A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Serzone Warnings, Precautions, Pregnancy, Nursing, Abuse - Nefazodone Hcl
Serzone Warnings, Precautions, Pregnancy, Nursing, Abuse - Nefazodone Hcl
WARNINGS
Hepatotoxicity (See BOXED WARNING.)
Cases of life-threatening hepatic failure have been reported
in patients treated with SERZONE.
The reported rate in the United States is about 1 case of liver
failure resulting in death or transplant per 250,000 -300,000 patient-years
of SERZONE treatment. This represents a rate of about 3-4 times the estimated
background rate of liver failure. This rate is an underestimate because of under
reporting, and the true risk could be considerably greater than this. A large
cohort study of antidepressant users found no cases of liver failure leading
to death or transplant among SERZONE users in about 30,000 patient-years of
exposure. The spontaneous report data and the cohort study results provide estimates
of the upper and lower limits of the risk of liver failure in nefazodone-treated
patients, but are not capable of providing a precise risk estimate.
The time to liver injury for the reported liver failure cases
resulting in death or transplant generally ranged from 2 weeks to 6 months on
SERZONE therapy. Although some reports described dark urine and nonspecific
prodromal symptoms (eg, anorexia, malaise, and gastrointestinal symptoms), other
reports did not describe the onset of clear prodromal symptoms prior to the
onset of jaundice.
The physician may consider the value of liver function testing.
Periodic serum transaminase testing has not been proven to prevent serious injury
but it is generally believed that early detection of drug-induced hepatic injury
along with immediate withdrawal of the suspect drug enhances the likelihood
for recovery.
Patients should be advised to be alert for signs and symptoms
of liver dysfunction (jaundice, anorexia, gastroin-testinal complaints, malaise,
etc) and to report them to their doctor immediately if they occur. Ongoing clinical
assessment of patients should govern physician interventions, including diagnostic
evaluations and treatment.
SERZONE should be discontinued if clinical signs or symptoms
suggest liver failure (see PRECAUTIONS: Information
for Patients). Patients who develop evidence of hepatocellular injury such as
increased serum AST or serum ALT levels ³3
times the upper limit of NORMAL, while on SERZONE should be withdrawn from the
drug. These patients should be presumed to be at increased risk for liver injury
if SERZONE is reintroduced. Accordingly, such patients should not be considered
for re-treatment.
Potential for Interaction with Monoamine Oxidase Inhibitors
In patients receiving antidepressants with pharmacological
properties similar to nefazodone in combination with a monoamine oxidase inhibitor
(MAOI), there have been reports of serious, sometimes fatal, reactions. For
a selective serotonin reuptake inhibitor (SSRI), these reactions have included
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid
fluctuations of vital signs, and mental status changes that include extreme
agitation progressing to delirium and coma. These reactions have also been reported
in patients who have recently discontinued that drug and have been started on
an MAOI. Some cases presented with features resembling neuroleptic malignant
syndrome. Severe hyperthermia and seizures, sometimes fatal, have been reported
in association with the combined use of tricyclic antidepressants and MAOIs.
These reactions have also been reported in patients who have recently discontinued
these drugs and have been started on an MAOI.
Although the effects of combined use of nefazodone and MAOI
have not been evaluated in humans or animals, because nefazodone is an inhibitor
of both serotonin and norepinephrine reuptake, it is recommended that nefazodone
not be used in combination with an MAOI, or within 14 days of discontinuing
treatment with an MAOI.At least 1 week should be allowed after stopping nefazodone
before starting an MAOI.
Clinical Worsening and Suicide Risk
Patients with major depressive disorder, both adult and pediatric,
may experience worsening of their depression and/or the emergence of suicidal
ideation and behavior (suicidality), whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Although
there has been a long-standing concern that antidepressants may have a role
in inducing worsening of depression and the emergence of suicidality in certain
patients, a causal role for antidepressants in inducing such behaviors has not
been established. Nevertheless, patients being treated with antidepressants
should be observed closely for clinical worsening and suicidality, especially
at the beginning of a course of drug therapy, or at the time of dose changes,
either increases or decreases. Consideration should be given to changing
the therapeutic regimen, including possibly discontinuing the medication, in
patients whose depression is persistently worse or whose emergent suicidality
is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.
Because of the possibility of co-morbidity between major depressive
disorder and other psychiatric and nonpsychiatric disorders, the same precautions
observed when treating patients with major depressive disorder should be observed
when treating patients with other psychiatric and nonpsychiatric disorders.
The following symptoms, anxiety, agitation, panic attacks,
insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor
restlessness), hypomania, and mania, have been reported in adult and pediatric
patients being treated with antidepressants for major depressive disorder as
well as for other indications, both psychiatric and nonpsychiatric. Although
a causal link between the emergence of such symptoms and either the worsening
of depression and/or the emergence of suicidal impulses has not been established,
consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication in patients for whom such symptoms are
severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants
for major depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of agitation,
irritability, and the other symptoms described above, as well as the emergence
of suicidality, and to report such symptoms immediately to health care providers.
Prescriptions for SERZONE should be written for the smallest quantity of
capsules consistent with good patient management, in order to reduce the risk
of overdose.
It should be noted that SERZONE is not approved for use in
treating any indications in the pediatric population.
A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase
the likelihood of precipitation of a mixed/manic episode in patients at risk
for bipolar disorder. Whether any of the symptoms described above represent
such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that SERZONE is not approved for use in treating bipolar
depression.
Interaction with Triazolobenzodiazepines
Interaction studies of nefazodone with two triazolobenzodiazepines,
ie, triazolam and alprazolam, metabolized by cytochrome P450 3A4, have revealed
substantial and clinically important increases in plasma concentrations of these
compounds when administered concomitantly with nefazodone.
Triazolam
When a single oral 0.25-mg dose of triazolam was coadministered
with nefazodone (200 mg BID) at steady state, triazolam half-life and AUC increased
4-fold and peak concentrations increased 1.7-fold. Nefazodone plasma concentrations
were unaffected by triazolam. Coadministration of nefazodone potentiated
the effects of triazolam on psychomotor performance tests. If triazolam
is coadministered with SERZONE, a 75% reduction in the initial triazolam dosage
is recommended. Because not all commercially available dosage forms of triazolam
permit sufficient dosage reduction, coadministration of triazolam with SERZONE
should be avoided for most patients, including the elderly. In the exceptional
case where coadministration of triazolam with SERZONE may be considered appropriate,
only the lowest possible dose of triazolam should be used (see CONTRAINDICATIONS
and PRECAUTIONS).
Alprazolam
When alprazolam (1 mg BID) and nefazodone (200 mg BID) were
coadministered, steady-state peak concentrations, AUC and half-life values for
alprazolam increased by approximately 2-fold.Nefazodone plasma concentrations
were unaffected by alprazolam. If alprazolam is coadministered with SERZONE,
a 50% reduction in the initial alprazolam dosage is recommended. No dosage adjustment
is required for SERZONE.
Potential Terfenadine, Astemizole, Cisapride, and Pimozide
Interactions
Terfenadine, astemizole, cisapride, and pimozide are all
metabolized by the cytochrome P450 3A4 (CYP3A4) isozyme, and it has been demonstrated
that ketoconazole, erythromycin, and other inhibitors of CYP3A4 can block the
metabolism of these drugs, which can result in increased plasma concentrations
of parent drug. Increased plasma concentrations of terfenadine, astemizole,
cisapride, and pimozide are associated with QT prolongation and with rare cases
of serious cardiovascular adverse events, including death, due principally to
ventricular tachycardia of the torsades de pointes type. Nefazodone has been
shown in vitro to be an inhibitor of CYP3A4. Consequently, it is recommended
that nefazodone not be used in combination with either terfenadine, astemizole,
cisapride, or pimozide (see CONTRAINDICATIONS
and PRECAUTIONS).
Interaction with Carbamazepine
The coadministration of carbamazepine 200 mg BID with nefazodone
200 mg BID, at steady state for both drugs, resulted in almost 95% reductions
in AUCs for nefazodone and hydroxynefazodone, likely resulting in insufficient
plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant
effect for SERZONE. Consequently, it is recommended that SERZONE not be used
in combination with carbamazepine (see CONTRAINDICATIONS
and PRECAUTIONS).
PRECAUTIONS
General
Hepatotoxicity (See BOXED WARNING.)
Postural Hypotension
A pooled analysis of the vital signs monitored during placebo-controlled
premarketing studies revealed that 5.1% of nefazodone patients compared to 2.5%
of placebo patients (p£0.01) met criteria for a potentially
important decrease in blood pressure at some time during treatment (systolic
blood pressure £90 mmHg and a change from
baseline of ³20 mmHg).While there was no difference
in the proportion of nefazodone and placebo patients having adverse events characterized
as ‘syncope’ (nefazodone, 0.2%; placebo, 0.3%), the rates for adverse events
characterized as ‘postural hypotension’ were as follows: nefazodone (2.8%),
tricyclic antidepressants (10.9%), SSRI (1.1%), and placebo (0.8%).Thus, the
prescriber should be aware that there is some risk of postural hypotension in
association with nefazodone use. SERZONE should be used with caution in patients
with known cardiovascular or cerebrovascular disease that could be exacerbated
by hypotension (history of myocardial infarction, angina, or ischemic stroke)
and conditions that would predispose patients to hypotension (dehydration, hypovolemia,
and treatment with antihypertensive medication).
Activation of Mania/Hypomania
During premarketing testing, hypomania or mania occurred in
0.3% of nefazodone-treated unipolar patients, compared to 0.3% of tricyclic-
and 0.4% of placebo-treated patients. In patients classified as bipolar the
rate of manic episodes was 1.6% for nefazodone, 5.1% for the combined tricyclic-treated
groups, and 0% for placebo-treated patients. Activation of mania/hypomania is
a known risk in a small proportion of patients with major affective disorder
treated with other marketed antidepressants. As with all antidepressants, SERZONE
(nefazodone hydrochloride) should be used cautiously in patients with a history
of mania.
Seizures
During premarketing testing, a recurrence of a petit mal seizure
was observed in a patient receiving nefazodone who had a history of such seizures.
In addition, one nonstudy participant reportedly experienced a convulsion (type
not documented) following a multiple-drug overdose (see OVERDOSAGE).
Rare occurrences of convulsions (including grand mal seizures) following nefazodone
administration have been reported since market introduction. A causal relationship
to nefazodone has not been established (see ADVERSE
REACTIONS).
Priapism
While priapism did not occur during premarketing experience
with nefazodone, rare reports of priapism have been received since market introduction.
A causal relationship to nefazodone has not been established (see ADVERSE
REACTIONS). If patients present with prolonged or inappropriate erections,
they should discontinue therapy immediately and consult their physicians. If
the condition persists for more than 24 hours, a urologist should be consulted
to determine appropriate management.
Use in Patients with Concomitant Illness
SERZONE has not been evaluated or used to any appreciable extent
in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were systematically excluded from clinical
studies during the product’s premarketing testing. Evaluation of electrocardiograms
of 1153 patients who received nefazodone in 6- to 8-week, double-blind, placebo-controlled
trials did not indicate that nefazodone is associated with the development of
clinically important ECG abnormalities. However, sinus bradycardia, defined
as heart rate £50 bpm and a decrease of at least
15 bpm from baseline, was observed in 1.5% of nefazodone-treated patients compared
to 0.4% of placebo-treated patients
(p£0.05).Because patients with a
recent history of myocardial infarction or unstable heart disease were excluded
from clinical trials, such patients should be treated with caution.
In patients with cirrhosis of the liver, the AUC values of
nefazodone and HO-NEF were increased by approximately 25%.
INFORMATION FOR PATIENTS
(See Patient Information.)
Physicians are advised to discuss the following issues with
patients for whom they prescribe SERZONE:
Hepatotoxicity
Patients should be informed that SERZONE therapy has been associated
with liver abnormalities ranging from asymptomatic reversible serum transaminase
increases to cases of liver failure resulting in transplant and/or death. At
present, there is no way to predict who is likely to develop liver failure.
Ordinarily, patients with active liver disease should not be treated with SERZONE.
Patients should be advised to be alert for signs of liver dysfunction (jaundice,
anorexia, gastrointestinal complaints, malaise, etc) and to report them to their
doctor immediately if they occur.
Suicide
Patients and their families should be encouraged to be alert
to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, impulsivity, akathisia, hypomania, mania, worsening of depression,
and suicidal ideation, especially early during antidepressant treatment. Such
symptoms should be reported to the patient’s physician, especially if they are
severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Time to Response/Continuation
As with all antidepressants, several weeks on treatment may
be required to obtain the full antidepressant effect. Once improvement is noted,
it is important for patients to continue drug treatment as directed by their
physician.
Interference With Cognitive and Motor Performance
Since any psychoactive drug may impair judgment, thinking,
or motor skills, patients should be cautioned about operating hazardous machinery,
including automobiles, until they are reasonably certain that SERZONE therapy
does not adversely affect their ability to engage in such activities.
Pregnancy
Patients should be advised to notify their physician if they
become pregnant or intend to become pregnant during therapy.
Nursing
Patients should be advised to notify their physician if they
are breast-feeding an infant (see PRECAUTIONS:
Nursing Mothers).
Concomitant Medication
Patients should be advised to inform their physicians if they
are taking, or plan to take, any prescription or over-the-counter drugs, since
there is a potential for interactions. Significant caution is indicated if SERZONE
is to be used in combination with XANAX®, concomitant use with
HALCION® should be avoided for most patients including the elderly,
and concomitant use with SELDANE®, HISMANAL®,
PROPULSID®, ORAP®, or TEGRETOL® is
contraindicated (see CONTRAINDICATIONS and
WARNINGS).
Alcohol
Patients should be advised to avoid alcohol while taking SERZONE
(nefazodone hydrochloride).
Allergic Reactions
Patients should be advised to notify their physician if they
develop a rash, hives, or a related allergic phenomenon.
Visual Disturbances
There have been reports of visual disturbances associated with
the use of nefazodone, including blurred vision, scotoma, and visual trails.
Patients should be advised to notify their physician if they develop visual
disturbances.(See ADVERSE REACTIONS.)
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
There is no evidence of carcinogenicity with nefazodone. The
dietary administration of nefazodone to rats and mice for 2 years at daily doses
of up to 200 mg/kg and 800 mg/kg,respectively, which are approximately 3 and
6 times, respectively, the maximum human daily dose on a mg/m2 basis,
produced no increase in tumors.
Mutagenesis
Nefazodone has been shown to have no genotoxic effects based
on the following assays: bacterial mutation assays, a DNA repair assay in cultured
rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells,
anin vivo cytoge-netics assay in rat bone marrow cells, and a rat dominant
lethal study.
Impairment of Fertility
A fertility study in rats showed a slight decrease in fertility
at 200 mg/kg/day (approximately three times the maximum human daily dose on
a mg/m2 basis) but not at 100 mg/kg/day (approximately 1.5 times
the maximum human daily dose on a mg/m2 basis).
Pregnancy
Teratogenic Effects—Pregnancy Category C
Reproduction studies have been performed in pregnant rabbits
and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately
6 and 5 times, respectively, the maximum human daily dose on a mg/m2 basis).
No malformations were observed in the offspring as a result of nefazodone treatment.
However, increased early pup mortality was seen in rats at a dose approximately
five times the maximum human dose, and decreased pup weights were seen at this
and lower doses, when dosing began during pregnancy and continued until weaning.
The cause of these deaths is not known. The no-effect dose for rat pup mortality
was 1.3 times the human dose on a mg/m2 basis. There are no adequate
and well-controlled studies in pregnant women. Nefazodone should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Labor and Delivery
The effect of SERZONE (nefazodone hydrochloride) on labor and
delivery in humans is unknown.
Nursing Mothers
It is not known whether SERZONE or its metabolites are excreted
in human milk. Because many drugs are excreted in human milk, caution should
be exercised when SERZONE is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in individuals below 18 years of age
have not been established (see WARNINGS: Clinical
Worsening and Suicide Risk).
Geriatric Use
Of the approximately 7000 patients in clinical studies who
received SERZONE for the treatment of depression, 18% were 65 years and older,
while 5% were 75 years and older. Based on monitoring of adverse events, vital
signs, electrocardiograms, and results of laboratory tests, no overall differences
in safety between elderly and younger patients were observed in clinical studies.
Efficacy in the elderly has not been demonstrated in placebo-controlled trials.
Other reported clinical experience has not identified differences in responses
between elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
Due to the increased systemic exposure to nefazodone seen in
single-dose studies in elderly patients (see CLINICAL
PHARMACOLOGY: Pharmacokinetics), treatment should be initiated
at half the usual dose, but titration upward should take place over the same
range as in younger patients (see DOSAGE AND ADMINISTRATION).
The usual precautions should be observed in elderly patients who have concomitant
medical illnesses or who are receiving concomitant drugs.
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