treated
patients meeting a weight gain criterion of ³7% of
body weight were compared in a pool of 6- to 8-week, placebo-controlled trials,
revealing a statistically significantly greater incidence of weight gain for
RISPERDAL® (18%) compared to placebo (9%).
Laboratory Changes
A between-group comparison for 6- to 8-week placebo-controlled
trials revealed no statistically significant RISPERDAL®/placebo
differences in the proportions of patients experiencing potentially important
changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly,
there were no RISPERDAL®/placebo differences in the incidence
of discontinuations for changes in serum chemistry, hematology, or urinalysis.
However, RISPERDAL® administration was associated with increases
in serum prolactin (see PRECAUTIONS).
ECG Changes
Between-group comparisons for pooled placebo-controlled trials
revealed no statistically significant differences between risperidone and placebo
in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals,
and heart rate. When all RISPERDAL® doses were pooled from randomized
controlled trials in several indications, there was a mean increase in heart
rate of 1 beat per minute compared to no change for placebo patients. In short-term
schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated
with a higher mean increase in heart rate compared to placebo (4-6 beats per
minute).
Other Events Observed During the Premarketing Evaluation
of RISPERDAL®
During its premarketing assessment, multiple doses of RISPERDAL®
were administered to 2607 patients in Phase 2 and 3 studies. The conditions
and duration of exposure to RISPERDAL® varied greatly, and included
(in overlapping categories) open-label and double-blind studies, uncontrolled
and controlled studies, inpatient and outpatient studies, fixed-dose and titration
studies, and short-term or longer-term exposure. In most studies, untoward events
associated with this exposure were obtained by spontaneous report and recorded
by clinical investigators using terminology of their own choosing. Consequently,
it is not possible to provide a meaningful estimate of the proportion of individuals
experiencing adverse events without first grouping similar types of untoward
events into a smaller number of standardized event categories. In two large
studies, adverse events were also elicited utilizing the UKU (direct questioning)
side effect rating scale, and these events were not further categorized using
standard terminology. (Note: These events are marked with an asterisk in the
listings that follow.)
In the listings that follow, spontaneously reported adverse
events were classified using World Health Organization (WHO) preferred terms.
The frequencies presented, therefore, represent the proportion of the 2607 patients
exposed to multiple doses of RISPERDAL® who experienced an event
of the type cited on at least one occasion while receiving RISPERDAL®.
All reported events are included, except those already listed in Table 1, those
events for which a drug cause was remote, and those event terms which were so
general as to be uninformative. It is important to emphasize that, although
the events reported occurred during treatment with RISPERDAL®,
they were not necessarily caused by it.
Events are further categorized by body system and listed in
order of decreasing frequency according to the following definitions: frequent
adverse events are those occurring in at least 1/100 patients (only those not
already listed in the tabulated results from placebo-controlled trials appear
in this listing); infrequent adverse events arethose occurring in 1/100 to 1/1000
patients; rare events are those occurring in fewer than 1/1000patients.
Psychiatric Disorders
Frequent: increased dream activity*, diminished sexual
desire*, nervousness. Infrequent: impaired concentration, depression,
apathy, catatonic reaction, euphoria, increased libido, amnesia. Rare: emotional
lability, nightmares, delirium, withdrawal syndrome, yawning.
Central and Peripheral Nervous System Disorders
Frequent: increased sleep duration*. Infrequent:
dysarthria, vertigo, stupor, paraesthesia, confusion. Rare: aphasia,
cholinergic syndrome, hypoesthesia, tongue paralysis, leg cramps, torticollis,
hypotonia, coma, migraine, hyperreflexia, choreoathetosis.
Gastrointestinal Disorders
Frequent: anorexia, reduced salivation*. Infrequent:
flatulence, diarrhea, increased appetite, stomatitis, melena, dysphagia,
hemorrhoids, gastritis. Rare: fecal incontinence, eructation, gastroesophageal
reflux, gastroenteritis, esophagitis, tongue discoloration, cholelithiasis,
tongue edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage, hematemesis.
Body as a Whole/General Disorders
Frequent: fatigue. Infrequent: edema, rigors,
malaise, influenza-like symptoms. Rare: pallor, enlarged abdomen, allergic
reaction, ascites, sarcoidosis, flushing. Respiratory System Disorders Infrequent:
hyperventilation, bronchospasm, pneumonia, stridor. Rare: asthma,
increased sputum, aspiration.
Skin and Appendage Disorders
Frequent: increased pigmentation*, photosensitivity*.
Infrequent: increased sweating, acne, decreased sweating, alopecia, hyperkeratosis,
pruritus, skin exfoliation. Rare: bullous eruption, skin ulceration,
aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis,
genital pruritus, urticaria.
Cardiovascular Disorders
Infrequent: palpitation, hypertension, hypotension,
AV block, myocardial infarction. Rare: ventricular tachycardia, angina
pectoris, premature atrial contractions, T wave inversions, ventricular extrasystoles,
ST depression, myocarditis.
Vision Disorders
Infrequent: abnormal accommodation, xerophthalmia. Rare:
diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation.
Metabolic and Nutritional Disorders Infrequent: hyponatremia, weight
increase, creatinine phosphokinase increase, thirst, weight decrease, diabetes
mellitus. Rare: decreased serum iron, cachexia, dehydration, hypokalemia,
hypoproteinemia, hyperphosphatemia, hypertriglyceridemia, hyperuricemia, hypoglycemia.
Urinary System Disorders
Frequent: polyuria/polydipsia*. Infrequent: urinary
incontinence, hematuria, dysuria. Rare: urinary retention, cystitis,
renal insufficiency.
Musculo-Skeletal System Disorders
Infrequent: myalgia. Rare: arthrosis, synostosis,
bursitis, arthritis, skeletal pain.
Reproductive Disorders, Female
Frequent: menorrhagia*, orgastic dysfunction*, dry vagina*.
Infrequent: nonpuerperal lactation, amenorrhea, female breast pain, leukorrhea,
mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal
hemorrhage.
Liver and Biliary System Disorders
Infrequent: increased SGOT, increased SGPT. Rare:
hepatic failure, cholestatic hepatitis, cholecystitis, cholelithiasis, hepatitis,
hepatocellular damage.
Platelet, Bleeding, and Clotting Disorders
Infrequent: epistaxis, purpura. Rare: hemorrhage,
superficial phlebitis, thrombophlebitis, thrombocytopenia. Hearing and Vestibular
Disorders Rare: tinnitus, hyperacusis, decreased hearing.
Red Blood Cell Disorders
Infrequent: anemia, hypochromic anemia. Rare: normocytic
anemia.
Reproductive Disorders, Male
Frequent: erectile dysfunction*. Infrequent: ejaculation
failure.
White Cell and Resistance Disorders
Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet
anomaly.
Endocrine Disorders
Rare: gynecomastia, male breast pain, antidiuretic hormone
disorder. Special Senses Rare: bitter taste.
* Incidence based on elicited reports.
Postintroduction Reports
Adverse events reported since market introduction which were
temporally (but not necessarily causally) related to RISPERDAL® therapy,
include the following: anaphylactic reaction, angioedema, apnea, atrial fibrillation,
cerebrovascular disorder, including cerebrovascular accident, hyperglycemia,
diabetes mellitus aggravated, including diabetic ketoacidosis, intestinal obstruction,
jaundice, mania, pancreatitis, Parkinson’s disease aggravated, pulmonary embolism.
There have been rare reports of sudden death and/or cardiopulmonary arrest in
patients receiving RISPERDAL®. A causal relationship with RISPERDAL®
has not been established. It is important to note that sudden and unexpected
death may occur in psychotic patients whether they remain untreated or whether
they are treated with other antipsychotic drugs.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
RISPERDAL® (risperidone) is not a controlled
substance.
Physical and Psychological Dependence
RISPERDAL® has not been systematically studied
in animals or humans for its potential for abuse, tolerance, or physical dependence.
While the clinical trials did not reveal any tendency for any drug-seeking behavior,
these observations were not systematic and it is not possible to predict on
the basis of this limited experience the extent to which a CNS-active drug will
be misused, diverted, and/or abused once marketed. Consequently, patients should
be evaluated carefully for a history of drug abuse, and such patients should
be observed closely for signs of RISPERDAL® misuse or abuse (e.g.,
development of tolerance, increases in dose, drug-seeking behavior).
DRUG INTERACTIONS
The interactions of RISPERDAL® and other drugs
have not been systematically evaluated. Given the primary CNS effects of risperidone,
caution should be used when RISPERDAL® is taken in combination
with other centrally acting drugs and alcohol.
Because of its potential for inducing hypotension, RISPERDAL®
may enhance the hypotensive effects of other therapeutic agents with this
potential.
RISPERDAL® may antagonize the effects of levodopa
and dopamine agonists.
Amytriptyline does not affect the pharmacokinetics of risperidone
or the active antipsychotic fraction. Cimetidine and ranitidine increased the
bioavailability of risperidone, but only marginally increased the plasma concentration
of the active antipsychotic fraction.
Chronic administration of clozapine with risperidone may decrease
the clearance of risperidone.
Carbamazepine and Other Enzyme Inducers
In a drug interaction study in schizophrenic patients, 11 subjects
received risperidone titrated to 6 mg/day for 3 weeks, followed by concurrent
administration of carbamazepine for an additional 3 weeks. During co-administration,
the plasma concentrations of risperidone and its pharmacologically active metabolite,
9-hydroxyrisperidone, were decreased by about 50%. Plasma concentrations of
carbamazepine did not appear to be affected. The dose of risperidone may need
to be titrated accordingly for patients receiving carbamazepine, particularly
during initiation or discontinuation of carbamazepine therapy. Co-administration
of other known enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital)
with risperidone may cause similar decreases in the combined plasma concentrations
of risperidone and 9-hydroxyrisperidone, which could lead to decreased efficacy
of risperidone treatment.
Fluoxetine and Paroxetine
Fluoxetine (20 mg QD) and paroxetine (20 mg QD) have been shown
to increase the plasma concentration of risperidone 2.5-2.8 fold and 3-9 fold
respectively. Fluoxetine did not affect the plasma concentration of 9-hydroxyrisperidone.
Paroxetine lowered the concentration of 9-hydroxyrisperidone an average of 13%.
When either concomitant fluoxetine or paroxetine is initiated or discontinued,
the physician should re-evaluate the dosing of RISPERDAL®. The
effects of discontinuation of concomitant fluoxetine or paroxetine therapy on
the pharmacokinetics of risperidone and 9-hydroxyrisperidone have not been studied.
Lithium
Repeated oral doses of risperidone (3 mg BID) did not affect
the exposure (AUC) or peak plasma concentrations (Cmax) of lithium
(n=13). Valproate Repeated oral doses of risperidone (4 mg QD) did not affect
the pre-dose or average plasma concentrations and exposure (AUC) of valproate
(1000 mg/day in three divided doses) compared to placebo (n=21). However, there
was a 20% increase in valproate peak plasma concentration (Cmax)
after concomitant administration of risperidone.
Digoxin
RISPERDAL® (0.25 mg BID) did not show a clinically
relevant effect on the pharmacokinetics of digoxin.
Drugs That Inhibit CYP 2D6 and Other CYPIsozymes
Risperidone is metabolized to 9-hydroxyrisperidone by CYP 2D6,
an enzyme that is polymorphic in the population and that can be inhibited by
a variety of psychotropic and other drugs (see CLINICAL
PHARMACOLOGY). Drug interactions that reduce the metabolism of risperidone
to 9-hydroxyrisperidone would increase the plasma concentrations of risperidone
and lower the concentrations of 9-hydroxyrisperidone. Analysis of clinical studies
involving a modest number of poor metabolizers (n 70) does not suggest that
poor and extensive metabolizers have different rates of adverse effects. No
comparison of effectiveness in the two groups has been made.
In vitro studies showed that drugs metabolized by other
CYPisozymes, including 1A1, 1A2, 2C9, 2C19, and 3A4, are only weak inhibitors
of risperidone metabolism. There were no significant interactions between risperidone
and erythromycin (see CLINICAL PHARMACOLOGY).
Drugs Metabolized by CYP 2D6
In vitro studies indicate that risperidone is a relatively
weak inhibitor of CYP 2D6. Therefore, RISPERDAL® is not expected
to substantially inhibit the clearance of drugs that are metabolized by this
enzymatic pathway. In drug interaction studies, risperidone did not significantly
affect the pharmacokinetics of donepezil and galantamine, which are metabolized
by CYP 2D6.
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