DISCLAIMER:
The following information was reproduced from literature received from
Bristol-Myers Squibb Canada Inc.. No warranty is made for clerical 
accuracy
or completeness and as this is a Canadian release it is highly 
recommended
that this be used as nothing more than an informal overview until such 
time
that the same literature is published and received from U.S. source. 
No
interpretation or judgment has been used in providing this information 
by
the writer but still should be considered third party information.

Nefazodone Hcl
TABLETS 100, 150 and 200mg
THERAPEUTIC CLASSIFICATION: Antidepressant

ACTIONS AND CLINICAL PHARMACOLOGY:
Nefazodone is a synthetically derived analog of the phenylpiperazine 
series
which
is metabolized in vivo to compounds which likewise exhibit 
pharmacological
activity.

Nefazodone (NEF) and one of its active metabolites, hydroxynefazodone, 
exert
dual effects on serotonergic neurotransmission through blockade of 
serotonin
type 2 (5-HT/2) receptors and inhibition of serotonin uptake. The 
parent
compound (NEF) and another active metabolite, m-chlorophenyl-
piperazine
(mCPP), also exhibit affinity for the 5-HT/1c receptor. Nefazodone 
lacks
anticholinergic or antihistaminic effects but exhibits some affinity 
for
alpha,
adrenergic receptors.

PHARMACOKINETCS and METABOLISM:
Orally administered nefazodone is rapidly and completely absorbed, 
with peak
plasma concentrations occurring 1 to 3 hours after dosing. However, 
nefazodone
is subject to extensive presystemic metabolism, and its systemic
bioavailability is
estimated to range between 15% and 23% at doses of 50 to 200mg. Single 
doses
of 50, 100 and 200 mg of nefazodone, administered as the hydrochloride 
salt in
capsule formulation, result in mean peak plasma concentrations of 84, 
196 and
392 ng/mL, respectively. Steady state is reached within 3 to 4 days of
initiation or
adjustment of bid dosing. At steady state,  both the peak plasma
concentrations
and the mean area under the plasma concentration vs. time profiles 
(AUC)
indicate that nefazodone's pharmacokinetic parameters are non-linear. 
The mean
peak plasma concentrations for doses of 50, 100 and 200 mg bid were 
270, 730
and 2050 ng/mL, respectively, and the corresponding AUC values were 
540,
2270 and 9250 ng-h/mL.

EFFECTS OF FOOD: Food delays the absorption of nefazodone and 
decreases
its systemic exposure by approximately 20%. These effects are small 
and are
unlikely to be clinically significant in light of the extensive inter- 
and
intra-subject
variability in pharmacokinetics.

DISTRIBUTION: Following a 5 mg. IV dose, the volume of distribution at 
steady
state (VD/ss) ranged from 0.23 - 0.87 L/kg, indicating that nefazodone 
is
widely
distributed in body tissues.

METABOLISM: A clinical pharmacokinetic study using orally administered 
^14C-
radiolabelled nefazodone has demonstrated extensive presystemic 
metabolism.
Nefazodone accounted for approximately 3% of the total radioactivity 
in the
plasma. Nefazodone undergoes N-dealkylation as well as aliphatic and 
aromatic
hydroxylation. Two metabolites of nefazodone (NEF), hydroxy-nefazodone 
(HO-
NEF) and triazole dione (dione) have been shown to possess 
qualitatively
similar
pharmacological profiles to NEF, though triazole dione is markedly 
less
potent. A
third metabolite, m-chlorophenyl-piperazine (mCPP), has broader 
serotonergic
effects. The pharmacokinetics of NEF, HO-NEF, and mCPP exhibit 
extensive
inter- and intra-subject variability in humans. In healthy male 
volunteers
receiving
multiple 50 mg bid, 100 gm bid, and 200 mg bid doses of nefazodone, 
the peak
plasma concentrations of HO-NEF and mCPP were approximately 25% and 
2%,
respectively, of those for the parent compound. The relative peak 
plasma
concentration ratio of mCPP to NEF decreased from 2.9% to 1.4% as the 
dose of
nefazodone was increased from 50mg bid to 200 mg bid. The 
pharmacokinetics
of HO-NEF are nonlinear; however, mCPP exhibits linear 
pharmacokinetics.
Triazole-dione, exhibits only weak 5-HT/2 antagonistic activity, but 
is
present at
steady state in peak plasma concentrations which are approximately 
125% of
those for nefazodone.

ELIMINATION: The plasma elimination half-life of nefazodone is dose-
dependent,
In a three way crossover study in healthy male volunteers, steady-
state
t/(1/2)
values were 1.9 h for a 50 mg bid dose. After oral administration, 
nefazodone
is
eliminated primarily by hepatic metabolism. When ~14C-labelled 
nefazodone is
administered orally, about 5--65%^ of the radioactivity was excreted 
in the
urine
as metabolites. Less than 1% of the administered nefazodone was 
detected
unchanged in urine; identified metabolites of nefazodone accounted for 
80% of
the radioactivity detected in urine. The excretion of nefazodone and 
HO-NEF is
negligible; approximately 1%  of the administered dose is excreted as 
mCPP and
about 7% as para-hydroxy-mCPP (p-OH-mCPP). Fecal excretion accounted 
for
20-40% of the administered radiolabel. In 24 healthy male volunteers, 
the oral
clearance (CL/F) at steady state decreased from 115 +/- 32 L/h (mean 
+/- sd)
at
a dose of 50 mg. to 29 +/- 13 L/h at dose of 300 mg.

IN ELDERLY SUBJECTS: A multiple-dose pharmacokinetic study in elderly
subjects indicated that the pharmacokinetics and metabolism of 
nefazodone are
similar in young and elderly male volunteers. In elderly women, plasma
concentrations of nefazodone were 60% higher than those in young 
female
volunteers and the elimination half-life was increased from 5.4 to 8.9 
hrs.
The
clinical significance of this finding is not known. Single doses of  
50-300 mg
nefazodone in elderly volunteers have been reported to result in peak 
plasma
concentrations and area under the plasma concentration time curve 
values which
are approximately double those observed in young volunteers. These 
data
suggest that treatment in elderly patients should be initiated at one 
half of
the
usual dose of nefazodone.

IN HEPATICALLY IMPAIRED PATIENTS: In a single dose study, mean AUC
values for subjects with hepatic cirrhosis (n=12) receiving nefazodone 
at
doses of
50-200 mg were double those observed in normal subjects (n=12). In a 
multiple-
dose study of patients with mild hepatic impairment (n=13), the steady 
state
AUC
values for nefazodone and HO-NEF were approximately 20% to 40% greater 
than
those observed in healthy volunteers. Therefore, if nefazodone is 
administered
to
patients with liver disease, treatment should be initiated at one-half 
the
usual
dose of nefazodone, with subsequent adjustments being performed on the 
basis
of tolerance and therapeutic response.

IN RENALLY IMPAIRED PATIENTS: The pharmacokinetics of nefazodone , HO-
NEF, and mCPP were investigated in a multiple dose study of nefazodone
involving patients with varying degrees of renal impairment 
(creatinite
clearance
ranging from 7 to 60 mL/min/1.73m^2). No significant relationships 
were
observed
between the pharmacokinetic parameters and the degree of renal 
impairment.
However, in patients with severely impaired renal function, SERZONE 
should be
used with caution.

PROTEIN BINDING: At concentrations of 25-2500 ng/mL, nefazodone is
extensively (> 99%) bound to plasma proteins in vitro.


PHARMACODYNAMICS:

HEMODYNAMIC EFFECTS: In one crossover study involving subjects at 
least 65
years old, nefazodone caused a modest decrease in mean supine blood 
pressure
and pulse rate without producing orthostatic hypotension or 
alterations in
cardiac
conduction compared to placebo.

PSYCHOMOTOR EFFECTS: In one study, psychomotor impairment in
nefazodone-treated patients was shown after seven days of bid 
treatment, but
not
after acute dosing. In 12 elderly subjects (>=60yrs), chronic 
administration
of
nefazodone resulted in statistically significant decreases in driving
performance
(200m mg bid) and increased reaction times (100-200 mg bid). In young 
adult
subjects (n=12), increased reaction times were observed during chronic 
dosing
with 200 mg bid nefazodone. In another 7-day study involving subjects 
at least
65
years old, psychomotor and cognitive function tests generally 
sensitive to the
effects of psychotropic medication were not markedly altered by 
nefazodone.

SLEEP ARCHITECTURE: When given to healthy volunteers (n=12) at 
bedtime,
nefazodone slightly decreased (15%) the time between sleep initiation 
and the
first rapid eye movement (REM) episode. significantly increased total 
REM
sleep
time, did not affect the number of timing of REM episodes through the 
night
and
significantly decreased Stage 2 sleep.

NOCTURNAL PENILE TUMESCENCE: In the sleep architecture study conducted
in healthy volunteers, the percent total sleep time spent in the 
tumescent
state
was 28% for placebo and 37% for a 400mg dose of nefazodone. The 
difference
between the two treatment groups was not statistically significant.

ENDOCRINE EFFECTS: In normal male volunteers (n=8), single 50, 100, 
and
200 mg doses of nefazodone were associated with dose dependent 
increases in
plasma prolactin and growth hormone levels. At 150 minutes post-
administration
of a 200 mg dose, mean plasma prolactin levels were double baseline 
values but
remained within the normal range. This increase in prolactin was not 
evident
following seven days of dosing with 100 mg bid of nefazodone. Mean 
plasma
levels of growth hormone were increased approximately 15 fold over 
baseline
levels 150 minutes after single 100 to 200 mg doses of nefazodone. 
When
nefazodone was administered for 7 days according to a 100 mg bid 
regimen,
plasma growth hormone levels were increased approximately 10 fold over
baseline. The peak levels of growth hormone were in excess of the 
normal
values
but declined to normal range within the dosing interval. Plasma levels 
of ACTH
and cortisol also tended to be increased  (not significant) after 
single doses
of
100 and 200 mg. The effects of nefazodone on hormonal levels in female
subjects have not been investigated.

INDICATIONS AND CLINICAL USE:

SERZONE (nefazodone HCl) is indicated for the symptomatic relief of 
depressive
illness. The effectiveness of nefazodone in long-term use (ie. for 
more than 6
to 8
weeks) has not been systematically evaluated in controlled trials. 
Therefore,
the
physician who elects to use nefazodone for extended periods should
periodically
reevaluate the long-term usefulness of the drug for the individual 
patient.

CONTRAINDICATIONS:

SERZONE (nefazodone HCl) is contraindicated in patients with known
hypersensitivity to nefazodone, any component of the formulation or 
other
phenylpiperazine antidepressants.

MONOAMINE OXIDASE INHIBITORS: SERZONE should not be used in
combination with monoamine oxidase inhibitors or within two weeks of
terminating
treatment with monoamine oxidase inhibitors. Monoamine oxidase 
inhibitors
should not be introduced until at least 2 weeks after the cessation of 
SERZONE
therapy.

WARNINGS:

GENERAL:
SUICIDE: The possibility of a suicide attempt in seriously depressed 
patients
is
inherent to the illness and may persist until significant remission 
occurs.
Close
supervision of high risk patients should continue through therapy and
consideration should be given to the possible need for 
hospitalization. In
order to
reduce the risk of overdose, prescriptions of SERZONE (nefazodone HCl) 
should
be written for the smallest quantity of tablets consistent with good 
patient
management.

SEIZURES: As with other antidepressants, nefazodone should be used 
with
caution in patients with a history of seizures. During clinical 
trials, the
overall
incidence of seizures was 0.04% in patients treated with SERZONE. 
However
patients with a history of convulsive disorders were excluded from 
these
studies.
The drug should be discontinued in any patient who develops seizures.

ACTIVATION OF MANI/HYPOMANIA: As with most antidepressant agents,
activation of mania/hypomania has been reported rarely in patients 
with Major
Affective Disorder treated with SERZONE. In unipolar depressed 
patients in
clinical trials, hypomania or mania occurred in 0.4%, 0.3% and 0.5% 
for
nefazodone, tricyclic antidepressants and placebo.

USE IN PATIENTS WITH CONCOMITANT ILLNESS: Clinical experience with
SERZONE in patients with concomitant systemic illness is limited. 
Caution is
advisable when using nefazodone in patients with diseases or 
conditions such
as
hepatic or renal impairment, that could affect the metabolism or 
hemodynamic
responses.

INTERFERENCE WITH COGNITIVE AND MOTOR PERFORMANCE: Patients
should be cautioned about operating hazardous machinery, including
automobiles, until they are reasonably certain that the drug treatment 
does
not
affect them adversely.  Psychomotor impairment in nefazodone-treated 
subjects
was evident after seven days of bid treatment, but not after acute 
dosing.

CARDIOVASCULAR EFFECTS: SERZONE treatment was associated with
modest blood pressure lowering effects in clinical trials. Orthostatic
hypotension
and syncope have been reported in some SERZONE-treated patients. 
Caution
should be observed when SERZONE treatment is initiated in patients 
with pre-
existing hypotension or a labile circulation. Sinus bradycardia and 
first
degree AV
block were observed in 1.2% and 1%% of patients who received 
recommended
therapeutic doses of the drug in clinical trials. Corresponding rates 
of
occurrence
during placebo treatment were 0.4% and 0.6%. SERZONE has not been
evaluated or used to any appreciable extent in patients with a recent 
history
of
myocardial infarction or unstable heart disease. Hence, the usual 
precautions
should be observed in these patients.

LABORATORY TEST: As with all new drugs for which post-marketing 
experience
is not available, consideration should be given to performing periodic 
white
blood
cell counts. During clinical trials, there was no difference in the 
incidence
of
leukopenia between the placebo and nefazodone groups (0.2%).

PROLACTIN LEVELS: In male volunteers, prolactin levels were increased 
to
twice the baseline values following the acute administration of 
nefazodone,
although individual values remained within the normal range (2-15 
ng/mL). Such
an increase was not seen following 7-day dosing. Prolactin levels were 
not
determined in women, however, no clinical evidence of 
hyperprolactinemia (eg.
amenorrhea, galactorrhea, abnormal menstrual cycle length) was 
observed in the
446 women who received nefazodone for more than 60 days in clinical 
studies.
In
women with existing breast cancer, or a history of this disease, the 
possible
risk
of hyperprolactinemia should be weighted against the benefits of 
therapy.
Tissue
culture experiments indicate that approximately 1/3 of human breast 
cancers
are
prolactin dependent in vitro. Neither clinical studies nor 
epidemiological
studies
conducted to date, however, have shown an association between 
administration
of hyperprolactinemia-inducing drugs and mammary tumorigenesis; 
available
evidence is considered too limited to be conclusive at this time.

MALE SEXUAL FUNCTION: Nefazodone, a phenylpiperazine compound is
structurally related to trazodone, a drug which has been associated 
with the
occurrence of priapism during post marketing use. Priapism has not 
been
reported in clinical trials with nefazodone. However, if patients 
present with
prolonged or inappropriate erections, they should discontinue therapy
immediately
and consult their physician. If the condition persists for more than 
24 hours,
a
urologist should be consulted to determine appropriate management.

USE IN PREGNANCY: There are no adequate and well-controlled studies 
with
nefazodone in pregnant women.

NURSING MOTHERS: It is not know whether and, if so, in what amount
nefazodone or its metabolites are excreted in human milk. In lactating 
rats,
nefazodone and two of its metabolites (HO-NEF and mCPP) are excreted 
in milk.
Because many drugs are excreted in human milk, lactating, women should 
not
nurse their infants while receiving SERZONE.

PEDIATRIC USE: Safety and effectiveness in children below the age of 
18 have
not been established.

USE IN THE ELDERLY: Serzone has not been systematically studied in 
geriatric
patients. No unusual adverse age-related phenomena were identified 
upon
careful evaluation of all safety assessments in a cohort of 271 
elderly
patients
treated with SERZONE. Due to the increased systemic exposure to 
nefazodone
in elderly women, nefazodone treatment should be initiated at half the 
usual
dose,
with titration upward as needed to achieve a therapeutic response 
without
producing limiting adverse experiences (see DOSAGE AND 
ADMINISTRATION).
In clinical trials, most elderly patients achieved optimal therapeutic
response at
daily doses of 200 to 400 mg. The usual precautions should be observed 
in
elderly patients who have concomitant medical illnesses or who are 
receiving
concomitant drugs.

DRUG ABUSE AND DEPENDENCE: Nefazodone showed no potential for abuse
in a controlled study of abuse liability. Nefazodone has not bee
systematically
studied in humans for its potential for tolerance, physical dependence 
or
withdrawal.

Continued.

- Victor G.L. Jasin
  jasin@uwo.ca
 "iki pasirasymo!"


                                                                                                                     

@FROM   :jasin@julian.uwo.ca                                          
@SUBJECT:SERZONE (nefazodone HCl) repost part 2 of 3                  
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..continued

DISCLAIMER:
The following information was reproduced from literature received from
Bristol-Myers Squibb Canada Inc.. No warranty is made for clerical 
accuracy
or completeness and as this is a Canadian release it is highly 
recommended
that this be used as nothing more than an informal overview until such 
time
that the same literature is published and received from U.S. source. 
No
interpretation or judgment has been used in providing this information 
by
the writer but still should be considered third party information.

DRUG INTERACTIONS:

WITH TRIAZOLAM: When a single oral 0.25 dose of triazolam was CO-
administered with nefazodone (200 mg bid) at steady state, triazolam 
peak
concentrations, half-life, and AUC were increased 1.7, 3 and 4 fold
respectively.
The pharmacokinetics of nefazodone were not altered. The concomitant 
use of
triazolam and nefazodone was also associated with an increase in 
psychomotor
impairment presumably due to increased triazolam plasma 
concentrations. The
interactive effects of higher doses of these agents have not been 
studied. The
concomitant use of SERZONE and triazolam should be avoided. The 
metabolism
of triazolam has bee attributed to the specific hepatic microsomal 
isozyme,
P450IIIA4. Potential interactions between nefazodone and other drugs
metabolized by this isozyme (eg. cyclosporine, midazolam, nifedipine,
quinidine,
lidocaine, and erythromycin) should be considered.

WITH ALPRAZOLAM: When alprazolam (1mg bid) and nefazodone (200 mg bid)
were CO-administered to steady state, peak concentrations, AUC and 
half-life
values for alprazolam increased by approximately 2 fold. Nefazodone 
plasma
concentrations were unaffected by alprazolam, although levels of the 
mCPP
metabolite were increased. The concomitant use of alprazolam and 
nefazodone
was also associated with an increase in psychomotor impairment 
presumably due
to increased alprazolam plasma concentrations. If alprazolam is
CO-administered
with SERZONE, a reduction in the alprazolam dosage may be appropriate; 
no
dosage adjustment is required for SERZONE. The interactive effects of 
higher
doses of these agents, such as the dosage levels of alprazolam used in 
panic
disorder, have not been studied.

WITH LORAZEPAM: When lorazepam (2 mg bid) and nefazodone (200 mg bid)
were CO-administered to steady state, there was no change in any
pharmacokinetic parameter for either drug compared to each drug 
administered
alone. Therefore, dosage adjustment is not necessary for either drug 
when CO-
administered.

WITH CNS-ACTIVE DRUGS: The risk of using SERZONE in combination with
other CNS-active drugs has not been systematically evaluated. 
Consequently,
caution is advised if concomitant administration of SERZONE and such 
drugs is
required.

WITH ALCOHOL: Even though nefazodone did not demonstrate statistically
significant alteration of the psychomotor or cognitive impairment 
caused by
alcohol in a controlled trial with young normal volunteers., it is 
prudent to
avoid
concomitant use of alcohol and nefazodone.

WITH HALOPERIDOL: In healthy volunteers, the AUC of haloperidol 
(single 5
mg. dose) was increased by 35%, with no significant increase in the 
C/max or
T/max when CO-administered with nefazodone (200 mg bid) at steady 
state.
Slight protein binding displacement of haloperidol (approximately 5% 
of
control)
was also noted. These changes are not considered clinically 
significant. There
were no changes in the pharmacokinetic parameters of nefazodone. 
Therefore,
dosage adjustment is not necessary for either drug when CO-
administered.

WITH LITHIUM: Concurrent administration of nefazodone (100 mg bid ) 
with
lithium (800 mg/day) did not cause any untoward effects (eg tremor,
hypothermia)
associated with serotonin syndrome.

WITH CIMETIDINE: No significant clinical or pharmacokinetic 
interactions
between nefazodone (200 mg bid) and cimetidine (300 mg q.i.d.) were 
observed
in a multiple dose clinical trial involving healthy volunteers.

WITH ANTIHYPERTENSIVES: Although nefazodone is not a potent alpha-
adrenergic blocking agent, there have been reports of orthostatic 
hypotension
and syncope occurring in nefazodone-treaded patients. In a study in 12 
elderly
volunteers, nefazodone produced a modes lowering of blood pressure 
without
accompanying orthostatic changes. Although interactions with 
cardiovascular
medications have not been formally studied, concomitant administration 
of
antihypertensive therapy and nefazodone should be initiated cautiously 
and a
reduction in the dose of the antihypertensive drug may be required.

WITH GENERAL ANESTHETICS:  Little is known about the potential for
interaction between nefazodone and general anesthetics; therefore, 
prior to
elective surgery, nefazodone should be discontinued for as long as 
clinically
feasible.

PROTEIN BINDING:  Nefazodone is extensively (>99%) bound to plasma
proteins in man. The effect of nefazodone on plasma protein binding of
potentially
CO-administered drugs should be considered. The protein binding of
chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, 
prazosin,
propranolol, verapamil and warfarin was not affected by nefazodone in 
vitro.

ADVERSE REACTIONS:

COMMONLY OBSERVED ADVERSE EVENTS: In clinical trials, the most
commonly observed adverse experiences associated with the use of 
SERZONE
(nefazodone HCl) which occurred at a higher rate than among placebo-
treated
patients were dry mouth, nausea, somnolence, dizziness, constipation,
asthenia,
light-headedness, and amblyopia. Adverse events are more frequent at 
the
beginning of treatment and tend to subside with continued use.

ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION OF
TREATMENT: Approximately 11 percent of the 2256 patients who received
SERZONE in short-term worldwide premarketing clinical trials 
discontinued
treatment due to adverse experiences. The most common events causing
discontinuation included: nausea (2.4%), headache (2.0%), dizziness 
(1.2%),
asthenia (1.0%), and insomnia (1.2%).

SERIOUS ADVERSE EVENTS: Serious adverse events occurring in all 
patients
treated with SERZONE in clinical trials were: syncope (1 case), 
abdominal
pain(1
case) and gastrointestinal bleeding (1 case).

INCIDENCE IN CONTROLLED CLINICAL TRIALS: The table which follows
enumerates adverse experiences that occurred at a frequency of 1% or 
more in
patients who received flexible doses of SERZONE within low and high 
dose
ranges in placebo-controlled clinical trials of 6 to 8 weeks duration. 
Adverse
event rates are provided for the total data base of 664 nefazodone-
treated
patients as well as for the subsets of patients who received dosages 
in the
low
(n=271) and high (n=393) dose ranges.

Patients included in the low dose range treatment groups were 
initiated at
doses
of 50 to 150 mg/day and were titrated to maximum doses of 250 to 300 
mg/day.
Mean modal doses of SERZONE at the last week of treatment ranged from
approximately 250 to 275 mg/day in these studies. Patients included in 
the
high
dose range treatment groups were initiated at doses of 100 to 300 mg 
per day
and were titrated to maximum doses of 500 to 600 mg/day. Mean modal 
doses of
SERZONE at the last week of treatment ranged from approximately 350 to 
500
mg/day in these studies.

OTHER EVENTS OBSERVED DURING THE PREMARKETING EVALUATION
OF NEFAZODONE: In the tabulations that follow, a dictionary based on
COSTART terminology has been used to classify reported adverse 
experiences.
The adverse events, arranged by body system, were reported on at least 
one
occasion by patients during clinical trials with SERZONE (nefazodone). 
The
frequencies reported are based on 2256 patients exposed to SERZONE. 
All
reported events are included except those already listed in the 
previous table
or
those for which a drug cause was remote or the event term was mative. 
It is
important to emphasize that, although the experiences reported did 
occur
during
treatment with SERZONE, they were not necessarily caused by it. 
Experiences
are further classified within body system categories and enumerated in 
order
of
decreasing frequency using the following definitions: 1 or more 
occasions in
at
least 1/100 patients; infrequent adverse experiences are those 
occurring in
less
than1/100 but at least 1/1000 patients; rare adverse experiences are 
those
occurring in less than 1/1000 patients.

BODY AS A WHOLE:  FREQUENT: Neck pain; INFREQUENT; Neck rigidity,
allergic reaction, photosensitivity reaction, hangover effect, 
malaise,
enlarged
abdomen and face edema; RARE; Hernia, overdose, halitosis and 
cellulitis.

CARDIOVASCULAR SYSTEM: FREQUENT: Hypotension; INFREQUENT:
Presyncope, migraine, hypertension, tachycardia, extrasystoles, 
peripheral
vascular disorder, AV block, bradycardia and syncope; RARE: Angina 
pectoris,
atrial fibrillation, pallor, phlebitis, congestive heart failure and 
coronary
artery
disease.

DIGESTIVE SYSTEM: FREQUENT: Anorexia and gastroenteritis;
INFREQUENT: Nausea and vomiting, liver function tests abnormality, 
gastritis,
abnormal stools, eructation, periodontal abscess, colitis, mouth 
ulceration,
stomatitis, gingivitis, peptic ulcer and rectal hemorrhage; RARE:  
Glossitis,
bloody
diarrhea, dysphagia, esophagitis, hepatitis, GI hemorrhage, oral 
moniliasis,
ulcerative colitis and salivary gland enlargement.

HEMIC AND LYMPHATIC: INFREQUENT: Ecchymosis, leukopenia,
lymphadenophathy and anemia; RARE: Eosinophilia and leukocytosis.

METABOLIC AND NUTRITIONAL: INFREQUENT: Thirst and weight loss; RARE:
Gout, hypercholesteremia, hypervolemia, hyponatremia and hypoglycemia.

MUSCULOSKELETAL SYSTEM: FREQUENT: Arthralgia; INFREQUENT:
Arthritis, muscle stiffness and tenosynovitis; RARE: Bursitis, 
myositis and
tendinous contracture.

NERVOUS SYSTEM: FREQUENT: CNS stimulation; INFREQUENT: Decreased
or increased libido, vertigo, emotional lability, dysphoria, 
hypertonia,
depersonalization, euphoria, amnesia, twitching, hallucinations, 
hypomanic
reaction, derealization, manic reaction, neuralgia, suicidal thoughts,
hostility,
suicide attempt, decreased attention, paranoid reaction, abnormal 
gait, apathy
and myoclonus; RARE: Affect abnormal, abnormal behavior, convulsion, 
delirium,
delusions, drug dependency (other drug), hyperesthesia, increased 
salivation,
neuropathy, neurosis, torticollis, disarthria, hypotonia, ptosis, 
ekathisia,
hyperalgesia and personality disorder.

RESPIRATORY SYSTEM: FREQUENT: Cough; INFREQUENT: Bronchitis
dyspnea, hiccup, epistaxis, pneumonia, asthma and laryngitis; RARE:
Emphysema, hyperventilation and pleural disorder.

SKIN AND APPENDAGES: INFREQUENT: Dry skin, acne, urticaria, alopecia,
herpes simples, herpes zoster, vesiculobullous rash and eczema; RARE:
Hersutism, skin carcinoma, furunculosis, subcutaneous nodule and 
increased
seating.

SPECIAL SENSES: INFREQUENT: Eye pain, ear pain, visual field defect, 
dry
eye, abnormality of accommodation, conjunctivitis, diplopia,
keratoconjunctivitis,
mydriasis and photophobia; RARE: Exophthalmos, glaucoma, hyperacusis, 
night
blindness, taste loss, otitis media and retinal degeneration.

UROGENITAL SYSTEM: FREQUENT: Dysmenorrhea and vaginitis;
INFREQUENT: Cystitis, dysuria, breast pain, urinary urgency, 
impotence,
metorrhagia, polyuria, amenorrhea, urinary retention, prostatic 
disorder,
breast
enlargement, breast neoplasm, hematuria, kidney calculus and urinary
incontinence; RARE:  Abnormal ejaculation, breast carcinoma, cervix 
neoplasm,
dyspareunia, mastitis, menopause, menorrhagia, oliguria, enlarged 
uterine
fibroids, vaginal hemorrhage, anorgasmia, nocturia and uterine 
hemorrhage.

SYMPTOMS AND TREATMENT OF OVERDOSAGE:

In clinical studies involving 2256 patients treated with nefazodone, 
there
were no
deaths attributed to overdose with nefazodone. Two patients attempted 
suicide
by overdose. One patient ingested 3400 mg of nefazodone and the other
ingested 3600 mg of nefazodone. Both patients recovered without 
important or
life threatening symptoms and without sequelae. The reactions reported 
most
frequently from overdose of SERZONE (nefazodone HCl) have been 
drowsiness
and vomiting. Overdosage may cause an increase in incidence or 
severity of any
of the reported adverse reactions. (See ADVERSE REACTIONS).

TREATMENT: There is no specific antidote for SERZONE. Treatment should 
be
symptomatic and supportive in the case of hypotension or excessive 
sedation.

DOSAGE AND ADMINISTRATION:
ADULTS: SERZONE (nefazodone HCl) should usually be initiated at 200 
mg/day
(100 mg bid) with dose increases for most patients after assessing 
response,
following the first week of treatment.  In controlled clinical trials 
designed
to
establish the efficacy of nefazodone, patients were given doses 
ranging from
100
mg to 600 mg per day, administered in divided doses. These studies 
indicate
that
most patients responded at daily doses ranging from 300 mg to 500 mg.  
The
full
antidepressant effect of SERZONE may be delayed for four weeks or 
longer.

ELDERLY, DEBILITATED AND HEPATIC IMPAIRMENT: Not therapeutic clinical
trials have been conducted to systematically investigate dose 
requirements in
patients who are elderly, debilitated or hepatically impaired. 
However, as
these
patients often have reduced nefazodone clearance and/or increased 
sensitivity
to
the side effects of CND-active drugs, the recommended initial dose is 
100
mg/day
(50 mg bid). It may be appropriate to modify the rate of subsequent 
dose
titration
as well as the final target dose based on a careful assessment of the
patient's
clinical response.

PHARMACEUTICAL INFORMATION:
I. DRUGS SUBSTANCE

Tradename:  SERZONE
Proper name: Nefazodone Hydrochloride
Chemical Name: 2-[3-[4-(3-chlorophenyl)-1-peperazinyl]propyl]-5-ethyl-
2,
                              4-dihydro-4-(2-phenoxyethyl)-3H-1,2,3-
triazol-3-
                               one monohydrochloride
Empirical Formula: C v H v CINvO v*HCL ( read v as the base number 
below it)
                                  25  32      5   2

Structural Formula omitted due to graphics incompatibility.

II. COMPOSITION:
In addition to the active ingredients, nefazodone hydrochloride, each 
tablet
contains microcrystalline cellulose, povidone, sodium starch 
glycolate,
colloidal
silicon dioxide, magnesium stearate, red ferric oxide (150 mg) and 
yellow
ferric
oxide (150 and 200 mg)

AVAILABILITY:
SERZONE (Nefazodone Hydrochloride) 100 mg. tablets are white, 
hexagonal, flat
faced, bevelled-edged tablets engraved with "BMS 100" and a bisect 
score on
one side and "32" and a bisect score on the other.
SERZONE 150 mg. tablets are peach, hexagonal, flat faced, bevelled-
edged
tablets engraved with "BMS 150" and a bisect score on one side and 
"39" and a
bisect score on the other.
SERZONE 200 Mg.  tablets are light yellow, hexagonal, flat faced, 
bevelled-
edged tablets engraved with "BMS 200" on one side and "33" on the 
other.
SERZONE 100, 150 and 200 mg tablets are available in bottles of 60. 
Store at
room temperature (15-30deg C). Keep container tightly closed

SERZONE is a schedule F drug.

REFERENCES:
1. Serzone Product Monograph, Bristol-Myers Squibb Canada Inc, 1994
2. Sussman N. J Clin Psychiatry 1994;55(suppl2);45-51
3. A comparison of Serzone, fluvoxamine maleate, paroxetine HCl, 
fluoxetine
HCl and sertraline HCl product monographs.
4. Fontaine R. Clin Neuropharmacol 1993;16(suppl 3);S45-S50
5. Sharpley AL Biol Psychiatry 1992;31;1070-1073.
6. Armitage R et al. The effects of nefazodone on sleep architecture 
in
depression. Neuropsychopharmacology 1994;10(2).
7. Fawcett J. The relative efficacy of nefazodone in the treatment of 
symptoms
of anxiety and agitation in major depression. In Pres: J Clin
     Psychiatry 1994.
8. Fontaine R. et al. A double-blind comparison of nefazodone, 
imipramine and
placebo in major depression. In Press.
Product Monographs available on request.
BRISTOL-MYERS SQUIBB Pharmaceutical Group Montreal, Quebec,
Member PMAC  PAAB

continue - Adverse Events Schedule follows

- Victor G.L. Jasin
  jasin@uwo.ca
 "iki pasirasymo!"


                                                                       

@FROM   :jasin@julian.uwo.ca                                          
@SUBJECT:SERZONE (nefazodone HCl) repost part 3 of 3                  
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From: jasin@julian.uwo.ca (Vic  Jasin)
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Subject: SERZONE (nefazodone HCl) repost part 3 of 3
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..........continued
DISCLAIMER:
The following information was reproduced from literature received from
Bristol-Myers Squibb Canada Inc.. No warranty is made for clerical 
accuracy
or completeness and as this is a Canadian release it is highly 
recommended
that this be used as nothing more than an informal overview until such 
time
that the same literature is published and received from U.S. source. 
No
interpretation or judgment has been used in providing this information 
by
the writer but still should be considered third party information.
-----------------------------------------------------------------------
-------
------------------------------
----------------
ADVERSE EVENTS (INCIDENCE >= 1%) IN PLACEBO-CONTROLLED TRIALS
(6-8 WEEKS)

Body System/             Nefazodone     Placebo        Nefazodone      
Placebo
Adverse Experience       Low                                          
High
                                        Dose                                  
     Dose
   50-300mg/day                    100-600mg/day
   n=271             n=272            n=393                n=394

BODY AS A WHOLE
     Headache                 121(44.7)      110(40.4)      142(36.1)         
 130(33.0)
     Asthenia                     25(  9.2)**        9( 3.3)        
42(10.7)**
         20(  5.1)
     Infection                     17(  6.3)         14( 5.2)        
30(  7.6)
             21(  5.3)
     Abdominal Pain          13( 4.8)          17( 6.3)        22(  
5.6)      
      27(  6.9)
     Flu Syndrome             12( 4.4)          10( 3.7)        13(  
3.3)     
         9(  2.3)
     Pain                            16( 5.9)          17( 6.3)        
19( 
4.8)             22(  5.6)
     Back Pain                   10( 3.7)          11( 4.0)        15(  
3.8)  
          15(  3.8)
     Accidental Injury           6( 2.2)           6( 2.2)          9(  
2.3)  
           12(  3.1)
     Chills                                 -                    -            
 7(  1.8)                2(  0.5)
     Fever                            5( 1.8)*          0( 0.0)          
6( 
1.5)               2(  0.5)
     Chest Pain                    3( 1.1)         10( 3.7)          
7(  1.8) 
           13(  3.3)
     Neck Rigidity                      -                   -              
4( 
1.0)               0(  0.0)

CARDIOVASCULAR SYSTEM
     Postural Hypotension   9( 3.3)          5( 1.8)         17( 
4.3)**       
    4(  1.0)
     Palpitation                        -                    -             
11( 2.8)             12(  3.1)
     Hypotension                     -                   -                 
7(
1,8)               2(  0.5)
     Migraine                           -                   -                
5( 1.3)               2(  0.5)

DIGESTIVE SYSTEM
     Dry Mouth                   58(21.4)*      37(13.6)        
98(24.9)**    
    53(13.5)
     Nausea                       40(14.8)        34(12.5)        
86(21.9)**  
      48(12.2)
     Constipation               31(11.4)        24(  8.8)        
55(14.0)**   
     33(  8.4)
     Diarrhea                     17(  6.3)        17(  6.3)        
33(  8.4) 
          29(  7.4)
     Dyspepsia                  16(  5.9)        14( 5.2)        34(  
8.7)    
        29(  7.4)
     Increased Appetite       7(  2.6)           6( 2.2)        19(  
4.8)     
      10(  2.5)
     Flatulence                    4(  1.5)         12( 4.4)        
11(  2.8) 
          11(  2.8)
     Vomiting                       5(  1.9)           5( 1.8)          
7( 
1.8)              7(  1.8)
     Nausea & Vomiting      3(  1.1)           1( 0.4)          6(  
1.5)      
       2(  0.5)
     Anorexia                      3(  1.1)            3( 1.1)             
-  
                     -
     Gastroenteritis            3(  1.1)            1( 0.4)            
-      
                   -

METABOLIC & NUTRITIONAL
     Peripheral Edema       3(  1.1)            4( 1.5)        10( 
2.5)       
       5( 1.3)
     Weight Gain                   -                        -              
8(
2.0)               6( 1.5)
     Edema                             -                         -           
4( 1.0)               3( 0.8)
     Thirst                             -                        -            
  4( 1.0)               1( 0.3)

MUSCULOSKELETAL
     Maylgia                       5(  1.9)            7( 2.6)          
8(
2.0)               7( 1.8)
     Cramp                              -                        -            
5( 1.3)               5( 1.3)
     Arthralgia                         -                        -            
4( 1.0)               1( 0.3)

NERVOUS SYSTEM
     Somnolence               47(17.3)         35(12.9)     
100(25.5)**       
 54(13.7)
     Dizziness                  27(10.0)*        13(  4.8)       
65(16.5)**   
      21( 5.3)
     Insomnia                   25(  9.2)          21(  7.7)       
42(10.7)   
         36( 9.1)
     Lightheadedness      17(  6.3)          12(  4.4)       
40(10.2)**       
  13( 3.3)
     Confusion                    5(  1.9)            3(  1.1)       
27( 
6.9)**            5( 1.3)
     Agitation                     13( 4.8)          12(  4.4)       
22(  5.6)
            27( 6.9)
     Paresthesia                  5( 1.9)            5(  1.8)       
16(  4.1)*
            6( 1.5)
     Vasodilatation               7( 2.6)           7(  2.6)        
16(  4.1) 
            7( 1.8)
     Abnormal Dreams         8( 3.0)           5(  1.8)        13(  
3.3)      
       7( 1.8)
     Memory Impairment     6( 2.2)           6(  2.2)         16( 4.1)        
      7( 1.8)
     Tremor                          5( 1.9)           4(  1.5)           
6( 
1.5)              3( 0.8)
     Incoordination                     -                   -             
11( 
2.8)**           2( 0.5)
     Ataxia                            4( 1.5)           0( 0.0)           
4( 
1.0)              0( 0.0)
     Decreased Concentration  -                   -               10(  
2.5)   
         4( 1.0)
     Hypesthesia                  5( 1.9)           1( 0.4)           
5(  1.3)
             2( 0.5)
     Anxiety                          7( 2.6)          13( 4.8)          
8( 
2.0)*           21( 5.3)
     Psychomotor Retard.    3( 1.1)            1( 0.4)          6(  
1.5)      
       2( 0.5)
     Depression                   4( 1.5)            3( 1.1)          
5(  1.3)
             3( 0.8)
     Euphoria                       3( 1.1)            3( 1.1)             
-  
                     -
     Hypertonia                         -                   -               
4(  1.0)              0( 0.0)
     Decreased Libido              -                   -                
4( 
1.0)              1( 0.3)

RESPIRATORY SYSTEM
     Pharyngitis                 10( 3.7)         16(  5.9)         
25(  6.4) 
          19( 4.8)
     Rhinitis                       19( 7.0)         16(  5.9)         
16( 
4.1)            16( 4.1)
     Sinusitis                     13( 4.8)         14(  5.2)         
25( 
6.4)            22( 5.6)
     Cough Increased               -                   -               
13( 
3.3)              5( 1.3)

SKIN & APPENDAGES
     Sweating                      5( 1.9)           5(  1.8)         
11( 
2.8)             12( 3.1)
     Rash                            3( 1.1)           4(  1.5)           
8( 
2.0)               5( 1.3)
     Pruritus                        5( 1.9)           3(  1.1)           
9( 
2.3)               5( 1.3)

SPECIAL SENSES
     Amblyopia                   8( 3.0)           6(  2.2)          
34( 
8.7)**          11( 2.8)
     Eye Disorder                  -                     -                
18( 
4.6)**            2( 0.5)
     Taste Perversion        3( 1.1)           2(  0.7)            7(   
1.8)  
           3( 0.8)
     Abnormal Vision               -                   -                
14( 
3.6)*             4( 1.0)
     Tinnitus                           -                   -                 
 8(  2.0)               5( 1.3)
     Visual Field Defect           -                   -                 
6( 
1.5)*              0( 0.0)

UROGENITAL SYSTEM
     Urinary Frequency      3( 1.1)           4(  1.5)           9(  
2.3)     
          5( 1.3)
     Urinary Retention             -                   -                 
8( 
2.0)               3( 0.8)
     Urinary Tract Infection      -                    -                
9( 
2.3)               3( 0.8)
     Impotence M^2            4( 3.6)           0(  0.0)                  
-   
                     -
     Dysmenorrhea F^1      4( 2.5)         11(  6.4)           9(  
3.7)       
       6( 2.3)
     Vaginitis F^1                3( 1.9)           2(  1.2)           
5( 
1.9)               2( 0.8)
     Dysuria                            -                   -                
5(  1.3)               5( 1.3)
     Breast Pain F^1               -                   -                  
3( 
1.1)              1( 0.4)
-----------------------------------------------------------------------
-------
------------------------------
--------------
     *    Significant difference from placebo, p<=0.05
     **   Significant difference from placebo, p<=0.01
     1    Percentage corrected for gender
          Females: Placebo overall n=283, low n=172, high n=244
                          Nefazodone overall n=423, low n=159, high 
n=264
     2    Percentage corrected for gender
          Males:    Placebo overall n=171, low n=110, high n=150
                         Nefazodone overall n=241, low n=112, high 
n=129

PREVIOUSLY OMMITTED UNDER DRUG ABUSE AND DEPENDENCE
     While the premarketing clinical experience with nefazodone did 
not reveal
any
tendency for a withdrawal syndrome or any drug seeking behaviour, 
these
observations were not systematic, and it is not possible to predict on 
the
basis of
this limited experience the extent to which a CNS-active drug will be 
misused,
diverted, and/or abused once marketed. Consequently, physicians should
carefully evaluate patients for a history of drug abuse and follow 
such
patients
closely, observing them for signs of misuse or abuse of SERZONE (eg.
development of tolerance, dose esalation, drug-seeking behaviour).

WITH ELECTRO-CONVULSIVE THERAPY (ECT): There are no clinical studies
establishing the benefit of the combined use of ECT and nefazodone.

=============================END OF SERZONE
INFO==============

- Victor G.L. Jasin
  jasin@uwo.ca
 "iki pasirasymo!"



