1. health and fitness
2. disorders
3. mental disorder
4. depression

ONCE-DAILY
20
MG
TM
: PAROXETINE I-IC!
I
Paxil’TMdearly relieves
depression
and associ#{225}t
symptoms
of anxiety.’
Studies show that 60% to 90% of depressed
associated
symptoms
of anxiety
Clinical studies
and associated
show Paxil to be effective
symptoms
of anxiety
patients
exhib,
in relieving
depression
Incidence of agitation
with Paxil is comparable
to placebo
(2.1% vs 1.9%); incidence of nervousness
and of anxiety
vs placebo is 5.2% vs 2.6% and 5.0% vs 2.9%), respectively
Please
see brief
summary
of prescribing
infoi
nation
on lot
2ii
of I
i
civ
‘0
1
ONCE-DAILY
t
#{149}MG20
PAROXETINEHC/
LIFTS DEPRESSION.
ASSOCIATED
ANXIETY
LOWERS
Sm,thKIsne
Pharmaceuticals
Philadelphia,
PA 19101
Beecham
JANSSEN
SYMPTOMS.
G2-L4JLY
PAKII
PAROXETINEHCI
References:
1. Dunbar
GC, Cohn
imipramine
JB, Fabre
and placebo
1991;159:394-398.
2. Data from controlled
LF, et a. A comparison
of paroxetine,
in depressed
out-patients.
clinical
On file, SmithKline
trials.
BrJPsychiatry.
Beecham
Pharmaceuticals.
3. Sheehan
D, Dunbar
and agitation
CC, Fuell DL. The effect
associated
with
depression.
1992;28:139-143.
4. Hamilton
M. Distinguishing
between
In: Last CA, Hersen M, eds. Handbook
Pergamon
Press;
(brand
on anxiety
Bull.
anxiety
and depressive
disorders.
ofAnxietyDisorders.
New York, NY:
1988:143-145.
5. PaxiITM (paroxetine
PAXIL
of paroxetine
Ps ychopharmacol
HCI) Prescribing
of paroxetine
Information.
hydrochloride)
See complete
prescribing
information
in SmithKline
Beecham
Pharmaceuticals literature
or PDR. The following
is a brief summary.
INDICATIONS
AND USAGE:
Paxil is indicated for the treatment
of depression.
CONTRAINDICATIONS:
Concomitant
use in patients taking monoamine
oxidase
inhibitors
(MAOlsl
is contraindicated.
lSee WARNINGS.)
WARNINGS:
Interactions
with MAOIs
may occur. Given the fatal interactions reported
with concomitant
or immediately
consecutive
administration ofMAOls
and other SSRls, do not use Paxilin combination
with a MAOI
or within 2 weeks of discontinuing
MAOI treatment
Allow at least 2 weeks
after stopping
Paxil before starting
a MAOI.
PRECAUTIONS:
As with all antidepressants,
use Paxi/cautiously
in patients with
a history of mania.
Use Paxil cautiously
in patients with a history of seizures.
Discontinue
it in any
patient who develops
seizures.
The possibility
of suicide attempt
is inherent in depression
and may persist until
significant
remission
occurs. Close supervision
of high-risk patients should accompany initial drug therapy.
Write Paxil prescriptions
for the smallest
quantity
of
tablets consistent
with good patient management
in order to reduce the risk of
overdose.
Reversible
hyponatremia
has been reported,
mainly in elderly patients,
patients
taking diuretics
or those who were otherwise
volume depleted.
Clinical experience
with Paxil in patients
with concomitant
systemic
illness is
limited.
Use cautiously
in patients
with diseases
or conditions
that could affect
metabolism
or hemodynamic
responses.
Observe
the usual cautions
in cardiac
patients.
In patients
with severe
renal impairment
)creatinine
clearance
<30
mL/min.)
or severe hepatic impairment,
a lower starting dose 110 mgI should be
used.
Caution patients
about operating
hazardous
machinery,
including
automobiles,
until they are reasonably
sure that Paxil therapy does not affect their ability to
engage in such activities.
Tell patients
11 to continue
therapy as directed;
2) to
inform physicians
about other medications
they are taking or plan to take; 3) to
avoid alcohol while taking
Paxil; 4) to notify their physicians
if they become
pregnant
or intend to become
pregnant
during therapy, or if they’re nursing.
Concomitant
use of Paxil with tryptophan
is not recommended.
Use cautiously
with warfarin.
When administering
Paxilwith
cimetidine,
dosage adjustment
of
Paxi/after
the 20 mg starting dose should be guided by clinical effect. When coadministering
Paxil with phenobarbital
or phenytoin,
no initial Paxil dosage
adjustment
is needed; base subsequent
changes on clinical effect. Concomitant
use of Paxilwith
drugs metabolized
by cytochrome
P4IlD6 )antidepressants
such
as nortriptyline,
amitriptyline,
imipramine,
desipramine
and fluoxetine;
phenothiazines such as thioridazine;
Type 1C antiarrhythmics
such as propafenone,
fecainide
and encainide)
or with drugs that inhibit this enzyme (e.g., quinidine)
may require
lower doses than usually prescribed
for either Paxil or the other drug; approach
concomitant
use cautiously.
Administration
of Paxil with another tightly proteinbound drug may shift plasma concentrations,
resulting
in adverse effects from
either drug. Concomitant
use of Paxil and alcohol in depressed
patients
is not
advised. Undertake
concomitant
use of Paxil and lithium or digoxin cautiously.
If
adverse effects are seen when co-administering
Paxil with procyclidine,
reduce
the procyclidine
dose.
In 2-year studies, a significantly
greater number of male rats in the 20 mg/kg/day
group developed
reticulum
cell sarcomas
vs. animals
given doses of 1 or 5
mg/kg/day.
There was also a significantly
increased
linear trend across dose
groups for the occurrence
of lymphoreticular
tumors in male rats. Although
there
was a dose-related
increase in the number of tumors in mice, there was no drugrelated increase
in the number of mice with tumors. The clinical significance
of
these findings
is unknown.
There is no evidence
of mutagenicity
with Paxil.
Serotonergic
compounds
are known to affect reproductive
function
in animals.
Impaired reproductive
function in rats (i.e., reduced pregnancy
rate, increased preand post-implantation
losses, decreased
viability of pups) wasfound
at Paxi/doses
15 or more times the highest recommended
human dose.
Pregnancy
Category
B. Reproduction
studies performed
in rats and rabbits at
doses up to 50 and 6 times the maximum
recommended
human dose have
revealed
no evidence
of teratogenic
effects or of selective
toxicity to the fetus.
However,
there are no adequate and well-controlled
studies in pregnant women.
Paxil should be used in pregnancy
only if the benefits
outweigh
the risks. The
effect of Paxilon labor and delivery in humans is unknown.
Paroxetine
is secreted
in human milk; exercise caution when administering
Paxilto a nursing woman.
Safety and effectiveness
in children have not been established.
In worldwide
Paxil clinical trials, 17% of Paxi/-treated
patients were 65 years of
age. Pharmacokinetic
studies
revealed
a decreased
clearance
in the elderly;
however,
there were no overall differences
in the adverse event profile between
older and younger
patients.
ADVERSE
REACTIONS:
Incidence in ControlledTrials-CommonlyObserved
Adverse
Events
in Controlled
Clinical
Trials: The most commonly
observed
adverse events associated
with the use of Paxil (incidence
of 5% or greater and
incidence for Paxilat least twice that for placebo): asthenia (15% vs. 6%), sweating
(1 1 % vs. 2%), nausea (26% vs. 9%), decreased
appetite
16% vs. 2%), somnolence (23% vs. 9%), dizziness (1 3% vs. 6%), insomnia (13% vs. 6%), tremor (8%
vs. 2%), nervousness
(5% vs. 3%), ejaculatory
disturbance
(13% vs. 0%) and
other male genital disorders
(1 0% vs. 0%). Twenty-one
percent (881/4,1261 of Paxil
patients
in worldwide
clinical trials discontinued
treatment
due to an adverse
event. The most common
events
(1 %) associated
with discontinuation
and
considered
to be drug related include: somnolence,
insomnia,
agitation,
tremor,
anxiety,
nausea, diarrhea,
dry mouth, vomiting,
asthenia,
abnormal
ejaculation,
sweating.
The following
adverse events occurred
in 6-week placebo-controlled
trials of similar design at a frequency
of 1 % or more.
Body as a Whole: headache,
asthenia, abdominal
pain, fever, chest pain, trauma,
back pain. Cardiovascular:
palpitation,
vasodilation,
postural hypotension.
Dermatologic:
sweating,
rash. Gastrointestinal:
nausea, dry mouth, constipation,
diarrhea, decreased appetite, flatulence,
vomiting, oropharynx
disorder, dyspepsia,
increased appetite. Musculoskeletal:
myopathy,
myalgia, myasthenia.
Nervous
System:
somnolence,
dizziness,
insomnia,
tremor,
nervousness,
anxiety,
paresthesia,
libido decreased,
agitation,
drugged feeling, myoclonus,
CNS stimulation, confusion.
Respiration:
respiratory
disorder,
yawn, pharyngitis.
Special
Senses: blurred vision, taste perversion.
Urogenital
System:
ejaculatory
disturbance, other male genital disorders,
urinary frequency,
urination disorder, female
genital disorders.
Studies show a clear dose dependency
for some of the more common
adverse
events associated
with Paxil use. There was evidence
of adaptation
to some
adverse events with continued
Paxi/therapy
(e.g., nausea and dizzinessl.
Significant weight loss may be an undesirable
result of Paxil treatment
for some patients
but, on average,
patients
in controlled
trials had minimal
(about 1 Ib) loss. In
placebo-controlled
clinical trials, Paxi/-treated
patients exhibited
abnormal
values
on liver function
tests no more frequently
than placebo-treated
patients.
Other Events Observed
During the Premarketing
Evaluation
of Paxil: During
premarketing
assessment,
multiple
doses of Paxil were administered
to 4,126
patients,
and the following
adverse
events were reported.
Note: frequent
=
events
occurring
in at least
1/100
patients;
infrequent
=
1/100
to
1/1000 patients;
rare
=
less than 1/1000 patients.
Events are classified
within
body system categories
and enumerated
in order of decreasing
frequency
using
the following
definitions.
It is important
to emphasize
that although
the events
occurred
during Paxil treatment,
they were not necessarily
caused by it.
Body as a Whole:
frequent:
chills, malaise; infrequent:
allergic reaction,
carcinoma, face edema, moniliasis,
neck pain; rare: abscess,
adrenergic
syndrome,
cellulitis,
neck rigidity, pelvic pain, peritonitis,
ulcer. Cardiovascular
System:
frequent:
hypertension,
syncope,
tachycardia;
infrequent:
bradycardia,
conduction abnormalities,
electrocardiogram
abnormal,
hypotension,
migraine,
peripheral vascular disorder;
rare: angina pectoris,
arrhythmia,
atrial fibrillation,
bundle
branch block, cerebral
ischemia,
cerebrovascular
accident,
congestive
heart
failure, low cardiac output, myocardial
infarct, myocardial
ischemia, pallor, phlebitis, pulmonary
embolus,
supraventricular
extrasystoles,
thrombosis,
varicose
vein, vascular
headache,
ventricular
extrasystoles.
Digestive
System:
infrequent: bruxism,
dysphagia,
eructation,
glossitis,
increased
salivation,
liver function tests abnormal, mouth ulceration, rectal hemorrhage;
rare:aphthous
stomatitis,
bloody diarrhea, bulimia, colitis, duodenitis,
esophagitis,
fecal impactions,
fecal
incontinence,
gastritis,
gastroenteritis,
gingivitis,
hematemesis,
hepatitis,
ileus,
jaundice,
melena,
peptic
ulcer, salivary
gland enlargement,
stomach
ulcer,
stomatitis,
tongue
edema,
tooth caries. Endocrine
System:
rare: diabetes
mellitus,
hyperthyroidism,
hypothyroidism,
thyroiditis.
Hemic and Lymphatic
Systems:
infrequent:
anemia, leukopenia,
lymphadenopathy,
purpura;
rare: abnormal erythrocytes,
eosinophilia,
leukocytosis,
lymphedema,
abnormal
lymphocytes,
lymphocytosis,
microcytic
anemia,
monocytosis,
normocytic
anemia.
Metabolic
and Nutritional:
frequent:
edema, weight gain, weight
loss; infrequent:
hyperglycemia,
peripheral
edema,
thirst; rare: alkaline
phosphatase
increased,
bilirubinemia,
dehydration,
gout, hypercholesteremia,
hypocalcemia,
hypoglycemia,
hypokalemia,
hyponatremia,
SGOT increased,
SGPT increased.
Musculoskeletal
System: infrequent:
arthralgia, arthritis; rare: arthrosis, bursitis,
myositis,
osteoporosis,
tetany. Nervous System: frequent: amnesia, CNS stimulation, concentration
impaired,
depression,
emotional
lability, vertigo; infrequent:
abnormal thinking, akinesia, alcohol abuse, ataxia, convulsions,
depersonalization,
hallucinations,
hyperkinesia,
hypertonia,
incoordination,
lack of emotion,
manic
reaction, paranoid reaction; rare: abnormal electroencephalogram,
abnormal gait,
antisocial
reaction,
choreoathetosis,
delirium,
delusions,
diplopia,
drug dependence, dysarthria,
dyskinesia,
dystonia,
euphoria, fasciculations,
grand mal convulsion,
hostility,
hyperalgesia,
hypokinesia,
hysteria,
libido increased,
manicdepressive
reaction,
meningitis,
myelitis,
neuralgia,
neuropathy,
nystagmus,
paralysis,
psychosis,
psychotic
depression,
reflexes
increased,
stupor,
withdrawal
syndrome.
Respiratory
System:
frequent:
cough increased,
rhinitis;
infrequent:
asthma, bronchitis,
dyspnea,
epistaxis,
hyperventilation,
pneumonia,
respiratory
flu, sinusitis;
rare: carcinoma
of lung, hiccups, lung fibrosis, sputum
increased.
Skin and Appendages:
frequent:
pruritus; infrequent:
acne, alopecia,
dry skin, ecchymosis,
eczema, furunculosis,
urticaria; rare: angioedema,
contact
dermatitis,
erythema
nodosum,
maculopapular
rash, photosensitivity,
skin disco)oration, skin melanoma.
Special Senses: infrequent:
abnormality
of accommodation, ear pain, eye pain, mydriasis, otitis media, taste loss, tinnitus; rare:amblyopia,
cataract, conjunctivitis,
corneal ulcer, exophthalmos,
eye hemorrhage,
glaucoma,
hyperacusis,
otitis externa, photophobia.
Urogenital
System:
infrequent:
abortion, amenorrhea,
breast pain, cystitis,
dysmenorrhea,
dysuria,
menorrhagia,
nocturia,
polyuria,
urethritis,
urinary incontinence,
urinary retention,
urinary urgency, vaginitis; rare: breast atrophy, breast carcinoma,
breast neoplasm,
female
lactation,
hematuria,
kidney calculus,
kidney function
abnormal,
kidney pain,
mastitis,
nephritis,
oliguria, prostatic carcinoma,
vaginal moniliasis.
Non-U.S.
Postmarketing
Reports
Voluntary
reports
of adverse
events that have been received
since market
introduction
and may have no causal relationship
with Paxil include elevated liver
function
tests (the most severe case was a death due to liver necrosis,
and one
other case involving grossly elevated transaminases
associated
with severe liver
dysfunction)
and toxic epidermal
necrolysis.
DRUG ABUSE AND DEPENDENCE:
Controlled
Substance
Class: Paxil is not
a controlled
substance.
Evaluate patients carefully for history of drug abuse and
observe such patients closely for signs of Paxil misuse or abuse (e.g., development of tolerance,
incrementations
of dose, drug-seeking
behavior).
BRS-PX:L6
3
Philadelphia,
SmirhKIine
Beecham
Pharmaceuticals
PA 19101
.JANSSEN
© SmithKline
Beecham,
1994
‘,[#{149}0
ci
.
0
/
S
9
44_i
THE
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A3
Prozace
.
fluoxetine hydrochloride
Brief smmary. CosuN the packas
IudIuUs:
Rssrt br complete prsscribIn
For the treatment of depression and obsessive-compulsive
disorder (OCO).
Known hypersensitivity
to Prozac
Monoamine Oxidase Inhibitors-There
have been reports of serious.
sometimes fatai, reacfions in patients receiving fluoxetine in combination
with an MAOi and in patients who have recentiy discontinued fluooetine
and are then started on an MAOI. Some cases presented with features
resembhng neuroleptic malignant syndrome.
Wait at east 14 days between discontinuing an MAOi and starting therapy
wtth Proc. Because of the ksnQhatf-lives of fluoxebne and do active metabobte.
wait at least 5 weeks )or longer, if fluoxetine has been prescribed chronically
anWor at higher doses) between dconbnuing Prozac and starting therapy with
an MAOI. Prozac should not be used concomitantly with MAOts
Wamlegs: Rash and Possibly Allergic Ents-Approoimately
4% of 5,600
tfuoxetine patients developed a rash and/or urticaria in premarketing testing.
Almost a third of these discontinued therapy because of rash and/or
associated systemic signs or symptoms. Reported in association with rash
were fever. leukocytosis. arthraigias. edema, carpal tunnel syndrome,
respiratory distress. lymphadenopathy, proteinuria. and mild transaminase
elevation. Most patients improved promptly upon discontinuation of
fluoxetine and/or adjunctive treatment with antihistamines or steroids, and
all were reported to recover completely.
of 2 patients who developed a serious cutaneous systemic illness during
premarketing clinical trials. 1 was considered to have a leukocytociastic
vasculitis, and the other. a severe desquamating syndrome considered
variously to be a vascuiitis or erythema multiforme. Other patients have had
systemic syndromes suggestive of serum sickness.
Since the introduction of Prozac, systemic events possibly related to
vascubtis have developed in patients wdh rash. Although these events are rare,
they may be serious. involving the lung, kidney, or liver. Death has been
reported to occur in association with these systemicevents.
Anaphylactoid events, including bronchospasm, angioedema, and urticana
shine and in combeabon, have been reported.
Pulmonary events. including inflammatory
processes of varying
fastopathofogy and/or hbrosis. have been reported rarely These events have
occurred with dyspnea as the only preceding symptom.
Whether these systemic events and rash have a common underlying cause
or represent immunologic responses is not known. Upon the appearance of
rash or of other possibly allergic phenomena for which an alternative etiOlOgy
cannot be entifIed, Prozac should be deconbnued
Pmcsutioris:-General--The
following events occurred in controlled clinical trials. See Tables 1 and 2 also.
. Anxiety,
lveriousness, and Insomnia.
AIteredApte
and Weighf-Signdicant weght lOss may be an undesirable
resuft of treatment.
. Activation ofManiafllypomania-Occurred
in approximately 1% of patients.
. Swirwsa-lntroduce
Prozac wdh care in patients with a history ofseizures. in
depression, 0.2% of patients experienced convulsions (or, possibly,
seizures). In OCD. 1 pahent experienced a seizure
. Suii-Close
supervision of high-risk patients should accompany initial
drug therapy.
. Long Elimination Half-Lives of FIuo.xetineand Its Metabolites-Because
of
the long elimination half-lives of the parent drug (1 to 3 days after acute
administration and 4 to 6 days after chronic administration)
and its major
active metabolite (4 to 16 days after acute and chronic administration).
changes in dose will not be fully reflected in plasma for several weeks,
S
both strategies
for titration
to final dose and withdrawal
from
treatment.
Use in Patients With Concomitant Illness-Caution is advisable in patients
with diseases or conditions that could affect metabolism or hemodynamic
responses.
. Interference
With Cognitive and Motor Performance-Patients shouid be
cautioned about operating hazardous machinery, including automobiles. until
they are reasonably certain that the drug does not affect them adversely.
. Infotmahon for Patients-Physicians
should advise their patients to notify
them if they:
-are taking or pian to take any prescription or over-the-counter drugs or
eicohei
- become pregnant or intend to become pregnant during therapy
- are breast feeding an infant
- develop a rash or hives
. Drug Interactions
- Drugs Metabolized by P45011DB-Therapy
with meditations that are
predominantly metabolized by the P4501ID6 system. especially those that
.
have a relatively
-
-
-
narrow
therapeutic
ides
leg. fletainide,
vinblastine.
carbamazepine. and tricycbc antidepressantsl shoule be Mated at the low
end ofthe dosage range ta Patient 5 receiving fluoxetine concurrently or has
taken it in the previous 5 weeks. Alternately. the addition of fluoxetine to the
treatment regimen of a patient already receiving a drug metabolized by
P4501106 may require a decreased dose of the original medication.
Tryptophan-Five
patients receiving tryptophan experienced adverse
reactions, including agdation. restlessness, and pastreintestinal distress
Monoamine Oxidase lnhibitors-SeeContrsndications,
Other Antidepressants-Greater
than 2-fold increases of previously stable
plasma levels of other antidepressants when concomitantly administered
with Prozac have occurred
Lithium-Reports ofboth increased and decreased lithium levels and lithium
toxicity.
Diazeoax Oearance-The haS-ide of diazepam may be prolonged in some
-5
-ilgin--Pabents
on stable doses of phenytoin have developed elevated
plasma phenytoin concentrations
and clinical phenytoin toxicity following
initiation of concomitant fluoxetine treatment.
- Druqs Tightly Bound to Plasma Proteins-A
shift in plasma concentrations
or displacement of fluoxetine may result in adverse effects.
-CNS-Active Drugs-Caution is advised
- Electmconvulsive
Therapy-Rare reports of prolonged seizures in patients
on ftuoxetine receioing Ed.
#{149}Ca’cinogenesis,
Mutagenesis, Impairment of Ferti/ity-There
is no evidence
of carcinogenicity. mutagenicity. or impairment offertility with Prozac
. Pregnancy-Teratogenic
Effects-Pregnancy
Category 8-use fluoxetine
dunng pregnancy only if clearly needed.
#{149}LaborandOefriety-Theeffect of Prozac is unknown
#{149}Nursing
Mothers-Prozac
is excreted in human milk. Nursing whiie on
Prozac is not recommended.
#{149}Usagein
Children-Safety and effectiveness have not been established.
. usage in the Elderly-Evaluation
of patients over age 60 who received
Prozac, 20 mg, daiP revealed no unusual pattern of adverse events relateto
the clinical experience in younger patients. However, these data are
eisuthcient to rule out possible age-related differences during chronic use.
particularly in elderly patients with concomitant systemic illnesses or those
receiving concomitant drugs
#{149}tponatremia-Hyponatrema lsome cases with serum Na <110 mmol/t.l
has been reported which appeared to be reversible on drug discontinuation
Some cases were possibly due to SIADH. and the majority have been in older
patients and those talang diuretics or were otherwise volume depleted
Prozac#{174}
Ifluoxetine hydrochloridel
Table 2.
TREATMENT-EMERGENTADVERSEEXPERIENCE
INCIDENCE
IN
FOR
Adverse Rsactlos,:
Commonly Observed-Nervous system complaints,
including anxiety. nervousness, and insomnia; drowsiness and fatigue or
asthenia;
Co*sIadIcstIoRs:
affecting
Platelet Function-There have been rare reports of altered platelet function
and/or abnormal results from laboratory studiex in patients taking ttuoxetine
White there have been reports of abnormal bleeding in several patients taking
fluoxetine, it is unclear whether fluoxetine had a causative role.
tremor;
sweating;
gastrointestinal
complaints,
including
hemorrhage,
hypertension,
hypotension,
migraine, postural hypotension,
syncope, and tachycardia; Rare: AV block first-degree, bradycardia. bundle
branch block, cerebral ischem myocarthal infarct, thrombophlebitis, vascutar
headache, and ventriculararrhythmia.
Digestive System-Frequent:
increased appetite; Infrequent; aphthous
stomatitis, dysphagia, eructation, esophagitis, gastritis, gingivitis, glossitis,
liver function tests abnormal, melena, stomatitis, thirst; Rare: bloody diarrhea,
cholecystitis, cholelithiasis, colitis, duodenal ulcer, ententis,fecal incontinence,
hematemesix, hepatitis, hepatomegaly, hyperchlorfiydria, increased salivation,
jaundice, liver tenderness, mouth ulceration, saiivary gland enlargement,
stomach ulcer, tongue diocoloration, and tongue edema.
Endocrine System-Infrequent:
hypothyroidism; Rare: goiter and
hyperthyroidism.
Hemic and Lymphatic System-Infrequent:
anemia and lymphadenopathy;
Rare: bleeding time Increased, blood dyscrasia, leukopenia, lymphocytosis.
petechia, purpura, sedimentation rate increased, and thrombocythema
Metabolic and Nutribo.nal-Frequent:
weight loss; Infrequent generalized
edema, hypoglycemia, peripheral edema, and weght gain; Rare: dehydration,
gout, hyperchoiesteremla,
hyperglycemia, hyperlipemia, hypoglycemic
reaction, hypokalemia, hyponatremia, and iron deficiencyanemia.
Musculoskeletal System-Infrequent:
arthritis,
bone pain, bursitis,
tenosynovitis, and twitch. , Rare: bone necrosis, chondrodystrophy,
muscle
hemorrhage. myositis, osteoporosis,
pathologicai
fracture, and rheumatoid
arthritis.
Nervous System-Frequent: abnormal dreams and agitation; Infrequent:
abnormal gait, acute brain syndrome, akathisia, amnesia, apathy, ataxia,
buccoglossal syndrome, CNS stimulation, convulsion, delusions,
depersonalization, emotional lability, euphoria. hallucinations. hostility.
hyperkinesia, hypesthesia, incoordination, libido increased, manic reaction,
neuraigia, neuropathy, paranoid reaction, psychosis, and vertigo; Rare:
abnormal electroencephalogram, antisociai reaction, chronic brain syndrome,
circumoral paresthesia, CNS depression, coma, dysarthria, dyxtonia,
extrapyramidal syndrome, hypertonia, hysteria, myoclonus, nystagmus.
parasix, reflexes decreased, stupor, and torticoifis.
Respiratory System-Frequent: bronchitis, rhinitis, and yawn; Infrequent:
asthma, epistaxis, hiccup, hyperventiiation, and pneumonia; Rare: apnea,
hemoptysis, hypoxia. larynx edema, iung edema, lung fibrosis/aiveolitis,
and
pleuraleffusion.
Table 1.
TREATMENT-EMERGENTADVERSEEXPERiENCE
iNCiOENCEIN P1.ACEBO-cONTROLL.E0CLiNiCAL TRiALs
Pnrcentageni
Patients Reporting
Percentage xl
Patients Reporltn
Even
Body Sysie’n/
Preferred Term
Neresee
Headache
Nervousness
insomnia
Ornwsiness
Anxiety
Prozac
iN.1.730i
20.3
14 9
13.0
116
9.4
Event
Placebo Body System/
iN.799i
Preferred Term
SeIyua
155
5.5
7.1
6.3
5.5
Wiele
34
Pain, urnS
fuver
i.t
14
13
12
12
Pain. chest
Alergy
influenza
7.9
24
57
3.3
Fatigue
4.2
19
1 1
1.3
1 7
2.0
16
-
syndrome
Pliaryngtts
16
-
Ns.oai
15
-
ile:stIon
decreased
Lqlti’
headedness
44
infection. vvai
Oimneos
Libido.
Piacebn
iN.799i
Aotttenia
Tremor
Sedated
5ensatisn
disturbance
Prozac
iN.i.73xi
in
3 1
i
-
11
11
15
Riry
renivrstn(y
60
Ru-tAr
25
27
19
13
Concentrat,nn.
decreased
oleesilve
Nausea
Diarrhea
211
12.3
101
70
Mouth
dryness
Anorexia
Dyspepsia
Constittat’on
Pain.
abdominal
vomiting
Taste change
Flatulence
Gastroententis
kie eed
*eees
Sweating.
encesoive
Real’
Pruntis
95
87
64
45
60
26
23
sinus
23
5inusifts
21
16
14
10
20
16
Cough
Ovopnea
Cardiee--’-
15
43
33
n
Body System/
Preferred Inns
I 0
14
20
24
I 2
1 1
1
2.6
2 1
19
17
0.4
Prozac
Dimness
54
27
24
29
1.3
-
11
14
3.8
16
14
Pain. back
PSfl. 0119
Pain. muocie
12
umeeettei
-
Fisqiset
ttttctunttnn
tract
intue
16
-
1.2
-
20
10
Unnary
Vision
disturbance
Events reported by at tiant t% nfpattents treatedwtttt Prozac are ntduded
tOenomittaioruued was iemaiessniyi?iO1210 Prnsac, N.523 placnltoi
toennmtnaior used was maieuoniyiN.520 Prozac: N .276 piaceboi
-inodence tins their 1%
Prozac#{174}
Ifluoxetine hydrochloride;
IN-Os)
17
22
7
14
7
13
decreased
r mon
ii
ii
2
3
Yasodiiaiat,on
5
2
2
-
Mesceloekeletel
Myaigia
Paip,tat,xns
2
1
S
Arthraigsa
3
4
2
-
1
1
12
10
Ureeeeltel
iJnnarj
4
7
-
13
irnqueocy
Abnormal
niacuiai,xnt
lleeiIcaMLyeipkeIIc
l3
Lymphadenopaiby
MCd
2
-
4
1 $ectef
2
-
7
6
3
-
3
2
1
1
33
24
15
10
7
4
10
6
4
1
UM111
Weight lOss
6
i;rocedurn
Alierpcneactton
Fever
Cough
‘ncrnased
0
-
1
2
27
kdya
Wief a
Headache
Autbenie
Fiusyndrome
Pain
inury. accidentie
5
1
2
ken
Sinutiuis
2
2
2
Sweating
Rasti
Pnifltus
11
7
Yawn
3
4
Arorerita
Orymouth
Dyspepoia
Gastrointestinie
disorder
Metres
esIe
Events
following
1
5
dreams
Thinking. abnormai
Pltaryngois
Placebo
iN.89i
2
9
Sleep disoncter
Conftisiiui
Myocinnus
Agditinn
Amnesia
DIgeettee
Nuses
Evest
Prozac
iN.2641
Prntnrred Term
Libido.
5
$eee
3
Ambiyopia
c:rtnal
vision
3
2
-
perversion
2
2
-
Ttnnttus
1
1
2
3
2
-
1
repo4ed by at
events
least 2% of patients treated with Prosac are included.
except the
which had an ocidence
on placebo
Front
ubdnminai pain. back pain.
constipation. depression. dysmenorrhea. flatulence. infection. menstrual disorder.
nervousoess,
tenths.tooth disorder, and twitclttttg
tDenominator
used was males only iN.116 Prozac,N.43 piacebol.
-Adverse
event ttot reported by placebo-treated patients
Skin and Arxpendages-Infrequent: acne, alopecia, contact dermatttis, dry
skin, herpes simpiex, macuiopapuiar rash, and urticaria; Rare: eczema,
erythema multiforme, fungal dermatitis, herpes zoster, hirsutism, psonasis,
purpuflc rash, pustular rash, seborrftea, skin discoloration, skin hypertrophy,
subcutaneous nodule, and vesiculobullousrash.
Special Senses-Infrequent:
amblyopia, conlunctivibs,
ear pain, eye pain,
mydriasis, photophobia, and tinnitus; Rare: blepharitis, cataract, corneal
iesion, deafness, dipiopia, eye hemorrhage, glaucoma, ntis, ptosis,
strabismus, and taste loss.
Urogenital System-Infrequent:
abnormal ejaculation, amenorrhea, breast
pain, Cystitis, dysuria. fibrocystic breast, ieukorrhea, menopause,
menorrhagia, ovarian disorder, urinary incontinence, urinary retention, urinary
urgency. urination impaired, and vaginitis; Rare: abortion, albuminuria, breast
enlargement. dyspareunia, epididymitis. female lactation. hematuria,
hypomenorrhea, kidney calculus, metrorrhagia. orchitis, poiyuria,
pyelonephritis, pyoria. saipingitis, urethral pain, urethritis, urinary tract
disorder, uroiithiasis, uterine hemorrhage, uterine spasm, and vaginai
hemorrhage.
Postintroduchon Reports-Voluntary reports of adverse events temporally
associated with Prozac that have been received since market introduction, that
are not itstedabove, and which may have no causai relationshipwith the drug
include the following: aplastic anemia, cerebral vascular accident, confusion,
dyskinesia, eosinophiiic pneumonia, hyperprolactinemia, immune-reiated
hemolytic anemia, movementdisorders
developing in patientswith risk factors
including drugs associated with such events and worsening of preexisting
movement disorders, neuroieptic malignant syndrome-like events,
pancreatitis, pancytopenia, suicidai ideation, thrombocytopenia.
thrombocytopenic purpura, vaginal bleeding after drug withdrawai, and violent
behaviors.
Overdosags: Prominent symptoms of overdose included nausea and vomiting as well as agitation.
restlessness.
hypomania,
and other signs
of CNS
excitation.
in managing overdosage, consider the possibility of muitipie drug
involvement. A specific caution involves patients taking or recently having
taken fluoxetine who might have ingested excessive quantities of a IdA.
Accumulation of the parent tricyciic and an active metabolite may increase the
possibility of clinicaliy significant sequelaeand extend the time needed for
close medicai observation low Other Antidepressants underPrecautionsl.
Reports of death attributed to overdosage of fiuoxetine alone have been
extremely rare
PV2479-OPP
Additionalinformahon available to the profession on request
U
U
u
#{149}
Diets Products
Company
Division of Eli Lilly and Company
Indianapolis,
Indiana 46285
Prozac#{174}
(tluoxeline hydrochiorido)
FL-4951-T-349341
Menstruation.
paintuit
Senoai
dysfunction
impotence5
Fnrcentaae of
Fatnts Reporting
Placebo Boity Sysienv
30
Anniety
eceleeEelstel
3 4
24
1.8
16
10
Eoue
(N.264i
Nenseee
insomnia
Somnolence
-
I3
CLiNiCAL TRIALS
OBSESSIVE’COMPULSIVEDISORDER
Percentage of
Patients Repovep
anorexia,
nausea, and diarrhea; and dizziness or lightheadedness.
In contro#ed chnicaltrials eii’ XO-Somnolence,
anxiety, tremor, nausea,
dyspepsia, pastrointestired disorder, vasoddatation, dry mouth, sweating, rash,
abnormal vision, yawn, decreased libido, and abnormal ejaculation.
Associated With Discontinuation of Treatment-Fifteen percent of 4,000
clinicaltrial patients discontinued fluoxetine dueto an adverse event. The more
common events included: psychiatric (5.3%), primarily nervousness, anxiety,
and insomnia: digestive 13.0%), primarily nausea; nervous system 11.6%),
primarily dim
, body ax a whole (1.5%), primarily axthenia and headache;
and skin (1.4%), primarily rash and pruritus.
In controlled clinical trials for OdD, 12% of fluoxetinepatientsdiscontinued
treatment dueto adverse events. The most common events were anxiety )2%l
and rash/urticana (2%I.
Incidence in Controlled Clinical TnaIe-Table 1 enumerates adverse events
that occurred at a frequency of 1% in premarketing cOntrOlledclinicaltrials.
Obsessive-Compulsive
Disorder-Table 2 enumerates adverse events that
occurred atafrequency
of a 2% in controlled clinical trials.
Other Events Observed During Premarketing Evaluation in 5.600
Ruoxeline Patients-Frequent adverse events are defined as those occurring
on 1 or more occasions in at least 1/100 patients; infrequent adverse events
are those occurring in 1/100 to 1/1,000 patients; rare events are those
occurring in less than 1/1,000 patients.
Body as a Whole-Frequent: chills; Infrequent: chills and fever, cyst, face
edema, hangover effect, jaw pain, malaise, neck pain, neck rigatity, and pelvic
pain; Rare: abdomen enlarged, celiuiitis, hydrocephalus, hypothermia, LE
syndrome,moniliasis,and serum sickness.
Cardiovascular System-Infrequent:
angina pectoris, arrhythmia.
PLACEBO-CONTROLLED
©i9trit,
ELI LILLY AND COMPANY
iosisxli
.1
I,.,. L:d
indicated
1’
#{149}
for both...
A
nl4petc’jop
..
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A13
a
increase in extrapyramidal
adverse effects. The safety of doses above 16 mg/day
has not been evaluated in clinical trials.
presumed to be meatated
of dopamine D2 and
serotonin 5-HI2 antagonism, although the exact
mechanism of action is unknown.
Anfipsychotic actknty
through a combinatIon
of Prescribing Information at
the end of this advertisement.
Please see brief summary
© Janssen Pharmaceutica Inc. 1994
3
SmsrhKlsn.
FarmaowutkaLs
Becham
JPI-RS-084
whole person is waiting to emerge.
A first choice to improve the positive and negative
fragments of psychosis.
Stofisfically significant improvement of posive and
negative symptoms
A first choice when considering EPS.
In clinical trials, extrapyramidal symptoms, while
dose dependent, are comparable to placebo at
recommended doses*
A first choice when considering safety.
Worldwide post-trial experience wh over 125,000
patients
Blood monitoring not required
The most common side effects reported in clinical trials
(n= >2600) were insomnia, agitation, EPS, headache,
anxiety, and thinis; less common were somnolence,
dizziness, constipation, nausea, and tachycardia
RISPERDAL may induce oritiostatic hypotension especially
during the initial titration period. The risk of orthostatic
hypotension and syncope may be minimized by adhenng
to the recommended initial titration regimen
RISPERDAL should be prescribed in a manner that is
most likely to minimize the occurrence of tardive
dyskinesia.If signs and symptoms of tardive dyskinesia
appear in a patient on RISPERDAL, drug discontinuation
should be considered
The only first-choice serotonin/dopamine
antagonist (SDA).t
#{149}
1234-mg
tablets
#{174}
Risperdcil
RISPERIDONE
A first choice in psychosis.
U
12.3-,4-rn#{231}reses
Rispeidal%r
#{149}
RISPERIDONE
A first choice in psychosis.
RISPERDAI.
(Riepefldone( Tablets
Before prescribing, please consult complete prescribing Information of
which thefollowing is a brief summery
INDICATIONS AND USAGE: RISPERDAL’ is indicatedfor the management of
the manifestations xl psychotic disorders.
CONTRAlNDICA’flON:
RISPERDAL is contraindicated in patients with a
Ne
MulignsntSyndmme(NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic
Mahgiant Syndrome )NMS) has been reportedis associationwith anhpsychohc
druge. a patent reqifiresantxsyshotu;drug treatment after recovery from tINS,
the potential reistrochiction xl drug therapy should be carelully considered. The
patientshould be carefully monitored, since recurrences of NMS have been
A sysdromeot potentially irreversible, invOluntary, dysiunetic movements may
devalop is s
treated with anbpsychotc drugs. Afthough the prevalence of
the syndrome appears to be highest among the elderly, especially elderly
women, it xi impossibleto rely upon prevalence estimates to predict,at the incephon xl anhpsysholic treatment which patients are Italy to developthe syndrome.
8
and synrptoms xl tardive dyslunesia appear is a patent on RISPERDAL,
drug diacontinuabon should be considered. However, some palients may require
treabsent with RISPERDALC despite the presence xl the syndrome.
Potential for Prosrrhythmic Effects: Risperidone and/or 9-hydroxyrispefldone appears to lenhen the OT litervie rn somepatients,afthougirthere
le no average mcrease xi treated pslient even at t2-16 mgieay, eel above the
recommended dose. Other drugs that prolong the 01 mterval have been associsled with the occurrence of torsades de puintes, a hfe.threateisng arrhythmia
Bradycardia, electrolyte imbalance, concomitant use with other drugs that pro
brig 01, or the presence xl congenitalprolongahonrirOT can uicreasethe fisk
for occurrence01 this arrhythmia
PRECAUTIONS
Orthostatk It,poteneion: RISPERDAL may induce orthostahc hypotension
associated with dizziness, tachycardia, and in somepatients syncope, especially
during the initial dose-titration period, probably reflecting its alpha-adrenergic
antagonistic properties. The riskof orthostahc hypotension and syncope may be
misimizedbyhmdingtheinitiiadoaetol
mgBlDinnormaladuttsand0.5mg
BID in the elderlyand patents with renal or hepahc inrpairment (See DOSAGE
AND ADMINISTRAT1ON). A dose reduction should be considered it hypotension
occurs. RISPERDALC
be used with particular caution in patents with
known cardiovascular disease (history xl myocardst infarction or ischenia. heart
takxre, or conductionabnormalities),cerebrovascula, disease, and conditions
which woubl predispose patients to hypolensron(dehy*ahon, hypovolemia arid
bsahnerdwithanthm.
Seizures: RISPERDALe
be used cautiously in patients with a history of
secures
Hypstproiactinemlls: As with other drugs that antagonize dopamine D2 recaptore, flsperidone elevates prolachn levels and the elevation persists dufln9 chronis adminietration. Tissue cufture experiments indicate that approximately onethird 01human breast cancers are prolachn dependent in vitro, a factor of potenhal itrrportance it the preacrtion of these drugs is contemplated in a patent with
previously detected breast cancer. As is common with compounds which
wtrease prisactie release, an iscrease in pituitary giand, mammary giand, and
pancreatic ielet cell hyperplasia and/or neoplasia was observed xi the nspefidone
carcinogerricity studies conducted in mice and rats See CARCINOGENESIS).
However, neither clinical studies nor epidemiolOgic studies conducted to date
have shown an asaociahon between chronc administrahon ci this dass of drugs
and tumori#{231}enesis
xi humsans;the available evidence e considered too hosted to
be conclusive at this bins.
pont
r coptitin, arid Mote, kreknsavt
Somnolence was a commonly
reported and dose-related adverse event associated with RISPERDAL’ treatment. Since RISPERDALe has the potential to impair judgment, thinking, or
motor sirius, patents shodd be cautioned about operahng hazardous mactdnery,
including automobiles, untilthey are reasonably certain that RISPERDAL5 there
py does not affect them adversely.
A single case of pnispismwas reported in a 50-year-old patient
A single case of ‘fTP was reported in a 28-year-old female patient receiving
RISPERDALeThe
ic
to RISPERDAL therapy si unknown.
Risdone
has an antismetic ilfect in anunals; this effect may also occur in
humans, and may mask signs and symptoms ot overdosage with certain drugs or
xl concittions such as intestinal obstruction, Rays’ssyndrome,andbraintumor.
Caution si advised when prescribing for patientswho w* be exposed to extreme
The possiblhty of a suicide aftempt is inherentxi SctsZOphrenia,and close supervision of 14s risk patents shouio accompany drug therapy. Preacrhons for
RISPERDALe
be written for the smallest quantity xl tleb consistent with
mind pwient management hr order to reducethe riskol overdose.
cenical experience with RISPERDAL#{149}
is patients with certain concomitant eye.
senile Uneeses si Idnited. Caution a advisable in patients with diseases or condutionsthat coubl affect metabOlism or hemodynamicresponses.Becauseof the
risks xl orthostatic hypolension and OT prolongahon,cautionshouldbe observed
in cardiac patients (See WARNINGS and PRECAUTIONS).
In patientswith severe renal impairment (creatirfine dearance (30 mL/mirtl.73
mS),or with severe hec
rinpainment, a iower starting dose should be used.
Patentsshould be advised of the flak of orthostatic hypotension, especialy durdig the period of initial dose titration.
Patients should be cautioned about operating hazardous machinery, erchucting
automobiles, unIt they are reasonably certain that RISPERDALe
not stIed them adversely. Tel patients to noblytheir physicianit they become
pregnant or intend to become pregnant during therapy: not to breast teed an
infant; to istormtheri physiciansit they are takiog,or plan to take, any prescflphon or over-the-counter drugs: to avoid alcohOl.
No specific taboratory tests are recommended.
The interactions of AISPERDAL and other drugs have not been systematically
evakiate Caution shoubl be used when taken in combination with other centrally
acbngdrugs and alcohol
RISPERDAL may enhance the effects ol certain anhhypertensive agents and it
may antagonice the effects xl levodopa and done
agoxists.
Chronic administration of catbamazepine- or clozapere with nspendonemay
iscrease the dearance of risperidone.
Risperidone is metabolized by cytochrome PusIID6,an enzyme that can be inhiebed by a variety of psychotropic and other drugs. Analysis ot clinical studies
isvohong a modest number of poor metabolizers (n.70) does not suggestthat
poor and extensive metabolizers have different rates of adverse effects. No coinpanson at eftechveness in the two groups has been made. In vitro studies
showed that drugs metabolized by other P450enzymesare only weak nhdvtors
of nspefldone metabolism.
In vitro studies indicate that risperidone is a relatively weak inhibitor of
cytochrome P4,IID, and is not expected to substantially inhdiitthe clearance of
drugs that are metabolizedby this enzymaticpathway.However,clerical data to
confirm thisexpectation are notavailable.
Carcinogenicity studies were conducted in Swiss steno moe and hostar rats
Reperdlone was admknstered is the diet at doses 010.6 2.5, and 10 mglkg for
18 monthsto mice and tor 25 monthsto rats.These doses are equivalent to 2.4,
9.4 and 37.5 times the maximum human dose (16 mgiday)on a rngthgbasisor
02 0.75and 3 timesthe maximumhumandose mice)or 0.4, 1.5, and 6 times
the mazamum human dose (rats) on a mgirrr2 basis. There were statisticaty signthCant iscreases xi pituitary gland adenomas, endocrine pancreasadenomas
and mammary gland adenocarcinomas. These neoplasms are considered to be
prolactin-mediated. The relevance for human risk of the findings of prolactinmediated endocrinetumors is rodentsis unknown.
Noevidenceof mutagenicpotentialfor nspefldonewas found.
RisperIdOne (0.16 to 5 mglkg) was shown to irrrpair mating, but not fertility, in
Wistar rats in three reproductive studies at doses 0.1 to 3 times the maximum
recommended human dose on a mg/m2 basis. The effect appeared to be in
tamales. In a subchronicstudy is Beagie dogs, sperm motility and concentration
were decreased at doses 0.6 to 10 hines the human dose on a mg/ma basis.
Dose-related decreases were also noted in serum testosterone at the same
doses. Serum testosterone and sperm parameters partially recovered but
remained decreased after treatment was discontinued. No no-effect doses were
noted in either rat or dog.
Pregnancy Category C: The teratogenic potential xl nspendone was studied in
Sprague-Daretey arid Wistar rats and is New Zealand rabbits. The rircidence of
maffoimabons was not increased corirpared to control in otfspnsg of rats or ratbits9iven0.4to6tknesthehumandoseonamg/m2bauis.
Inthree reproductive
studies in rats there was an iscrease is pup deaths dufingthe first 4 days of actation at doses 0.1 to 3 times the human dose on a mglm2 basis. It is not known
whether these deaths were due to a direct effect on the fetuses or pups or to
effects on the dams.There was no no-effect dose for increased rat pup mortality.
In oneSegmentIII study,there was an increase in sbHbomrat pups at a dose 1.5
hines lagher than the human dose on a mgim2 basis.
Placental transler at flspefldone ocairs ‘in rat pups. There are no adequate and
wel-controlled studies is pregoantwomen. However, there was one report xl a
case of agenesis of the corpus caltusum is an infantexposed to rispendone is
titers. The causal relationsh to RISPERDALtherapy is unknown.
RISpERDALeshouldbe useddurisgpregnancyonlyit the potential benefit ustities the potential risk to the fetus.
The effect on labor and deliveryis humansis unknown.
It not knownwhetheror not fisperidoneis excreted is human milk In animal
studies, risperidone and 9.hydroxyflsperidone were excreted in breast milk.
Therefore, women receiving RISPERDAL frJ
.
f
Safety and effectiveness is childrenhave not been established.
Clinical studies did not iridude suthdent numbers of patients aged 65 and over
to determine whether they respond differently from younger patients. In general,
a lower starting dose is recommended for an elderly patient, reflecting a
decreased pharmacokinebc clearance in the elderly, as well as a greater frequency of decreased hepatic renal, or cardiac function,and a greater tendency
to postural hypotension (See CLINICAL PHARMACOLOGY and DOSAGE ANtI
ADMINISTRAtIONI.
ADVERSE REACTiONS
Associed with Dtecontinuetlon Of Trestm.nt
Approximately 9% percent (244/2607) at RISPERDAL treated patients in phase
2-3 studies discontinued treatment due to an adverse event, compared with
about 7% on placebo and 10% on active control drugs. The more common
events I? 0.3%)associated with discontinuation and considered to be possiblyor
probably drug-related included: extrapyranridal symoma, dizziness, hyperkinesi& somnolence, and nausea
SuicideatIe,nit was associated with ctiscontisuabonin 1,2% of RISPERDAL-trealed
patients compared to 0.6% of placebo patents, but, given the almost 40-fda
greater exposure time in RISPERDAL ccsopared to placebo patients, it is unlkely
tlsalSUicidea8enit isa RISPERDAL’ mfeledactverseevent(See PRECAU11ONS).
kicldence fe Controlled Trials
Comn
ObeerwdAdbwse
Esenta hi Controlled ciknicai Trials: In twoSto 8-weekplacebo-controfledtflals, spOntaneOUSIy.repOiled,treatment-emergent
adverse events with an incidence of 5% or greater in at least one of the
RISPERDALe
at least twice that of placebo were: anxiety, somno
fence, extrapyramdal symptoms, dizziness, constipation, nausea, dyspepsia,
dante, ras and tach.
Eticited adverse events is one at these two trials presentat at least 5%andtwice
the rate of bo
were: increased dream activity, increased duration of steep,
accommodation disturbances, reduced sativahon, mictufltion dietuthances, diarthea, weight gain, menorrfsagia, diminished sexual desire, erectile dysfunction,
ejaojlatory dysfunction, and orgastic dystuncton.
The following adverse events occurred at an incidence of 1% or more. and were
at leastas frequentamong RlSPERDALetreated patients treated at doses of
10 mgiday than among placebo.treatedpahents is the pooledresultsof two 6- to
8-week controlled tflala Psychiatric Disorders: insomnIa, agitation, ansety,
somnolence, aggressive reaction. Nervous System: extrepyramidal syrrrptoms’,
headache, dizisness. Oastmlnlsstlnal System: consabon
nause& dyspepsi& vomiting, abdomisal pait salve iscreased, toothache. AsepleMory System:
rhinitis, coughing, sinusitis,_pharyngitia, dyspnea. Body as a Whole: back pain,
cheat peer, fever. Dermoio#{216}cal:rash, dry dan, seborrhea. Infections: upper
respiratory. Visual: abnormal vision. Musculo#{149}Skeletsl:
arthralgia.
Csrdioveeculw: taa
I Includes tremor, dystonia, hypokinesia, hypertonia, hyperkinesia, oculo-
gyric crisis, ataxia, abnormal gait, involuntary muscle contractions,
hyporetlesia, and estrapyramidal disorders. Although the incidence of
‘estrapyramidal symptoms does not appear to differ for the ‘s 10 mg/da
group and placebo,the data for individual dose
in fixed dose lea
do suggest a dose/response relationship (See OS DEPENDENCY OF
ADVERSE EVENTS).
Dose Dependency ofAdvarse Events: Datafrom two fixed dose trials provided
evidence of dose-relatednessfor extrapyramidal symptomsassociated with
risperidone treatment Adverse event data elicited by a checklist for side effects
from a large study comparing 5 fixed doses of RISPERDAL(t, 4, 8, 12, and 16
mg/day) revealed a positive trend for the followingadverseevents:sleepiness,
iscreaaed duration of sleep, eccommodalion disluibances, orthostatic dtzzisess,
ahons,
weirt gain, erectile dysfunction, ejaculatory dysfunction, orgastic
dysfunction, astheniaulsaaitude/ iscreased fatiguability, and increased pigmenta-
ban
Vital Sign changes: RISPERDAL’ is associatedwith orthostatic hypotension
andtachycardia(SeePRECAUTIONS).
Weight hangea:The proportions of RISPERDAL’and placebo-treated patients
meeting a weigirt gain criterion of 7% of body weight were compared in a pool
of 6- to 8-week placebo-controlled trials, revealing a statistically significantly
greater iscidence of weiif gain for RISPERDALC(18%)comparedto placebo
(9%).
Laboratory fhaagss: A betweengroup comparison for 6- to 8-week placebocontrolled trials revealed no statistically significant RISPERDAL/pIaCebO differencesmthepropoitionsofpabentsexperiencingpotentially
Eopoitantchangesis
routine serum chemistry, hematology, or sflnalysis parameters. Skniarty, there
were no RISPERDALe/PlaCebOctifferences is the iscidence of discontisuabons
for changes in serum chemistry, hematology, or urinalysis. However,
RISPERDALe
wasassociatedwith iscreases is serum prolactin
(See PRECAUTtONS).
ECG Chang.s: The electrocardiograms ot 8 out of 380 patients taking
RISPERDALC whose baseline OTc interval was less than 450 msec were
observed to have OTc intervals greater than 450 msec duhng treatment see
WARNINGS).Changesof this type were not seen among about 120 placebo
patients, but were seen in patients receivng halopendri (126l.
Other Events Observed During the PreMarketing Evaluation of
RISPERDAL’
During its premarketing assessment, multiple doses of RISPERDAL’ were
adminetered to 2607 patients in phase 2 and 3 studiesand the t*wusg reac
tions were reported; (Note frequent are those occurring in at least 11100
patients; infrequenr are those occurring in 1/100 to 1/1000 patients: rare are
those occumng in tewer than 1/1000 patients. It is important to emphasize that,
athough the events reportedoccurred dunng treatment wet RISPERDAL’, they
were not necessarily caused by it. Psychiatric Disorders: Frequent: increased
dream adivity, diminished sexual desireS, nervousness. Infrequent: impaired
concentration, depression, apathy, catatomc reaction, euphoria, increased hbido,
amnesia. Rare: emotional laiskty. nightmares. delinum, withdrawal syndrome,
yawning. C.ntral and Peripheral Nervous System Disorders: Frequent.
increased sleep duraten. Infrequent: dysarthna, vertigo, stupor.paraesthesia,
contusion. Rare: aphasia. chotinergic syndrome. hypOsthesia.tongue paralysis,
leg cmrrs, tortkntis, hypotoma, coma, rmgraine. hyperretexia. choreoathetosss.
Gastro.Intutinel
Disorders: Frequent: anorexia, reduced salivation.
Infrequent: flatulence,tharrhea,increased appetite, stomatitis,melena, dysphagia, hemorrhoids. gastritis. Rare: tecal incontinence, eructation, gastroe
roph
reflex, gastrsenteritis, esoptiati
tongue decoisrahon, chOleletsasis,
tongue edema, diverticulitis, gingivitis, discolored feces, GI hemorrhage.
hematemesis. Body as a Whole/General Disorders: Frequent’ tatigue.
Infrequent: edema, rigors. malaise, intluenzalike symptoms. Rare: pallor,
enlargedabdomen,allergic reaction, asotes, sarcoidosis, tustring. R.aplratery
System Disorders: Infrequent: hyperventilation, bronchospasm, pneumonia,
stridor. Rare: asthma, increased sputum, aspiration. Skin and Appendage
Disorders:
Frequent: increased pigmentation, photosensitivity. Infrequent:
ecreased sweating, acne, decreased sweating, aispeoa, hyperkeratosis, prodtus, skis exfoliation. Rare butous ersptron, she utrerahon, aggravated psoflasis,
fursnculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritss,
urticana. Cardiovascular Disorders: Infrequent: palpitation, hypertension,
hypotension, AV block, myocardialinfarction.Rare: ventnoiar tachycardia, angina pectoris, premature atrial contractions, I wave inversions, ventricular
extrasystoles, ST depression,myocarthtis.Vision sordars: infrequent: ebnormis accommodation, xerophthisme Rare: diplopia, eye pais, blephafltis, photopisa, photophobia,abnormal lacflmation. Mitabolk and Nutritional Disor*rs:
Infrequent: hyponatremie weight increase, creatine phosphokinaseiscrease,
thirst, weight decrease, diabetes meittus. Rare: decreased setum iron, cachexia,
dehydration, hypokalerisa, hypoproteinemia. hyperphosphatemia, hypertriglycefidemia, hypersncemia, hypoglycemia. Urinary System Disorders: Frequent:
polpol-pxia.
Infrequent uflnarymconhnence,hematufl dysufla. Rare:
urinary retention, cystitis. renal insufficiency. Muacuio#{149}sk&etai
System
Oisordars: Infrequent: myalgia. Rare: arthrosis, synostosis, bursdis, arthritis,
skeletal pain. Reproductive Disorders, Female: Frequent: menorrhagia,
orgast dystunchon, dry vagina. Infrequent: nonpuerperal lactation, amenor#{149}
thea, female breast pain, leukorrhea, mastihs dystnenorrhea, tamale perineal
pare, intermenstrual bleeding vagnal hemorrhage. Liver and BiNary System
Disorders: Infrequent:nncreased SGOT, increased SGPT. Rare: hepatic tarhire,
cholestatic hepatitis, cholecystdis, cholehthsasrs, hepatitis, hepatoceltular damage. Platelet 8te.ng and clottkig Otsordars: Infrequent: epistaxis, purpura
Rare: hemorrhage, superficial phlebitis, thrombophlebitis, thrsrnbocytopenia.
Hearing and Vestibular Disorders: Rare: tinnitus, hyperacusis, decreased
heanng. Red Blood Cell Oiwi*rs:
Infrequent: anemia, hypochronric anemia.
Rare: normocyfic anemia. Reproductive Disorders, Male: Frequent: erechle
dystunction. infrequent: ejaculation failure. White Ciii and Resistance
Disorders: Rare: leukocytosis, lymphadenopathy, leucopenia, Pelger.Huet
anomaly. Endocrine Olwrrs:
Rare: gynecomasha, male breast pain, antisuret hormone issorder. SpecislSenses: Rare: bitter taste.
. Inodence based on eknted reports.
ORUGABUSEAND DEPENOENE
Controlled Substance Class: RISPERDAL5 is not a controlled substance.
Patients should be evaluated caretulty for a history ot drug,,abuse, and such
patents storM be observed cissely tor siprs ot RISPERDAL misuse or abuse
(e.g., development xi tolerance, iscreases in dose, drsg-seelung behavior(.
OOSAG.EAt4OADWSTRAT1Ct.4
Ustailnitisi Dose: RISPERDAL’ (nspefldsne(shoutdbe admmistered on a BID
schedae, generally begmnmg with 1 mg BID misally, with increases in #{252}rcrements
oIl mgBlDxnthesecondandttflrdday,astolerated,toatargetdoseof3mg
BID by the third day. In some patients, slower titration may be medically
appropnate. Further dosage adjustments, if indicated, should generally occur at
intervals of not less than 1 week, since steady state for the active metabolite
would not be achieved for approximately 1 week in the typical patient. When
dosage adjustments are necessary, small dose increrrientsldecrementsot 1 mg
BID are recommended.
Antipsychotic efficacy was demonstrated in a dose ra
of 4 to 16 mg/day in the
cbnical tints supporhng effectiveness of RISPERDAL, however, maximal effect
was generaSy seen Era range xi 4 to 6 rngiday. Doses above 6 mg/day were not
demonstrated to be more efficacious than lower doses, were associated with
more extrapyramidal syntoms and other adverse effects, and are not generally
recommended. The safety of doses above 16 mday has not been evaluated rn
chnisaltflals. Oceagein SpeciaiPopulstions: The recommended initial dose is
0.5 togBID in patients who are elderlyor debittated, patientswithsevere renal or
hepatic knparnment, and patents either predisposed to’hypotensionor tor whom
hypotension would pose a risk. Dosage increases xi these patients shouta be in
increments of no more than 0.5 mg BID. Increases to dosages above 1.5 ag BID
shouldgenerally occur at intervals ot at least 1 week. In some patents, slower
htrahon may be meiscaffy appropriate.
Bderty or debietated patients, and patientswith renal impanment,may have iass
ability to eliminate RISPERDAL’ than normal adults. Patients with impaired
hepatic unction may have increases in the tree traction of the risperidone,
possibly resulting in an enhanced effect (See CLINICAL PHARMACOLOGY).
Patients with a predisposition to hypotensee mactons ortorwhom such reachons
wndd pose a parhcuiar yak likewee need to be titrated cauhouslyand caretuey
monitored)See PRECAUTIONS). Swltehing from herAntaho&a:There
are no systemahcaty collected data to specificallyaddressswitchis9 from other
antipsychotics to RISPERDAL’. or concemn concomitant administration with
other antipsychotics. While immediate discontinuation of the previous
antipsychotic treatment may be acceptable for some patients, more gradual
discontinuation may be most appropriate for other patients. In all cases, the
period of overlapping antipsyctroticadministrationshouldbe minimized. When
switching patients trom depot antipsychotics, if medically appropriate, initiate
RISPERDAL’ therapy in place of the next scheduled inlection. The need for
continuing existing EPSmedicahonshould be reevaluated penodicalty.
US Patent4,804,663
March 1994, August 1994
Janssen Pharmacextica Inc
Titusoile, NJ 08560
JANSSEN
TITLJS,ILLE.
JPI-RS-084
NJ 08560
October 1994
Printed in U.S.A.
(I)
4J
nE
p
N
0
E
.
p_
St.hviMs..a.c.Me*.
:--‘“
-.-For more information call
EF:Tuu1
1-800-292-GATE.
“I
D211
GATE
GATE Pharmaceuticals,
Sellersville, PA 18960
© 1993,
GATE Pharmaceuticals
Reprinted
for the information
THE
BRITISH
of the readers of the American
JOURNAL
December
1994,
Consent
to treatment
during
childhood.
713
Psychological
debriefing
of posttraumatic
stress.
and
prevention
J.I. Bisson
717
of schizophrenia.
W.T.
The classic
Carpenter
literature.
P. Liddle,
and T. Crow
Extrapyramidal
serotonin
symptoms
reuptake
London
in two
inhibitors.
D.K.
Arya
audit
sions
in two
audit
sions
London
in two
audit
743
Adolescent
girls. I: Self-reported
mood disturbance
in a community
population.
E. Monck,
P. Graham,
N. Richman
and
R. Dobbs
Adolescent girls. II: Background
factors in
anxiety and depressive states. E. Monck,
Predictors
behavioural
A18
of treatment
treatment
792
and R. Dobbs
outcome
797
pain.
Elton,
Some
patients
M.M.H.
Hanna
Treasure
802
phenomena.
Berrios
thought
deaf
people
A.J.
Thacker
Short
Papers
T.R.
808
disorder.
with
Dening
Sign language
in
schizophrenia.
818
Survival analysis and readmission
in mood
disorder.
S. Pridmore,
H. Hornsby,
D. Hay and I. Jones
antipsychotics
of bipolar
for acute admission
to psychiC.B. Flannigan,
G.R. Glover,
J.K. Wing, S. W. Lewis, P.E. Bebbington
and S.T. Feeney
N. Richman
J.
Depot
of admis-
districts.
in the
of obsessive-com-
and
The Salford
7cr5
3’-,
relapse
eight
in the prophylaxis
R. Littlejohn,
Cookson
affective
F. Leslie
wards.
P. Graham,
benzodiazepine
C.J. Hawley,
C. Dellaportas
with chronic
more. N.H.
Formal
734
III: Reasons
atric
787
Lader
Autoscopic
and G.E.
districts.
collaborative
health
drug concentradeaths.
N. Jusic
of admis-
II: Ethnicity
and the use of the Mental
Health Act. P.E. Bebbington,
S.T. Feeney,
C.B.
Flannigan,
G.R. Glover,
S. W. Lewis
andJ.K.
Wing
Inner
781
N. Davis
Coping
suffer
and
districts.
collaborative
health
M.
antipsychotic
unexplained
Comparison
of long-term
users in three settings.
and
728
of admis-
I: Introduction,
methods
and preliminary
findings.
C.B. Flannigan,
G.R. Glover,
S.T. Feeney, J.K. Wing, P.E. Bebbington
and S. W. Lewis
London
Post-mortem
tions and
Schaap
Outcome
of deliberate
self-poisoning.
An examination
of risk factors for repetition. D. Owens,
M. Dennis, S. Read
with selective
collaborative
health
Keijsers,
and C.P.D.R.
Hoogduin
721
Papers
Inner
165
M. Tattersall,
and C. Hallstrom
Review
sions
Volume
and
and
Deahi
Syndromes
Inner
OF PSYCHIATRY
C.A.L.
Pearce
M.P.
of Psychiatry
pulsive disorder. G.P.J.
Editorials
I.
Journal
J.
family
disorder.
intervention
years.
N.
Tarrier,
C.
at five and
Barrowclough,
and E. Fitzpatrick
Columns
760
Correspondence
770
A hundred
years ago
Reading
about.
. . Social and
community
psychiatry. D.P. Forster
Books reconsidered. Gaze and Mutual
Gaze
(M. Argyle
and M. Cook).
D. Cramer
Book
Reviews
827
project:
rates of schizophrenia
K. Porceddu
824
829
833
843
844
848
851
FIRST
FOR
LINE
DEPRESSION
VENLAFAXINE
HCI
EXPAND
TREATMENT
YOUR
POSSIBILITIES
EFFEXOR1
Steady
(days)
PaxiITM
Prozac#{174}
(fluoxetine
HCI)’
(sertraline
HCI)’
State
96-144
(4-6
Half-life,
Active Metabolite
hours
(days)
days)
96-384
(4-16 days)
62-I
(2.6-4.3
04
days)
(paroxeune
HCI)31’
Adverse Events Occurring atan Incidence of 1% or More Among Effexor-Treated Patients: The 101-
lowing occurred in 4- to 8- week placebo-controlled trials, with doses of 75 to 375 mg/day, at a
EFOR
frequency of 1% or more. This includes patients with at least one episode of an event at some time
during treatment. Body as a Whole: headache, asthenia, infection, chills, chest pain, trauma.
Cardiovascular: vasodilatation, increased blood pressure/ hypertension, tachycardia, postural
VENLAFAX/NE
HCI
25 mg, 375 mg, SO mg, 75 mg, and 100 mg
Brief Summary
See package Insert for full prescribing Information.
Clinical Pharmacology: The antidepressant action of venlataxine is believed to be associated with
potentiation of neurotransmitter activity in the CNS. In preclinical studies, venlafaxine and its
active metabotite, 0-desmethylvenlafaxine
(ODV), were potent inhibitors
of neuronat serotonin
and
norepinephrine resptake and weak inhibitors of dopamine reuptake.Venlataxine and ODV have no
significant affinity for muscarinic, histaminergic, or a-i adrenergic receptors in vitro.
Pharmacologic
activity at these receptors is hypothesized
to be associated
with the various anti-
cholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlataxine
and ODV do not possess monoamine oxidase (MAO) inhibitory activity.
Indications and Usage: Effexor is indicated for the treatment of depression.
Contraindicatlons: Contraindicated in patients with known hypersensitivity. Concomitant use in
patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see “Warnings”).
Warnings: POTENTIAL FOR INTERACTION WITH MONOAMINE OXIDASE INHIBITORS (MAOts)Adverse reactions, some serious, have been reported when venlafaxlne therapy Is Initiated
soon after discontinuation
of an MAOI and when an MAOI Is Initiated soon after dlscontlnualion of venlataxine. Reactions have Included tremor, myoclonus, dlaphoresls, nausea, vomitIng, flushing, dizziness, hyperthermia with testers: resembling neuroleptic malignant syndrome, seizures, and death. Given these reactions as well as the serious, sometimes fatal
Interactions reported with concomitant or Immediately consecutive administration of MAOIs
and other antldepressants
with pharmacological properties similar to Effezor, do not use
Effazor In combination with an MAOI or within at least 14 days of discontinuing MAOI treatment.
Allow at least 7 days after stopping Effexor before starting an MAOI. Hyperthermia.
rigidity,
myoclonus, autonomic InstabilIty, mental stakes changes Including extreme agItation prograssing to delirium and coma, and features resembling neuroleptic malignant syndrome have
been reported with concomItant selectIve serotonln reuptake lnhlbltorlMAOl therapy. Severe
hyperthermla and seizures, sometImes fatal, have been reported with concomItant tricyctic
antldepressantslMAOl therapy.
SUSTAINED HYPERTENSION-Etfexor treatment is associated with dose-related sustained
increases in supine diastolic
blood pressure.
Regular monitoring
of blood pressure
is recom-
mended, and, when appropriate, consider dose reduction or discontinuation.
Precautions: GENERAL-Anxiety and Insomnia: Anxiety, nervousness, and insomnia have been
reported in short-term studies.
Changes in Appetiteiweight: Anorexia has been reported in short-term studies, and a dose-dependent weight loss has been reported in patients taking Effexor for several weeks.
Activation of ManialHypomania: Hypomania or mania has been reported: as with alt antidepressants, use cautiously in patients with a history of mania.
Seizures: Seizures were reported in premarketing testing (0.26%). Use cautiously in patients with
a history of seizures. Discontinue it in any patient who develops seizures.
Suicide: The possibility of suicide attempt is inherent in depression and may persist until signiticant remission occurs. Closely supervise high-risk patients during initial drug therapy. Write
Effexor prescriptions for the smallest quantity consistent with good patient managementto
reduce
risk of overdose.
Use in Patients with Concomitant Illness: Clinical experience with Effexor in patients with concoinsitant systemic illness is limited. Use cautiously in patients with diseases or conditions that
could affect metabolism or hemodynamic responses. In patients with renal impairment (GFR=107OmLJmin) or liver cirrhosis, clearance of ventataxine and its active metabolite were decreased,
resulting in prolonged elimination half-lives. A lower dose may be necessary: use with caution in
such patients.
INFORMATION FOR PATIENTS-Clinical studies revealed no clinically significant impairment of psychomotor, cognitive, or complex behavior performance. However, caution patients about operating
hazardous machinery, including automobiles, until they are reasonably sure that Effexor does not
adversely affect their ability to engage in such activities. Tell patients to 1 ) notify their physician if
they become pregnant or intend to become pregnant during therapy, or if they are nursing; 2) inform
physicians about other medications they are taking or plan to take; 3) avoid alcohol while taking
Etfexor; 4) notify their physicians it they develop a rash, hives, or related allergic phenomena.
DRUG INTERACTIONS-Cimetidine:
Use caution when administering Effexor with cimetidine to
patients with pre-existing hypertension or hepatic dysfunction, and the elderly. Drugs Inhibiting
Cytochrome PIIO6 Metabolism: In vitro, venlafaxine is metabolized to its active metabolite,
0-desmethylventafaxine (ODV), via cytochrome PllD6.
Therefore drugs inhibiting this isoenzyme
could potentially increase plasma concentrations of venlafaxine and decrease concentrations of
ODV. Drugs Metabolized by Cytochrome P,,IlO6: In vitro, ventataxine is a relatively weak inhibitor
of this isoenzyme; clinical significance is unknown. Monoamine Oxidase Inhibitors: See
Contralndlcatlons’ and “Warnings.” CNS-Active Drugs: Use of venlataxine with CNS-active
drugs has not been systematically evaluated; therefore, use caution when administering
Effexor
with such drugs.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY-Carcinogenesis:
In 18-month
studies, there was no evidence of carcinogenicity in mice given 120mg/kg/day [16 times the maxmum recommended human dose (MRHO)I. In 24-month studies, there was no evidence of carcinogenicity in rats given 120mg/kg/day. Mutagenicity: In male rats receiving 200 times (on a
mg/kg basis) the MRHO, chromosomal aberrations were found in the bone marrow in vivo.
ImpairmentofFertihly:
No impaired reproductive function was found in ruts given 8 times (mg/kg)
the MRHD.
PREGNANCY-Teratogenic
Effects-Pregnancy
Category C. Reproduction studies in rats given 11
times, and rabbits given 12 times the MRHO (on a mg/kg basis) revealed no malformations of offspring. However, in rats given 10 times the MRHD, there was a decrease in pup weight, increase
in stillborn pups, and an increase in pup deaths during the tirst 5 days of lactation when dosing
began during pregnancy and continued until weaning. There are no adequate and welt-controlled
studies in pregnant women; use Effexor during pregnancy only if clearly needed.
LABOR, DELIVERY, NURSING-The
effect on labor and delivery in humans is unknown. It is also
not known whether Eftexor or its metabolites are excreted in human milk; exercise caution when
administering to a nursing woman.
PEDIATRIC USE-Safety
and effectiveness in children (<18 years) have not been established.
GERIATRIC USE-tn clinical trials, 12% of Effexor-treated patients were 65 years of age. Overall
differences in efficacy or safety in the elderly have not been demonstrated, however, greater sensitivity of older patients should not be ruled out.
Adverse Reactions: ASSOCIATED WITH DISCONTINUATION OF TREATMENT-Nineteen
percent
(537/2897) of Effexor patients in clinical trials discontinued treatment due to an adverse event The
more common events (1% associated with discontinuation and considered to be drug-related
included: somnolence, insomnia, dizziness, nervousness, dry mouth, anxiety, nausea, abnormal
ejaculation (male), headache, asthenia, and sweating.
INCIDENCE IN CONTROLLED TRIALS-Commonly
Observed Adverse Events in Controlled
Clinical Trials: The most commonly observed adverse events associated with the use of Effexor
incidence of 5% or greater and incidence for Effexor at least twice that for placebo): asthenia
12% vs. 6%), sweating (12% vs. 3%), nausea (37% vs. 11%), constipation (15% vs. 7%),
anorexia (11% vs. 2%), vomiting (6% vs. 2%), somnolence (23% vs. 9%), dry mouth (22% vs.
11%), dizziness (19% vs. 7”/o), nervousness (13% vs. 6%), anxiety (6% vs. 3%), tremor (5% vs.
1%), blurred vision (6% vS. 2%), abnormal ejaculation/orgasm male (12% vs. <1%), and male
impotence (6% vs. <1%).
hypotension. Dermatologlcal:
sweating, rash, pruritus. Gastrointestinal: nausea, constipation,
anorexia, diarrhea, vomiting, dyspepsia, flatulence. Metabolic: weight loss. Nervous System:
somnolence, dry mouth, dizziness, insomnia, nervousness, anxiety, tremor, abnormal dreams,
hypertonia, paresthesia, libido decreased, agitation, confusion, thinking abnormal, depersonalization, depression, urinary retention, twitching. Respiration: yawn. Special Senses: blurred vision,
taste perversion, tinnitus, mydriasis. Urogenital System: abnormal ejaculation/orgasm, impofence, urinary frequency, urination impaired, orgasm disturbance, menstrual disorder.
Studies indicate a dose dependency for some otthe more common adverse events associated with
Effexor use. There also was evidence of adaptation to some adverse events with continued Effexor
therapy over a 6-week period.
Vital Sign Changes: In clinical trials, Effexor was associated with a mean increase in pulse rate of
about 3 beats/mix, and a dose-dependent increase in mean diastolic blood pressure of 0.7 to
2.5 mmHg.
Laboratory Changes: During clinical trials, only serum cholesterol exhibited statistically significant
differences from placebo (increases of 3 mg/dL from baseline); clinical significance is unknown.
ECG Changes: Only heart rate exhibited a statistically signiticant difference, with mean increases
of 4 beats per minute from baseline.
OTHER EVENTS OBSERVED DURING THE PREMARKETING EVALUATION OF EFFEXOR-During
premarketing assessment, multiple doses of Effexor were administered to 2,181 patients, and the
following adverse events were reported. Note: “frequent” = events occurring in at least 1/100
patients; infrequent” = 1/100 to 1/1000 patients; “rare” = less than 1/1000 patients. Events are
classified within body system categories and enumerated in order of decreasing frequency using
the definitions above. It is important to emphasize that although the events occurred during
Eflexor treatment, they were not necessarily caused by it.
Body as a Whole - Frequent: accidental injury, malaise, neck pain; Infrequent: abdomen enlarged,
allergic reaction, cyst, face edema, generalized edema, hangover effect, hernia, intentional injury,
moniliasis, neck rigidity, overdose, chest pain substernal, pelvic pain, photosensitivity reaction,
suicide attempt; Rare: appendicitis, body odor, carcinoma, cellulitis, halitosis, ulcer, withdrawal
syndrome. Cardiovascular system - Frequent: migraine; Infrequent: angina pectoris, extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope,
thrombophlebitis; Rare: arrhythmia, first-degree atrioventricular
block, bradycardia,
bundle
branch block, mitral valve disorder, mucocutaneous hemorrhage, sinus bradycardia, varicose
vein. Digestive system - Frequent: dysphagia, eructation; Infrequent: colitis, tongue edema,
esophag’ttis, gastritis, gastroenteritis,
gingivitis, glossitis, rectal hemorrhage,
hemorrhoids,
melena, stomatitis, stomach ulcer, mouth ulceration; Rare: cheilitis, cholecystitis, cholelithiasis,
hematemesis, gum hemorrhage, hepatitis, ileitis, jaundice, oral moniliasis, intestinal obstruction,
proctitis, increased salivation, soft stools, tongue discoloration, esophageal ulcer, peptic ulcer
syndrome. Endocrine system - Rare: goiter, hyperthyroidism, hypothyroidism. Hemic and lymphatic system - Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia, lymphadenopathy, lymphocytosis, thrombocythemia,
thrombocytopenia,
WBC abnormal; Rare:
basophilia, cyanosis, eosinophilia, erythrocytes abnormal. Metabolic and nutritional - Frequent:
peripheral edema, weight gain; Infrequent: alkaline phosphatase increased, creatinine increased,
diabetes mellitus, edema, glycosuria, hypercholesteremia, hyperglycemia, hyperlipemia, hyperuricemia, hypoglycemia, hypokalemia, SGOT increased, thirst; Rare: alcohol intolerance, biliru-
binemia, BUN increased, gout, hemochromatosis,
hyperkalemia, hyperphosphatemia,
hypo-
glycemic reaction, hyponatremia, hypophosphatemia, hypoproteinemia, SGPT increased, uremia.
Musculoskeletal system - Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, joint
disorder, myasthenia, tenosynovitis; Rare: osteoporosis. Nervous system - Frequent: emotional
lability, trismus, vertigo; Infrequent: apathy, ataxia, circumoral paresthesia, CNS stimulation,
euphoria, hallucinations, hostility, hyperesthesia, hyperkinesia, hypertonia, hypotonia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, paranoid reaction, psychosis, psychotic
depression, sleep disturbance, abnormal speech, stupor, torticollis; Rare: akathisia, akinesia, alcohol abuse, aphasia, bradykinesia, cerebrovascular accident, loss of consciousness, delusions,
dementia, dystonia, hypokinesia, neuritis, nystagmus, reflexes increased. Respiratory system Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion, epistaxis, hyperventilation,
laryngismus,
laryngitis, pneumonia, voice alteration; Rare: atelectasis, hemoptysis, hypoxia,
pleurisy, pulmonary embolus, sleep apnea, sputum increased. Skin and appendages - Infrequent:
acne, alopecia, brittle nails, contact dermatitis, dry skin, herpes simplex, herpes zoster, maculopapular rash, urticaria; Rare:skin atrophy, exfoliative dermatitis, tungal dermatitis, lichenoid dermatitis, hair discoloration, eczema, turunculosis, hirsutism, skin hypertrophy, leukoderma, psoriasis, pustular rash, vesiculobullous rash. Special senses - Frequent: abnormal vision, ear pain;
Infrequent: cataract, conjunctivitis, corneal lesion, diplopia, dry eyes, exophthalmos, eye pain, otitis media, parosmia, photophobia, subconjunctival hemorrhage, taste loss, visual field detect;
Rare: blepharitis, chromatopsia, conjunctival edema, deafness, glaucoma, hyperacusis, keratitis,
labyrinthitis, miosis, papiltedema, decreased pupillary reflex, scleritis. Urogenital system Frequent: anorgasmia, dysuria, hematuria, metrorrhagia . urination impaired, vaginitis”;
Infrequent: albuminuria, amenorrhea”, kidney calculus, cystitis, leukorrfrea, menorrhagia’ , noctuna, bladder pain, breast pain, kidney pain, polyuria, prostatitis” , pyelonephritis, pyuria, urinary
incontinence, urinary urgency, uterine fibroids enlarged” , uterine hemorrhage” , vaginal hemorrtrage”, vaginal monitiasis;
Rare: abortion,
breast engorgement, breast enlargement, calcium
crystalluria, female lactation”,
hypomenorrhea” , menopause’, prolonged erection’, uterine
spasm’ . (Based on the number of male or female patients as appropriate.)
Drug Abuse And Dependence: CONTROLLED SUBSTANCE CLASS-Effexor is not a controlled
substance. In a retrospective survey of new events occurring during taper or following discontin-
uation, the following occurred at an incidence ot5”/,
with incidence for Effexor at least twice that
for placebo: asthenia, dizziness, headache, insomnia, nausea, and nervousness. Taper the dose
gradually and monitor the patient. Evaluate patients carefully for history of drug abuse and
observe such patients closely for signs of Effexor misuse or abuse (e.g. development of tolerance,
incrementations of dose, drug-seeking behavior).
Dosage and AdminIstratIon: The recommended starting dose is 75mglday in 2 or 3 divided
doses, taken with food. If needed, dose increments of up to 75mg/day should be made at intervals of no less than 4 days. Maximum recommended dose, for use in severely depressed patients,
is 375mg/day, in 3 divided doses. When discontinuing Eflexor after more than 1 week of therapy,
the dose should be tapered to minimize the risk of discontinuation symptoms.
SWITCHING PATiENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR
least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with
Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting
an MAOI (see “Contralndlcatlons” and “Warnings”).
Please consult full prescribing information for detailed dosing instructions.
This brief summary is based on CI 4193-2, issued May 23, 1994.
At
References: 1. EFFEXOR’ prescribing information, Wyeth-Ayerst Laboratories, Philadelphia, PA.
Data on file, Wyeth-Ayerst Laboratories. 3. Physicians’ Desk Reference’. 48th ed. Montvale, NJ:
Medical Economics Co Inc; 1994; Prozacx:877880; Zolott”:2000-2003;
PaxiP:2267-2270.
Prozac is a registered trademark of Dista Products Company, division of Eli Lilly and Company.
Zoloft is a registered trademark of Roerig, division of Pfizer Incorporated.
Paxil is a trademark of SmithKline Beecham Pharmaceuticals.
2.
#{174}
© 1994, Wyeth-Ayerst Laboratories
83520
WVETH-AYER&F
LABORATORIES
1994
r
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I dysfunction,’4
Bchanism
of action9 with
L
minimal
ii
A1
ntr#{244}l
study of 119 patients,WELLBUTRIN
ai
in relieving depression
and accompanying
‘
Important
.,....
‘escnbing
i.
adverse reaction
For more information,
information.
isons have been made.
_____
tj
s9.
References: 1. Data on file, Burroughs Weilcome Co. 2. Walker PW, Cole JO. Gardner EA, et al.
Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion. J Ciin Psychiatry.
1993;54:459465.
3. Gardner EA, Johnston JA. Bupropion-an
antidepressant
without sexual
pathophysixiogical action. J CIin Psychopharmacol. 1985;5lll:24-29.
4. American Psychiatnc Association.
Practice Guideline for Major Depressive Disorder in Adults. 1993. 5. Jacobsen FM. Fluooetine.induced
sexual dysfunction and an open trial of yohimbine. J Clin Psychiatry. 1992;53(4l:119122.
6. Segraves RI.
Sexual dysfunction
complicating
the treatment
of depression.
J Clin Psychiatry
Monograph.
1992;1Ol1l:7579.
7. Reimherr PA, Chouinard G, Cohn CK, en al. Antidepressant efficacy of sertraline: a
doubleblind, placebo and amitriptyline.connrolled
multicenter comparison study iii outpatients with major
depression. J Clin Psychiatry. 1990;51l12, suppl B):1&27. 8. Cohn CK, Shrivastava R, Mendels J, et al.
Double’blind. multicenter comparison of sertraline and amitriptyline in elderly depressed patients. J Clin
Psychiatry. 1990;51l12.
suppl B):2833. 9. Ferris RM, Cooper BR. Mechanism of antidepressant activity of
bupropion. J Clin Psychiatry Monograph. 1993;lllll:2-14.
10. Feighner JP, Gardner EA, Johnston JA, en al.
Double.blind
comparison
of bupropion and fluoxetine in depressed outpatients.
J Clin Psychiatry.
1991;52:329335.
11, Depression in Primary Care: Volume 2. Treatment of Major Depression.
Clinical
Practice Guideline, Number 5. Rockville, Md: US Department of Health and Human Services, Public Health
Service, Agency for Health Care Policy and Research; 1993. AHCPR publication 93-0551. 12, Lineberry CG,
Johnston JA. Raymond RN, et al. A fixeddose 1300 mgI efficacy study of bupropion and placebo in
depressed outpatients. J Clin Psychiatry. 1990;51:194’199.
13. Feighner J, Hendrickson G. Miller L Stern
W. Doubleblind comparison of dosepin versus bupropion in outpatients with a major depressive disorder.
J Clin Psychopharmacol. 1986;6l1):2732.
Because bupropion HCI and its metabolites are almost completely excreted through the kidney and metabolites
are likely to undergo conjugation in the liver pnorto urinary excretion, treatment of patients with renal or hepatic
impairment
should be initiated at reduced
dosage as bupropion
and its metaboliles
may accumulate
in such
patients beyond concentrations expected in patients without renal or hepatic impairment. The patient should
be closely monitored for possible toxic effects of elevated blood and tissue levels of drug and metxbolites.
information for Patients: Consult complete product information.
Drug Interactions: No systematic data have been collected on the consequences of the concomitant
administration of WELLBUTRIN and other drugs.
However, animal data suggestthat WELLBUTRIN may be an inducer of drug metabolizing enzymes This may
be of pofential clinical imporlance because the blood levels of co-administered drugs may be altered.
Alternatively. because bupropion is extensively metabolized, the co-administration of other drugs may affect
its clinical activity. In particular, care should be exercised when administering drugs known to affect hepatic
drug-metabolizing enzyme systems (e.g., carbamazepine, cimetidine, phenobarbital, phenytoin).
Studies in animals demonstrate that the acute toxicity of bupropiori is enhanced by the MAO inhibitor
phenelzine (see CONTRAINDICATIONS).
Limited ctinice/ data suggest a tsgher incidence of adverse espenences in patients receiving concurrent adminatration
of WLLBUTRIN and L-dopa. Administration of WELLBUTRIN to patients receiving L-dopa concurrently should
be undertaken with caution, using small initial doses and small gradual dose increases.
Concurrent administration of WELLBUTRIN and agents which lower seizure threshold should be undertaken
only with extreme caution (see WARNINGS) Low initial dosing and small gradual dose increases should be
employed.
Carcinogenesis,
Mutagenesis, impairment of Fertility: Lifetime carcinxgenicity studies were performed in
rats and mice at doses up to 300 and 150 mg/kg/day, respectively. in the rat study there was an increase in nodular
proliferative lesions ofthe liver at doses of 100 to 300 mg/kg/day; lower doses were nottested. The question
of whether or not such lesions may be precursors of neoplasms ofthe liver is currently unresolved. Similar liver
lesions were not seen in the mouse study, and no increase
WELLBUTRIN#{174}(bupropion
Before prescribing,
hydrochloride)
please consult complete product informatIon,
Tablets
a summary
of which follows:
INDICATIONS AND USAGE: WELLBUTRIN is indicated for the treatment of depression. A physician
considering the initiation of WELLBUTRIN should be aware thatthe drug may cause generalized seizures with
an approximate incidence of 0.4% (4/1000). This incidence may exceed that of other antidepressants as much
as fourfold. This relative risk is only an approximation since no direct comparative studies have been
conducted.
CONTRAINDICATIONS:
WELLBUTRIN
is contraindicated in patients: with a seizure disorder; with a current
or prior diagnosis of bulimia or anorexia nervosa, because of a higher incidence of seizures noted in such patients;
who have shown an allergic response to it; or who are currently being treated with an MAO inhibitor. At least
14 days should elapse between discontinuation
of an MAO inhibitor and initiation of treatment with
WELLBUTRIN.
WARNINGS: SEIZURES: WELLBUTRIN is associated with seizures in approximately O.4%(4/1000)of patients
treated at doses up to 450 mg/day. This incidence of seizures may exceed that of other marketed
antldepreuants
by as much asfourfoid, This relative risk is only an approximate estimate because no
direct comparative studies have been conducted. The estimated seizure incidence for WELLBUTRIN
Increases almost tenfold between 450 and 600 mg/day, which Is twice the usually required daily
dose (300 mg) and one and one.thlrd the maximum recommended daily dose (450 mg). Given the wide
variability among individuals and their capacity to metabolize and eliminate drugs, this disproportionate
increase in seizure incidence with dose incrementation calls for caution in dosing.
During the kilti& development, 25 wnong approximately 2400 patIents tmated wtm WELLBUTRIN experienced
seizures. At the time of seizure, seven patients were receiving daily doses of 450 mg or below, for an
incidence of 0.33% (311000) withIn the recommended dose range. Twelve patients experienced
seizures at 600 mg per day (2.3% incidence); six additional patients had seizures at daily doses
between 600 and 900 mg (2.8% incidence).
A separate, prospective study was conducted to determine the incidence of seizure during an 8
week treatment exposure in approximately 3200 addItional patients who received daily doses of up to
450 mg. Patients were permitted to continue treatment beyond 8 weeks If clinically indicated. Eight (8)
seizures occurred during the initial 8 week treatment period and five seizures were reported in
patients continuing treatment beyond 8 weeks, resulting In a total seizure incidence of 0.4%.
The risk of seizure appears to be strongly associated with dose and the presence of predisposing factort
A significant predispoeing factor(e.g,, history ofhead trauma or prior seizure, CNS tumor, concomitant
medications that lower seizure threshold, etc.) was present In approximately
one’half ofthe patients
experiencing a seizure. Sudden and large Increments In dose may contributeto increased risk. While
many seizures occurred early In the course of treatment, some seizures did occur after several
weeks at fixed dose.
RecommendatIons
for reducing the rIsk of seizure: Retrospective
analysis of clinical experience
gained during the development of WELLBUTRIN suggests that the risk of seizure may be minimized If
(1)the total daily dose of WELLBUTRIN does notexceed 450 mg (2)the daily dose Is administered Lid.,
with each single dose not to exceed 150 mg to avoid high peak concentrations of buproplon and/or its
metaboiftes, and (3)the rate of Incrementation of dose is very gradual Extreme caution should be used
when WELLBUTRIN is (1) admInistered to patients with a history of seizure, cranial trauma, or other
predisposition(s)
toward seizure, or (2) prescribed with other agents (e.g., antipsychotics, other
antldepreuanta,
etc.)or treatment regimens (e.g., abrupt discontinuation
of a benzodiazepine)that
lower
seizure threshold.
Potentialfor Hepatotoxicity: In rats receiving large doses of bupropion chronically, there was an increase
in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of
buprxpion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild
hepatocellular injury were noted. Although scattered abnormalities in liver function tests were detected in patients
participating in clinical trials, there is no clinical evidence that bupropion acts as a hepatolonin in humans.
PRECAUTIONS: General:
Agitation andinsomnia:
A substantial proportion of patients treated with WELLBUTRIN espenencesome degree
of increased restlessness, agitation. anxiety, and insomnia, especially shortly after initiation oftreatment. In
dinizal studies. these symptoms were sometimes of sufficient magnitude lx require treatmentwith sedative/hypnotic
drugs. In approximately 2#{176}/a
of patients. symptoms were sufficiently severe to require discontinuation of
treatment with WELLBUTRIN.
Psychosis, Confusion, and Other Neuropsychlatric Phenomena: Patients treated with WELLBUTRIN have
been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations,
psychotic episodes, contusion, and paranoia. Because of the uncontrolled nature of many studies, it is
impossible to provide a precise estimate of the extent of risk imposed by treatment with WELLBUTRIN.
In several
cases, neuropsychiatric phenomena abated upon dose reduction and/or withdrawal of treatment.
Activation ofPssosisMsnis:Antidepressants
can precipitate manc episodes in Bipolar Manc Depressde
patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients.
WELLBUTRIN is expected to pose similar risks.
AlteredAppetlte
snd Weight: A weight loss of greater than 5 pounds occurred in 28% of patients receiving
WELLBUTRIN. This incidence is approximately double that seen in comparable patients treated with tricyclics
or placebo. Furthermore, while 34.5% of patients receiving tricyclic antidepressants gained weight, only
.4% of patients treated with WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a
patient’s depressive illness, the anorectic and/or weight reducing potential of WELLBUTRIN should be
considered.
Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant
remission occurs. Accordingly, prescriptions for WELLBUTRIN should be written for the smallest number of
tablets consistent with good patient management.
Use In Patients with Systemic Illness: There is no clinical espenence establishing the safety of WELLBUTRIN
in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be
exercised if it is used in these groups.
in malignanttumors
ofthe
liver and other organs
was seen in either study.
Bupropion produced a borderline positive response 2 to 3 times control mutation rate) in some strains in the
Ames bactenal mutagenicity test, and a high oral dose (300. but not 100 or 200 mg/kg) produced a low incidence
of chrxmosomal aberrations in rats. The relevance ofthese results in estimating the risk of human exposure
to therapeutic doses is unknown.
A fertility study wax performed in rats: no evidence of impairment offertility wax encountered at oral doses up
to 300 mg/kg/day.
Pregnancy: Terafogenic Effecfs: Pregnancy Categorr B: Reproduction studies have been performed in rabbits
and rats at doses up to 15 to 45 times the human daily dose and have revealed no definitive evidence of impaired
fertility or harm to the fetus due to bupropion. (In rabbits, a slightly increased incidence offetal abnormalities
was seen in two studies, butthere was no increase in any specific abnormality.) There are no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of
human response, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery: The effect of WELLBUTRIN on labor and delivery in humans is unknown.
Nursing Mothers: Because ofthe potentialfor venous adverse reactions in nursing infants from WELLBUTRIN,
a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother
Pediatric Use: The safety and effectiveness of WELLBUTRIN in individuals under 18 years old have not been
established.
Use in the Elderly: WELLBUTRIN
has not been systematically
evaluated in older patients
ADVERSE REACTIONS: (See also WARNINGS and PRECAUTIONS) Adverse events commonly encountered
in patients treated with WELLBUTRIN are agitation. dry mouth, insomnia, headache/migraine. nausea/vomiting,
constipation. and tremor.
Adverse events were sufficiently troublesome to cause discontinuation of treatment with WELLBUTRIN in
approximately ten percent of the 2400 patients and volunteers who participated in clinical tnals during the product’s
initial development. The more common events causing discontinuation include neuropsychiatric disturbances
(3.0%), primarily agitation and abnormalities in mental status: gastrointestinal disturbances )2.1#{176}/),
primarily
nausea and vomiting: neurological disturbances (1.7%), pnmanly seizures, headaches, and sleep disturbances;
and dermatologic problems (1.4#{176}/C),
pnmarily rashes. It is importantto note, however, that many xfthese events
occurred at doses that exceed the recommended daily dose.
The table below is presented solely to indicate the relative frequency of adverse events reported in
representative controlled clinical studies conducted to evaluate the safety and efficacy of WELLBUTRIN under
relatively similar conditions of daily dosage (300 to 600 mg). setting, and duration (3 to 4 weeks). The
figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical
practice where patient charactenstics and other factors must differ from those which prevailed in the clinical
trials. These incidence figures also cannot be compared with Ihose obtained from other clinical studies
involving related drug products as each group of drug trials is conducted under a different set of conditions.
Finally, it is importantto emphasize thatthe tabulabon does not reflect the relative seventy and/or clinical importance
otthe events. A better perspective on the serious adverse events associated with the use of WELLBUTRIN ix
provided
in WARNINGS
and PRECAUTIONS.
TREATMENT EMERGENT ADVERSE EXPERIENCE INCIDENCE IN PLACEBO.CONTROLLED CLINICAL TRIALS’
(Percent of Patients Reporting)
Adverse Experience
WELLBUTRIN Piacebo
Patients
Patients
(n = 323)
(n = 185)
CARDIOVASCULAR
Cardiac
Arrhythmias
Dizziness
Hypertension
Hypotension
Palpitations
Syncope
Tachycardia
53
22.3
4.3
25
3.7
1.2
108
4.3
16.2
1.6
2.2
2.2
05
86
2.2
8.0
0.0
6.5
18.3
37
26.0
6.8
184
2.2
DERMATOLOGIC
Pruritus
Rash
GASTROINTESTINAL
Anorexia
Appetite Increase
Constipation
Diarrhea
Dyspepsia
Weight Gain
Weight Loss
GENITOURINARY
Impotence
Menstrual
Complaints
Urinary Frequency
Urinary Retention
MUSCULOSKELETAL
Arthritis
NEUROLOGICAL
Akathisia
Akinesia/Bradykinesia
Cutaneous Temperature
Disturbance
Dry Mouth
Excessive Sweating
Headache/Migraine
Impaired Sleep Quality
Increased
Salivary
Flow
Insomnia
Muscle Spasms
Pseudoparkinsonism
Sedation
173
22.9
13.6
23.2
86
2.2
189
22.7
23.2
3.4
4.7
2.5
1.9
3.1
1.1
22
2.2
3.1
27
3.1
Nausea/Vomiting
Adverse Experience
1.5
11
8.0
86
t.9
1.6
Sensory Dislurbance
Tremor
NEUROPSYCHIATRIC
Agitation
Anxiety
Confusion
Decreased Libido
Delusions
Disturbed Concentration
Euphoria
Hostility
NONSPECIFIC
Fatigue
Fever/Chills
RESPIRATORY
Upper Respiratory
Complaints
SPECIAL SENSES
Auditory Disturbance
Blurred Vision
Gustatory
‘Events reported by at least 1% of patients receiving WELLBUTRIN
Disturbance
are included.
WELLBUTRIN Placebo
Patients
Patients
(n = 323)
(n #{149}
185)
27.6
22.3
25.7
4.0
18.4
14.6
22.2
1.6
3.4
3.8
18.6
15.7
1 .9
3.2
1.5
1.6
19.8
19.5
4.0
21.1
3.2
7.6
31.9
3.1
8.4
3.1
1.2
3.1
1.2
5.6
22.2
1.1
4.9
1.6
1.1
3.8
0.5
3.8
5.0
12
8.6
05
5 0
11 4
5.3
14.6
3.2
10.3
3.1
1.1
WELLBUTRINn (bupropion hydrochloride)
Tablets
Other Events Observed During the Development of WELL.BUTRIN: The condeons and duration of exposure
to WELLBUTRIN varied greatly and a substantial proportion of the experience was gained in open and
uncontrolled clinical settings. During this experience. numerous adverse events were reported; however,
without appropnate controls, it is impossible to determine with certainty which events were or were not caused
by WELLBUTRIN The following enumeration is organized by organ system and describes events in
terms oftheir relative frequency of reporting in the data base Events of malor clinical importance are also
described in WARNINGS and PRECAUTIONS
The following definitions of frequency are used: Frequent adverse events are defined as those occurring
in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1000 patients. while
rare events are those occurring in less than 1/1000 patients.
:i
Cardiovascular: Frequent was edema: infrequent were chest pain, EKG abnormalities (premature beats
and nonspecific 51.1 changes). and shortness of breath/dyspnea: rare were flushing. pallor, phlebitis. and
myocardial infarction
Dermatologic: Frequent were nonspecific rashes: infrequent were alopecta and dry skin; rare were
change in hair color, hirsuhsm, and acne.
Endocrine: Infrequent was gynecomastia: rare were glycosuria and hormone level change.
Gastroinfesfinal: Infrequent were dysphagia. thirst disturbance, and liver damage/jaundice: rare were rectal
complaints. colitis, G I bleeding. intestinal perforation, and stomach ulcer.
Genitourinary:
Frequent wax nocturia, infrequent were vaginal irritation, testicular swelling, urinary
tract infection. painful erection, and retarded elaculation: rare were dysuria, enuresix, urinary incontinence,
menopause, ovarian disorder, pelvic infection. cystitis, dyspareunia, and painful elaculation
HemafologiclOncologic:
Rare were lymphadenopathy. anemia. and pancytopenia.
Musculoskelefal: Rare was musculoskeletal chest pain.
Neurological:(see
WARNINGS) Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and
dystonia; infrequent were mydriasis, vertigo. and dysarthria: rare were EEG abnormality, abnormal
neurological exam, impaired attention, sciatica, and aphasia.
Neuropsychiatrlc:
(see PRECAUTIONS) Frequent were mania/hypomania, increased libido, hallucinations,
decrease in sexual function, and depression; infrequent were memory impairment,
depersonalization, psychosis.
dysphoria. mood instability, paranoia, formal thought disorder, and frigidity: rare was suicidal ideation.
OralComplaints: Frequent was stomatitis: infrequent were toothache, brusism, gum irntation, and oral edema;
rare was glossitis.
Respirsfory: Infrequent were bronchitis and shortness of breath/dyspnea:
disorder, pneumonia, and pulmonary embolism.
rare were epistaxis, rate or rhythm
Special Senses: Infrequent was visual disturbance: rare was diplopia.
Nonspecific: Frequent were fu-like symptoms; infrequent was nonspecific pain: rare were body odor, surgically
related pain, infection, medication reaction, and overdose.
.
.
.
Th Only
jnstrument
x,gfr
more
paresthesia,
tod
(800) 642-6761
,
-
-
information
-
SOMATICS, INC.
910 Sher.’iood Drive
,,.
#{149}
Unit 17
us andCanadatoll
08l
234 6/61
free 18OO-642-6761
,‘
,
Lake Bluff IL 60044
Gastrointestinal: esophagitis. hepatitis
Hemic and Lymphatic: ecchymosis, leukocytosis. leukopenia
Musculoskeletal: arthralgia. myalgia, muscle rigidity/fever/rhabdomyolysis
Stevens-Johnson
New ECT
for the 1990s
q
Cafli
Cardiovascular: orthoxtatic hypotenxixn. third degree heartblxck
Endocrine: syndrome of inappropriate antidiuretic hormone secretion
Skin and Appendages:
DGx
e’*;
Postintroduction Reports: Voluntary reports of adverse events temporally associated with WELLBUTRIN
that have been received since market introduction and which may have no causal relationship with the drug
include the following:
Nervous: coma, delirium, dream abnormalities,
___
pgr#{224}de to a
‘.1995....THYMATRON’
‘
s..:
Ho i 081 234 6 62
unmasking of tardive dyskinesia
syndrome. angioedema.
esfoliative dermatitis, urticaria
Special Senses: tinnitus
April 1994
aco..
646042
Burroughs Wellcome Co
Research Triangle Park, NC 27709
Copr. © 1994 Burroughs Wellcome Co All rights reserved.
Printed in U.S.A. WB-Y06321
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bral glucose
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emission
in schizophrenic
patients
as determined
tomography.
Psychopharmacology
(Berl)
1989; 97:309-318
I 6. Keshavan
MS. Pettegrew
J, Campbell
K: In vivo
spectroscopy
of the
I 7.
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JW, Panchalingam
nuclear magnetic
lobe
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Stanley
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1992;
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Schizo-
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study
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