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ZOLOFT
Source:
FDA
(sertraline hydrochloride)
Tablets and Oral Concentrate
CONTRAINDICATIONS
All Dosage Forms of ZOLOFT:
Zoloft Side Effects Defined
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Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is
contraindicated (see
WARNINGS). Concomitant use in patients taking pimozide is contraindicated
(see PRECAUTIONS).
ZOLOFT is
contraindicated in patients with a hypersensitivity to sertraline or any of
the inactive
ingredients in ZOLOFT.
Oral Concentrate:
ZOLOFT oral concentrate is contraindicated with ANTABUSE
(disulfiram) due to the alcohol content of the concentrate.
WARNINGS
Cases of serious sometimes fatal reactions have been
reported in patients receiving ZOLOFT
(sertraline hydrochloride), a selective
serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase
inhibitor (MAOI). Symptoms of a drug interaction between an SSRI and an MAOI
include: hyperthermia, rigidity, myoclonus, autonomic instability with
possible rapid fluctuations of vital signs, mental status changes that
include confusion, irritability, and extreme agitation progressing to
delirium and coma. These reactions have also been reported in patients who
have recently discontinued an SSRI and have been started on an MAOI. Some
cases presented with features resembling neuroleptic
malignant syndrome.
Therefore, ZOLOFT should not be used in combination with an MAOI, or within
14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days
should be
allowed after stopping ZOLOFT 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
ZOLOFT should be written for the smallest quantity of tablets consistent
with good patient management, in order to reduce the risk of overdose.
If the decision has been made to discontinue treatment,
medication should be tapered, as rapidly as is feasible, but with
recognition that abrupt discontinuation can be associated with certain
symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of
Treatment with ZOLOFT, for a description of the risks of discontinuation of
ZOLOFT).
It should be noted that ZOLOFT is approved in the pediatric population only
for obsessive
compulsive disorder.
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 ZOLOFT is not approved for use in treating bipolar
depression.
PRECAUTIONS
General
Activation of Mania/Hypomania?During
premarketing
testing, hypomania or mania occurred in
approximately 0.4% of ZOLOFT
(sertraline hydrochloride) treated
patients.
Weight Loss?Significant
weight loss may be an undesirable result of treatment with sertraline for
some patients, but on average, patients in controlled trials had minimal, 1
to 2 pound weight loss, versus smaller changes on placebo. Only rarely have
sertraline patients been discontinued for weight loss.
Seizure ?ZOLOFT
has not been evaluated in patients with a seizure disorder. These patients
were excluded
from clinical studies during the product?s premarket testing. No seizures
were observed among approximately 3000 patients treated with ZOLOFT in the
development program for major depressive disorder. However, 4 patients out
of approximately 1800 (220<18 years of age) exposed during the development
program for obsessive-compulsive disorder experienced seizures, representing
a crude incidence of 0.2%. Three of these patients were adolescents, two
with a seizure disorder and one with a family history of seizure disorder,
none of whom were receiving anticonvulsant medication. Accordingly, ZOLOFT
should be introduced with care in patients with a seizure disorder.
Discontinuation of Treatment with
Zoloft
During marketing of Zoloft and other SSRIs and SNRIs
(Serotonin and Norepinephrine Reuptake Inhibitors), there have been
spontaneous reports of adverse events occurring upon discontinuation of
these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g.
paresthesias such as electric shock sensations), anxiety, confusion,
headache, lethargy, emotional lability, insomnia, and hypomania. While these
events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment
with Zoloft. A gradual reduction in the dose rather than abrupt cessation is
recommended whenever possible. If
intolerable symptoms
occur following a decrease in the dose or upon discontinuation of treatment,
then resuming
the previously prescribed dose may be considered. Subsequently, the
physician may
continue decreasing the dose but at a more gradual rate (see DOSAGE AND
ADMINISTRATION).
Abnormal Bleeding
Published case reports have documented the occurrence of
bleeding episodes in patients treated with psychotropic drugs that interfere
with serotonin reuptake. Subsequent epidemiological studies, both of the
case-control and cohort design, have demonstrated an association between use
of psychotropic drugs that interfere with serotonin reuptake and the
occurrence of upper gastrointestinal bleeding. In two studies, concurrent
use of a non-selective nonsteroidal anti-inflammatory drug (i.e., NSAIDs
that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin
potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these
studies focused on upper gastrointestinal bleeding, there is reason to
believe that bleeding at other sites may be similarly potentiated. Patients
should be cautioned regarding the risk of bleeding associated with the
concomitant use of ZOLOFT with non-selective NSAIDs (i.e., NSAIDs that
inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin, or other
drugs that affect coagulation.
Weak Uricosuric Effect?ZOLOFT
(sertraline
hydrochloride) is associated with a mean decrease in serum uric acid of
approximately 7%. The clinical significance of this weak uricosuric effect
is unknown.
Use in Patients with Concomitant Illness?Clinical
experience with ZOLOFT in patients with certain concomitant systemic illness
is limited. Caution is advisable in using ZOLOFT in patients with diseases
or conditions that could affect metabolism or hemodynamic responses.
Patients with a recent history of myocardial infarction
or unstable heart disease were excluded from clinical studies during the
product?s premarket testing. However, the electrocardiograms of 774 patients
who received ZOLOFT in double-blind trials were evaluated and the data
indicate that ZOLOFT is not associated with the development of significant
ECG abnormalities.
ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose
of 89 mg/day) was
evaluated in a post-marketing, placebo-controlled trial of 372 randomized
subjects with a DSM-IV diagnosis of major depressive disorder and recent
history of myocardial infarction or unstable angina requiring
hospitalization. Exclusions from this trial included, among others, patients
with uncontrolled hypertension, need for cardiac surgery, history of CABG
within 3 months of index event, severe or symptomatic bradycardia,
non-atherosclerotic cause of angina, clinically significant renal impairment
(creatinine > 2.5 mg/dl), and clinically significant hepatic dysfunction.
ZOLOFT treatment initiated during the acute phase of recovery (within 30
days post-MI or post-hospitalization for unstable angina) was
indistinguishable from placebo in this study on the following week 16
treatment endpoints: left ventricular ejection fraction, total
cardiovascular events (angina, chest pain, edema, palpitations, syncope,
postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP),
and major cardiovascular events involving death or requiring hospitalization
(for MI, CHF, stroke, or angina).
ZOLOFT is extensively metabolized
by the liver. In patients with chronic mild liver impairment, sertraline
clearance was reduced, resulting in increased AUC, Cmax and elimination
half-life. The effects of sertraline in patients with moderate and severe
hepatic impairment have not been studied. The use of sertraline in patients
with liver disease must be approached with caution. If sertraline is
administered to patients with liver impairment, a lower or less frequent
dose should be used (see CLINICAL PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
Since ZOLOFT is extensively metabolized, excretion of
unchanged drug in urine is a minor route of elimination. A clinical study
comparing sertraline pharmacokinetics in healthy volunteers to that in
patients with renal impairment ranging from mild to severe (requiring
dialysis) indicated that the pharmacokinetics and protein binding are
unaffected by renal disease. Based on the pharmacokinetic results, there is
no need for dosage adjustment in patients with renal impairment (see
CLINICAL PHARMACOLOGY).
Interference with Cognitive and Motor Performance?In
controlled
studies, ZOLOFT did not
cause sedation and did not interfere with psychomotor performance. (See
Information for Patients.)
Hyponatremia?Several
cases of hyponatremia have been reported and
appeared to be reversible
when ZOLOFT was
discontinued. Some cases were possibly due to the syndrome of inappropriate
antidiuretic hormone secretion. The majority of these occurrences have been
in elderly individuals, some in patients taking diuretics or who were
otherwise volume depleted.
Platelet Function?There
have been rare reports of altered platelet
function and/or abnormal results from laboratory studies in patients taking
ZOLOFT. While there have been reports of
abnormal bleeding or
purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT
had a causative role.
Information for Patients
Physicians are advised to discuss the following issues
with patients for whom they prescribe ZOLOFT:
Patients should be told that although ZOLOFT has not been shown to impair
the ability of normal subjects to perform tasks requiring complex motor and
mental skills in laboratory experiments, drugs that act upon the central
nervous system may affect some individuals
adversely. Therefore,
patients should be told that until they learn how they respond to ZOLOFT
they should be careful doing activities when they need to be alert, such as
driving a car or operating machinery.
Patients should be cautioned about the concomitant use of ZOLOFT and
non-selective NSAIDs
(i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2),
aspirin, or other drugs that affect coagulation since the combined use of
psychotropic drugs that interfere with serotonin reuptake and these agents
has been associated with an increased risk of bleeding.
Patients should be told that although ZOLOFT has not been shown in
experiments with normal
subjects to
increase the mental and motor skill impairments caused by alcohol, the
concomitant use
of ZOLOFT and alcohol is not advised.
Patients and their families should be encouraged to be alert to the
emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility (aggressiveness), impulsivity, akathisia
(psychomotor
restlessness), 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.
Patients should be told that while no adverse interaction of ZOLOFT with
over-the-counter
(OTC) drug products is
known to occur, the potential for interaction exists. Thus, the use of any
OTC product should be initiated cautiously according to the directions of
use given for the OTC product.
Patients should be advised to notify their physician if they become pregnant
or intend to
become pregnant during therapy.
Patients should be advised to notify their physician if
they are breast feeding an infant.
ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to
the alcohol
content of the concentrate.
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the
hydrochloride) as the active ingredient and 12% alcohol. ZOLOFT Oral
Concentrate must be diluted before use. Just before taking, use the dropper
provided to remove the required amount of ZOLOFT Oral Concentrate and mix
with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or
orange juice
ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the
liquids listed.
The dose should be taken immediately after mixing. Do not mix in advance. At
times, a slight haze may appear after mixing; this is normal. Note that
caution should be exercised for persons with latex sensitivity, as the
dropper dispenser contains dry natural rubber.
Laboratory Tests
None.
Drug Interactions
Potential Effects of Coadministration of Drugs Highly Bound to Plasma
Proteins?Because
sertraline is tightly bound to plasma protein, the administration of ZOLOFT
(sertraline
hydrochloride) to a
patient taking another drug which is tightly bound to protein (e.g.,
warfarin,
digitoxin) may cause a shift in plasma concentrations potentially resulting
in an adverse effect. Conversely, adverse effects may result from
displacement of protein bound ZOLOFT by other tightly bound drugs.
In a study comparing prothrombin time AUC (0-120 hr)
following dosing with warfarin
(0.75 mg/kg) before and after 21 days of dosing with
either ZOLOFT (50-200 mg/day) or placebo,
there was a mean increase in prothrombin time of 8% relative to baseline for
ZOLOFT compared to a 1% decrease for placebo (p<0.02). The normalization of
prothrombin time for the ZOLOFT group was delayed compared to the placebo
group. The clinical significance of this change is
unknown. Accordingly,
prothrombin time should be carefully monitored when ZOLOFT therapy is
initiated or stopped.
Cimetidine?In
a study assessing disposition of ZOLOFT (100
mg) on the second of 8 days of cimetidine administration (800 mg daily),
there were significant increases in ZOLOFT mean AUC (50%), Cmax (24%) and
half-life (26%) compared to the placebo group. The clinical significance of
these changes is unknown.
CNS Active Drugs?In
a study comparing the disposition of
intravenously administered diazepam before and after 21 days of dosing with
either ZOLOFT (50 to 200 mg/day escalating dose) or placebo, there was a 32%
decrease relative to baseline in diazepam clearance for the ZOLOFT group
compared to a 19% decrease relative to baseline for the placebo group
(p<0.03). There was a 23% increase in Tmax for desmethyldiazepam in the
ZOLOFT group compared to a 20% decrease in the placebo group (p<0.03). The
clinical significance of these changes is unknown.
In a placebo-controlled trial in
normal volunteers, the administration of two doses of ZOLOFT did not
significantly alter steady-state lithium levels or the renal clearance of
lithium.
Nonetheless, at this time, it is recommended that plasma
lithium levels be monitored following initiation of ZOLOFT therapy with
appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline
(q.d.) co-administration to steady state was associated with a mean increase
in pimozide AUC and Cmax of about 40%, but was not associated with any
changes in EKG. Since the highest recommended pimozide dose (10 mg) has not
been evaluated in combination with sertraline, the effect on QT interval and
PK parameters at doses higher than 2 mg at this time are not known. While
the mechanism
of this interaction is unknown, due to the narrow therapeutic index of
pimozide and due
to the interaction noted at a low dose of pimozide, concomitant
administration of ZOLOFT and pimozide should be contraindicated (see
CONTRAINDICATIONS).
The risk of using ZOLOFT in combination with other CNS active drugs has not
been systematically
evaluated.
Consequently, caution is advised if the concomitant administration of ZOLOFT
and such drugs
is required.
There is limited controlled
experience regarding the optimal timing of switching from other drugs
effective in the treatment of major depressive disorder,
obsessive-compulsive disorder, panic disorder, posttraumatic stress
disorder, premenstrual dysphoric disorder and social anxiety disorder to
ZOLOFT. Care and prudent medical judgment should be exercised when
switching, particularly from long-acting agents. The duration of an
appropriate washout period which should intervene before switching from one
selective serotonin reuptake inhibitor (S SRI) to another has not been
established.
Monoamine Oxidase Inhibitors?See
CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4?In
three separate
in vivo
interaction studies,
sertraline was co-administered with cytochrome P450 3A4 substrates,
terfenadine, carbamazepine, or cisapride under steady-state conditions. The
results of these studies indicated that sertraline did not increase plasma
concentrations of terfenadine, carbamazepine, or cisapride. These data
indicate that sertraline?s extent of inhibition of P450 3A4 activity is not
likely to be of clinical significance. Results of the interaction study with
cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of
cisapride (cisapride AUC and Cmax were reduced by about 35%).
Drugs Metabolized by P450 2D6?Many
drugs effective in the treatment of major
depressive disorder, e.g., the SSRIs, including sertraline, and most
tricyclic antidepressant drugs effective in
the treatment of major
depressive disorder inhibit the biochemical activity of the drug
metabolizing
isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may
increase the plasma concentrations of co-administered drugs that are
metabolized by P450 2D6. The drugs for which this potential interaction is
of greatest concern are those metabolized primarily by 2D6 and which have a
narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective
in the treatment of major depressive disorder and the Type 1C
antiarrhythmics propafenone and flecainide. The extent to which this
interaction is an important clinical problem depends on the extent of the
inhibition of
P450 2D6 by the antidepressant and the therapeutic index of the
co-administered drug.
There is variability among the drugs effective in the treatment of major
depressive disorder in the extent of clinically important 2D6 inhibition,
and in fact sertraline at lower doses has a less prominent inhibitory effect
on 2D6 than some others in the class. Nevertheless, even sertraline has the
potential for clinically important 2D6 inhibition. Consequently, concomitant
use of a drug metabolized by P450 2D6 with ZOLOFT may require lower doses
than usually prescribed for the other drug. Furthermore, whenever ZOLOFT is
withdrawn from co-therapy, an increased dose of the co-administered drug may
be required (see Tricyclic Antidepressant Drugs Effective in the Treatment
of Major Depressive Disorder under PRECAUTIONS).
Sumatriptan?There
have been rare postmarketing reports
describing patients with weakness, hyperreflexia, and incoordination
following the use of a selective serotonin reuptake inhibitor
(S SRI) and sumatriptan. If concomitant treatment with
sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine,
paroxetine, sertraline) is clinically warranted, appropriate observation of
the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major
Depressive Disorder (TCAs)?The
extent to which SSRI?TCA interactions may pose
clinical problems will depend on the degree of inhibition and the
pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in
the co-administration of TCAs with ZOLOFT, because sertraline may inhibit
TCA metabolism. Plasma TCA concentrations may need to be monitored, and the
dose of TCA may need to be reduced, if a TCA is co-administered with ZOLOFT
(see Drugs Metabolized by P450 2D6 under PRECAUTIONS).
Hypoglycemic Drugs?In
a placebo-controlled trial in normal
volunteers, administration of
ZOLOFT for 22 days
(including 200 mg/day for the final 13 days) caused a statistically
significant 16%
decrease from baseline in the clearance of tolbutamide following an
intravenous 1000 mg
dose. ZOLOFT administration did not noticeably change
either the plasma protein binding or the apparent volume of distribution of
tolbutamide, suggesting that the decreased clearance was due to a change in
the metabolism of the drug. The clinical significance of this decrease in
tolbutamide clearance is unknown.
Atenolol?ZOLOFT
(100 mg) when
administered to 10 healthy male subjects had no effect on the
beta-adrenergic blocking ability of atenolol.
Digoxin?In
a
placebo-controlled trial in normal volunteers, administration of ZOLOFT for
17 days
(including 200 mg/day for the last 10 days) did not change serum digoxin
levels or digoxin renal clearance.
Microsomal Enzyme Induction?Preclinical
studies have shown ZOLOFT to induce hepatic microsomal enzymes. In clinical
studies, ZOLOFT was shown to induce hepatic enzymes minimally as determined
by a small (5%) but statistically significant decrease in antipyrine
half-life following administration of 200 mg/day for 21 days. This small
change in antipyrine half-life reflects a clinically insignificant change in
hepatic metabolism.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin,
Warfarin, etc.)
Serotonin release by
platelets plays an important role in hemostasis. Epidemiological studies of
the case-control and cohort design that have demonstrated an association
between the use of psychotropic drugs that interfere with serotonin reuptake
and the occurrence of upper gastrointestinal bleeding have also shown that
concurrent use of a non-selective NSAID (i.e.,
NSAIDs that inhibit
both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated the risk
of bleeding. Thus, patients should be cautioned about the use of such drugs
concurrently with ZOLOFT.
Electroconvulsive Therapy?There
are no clinical studies establishing the risks
or benefits of the combined use of electroconvulsive therapy (ECT) and
ZOLOFT.
Alcohol?Although
ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol
in experiments
with normal subjects, the concomitant use of ZOLOFT and alcohol is not
recommended.
Carcinogenesis?Lifetime
carcinogenicity studies were carried out in
CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses
correspond to 1 times (mice) and 2 times (rats) the maximum recommended
human dose (MRHD) on a mg/m2
basis. There was a dose-related increase of liver adenomas in male mice
receiving sertraline at 10-40 mg/kg (0.25-1.0 times the MRHD on a mg/m2
basis). No increase was seen in female mice or in rats of either sex
receiving the same treatments, nor was there an increase in hepatocellular
carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in
the CD-1 mouse and are of unknown significance to humans. There was an
increase in follicular adenomas of the thyroid in female rats receiving
sertraline at 40 mg/kg (2 times the MRHD on a mg/m2
basis); this was not accompanied by thyroid
hyperplasia. While there was an increase in uterine adenocarcinomas in rats
receiving sertraline at
10-40 mg/kg (0.5-2.0
times the MRHD on a mg/m2
basis) compared to placebo controls, this effect
was not clearly drug related.
Mutagenesis?Sertraline
had no genotoxic effects, with or without
metabolic activation, based on the following assays: bacterial mutation
assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations
in vivo
in mouse bone
marrow and in
vitro in human
lymphocytes.
Impairment of Fertility?A
decrease in fertility was seen in one of two
rat studies at a dose of 80 mg/kg (4 times the maximum recommended human
dose on a mg/m2
basis).
Pregnancy?Pregnancy Category C?Reproduction
studies have been performed in rats and rabbits at doses up to 80 mg/kg/day
and 40 mg/kg/day, respectively. These doses correspond to
approximately 4 times
the maximum recommended human dose (MRHD) on a mg/m2
basis. There
was no evidence of teratogenicity at any dose level. When pregnant rats and
rabbits were given sertraline during the period of organogenesis, delayed
ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the
MRHD on a mg/m2
basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m2
basis) in rabbits. When female rats received sertraline during the last
third of gestation and throughout lactation, there was an increase in the
number of stillborn pups and in the number of pups dying during the first 4
days after birth. Pup body weights were also decreased during the first four
days after birth. These effects occurred at a dose of 20 mg/kg (1 times the
MRHD on a mg/m2
basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the
MRHD on a mg/m2
basis). The decrease in pup survival was shown to be due to
in utero
exposure to
sertraline. The clinical significance of these effects is unknown. There are
no adequate and well-controlled studies in pregnant women. ZOLOFT
(sertraline hydrochloride) should be
used during pregnancy only if the potential benefit justifies the potential
risk to the fetus.
Pregnancy-Nonteratogenic Effects?Neonates
exposed to Zoloft and other SSRIs or SNRIs,
late in the third trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding. These findings are
based on postmarketing reports. Such complications can arise immediately
upon delivery. Reported clinical findings have included respiratory
distress, cyanosis, apnea, seizures, temperature instability, feeding
difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia,
tremor, jitteriness, irritability, and constant crying. These features are
consistent with either a direct toxic effect of SSRIs and SNRIs or,
possibly, a drug discontinuation syndrome. It should be noted that, in some
cases, the clinical picture is consistent with serotonin syndrome (see
WARNINGS).
When treating a pregnant woman with ZOLOFT during the third trimester, the
physician should
carefully consider the potential risks and benefits of treatment (see DOSAGE
AND ADMINISTRATION).
Labor and Delivery?The
effect of ZOLOFT on labor and delivery in
humans is unknown.
Nursing Mothers?It
is not known
whether, and if so in what amount, sertraline or its metabolites
are excreted in human milk. Because many drugs are excreted in human milk,
caution should be exercised when ZOLOFT is administered to a nursing woman.
Pediatric Use?The
efficacy of ZOLOFT for the treatment of
obsessive-compulsive disorder was demonstrated in a 12-week, multicenter,
placebo-controlled study with 187 outpatients ages 6-17
(see Clinical Trials
under CLINICAL PHARMACOLOGY). The efficacy of ZOLOFT in pediatric
patients with major depressive disorder, panic disorder, PTSD, PMDD or
social anxiety disorder has not been established.
The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18,
was evaluated in a
12-week, multicenter, placebo-controlled study with 187 outpatients, ages
6-17, and in a flexible dose, 52 week open extension study of 137 patients,
ages 6-18, who had completed the initial 12-week, double-blind,
placebo-controlled study. ZOLOFT was administered at doses of either 25
mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then
titrated in weekly
25 mg/day or 50 mg/day
increments, respectively, to a maximum dose of 200 mg/day based upon
clinical response. The mean dose for completers was 157 mg/day. In the acute
12 week pediatric study and in the 52 week study, ZOLOFT had an adverse
event profile generally similar to that observed in adults.
Sertraline pharmacokinetics were evaluated in 61
pediatric patients between 6 and 17 years of age with major depressive
disorder or OCD and revealed similar drug exposures to those of adults when
plasma concentration was adjusted for weight (see Pharmacokinetics under
CLINICAL PHARMACOLOGY).
Approximately 600 patients with major depressive disorder or OCD between 6
and 17 years of age have received ZOLOFT in clinical trials, both controlled
and uncontrolled. The adverse event profile observed in these patients was
generally similar to that observed in adult studies with ZOLOFT (see ADVERSE
REACTIONS). As with other SSRIs, decreased appetite and weight loss have
been observed in association with the use of ZOLOFT. In a pooled analysis of
two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg)
outpatient trials for major depressive disorder (n=373), there was a
difference in weight change between sertraline and placebo of roughly 1
kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in
both cases representing a slight weight loss for sertraline compared to a
slight gain for placebo. At baseline the mean weight for children was 39.0
kg for sertraline and 38.5 kg for placebo. At baseline the mean weight for
adolescents was 61.4 kg for sertraline and 62.5 kg for placebo. There was a
bigger difference between sertraline and placebo in the proportion of
outliers for clinically important weight loss in children than in
adolescents. For children, about 7% had a weight loss > 7% of body weight
compared to none of the placebo patients; for adolescents, about 2% had a
weight loss > 7% of body weight compared to about 1% of the placebo
patients. A subset of these patients who completed the randomized controlled
trials (sertraline n=99, placebo n=122) were continued into a 24-week,
flexible-dose, open-label, extension study. A mean weight loss of
approximately 0.5 kg was seen during the first eight weeks of treatment for
subjects with first
exposure to sertraline
during the open-label extension study, similar to mean weight loss observed
among sertralinetreated subjects during the first eight weeks of the
randomized controlled trials. The subjects continuing in the open label
study began gaining weight compared to baseline by week 12 of sertraline
treatment. Those subjects who completed 34 weeks of sertraline treatment (10
weeks in a placebo controlled trial + 24 weeks open label, n=68) had weight
gain that was similar to that expected using data from age-adjusted peers.
Regular monitoring of weight and growth is recommended if treatment of a
pediatric patient with an SSRI is to be continued long term. Safety and
effectiveness in pediatric patients below the age of 6 have not been
established.
The risks, if any, that may be associated with ZOLOFT?s use beyond 1 year in
children and adolescents with OCD or major depressive disorder have not been
systematically assessed. The prescriber should be mindful that the evidence
relied upon to conclude that sertraline is safe for use in children and
adolescents derives from clinical studies that were 10 to 52 weeks in
duration and from the extrapolation of experience gained with adult
patients. In particular, there are no studies that directly evaluate the
effects of long-term sertraline use on the growth, development,
and maturation of
children and adolescents. Although there is no affirmative finding to
suggest that
sertraline
possesses a capacity to adversely affect growth, development or maturation,
the absence
of such findings is not compelling evidence of the absence of the potential
of sertraline to have adverse effects in chronic use (see
WARNINGS ? Clinical Worsening and Suicide Risk).
Geriatric Use?U.S.
geriatric clinical studies of ZOLOFT in major depressive disorder included
663 ZOLOFT-treated subjects ?
65 years of age, of
those, 180 were ?
75 years of age.
No overall differences in the pattern of adverse reactions were observed in
the geriatric clinical trial subjects relative to those reported in younger
subjects (see ADVERSE REACTIONS), and other reported experience has not
identified differences in safety patterns between the elderly and younger
subjects. As with all medications, greater sensitivity of some older
individuals cannot be ruled out. There were 947 subjects in
placebo-controlled geriatric clinical studies of ZOLOFT in major depressive
disorder. No overall differences in the pattern of efficacy were observed in
the geriatric clinical trial subjects relative to those reported in younger
subjects.
Other Adverse
Events in Geriatric Patients. In 354 geriatric subjects treated with ZOLOFT
in placebo-controlled trials, the overall profile of adverse events was
generally similar to that shown in Tables 1 and 2. Urinary tract infection
was the only adverse event not appearing in Tables 1 and 2 and reported at
an incidence of at least 2% and at a rate greater than placebo in
placebo-controlled trials.
As with other SSRIs, ZOLOFT has been associated with
cases of clinically significant hyponatremia in elderly patients (see
Hyponatremia under PRECAUTIONS).
ADVERSE REACTIONS
During its premarketing assessment, multiple doses of
ZOLOFT were administered to over
4000 adult subjects as of February 18, 2000. The
conditions and duration of exposure to ZOLOFT
varied greatly, and included (in overlapping categories)
clinical pharmacology studies, open and double-blind studies, uncontrolled
and controlled studies, inpatient and outpatient studies, fixed-dose and
titration studies, and studies for multiple indications, including major
depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety
disorder.
Untoward events associated with this exposure were
recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the
proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event
categories.
In the tabulations that follow, a World Health Organization dictionary of
terminology has been used to classify reported adverse events. The
frequencies presented, therefore, represent the proportion of the over 4000
adult individuals exposed to multiple doses of ZOLOFT who experienced a
treatment-emergent adverse event of the type cited on at least one occasion
while receiving
ZOLOFT. An event was considered treatment-emergent if it occurred for the
first time or
worsened while receiving therapy following baseline evaluation. It is
important to emphasize that events reported during therapy were not
necessarily caused by it.
The prescriber should be aware that the figures in the
tables and tabulations cannot be used to predict the incidence of side
effects in the course of usual medical practice where patient
characteristics and other factors differ from those that prevailed in the
clinical trials. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, do provide
the prescribing physician with some basis for estimating the relative
contribution of drug and nondrug factors to the side effect incidence rate
in the population studied.
Incidence in Placebo-Controlled Trials?Table
1 enumerates the most common
treatment-emergent adverse events associated with the use of ZOLOFT
(incidence of at least 5% for ZOLOFT and at least twice that for placebo
within at least one of the indications) for the treatment of adult patients
with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder in placebo-controlled clinical trials. Most patients
in major depressive disorder/other*, OCD, panic disorder, PTSD and social
anxiety disorder studies received doses of 50 to 200 mg/day. Patients in the
PMDD study with daily dosing throughout the menstrual cycle received doses
of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal
phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 2
enumerates treatment-emergent adverse events that occurred in 2% or more of
adult patients treated with ZOLOFT and with incidence greater than placebo
who participated in controlled clinical trials comparing ZOLOFT with placebo
in the treatment of major depressive disorder/other*, OCD, panic disorder,
PTSD, PMDD and social anxiety disorder. Table 2 provides combined data for
the pool of studies that are provided separately by indication in Table 1.
TABLE 1
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
|
|
Percentage
of Patients Reporting Event
|
|
|
Major Depressive
Disorder/Other*
|
OCD
|
Panic Disorder
|
PTSD
|
|
Body System/Adverse Event
|
ZOLOFT
|
Placebo
|
ZOLOFT
|
Placebo
|
ZOLOFT
|
Placebo
|
ZOLOFT
|
Placebo
|
|
|
(N=861)
|
(N=853)
|
(N=533)
|
(N=373)
|
(N=430)
|
(N=275)
|
(N=374)
|
(N=376)
|
|
Autonomic Nervous System
Disorders
|
|
|
|
|
|
|
|
|
|
Ejaculation Failure(1)
|
7
|
<1
|
17
|
2
|
19
|
1
|
11
|
1
|
|
Mouth Dry
|
16
|
9
|
14
|
9
|
15
|
10
|
11
|
6
|
|
Sweating Increased
|
8
|
3
|
6
|
1
|
5
|
1
|
4
|
2
|
|
Centr. & Periph. Nerv. System
Disorders
|
|
|
|
|
|
|
|
|
|
Somnolence
|
13
|
6
|
15
|
8
|
15
|
9
|
13
|
9
|
|
Tremor
|
11
|
3
|
8
|
1
|
5
|
1
|
5
|
1
|
|
Dizziness
|
12
|
7
|
17
|
9
|
10
|
10
|
8
|
5
|
|
General
|
|
|
|
|
|
|
|
|
|
Fatigue
|
11
|
8
|
14
|
10
|
11
|
6
|
10
|
5
|
|
Pain
|
1
|
2
|
3
|
1
|
3
|
3
|
4
|
6
|
|
Malaise
|
<1
|
1
|
1
|
1
|
7
|
14
|
10
|
10
|
|
Gastrointestinal Disorders
|
|
|
|
|
|
|
|
|
|
Abdominal Pain
|
2
|
2
|
5
|
5
|
6
|
7
|
6
|
5
|
|
Anorexia
|
3
|
2
|
11
|
2
|
7
|
2
|
8
|
2
|
|
Constipation
|
8
|
6
|
6
|
4
|
7
|
3
|
3
|
3
|
|
Diarrhea/Loose Stools
|
18
|
9
|
24
|
10
|
20
|
9
|
24
|
15
|
|
Dyspepsia
|
6
|
3
|
10
|
4
|
10
|
8
|
6
|
6
|
|
Nausea
|
26
|
12
|
30
|
11
|
29
|
18
|
21
|
11
|
|
Psychiatric Disorders
|
|
|
|
|
|
|
|
|
|
Agitation
|
6
|
4
|
6
|
3
|
6
|
2
|
5
|
5
|
|
Insomnia
|
16
|
9
|
28
|
12
|
25
|
18
|
20
|
11
|
|
Libido Decreased
|
1
|
<1
|
11
|
2
|
7
|
1
|
7
|
2
|
|
|
PMDD
Daily Dosing
|
PMDD
Luteal Phase Dosing(2)
|
Social
Anxiety Disorder
|
|
|
Body System/Adverse Event
|
ZOLOFT
(N=121)
|
Placebo
(N=122)
|
ZOLOFT
(N=136)
|
Placebo
(N=127)
|
ZOLOFT
(N=344)
|
Placebo
(N=268)
|
|
|
|
Autonomic Nervous System
Disorders
|
|
|
|
|
|
|
|
|
|
Ejaculation Failure(1)
|
N/A
|
N/A
|
N/A
|
N/A
|
14
|
-
|
|
|
|
Mouth Dry
|
6
|
3
|
10
|
3
|
12
|
4
|
|
|
|
Sweating Increased
|
6
|
<1
|
3
|
0
|
11
|
2
|
|
|
|
Centr. & Periph. Nerv. System
Disorders
|
|
|
|
|
|
|
|
|
|
Somnolence
|
7
|
<1
|
2
|
0
|
9
|
6
|
|
|
|
Tremor
|
2
|
0
|
<1
|
<1
|
9
|
3
|
|
|
|
Dizziness
|
6
|
3
|
7
|
5
|
14
|
6
|
|
|
|
General
|
|
|
|
|
|
|
|
|
|
Fatigue
|
16
|
7
|
10
|
<1
|
12
|
6
|
|
|
|
Pain
|
6
|
<1
|
3
|
2
|
1
|
3
|
|
|
|
Malaise
|
9
|
5
|
7
|
5
|
8
|
3
|
|
|
|
Gastrointestinal Disorders
|
|
|
|
|
|
|
|
|
|
Abdominal Pain
|
7
|
<1
|
3
|
3
|
5
|
5
|
|
|
|
Anorexia
|
3
|
2
|
5
|
0
|
6
|
3
|
|
|
|
Constipation
|
2
|
3
|
1
|
2
|
5
|
3
|
|
|
|
Diarrhea/Loose Stools
|
13
|
3
|
13
|
7
|
21
|
8
|
|
|
|
Dyspepsia
|
7
|
2
|
7
|
3
|
13
|
5
|
|
|
|
Nausea
|
23
|
9
|
13
|
3
|
22
|
8
|
|
|
|
Psychiatric Disorders
|
|
|
|
|
|
|
|
|
|
Agitation
|
2
|
<1
|
1
|
0
|
4
|
2
|
|
|
|
Insomnia
|
17
|
11
|
12
|
10
|
25
|
10
|
|
|
|
Libido Decreased
|
11
|
2
|
4
|
2
|
9
|
3
|
|
|
(1)Primarily
ejaculatory delay. Denominator used was for male patients only (N=27 1
ZOLOFT major depressive disorder/other*; N=27 1 placebo major depressive
disorder/other*; N=296 ZOLOFT OCD; N=2 19 placebo OCD; N=2 16 ZOLOFT panic
disorder; N=134 placebo panic disorder; N=130 ZOLOFT PTSD; N=149 placebo
PTSD; No male patients in PMDD studies; N=205 ZOLOFT social anxiety
disorder; N=1 53 placebo social anxiety disorder). *Major depressive
disorder and other premarketing controlled trials.
(2)The
luteal phase and daily dosing PMDD
trials were not designed for making direct comparisons between the two
dosing regimens. Therefore, a comparison between the two dosing regimens of
the PMDD trials of incidence rates shown in Table 1 should be avoided.
TABLE 2
TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS
Percentage of Patients Reporting Event
Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social
Anxiety
Disorder combined
|
Body
System/Adverse Event**
|
ZOLOFT
|
Placebo
|
|
|
(N=2799)
|
(N=2394)
|
|
|
|
|
|
Autonomic Nervous System Disorders
|
|
|
|
Ejaculation Failure(1)
|
14
|
1
|
|
Mouth Dry
|
14
|
8
|
|
Sweating Increased
|
7
|
2
|
|
Centr. & Periph. Nerv. System Disorders
|
|
|
|
Somnolence
|
13
|
7
|
|
Dizziness
|
12
|
7
|
|
Headache
|
25
|
23
|
|
Paresthesia
|
2
|
1
|
|
Tremor
|
8
|
2
|
|
Disorders of Skin and Appendages
|
|
|
|
Rash
|
3
|
2
|
|
Gastrointestinal Disorders
|
|
|
|
Anorexia
|
6
|
2
|
|
Constipation
|
6
|
4
|
|
Diarrhea/Loose Stools
|
20
|
10
|
|
Dyspepsia
|
8
|
4
|
|
Nausea
|
25
|
11
|
|
Vomiting
|
4
|
2
|
|
General
|
|
|
|
Fatigue
|
12
|
7
|
|
Psychiatric Disorders
|
|
|
|
Agitation
|
5
|
3
|
|
Anxiety
|
4
|
3
|
|
Insomnia
|
21
|
11
|
|
Libido Decreased
|
6
|
2
|
|
Nervousness
|
5
|
4
|
|
Special Senses
|
|
|
|
Vision Abnormal
|
3
|
2
|
(1)Primarily
ejaculatory delay. Denominator used was for male patients only (N=1 118
ZOLOFT; N=926 placebo).
*Major depressive disorder and other premarketing controlled trials.
* *Included are
events reported by at least 2% of patients taking ZOLOFT except the
following events, which had
an incidence on placebo greater than or equal
to ZOLOFT: abdominal pain, back pain, flatulence, malaise, pain,
pharyngitis, respiratory disorder, upper respiratory tract infection.
Associated with Discontinuation in Placebo-Controlled
Clinical Trials
Table 3 lists the adverse events associated with discontinuation of ZOLOFT
(sertraline hydrochloride) treatment (incidence at least twice that for
placebo and at least 1% for ZOLOFT in clinical trials) in major depressive
disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety
disorder.
TABLE 3
MOST COMMON ADVERSE EVENTS ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
|
Adverse
Event
|
Major Depressive
Disorder/Other*,
OCD, Panic
Disorder, PTSD,
PMDD and Social
Anxiety Disorder
combined
|
Major
Depressive
Disorder/
Other*
(N=861)
|
OCD
(N=533)
|
Panic
Disorder
(N=430)
|
PTSD
(N=374)
|
PMDD
Daily
Dosing
(N=121)
|
PMDD
Luteal
Phase
Dosing
(N=136)
|
Social
Anxiety
Disorde
r
(N=344)
|
|
|
(N=2799)
|
|
|
|
|
|
|
|
|
Abdominal
Pain
|
?
|
?
|
?
|
?
|
?
|
?
|
?
|
1%
|
|
Agitation
|
?
|
1%
|
?
|
2%
|
?
|
?
|
?
|
?
|
|
Anxiety
|
?
|
?
|
?
|
?
|
?
|
?
|
?
|
2%
|
|
Diarrhea/
Loose
Stools
|
2%
|
2%
|
2%
|
1%
|
?
|
2%
|
?
|
?
|
|
Dizziness
|
?
|
?
|
1%
|
?
|
?
|
?
|
?
|
?
|
|
Dry Mouth
|
?
|
1%
|
?
|
?
|
?
|
?
|
?
|
?
|
|
Dyspepsia
|
?
|
?
|
?
|
1%
|
?
|
?
|
?
|
?
|
|
Ejaculation
Failure(1)
|
1%
|
1%
|
1%
|
2%
|
?
|
N/A
|
N/A
|
2%
|
|
Fatigue
|
?
|
?
|
?
|
?
|
?
|
?
|
?
|
2%
|
|
Headache
|
1%
|
2%
|
?
|
?
|
1%
|
?
|
?
|
2%
|
|
Hot Flushes
|
?
|
?
|
?
|
?
|
?
|
?
|
1%
|
?
|
|
Insomnia
|
2%
|
1%
|
3%
|
2%
|
?
|
?
|
1%
|
3%
|
|
Nausea
|
3%
|
4%
|
3%
|
3%
|
2%
|
2%
|
1%
|
2%
|
|
Nervousness
|
?
|
?
|
?
|
?
|
?
|
2%
|
?
|
?
|
|
Palpitation
|
?
|
?
|
?
|
?
|
?
|
?
|
1%
|
?
|
|
Somnolence
|
1%
|
1%
|
2%
|
2%
|
?
|
?
|
?
|
?
|
|
Tremor
|
?
|
2%
|
?
|
?
|
?
|
?
|
?
|
?
|
(1)Primarily
ejaculatory delay. Denominator used was for male patients only (N=271 major
depressive disorder/other*; N=296 OCD; N=216
panic disorder; N=130 PTSD; No male patients in PMDD studies; N=205
social anxiety disorder).
*Major depressive disorder and
other premarketing controlled trials.
Male and Female Sexual Dysfunction with SSRIs
Although changes in sexual desire, sexual
performance and sexual satisfaction often occur as manifestations of a
psychiatric disorder, they may also be a consequence of pharmacologic
treatment. In particular, some evidence suggests that selective serotonin
reuptake inhibitors (SSRIs) can cause such untoward sexual experiences.
Reliable estimates of the incidence and
severity of untoward experiences
involving sexual desire, performance and satisfaction are
difficult to obtain,
however, in part because patients and physicians may be reluctant to discuss
them. Accordingly,
estimates of the incidence of untoward sexual experience and performance
cited in product labeling, are likely to underestimate their actual
incidence.
Table 4 below displays
the incidence of sexual side effects reported by at least 2% of patients
taking ZOLOFT in placebo-controlled trials.
TABLE 4
|
Adverse Event
|
ZOLOFT
|
Placebo
|
|
Ejaculation
failure*
(primarily delayed
ejaculation)
|
14%
|
1%
|
|
Decreased libido**
|
6%
|
1%
|
*Denominator used
was for male patients only (N=1 118 ZOLOFT; N=926 placebo) **Denominator
used was for male and female patients (N=2799 ZOLOFT; N=2394 placebo)
There are no adequate
and well-controlled studies examining sexual dysfunction with sertraline
treatment.
Priapism has been reported with
all SSRIs.
While it is difficult
to know the precise risk of sexual dysfunction associated with the use of
SSRIs, physicians should routinely inquire about such possible side effects.
Other Adverse Events in Pediatric Patients?In
over 600 pediatric patients treated with
ZOLOFT, the
overall profile of adverse events was generally similar to that seen in
adult studies. However, the following adverse
events, from controlled trials, not appearing in Tables 1 and 2, were
reported at an incidence of at least 2% and occurred at a rate of at least
twice the placebo
rate (N=281 patients
treated with ZOLOFT): fever, hyperkinesia, urinary incontinence, aggressive
reaction, sinusitis, epistaxis and purpura.
Other Events Observed During the
Premarketing Evaluation of ZOLOFT
(sertraline hydrochloride)?Following
is a list of treatment-emergent adverse events
reported during
premarketing
assessment of ZOLOFT in clinical trials (over 4000 adult subjects) except
those already listed in the previous tables or
elsewhere in labeling.
In the tabulations that follow,
a World Health Organization dictionary of terminology has been used to
classify reported adverse events. The frequencies presented, therefore,
represent the proportion of the over 4000 adult individuals exposed to
multiple doses of ZOLOFT who experienced an event of the type cited on at
least one occasion while receiving ZOLOFT. All
events are included
except those already listed in the previous tables or elsewhere in labeling
and those
reported in terms so general as to be uninformative and those for which a
causal relationship
to ZOLOFT treatment
seemed remote. It is important to emphasize that although the events
reported
occurred during treatment with ZOLOFT, they were not necessarily caused by
it.
Events are further categorized by body system and listed
in order of decreasing frequency according to the following definitions:
frequent adverse events are those occurring on one or more occasions in at
least 1/100 patients; infrequent adverse events are those occurring in 1/100
to 1/1000 patients; rare events are those occurring in fewer than 1/1000
patients. Events of major clinical importance are also described in the
PRECAUTIONS section.
Autonomic Nervous System Disorders?Frequent:
impotence;
Infrequent:
flushing, increased
saliva, cold clammy skin, mydriasis;
Rare:
pallor, glaucoma,
priapism, vasodilation.
Body as a Whole?General Disorders?Rare:
allergic
reaction, allergy.
Cardiovascular?Frequent:
palpitations,
chest pain;
Infrequent:
hypertension, tachycardia, postural dizziness, postural hypotension,
periorbital edema, peripheral edema, hypotension, peripheral ischemia,
syncope, edema, dependent edema;
Rare:
precordial chest pain,
substernal chest pain, aggravated hypertension, myocardial infarction,
cerebrovascular disorder.
Central and Peripheral Nervous System Disorders?Frequent:
hypertonia,
hypoesthesia; Infrequent:
twitching, confusion,
hyperkinesia, vertigo, ataxia, migraine, abnormal coordination,
hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia;
Rare:
dysphonia, coma,
dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Disorders of Skin and Appendages?Infrequent:
pruritus, acne,
urticaria, alopecia, dry skin,
erythematous rash,
photosensitivity reaction, maculopapular rash;
Rare:
follicular rash,
eczema,
dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin
discoloration, pustular rash.
Endocrine Disorders?Rare:
exophthalmos,
gynecomastia.
Gastrointestinal Disorders?Frequent:
appetite
increased;
Infrequent:
dysphagia, tooth caries aggravated, eructation, esophagitis,
gastroenteritis;
Rare:
melena, glossitis, gum
hyperplasia, hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal
incontinence, gastritis, rectum hemorrhage, hemorrhagic peptic ulcer,
proctitis, ulcerative stomatitis, tongue edema, tongue ulceration.
General?Frequent:
back pain,
asthenia, malaise, weight increase;
Infrequent:
fever, rigors,
generalized edema;
Rare:
face edema, aphthous
stomatitis.
Hearing and Vestibular Disorders?Rare:
hyperacusis,
labyrinthine disorder.
Hematopoietic and
Lymphatic?Rare:
anemia,
anterior chamber eye hemorrhage.
Liver and Biliary System Disorders?Rare:
abnormal
hepatic function.
Metabolic and Nutritional Disorders?Infrequent:
thirst;
Rare:
hypoglycemia,
hypoglycemia
reaction.
Musculoskeletal System Disorders?Frequent:
myalgia;
Infrequent:
arthralgia, dystonia,
arthrosis, muscle cramps, muscle weakness.
Psychiatric
Disorders?Frequent:
yawning, other
male sexual dysfunction, other female sexual
dysfunction;
Infrequent:
depression, amnesia,
paroniria, teeth-grinding, emotional lability, apathy,
abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive
reaction, aggravated depression, delusions;
Rare:
withdrawal syndrome,
suicide ideation, libido increased, somnambulism, illusion.
Reproductive?Infrequent:
menstrual
disorder, dysmenorrhea, intermenstrual bleeding, vaginal
hemorrhage, amenorrhea, leukorrhea;
Rare:
female breast pain,
menorrhagia, balanoposthitis, breast enlargement, atrophic vaginitis, acute
female mastitis.
Respiratory System Disorders?Frequent:
rhinitis;
Infrequent:
coughing,
dyspnea, upper respiratory tract infection, epistaxis, bronchospasm,
sinusitis; Rare:
hyperventilation, bradypnea, stridor, apnea, bronchitis, hemoptysis,
hypoventilation, laryngismus, laryngitis.
Special Senses?Frequent:
tinnitus;
Infrequent:
conjunctivitis,
earache, eye pain, abnormal
accommodation;
Rare:
xerophthalmia,
photophobia, diplopia, abnormal lacrimation, scotoma,
visual field defect.
Urinary System Disorders?Infrequent:
micturition
frequency, polyuria, urinary retention, dysuria, nocturia, urinary
incontinence;
Rare: cystitis,
oliguria, pyelonephritis, hematuria, renal pain, strangury.
Laboratory Tests?In
man,
asymptomatic elevations in serum transaminases (SGOT [or AST] and
SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in
association with ZOLOFT
(sertraline hydrochloride)
administration. These hepatic enzyme elevations usually occurred within the
first 1 to 9 weeks of drug treatment and promptly diminished upon drug
discontinuation.
ZOLOFT therapy was associated with
small mean increases in total cholesterol (approximately 3%) and
triglycerides (approximately 5%), and a small mean decrease in serum uric
acid (approximately 7%) of no apparent clinical importance.
The safety profile observed with ZOLOFT treatment in
patients with major depressive disorder, OCD, panic disorder, PTSD, PMDD and
social anxiety disorder is similar.
Other Events Observed During the Postmarketing Evaluation of ZOLOFT?Reports
of adverse events temporally associated with
ZOLOFT that have been received since market introduction, that are not
listed above and that may have no causal relationship with the drug, include
the following: acute renal failure, anaphylactoid reaction, angioedema,
blindness, optic neuritis, cataract, increased coagulation times,
bradycardia, AV block, atrial arrhythmias, QT‑interval prolongation,
ventricular tachycardia (including torsade de pointes-type arrhythmias),
hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia,
leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness,
hyperglycemia, galactorrhea, hyperprolactinemia, neuroleptic malignant
syndrome -like events, extrapyramidal symptoms, oculogyric crisis, serotonin
syndrome, psychosis, pulmonary hypertension, severe skin reactions,
which
potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis,
photosensitivity and
other severe cutaneous disorders, rare reports of pancreatitis, and liver
events?clinical features (which in the majority of cases appeared to be
reversible with discontinuation of ZOLOFT) occurring in one or more patients
include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis,
jaundice, abdominal pain, vomiting, liver failure and death.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class?ZOLOFT
(sertraline hydrochloride) is not a
controlled substance.
Physical and Psychological Dependence?In
a placebo-controlled, double-blind, randomized
study of the comparative abuse liability of ZOLOFT, alprazolam, and
d-amphetamine in humans, ZOLOFT did not produce the positive subjective
effects indicative of abuse potential, such as euphoria or drug liking, that
were observed with the other two drugs. Premarketing clinical experience
with ZOLOFT did not reveal any tendency for a withdrawal syndrome or any
drug-seeking behavior. In animal studies ZOLOFT does not demonstrate
stimulant or barbiturate-like (depressant) abuse potential. As with any CNS
active drug, however, physicians should carefully evaluate patients for
history of drug abuse and follow such patients closely, observing them for
signs of ZOLOFT misuse or abuse (e.g., development of tolerance,
incrementation of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience?
Of 1,027 cases of
overdose involving sertraline hydrochloride worldwide, alone or with other
drugs, there were 72 deaths (circa 1999).
Among 634 overdoses in which
sertraline hydrochloride was the only drug ingested, 8 resulted in fatal
outcome, 75 completely recovered, and 27 patients experienced sequelae after
overdosage to include alopecia, decreased libido, diarrhea, ejaculation
disorder, fatigue, insomnia, somnolence and serotonin syndrome. The
remaining 524 cases had an unknown outcome. The most common signs and
symptoms associated with non-fatal sertraline hydrochloride overdosage were
somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.
The largest known ingestion was 13.5 grams in a patient
who took sertraline hydrochloride alone and subsequently recovered. However,
another patient who took 2.5 grams of sertraline hydrochloride alone
experienced a fatal outcome.
Other important adverse events reported with sertraline
hydrochloride overdose (single or multiple drugs) include bradycardia,
bundle branch block, coma, convulsions, delirium, hallucinations,
hypertension, hypotension, manic reaction, pancreatitis, QT-interval
prolongation, serotonin syndrome, stupor and syncope.
Overdose Management?Treatment
should consist of those general measures
employed in the management of overdosage with any antidepressant.
Ensure an
adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and
vital signs. General supportive and symptomatic measures are also
recommended. Induction of emesis is not recommended. Gastric lavage with a
large-bore orogastric tube with appropriate airway protection, if needed,
may be indicated if performed soon after ingestion, or in symptomatic
patients.
Activated charcoal should be administered. Due to large
volume of distribution of this drug, forced diuresis, dialysis,
hemoperfusion and exchange transfusion are unlikely to be of benefit. No
specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug
involvement. The physician
should consider
contacting a poison control center on the treatment of any overdose.
Telephone
numbers for certified poison control centers are listed in the
Physicians ? Desk
Reference
(PDR
).
DOSAGE AND
ADMINISTRATION
Initial Treatment
Dosage for Adults
Major Depressive Disorder and Obsessive-Compulsive Disorder?ZOLOFT
treatment
should be
administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder?ZOLOFT
treatment should be initiated with a dose of 25 mg once daily. After one
week, the dose should be
increased to 50 mg once daily.
While a relationship between dose and effect has not been
established for major depressive disorder, OCD, panic disorder, PTSD or
social anxiety disorder, patients were dosed in a range of 50-200 mg/day in
the clinical trials demonstrating the effectiveness of ZOLOFT for the
treatment of these indications. Consequently, a dose of 50 mg, administered
once daily, is recommended as the initial therapeutic dose. Patients not
responding to a 50 mg dose may benefit from dose increases up to a maximum
of 200 mg/day. Given the 24 hour elimination half-life of ZOLOFT, dose
changes should not occur at intervals of less than 1 week.
Premenstrual Dysphoric Disorder?ZOLOFT
treatment
should be initiated with a dose of
50 mg/day, either daily throughout the menstrual cycle or limited to the
luteal phase of the menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for
PMDD, patients were
dosed in the range of
50-150 mg/day with dose increases at the onset of each new menstrual cycle
(see Clinical Trials under CLINICAL PHARMACOLOGY). Patients not responding
to a 50 mg/day dose may benefit from dose increases (at 50 mg
increments/menstrual cycle) up to 150
mg/day when dosing
daily throughout the menstrual cycle, or 100 mg/day when dosing during the
luteal phase of the menstrual cycle. If a 100 mg/day dose has been
established with luteal phase dosing, a 50 mg/day titration step for three
days should be utilized at the beginning of each luteal phase dosing period.
ZOLOFT should be administered once
daily, either in the morning or evening.
Dosage for Pediatric Population (Children and
Adolescents)
Obsessive-Compulsive Disorder?ZOLOFT
treatment should be initiated with a dose of
25 mg once daily in children (ages 6-12) and at a dose of 50 mg once daily
in adolescents (ages 13-17).
While a relationship between dose and effect has not been established for
OCD, patients were dosed in a range of 25-200 mg/day in the clinical trials
demonstrating the effectiveness of ZOLOFT for pediatric patients (6-17
years) with OCD. Patients not responding to an initial dose
of 25 or 50 mg/day may
benefit from dose increases up to a maximum of 200 mg/day. For children
with OCD, their generally lower body weights compared to adults should be
taken into consideration in advancing the dose, in order to avoid excess
dosing. Given the 24 hour elimination half-life of ZOLOFT, dose changes
should not occur at intervals of less than 1 week.
ZOLOFT should be administered once
daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment
Major Depressive Disorder?It
is generally agreed that acute episodes of
major depressive disorder require several months or longer of sustained
pharmacologic therapy beyond response to the acute episode. Systematic
evaluation of ZOLOFT has demonstrated that its antidepressant efficacy is
maintained for periods of up to 44 weeks following 8 weeks of initial
treatment at a dose of 5 0-200 mg/day (mean dose of 70 mg/day) (see Clinical
Trials under CLINICAL PHARMACOLOGY). It is not known whether the dose of
ZOLOFT needed for maintenance treatment is identical to the dose needed to
achieve an initial response. Patients should be periodically reassessed to
determine the need for maintenance treatment.
Posttraumatic Stress Disorder?It
is generally agreed that PTSD requires several
months or longer of sustained pharmacological therapy beyond response to
initial treatment. Systematic
evaluation of ZOLOFT
has demonstrated that its efficacy in PTSD is maintained for periods of up
to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day (see
Clinical Trials
under CLINICAL
PHARMACOLOGY). It is not known whether the dose of ZOLOFT needed for
maintenance treatment is identical to the dose needed to achieve an initial
response. Patients should be periodically reassessed to determine the need
for maintenance treatment.
Social Anxiety Disorder?Social
anxiety disorder is a chronic condition that
may require several months or longer of sustained pharmacological therapy
beyond response to initial treatment. Systematic evaluation of ZOLOFT has
demonstrated that its efficacy in social anxiety disorder is maintained for
periods of up to 24 weeks following 20 weeks of treatment at a dose of
50-200
mg/day (see Clinical Trials under CLINICAL PHARMACOLOGY). Dosage adjustments
should be made
to maintain patients on the lowest effective dose and patients should be
periodically reassessed to determine the need for long-term treatment.
Obsessive-Compulsive Disorder and Panic Disorder?It
is generally
agreed that OCD and Panic
Disorder require several months or longer of sustained pharmacological
therapy beyond response
to initial treatment.
Systematic evaluation of continuing ZOLOFT for periods of up to 28 weeks in
patients with OCD and Panic Disorder who have responded while taking ZOLOFT
during initial
treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200
mg/day has demonstrated a benefit of such maintenance treatment (see
Clinical Trials under CLINICAL
PHARMACOLOGY). It is
not known whether the dose of ZOLOFT needed for maintenance
treatment is identical to the dose needed to achieve an initial response.
Nevertheless, patients should be periodically reassessed to determine the
need for maintenance treatment.
Premenstrual Dysphoric Disorder?The
effectiveness of ZOLOFT in long-term use, that
is, for
more than 3 menstrual cycles, has not been systematically evaluated in
controlled trials. However,
as women commonly report that symptoms worsen with age until relieved by the
onset of menopause, it is reasonable to consider continuation of a
responding patient. Dosage adjustments, which may include changes between
dosage regimens (e.g., daily throughout the menstrual cycle
versus during the
luteal phase of the menstrual cycle), may be needed to maintain the patient
on the lowest
effective dosage and patients should be periodically reassessed to determine
the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor?At
least 14 days
should elapse
between
discontinuation of an MAOI and initiation of therapy with ZOLOFT. In
addition, at least
14 days should be allowed after stopping ZOLOFT before starting an MAOI (see
CONTRAINDICATIONS and WARNINGS).
Special Populations
Dosage for Hepatically Impaired Patients?The
use of sertraline in patients with liver
disease should be approached with caution. The effects of sertraline in
patients with moderate and severe hepatic impairment have not been studied.
If sertraline is administered to patients with liver impairment, a lower or
less frequent dose should be used (see CLINICAL PHARMACOLOGY and
PRECAUTIONS).
Treatment of Pregnant Women During the Third Trimester?Neonates
exposed to ZOLOFT and other SSRIs or SNRIs,
late in the third trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding (see PRECAUTIONS).
When
treating pregnant women with ZOLOFT during the third trimester, the
physician should carefully
consider the potential risks and benefits of treatment. The physician may
consider tapering ZOLOFT in the third trimester.
Discontinuation of Treatment with Zoloft
Symptoms associated with discontinuation of ZOLOFT and other SSRIs and
SNRIs, have been reported (see PRECAUTIONS). Patients should be monitored
for these symptoms when discontinuing treatment. A gradual reduction in the
dose rather than abrupt cessation is recommended whenever possible. If
intolerable symptoms occur following a decrease in the dose or upon
discontinuation of treatment, then resuming the previously prescribed dose
may be
considered. Subsequently, the physician may continue decreasing the dose but
at a more gradual
rate.
ZOLOFT Oral Concentrate
ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the
hydrochloride) as the active ingredient and 12% alcohol. ZOLOFT Oral
Concentrate must be diluted before use. Just before
taking, use the
dropper provided to remove the required amount of ZOLOFT Oral Concentrate
and mix with 4
oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice
ONLY. Do not
mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The
dose should
be taken
immediately after mixing. Do not mix in advance. At times, a slight haze may
appear after
mixing; this is normal. Note that caution should be exercised for patients
with latex sensitivity, as the dropper dispenser contains dry natural
rubber.
ZOLOFT Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to
the alcohol
content of the concentrate.
Description
ZOLOFT
(sertraline hydrochloride) is a
selective serotonin reuptake inhibitor (S SRI) for oral administration.
It has a molecular weight of 342.7. Sertraline hydrochloride has the
following
chemical name: (1
S-cis)-4-(3 ,4-dichlorophenyl)- 1,2,3 ,4-tetrahydro-N-methyl- 1
-naphthalenamine
hydrochloride. The empirical formula
C17H17NCl2?HCl
is represented by the following structural
formula:
Sertraline hydrochloride is a white crystalline
powder that is slightly soluble in water and isopropyl alcohol, and
sparingly soluble in ethanol.
ZOLOFT is supplied for oral administration as scored
tablets containing sertraline hydrochloride equivalent to 25, 50 and 100
mg of sertraline and the following inactive ingredients: dibasic calcium
phosphate dihydrate, D & C Yellow #10 aluminum lake (in 25 mg tablet),
FD & C Blue #1 aluminum lake (in 25 mg tablet), FD & C Red #40 aluminum
lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 50 mg tablet),
hydroxypropyl cellulose, hypromellose, magnesium stearate,
microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium
starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and
titanium dioxide.
ZOLOFT oral
concentrate is available in a multidose 60 mL bottle. Each mL of
solution contains sertraline hydrochloride equivalent to 20 mg of
sertraline. The solution contains the following inactive ingredients:
glycerin, alcohol (12%), menthol, butylated hydroxytoluene (BHT). The
oral
concentrate must be diluted prior to administration (see PRECAUTIONS,
Information for Patients
and DOSAGE AND ADMINISTRATION).
CLINICAL PHARMACOLOGY
Pharmacodynamics
The
mechanism of action of sertraline is presumed to be linked to its
inhibition of CNS neuronal uptake of serotonin (5HT). Studies at
clinically relevant doses in man have demonstrated that sertraline
blocks the uptake of serotonin into human platelets.
In vitro
studies in animals
also suggest that sertraline is a potent and selective inhibitor of
neuronal serotonin reuptake and has only very weak effects on
norepinephrine and dopamine neuronal reuptake.
In vitro
studies have shown
that sertraline has no significant affinity for adrenergic (alpha1,
alpha2,
beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A,
5HT1B,
5HT2),
or benzodiazepine receptors; antagonism of such receptors has been
hypothesized to be associated with various anticholinergic, sedative,
and cardiovascular effects for other psychotropic drugs. The chronic
administration of sertraline was found in animals to downregulate brain
norepinephrine receptors, as has been observed with other drugs
effective in the treatment of major depressive disorder. Sertraline does
not inhibit monoamine oxidase.
Pharmacokinetics
Systemic
Bioavailability?In
man,
following oral once-daily dosing over the range of 50 to 200 mg
for 14 days, mean peak plasma concentrations (Cmax) of sertraline
occurred between 4.5 to 8.4 hours post-dosing. The average terminal
elimination half-life of plasma sertraline is about 26 hours. Based on
this pharmacokinetic parameter, steady-state sertraline plasma levels
should be achieved after approximately one week of once-daily dosing.
Linear dose-proportional pharmacokinetics were demonstrated in a single
dose study in which the Cmax and area under the plasma concentration
time curve (AUC) of sertraline were proportional to dose over a range of
50 to 200 mg. Consistent with the terminal elimination half-life, there
is an approximately two-fold accumulation, compared to a single dose, of
sertraline with repeated dosing over a 50 to 200 mg dose range. The
single dose bioavailability of sertraline tablets is approximately equal
to an equivalent dose of solution.
In a relative bioavailability study comparing the
pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg
sertraline tablet in 16 healthy adults, the solution to tablet ratio of
geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively.
90% confidence intervals (CI) were within the range of 80-125% with the
exception of the upper 90% CI limit for Cmax which was 126.5%.
The effects of
food on the bioavailability of the sertraline tablet and oral
concentrate were studied in subjects administered a single dose with and
without food. For the tablet, AUC was slightly
increased when
drug was administered with food but the Cmax was 25% greater, while the
time to
reach peak plasma concentration (Tmax) decreased from 8 hours
post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly
prolonged from 5.9 hours to 7.0 hours with food.
Metabolism?Sertraline
undergoes extensive first pass metabolism.
The principal initial pathway of metabolism for sertraline is
N-demethylation. N-desmethylsertraline has a plasma terminal elimination
half-life of 62 to 104 hours. Both
in vitro
biochemical and
in vivo
pharmacological testing have shown N-desmethylsertraline to be
substantially less active than sertraline. Both sertraline and
N-desmethylsertraline undergo oxidative deamination and subsequent
reduction, hydroxylation, and glucuronide conjugation. In a study of
radiolabeled sertraline involving two healthy male subjects, sertraline
accounted for less than 5% of the plasma radioactivity. About 40-45% of
the administered radioactivity was recovered in urine in 9 days.
Unchanged sertraline was not detectable in the urine. For the same
period, about 40-45% of the administered radioactivity was accounted for
in feces, including 12-14% unchanged sertraline.
Desmethylsertraline exhibits time -related, dose
dependent increases in AUC (0-24 hour), Cmax and Cmin, with about a 5-9
fold increase in these pharmacokinetic parameters between day 1 and day
14.
Protein Binding?In
vitro
protein
binding studies performed with radiolabeled
3H-sertraline
showed that sertraline is highly bound to serum proteins (9 8%) in the
range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL
concentrations, respectively, sertraline and N-desmethylsertraline did
not alter the plasma protein binding of two other highly protein bound
drugs, viz., warfarin and propranolol (see PRECAUTIONS).
Pediatric
Pharmacokinetics?Sertraline
pharmacokinetics were evaluated in a group
of
61 pediatric patients (29 aged 6-12 years, 32 aged
13-17 years) with a DSM-III-R diagnosis of major depressive disorder or
obsessive-compulsive disorder. Patients included both males (N=28) and
females (N=33). During 42 days of chronic sertraline dosing, sertraline
was titrated up to 200 mg/day and maintained at that dose for a minimum
of 11 days. On the final day of sertraline 200 mg/day, the 6-12 year old
group exhibited a mean sertraline AUC (0-24 hr) of
3107 ng-hr/mL,
mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year
old group
exhibited a
mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL,
and mean
half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group
were largely attributable to patients with lower body weights. No gender
associated differences were observed. By comparison, a group of 22
separately studied adults between 18 and 45 years of age (11 male, 11
female) received 30 days of 200 mg/day sertraline and exhibited a mean
sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and
mean half-life of 27.2 hr. Relative to the adults, both the 6-12 year
olds and the 13-17 year olds showed about 22% lower AUC (0-24 hr) and
Cmax values when plasma concentration was adjusted for weight. These
data suggest that pediatric patients metabolize sertraline with slightly
greater efficiency than adults. Nevertheless, lower doses may be
advisable for pediatric patients given their lower body weights,
especially in very young patients, in order to avoid excessive plasma
levels (see DOSAGE AND ADMINISTRATION).
Age?Sertraline
plasma clearance in a group of 16 (8 male, 8 female) elderly patients
treated for 14 days at a dose of 100 mg/day was approximately 40% lower
than in a similarly studied group of younger (25 to 32 y.o.)
individuals. Steady-state, therefore, should be achieved after 2 to 3
weeks in older patients. The same study showed a decreased clearance of
desmethylsertraline in older males, but not in older females.
Liver Disease?As
might be predicted from its primary site
of metabolism, liver impairment can affect the elimination of
sertraline. In patients with chronic mild liver impairment (N=10, 8
patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh
scores of 7-8) who received 50 mg sertraline per day maintained for 21
days, sertraline clearance was reduced, resulting in approximately
3-fold greater exposure compared to age-matched volunteers with no
hepatic impairment (N=10). The exposure to desmethylsertraline was
approximately 2-fold greater compared to age-matched volunteers with no
hepatic impairment. There were no significant differences in plasma
protein binding observed between the two groups. The effects of
sertraline in patients with moderate and severe hepatic impairment have
not been studied. The results suggest that the use of sertraline in
patients with liver disease must be approached with caution. If
sertraline is administered to patients with liver impairment, a lower or
less frequent dose should be used (see PRECAUTIONS and DOSAGE AND
ADMINISTRATION).
Renal Disease?Sertraline
is extensively metabolized and excretion of unchanged drug in urine is a
minor route of elimination. In volunteers with mild to moderate
(CLcr=30-60 mL/min), moderate to severe (CLcr=10-29 mL/min) or severe
(receiving hemodialysis) renal impairment (N=10 each group), the
pharmacokinetics and protein binding of 200 mg sertraline per day
maintained for 21 days were not altered compared to age-matched
volunteers (N=12) with no renal impairment. Thus sertraline multiple
dose pharmacokinetics appear to be unaffected by renal impairment (see
PRECAUTIONS).
Clinical Trials
Major Depressive
Disorder?The
efficacy of ZOLOFT as a treatment for
major depressive disorder was established in two placebo-controlled
studies in adult outpatients meeting DSM-III criteria for major
depressive disorder. Study 1 was an 8-week study with flexible dosing of
ZOLOFT in a range of 50 to 200 mg/day; the mean dose for completers was
145 mg/day. Study 2 was a 6-week fixed-dose study, including ZOLOFT
doses of 50, 100, and 200 mg/day. Overall,
these studies
demonstrated ZOLOFT to be superior to placebo on the Hamilton Depression
Rating
Scale and the Clinical Global Impression Severity and Improvement
scales. Study 2 was not readily interpretable regarding a dose response
relationship for effectiveness.
Study 3 involved depressed outpatients who had
responded by the end of an initial 8-week open treatment phase on ZOLOFT
50-200 mg/day. These patients (N=295) were randomized to continuation
for 44 weeks on double-blind ZOLOFT 50-200 mg/day or placebo. A
statistically significantly lower relapse rate was observed for patients
taking ZOLOFT compared to those on placebo. The mean dose for completers
was 70 mg/day.
Analyses for
gender effects on outcome did not suggest any differential
responsiveness on the basis
of sex.
Obsessive-Compulsive Disorder (OCD)?The
effectiveness of ZOLOFT in the treatment of OCD
was demonstrated in three multicenter placebo-controlled studies of
adult outpatients (Studies 1-3). Patients in all studies had moderate to
severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the
Yale?Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from
23 to 25.
Study 1 was an
8-week study with flexible dosing of ZOLOFT in a range of 50 to 200
mg/day; the
mean dose for completers was 186 mg/day. Patients receiving ZOLOFT
experienced a mean
reduction of
approximately 4 points on the YBOCS total score which was significantly
greater than
the mean reduction of 2 points in placebo-treated patients.
Study 2 was a
12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200
mg/day.
Patients receiving ZOLOFT doses of 50 and 200 mg/day experienced mean
reductions of approximately 6 points on the YBOCS total score which were
significantly greater than the approximately 3 point reduction in
placebo-treated patients.
Study 3 was a
12-week study with flexible dosing of ZOLOFT in a range of 50 to 200
mg/day; the mean dose for completers was 185 mg/day. Patients receiving
ZOLOFT experienced a mean
reduction of
approximately 7 points on the YBOCS total score which was significantly
greater than
the mean reduction of approximately 4 points in placebo-treated
patients.
Analyses for age
and gender effects on outcome did not suggest any differential
responsiveness on
the basis of age or sex.
The effectiveness of ZOLOFT for the treatment of OCD
was also demonstrated in a 12-week, multicenter, placebo-controlled,
parallel group study in a pediatric outpatient population (children and
adolescents, ages 6-17). Patients receiving ZOLOFT in this study were
initiated at doses of either 25 mg/day (children, ages 6-12) or 50
mg/day (adolescents, ages 13-17), and then titrated over the next four
weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for
completers was 178 mg/day. Dosing was once a day in the morning or
evening. Patients in this study had moderate to severe OCD (DSM-III-R)
with mean baseline ratings on the Children?s Yale-Brown
Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients
receiving sertraline experienced a mean reduction of approximately 7
units on the CYBOCS total score which was significantly greater than the
3 unit reduction for placebo patients. Analyses for age and gender
effects on outcome did not suggest any differential responsiveness on
the basis of age or sex.
In a longer-term
study, patients meeting DSM-III-R criteria for OCD who had responded
during a 52-week single-blind trial on ZOLOFT 50-200 mg/day (n=224) were
randomized to continuation of ZOLOFT or to substitution of placebo for
up to 28 weeks of observation for discontinuation due to relapse or
insufficient clinical response. Response during the single-blind phase
was defined as a decrease in the YBOCS score of
?
25% compared to
baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3
(minimally improved). Relapse during the double-blind phase was defined
as the following conditions being met (on three consecutive visits for 1
and 2, and for visit 3 for condition 3): (1) YBOCS score increased by
?
5 points, to a
minimum of 20, relative to baseline; (2) CGI-I increased by
?
one point;
and (3) worsening of the patient?s condition in the investigator?s
judgment, to justify alternative treatment. Insufficient clinical
response indicated a worsening of the patient?s condition that resulted
in study discontinuation, as assessed by the investigator. Patients
receiving continued ZOLOFT treatment experienced a significantly lower
rate of discontinuation due to relapse or insufficient clinical response
over the subsequent 28 weeks compared to those receiving placebo. This
pattern was demonstrated in male and female subjects.
Panic Disorder?The
effectiveness of ZOLOFT in the treatment
of panic disorder was demonstrated in three double-blind,
placebo-controlled studies (Studies 1-3) of adult outpatients who had a
primary diagnosis of panic disorder (DSM-III-R), with or without
agoraphobia.
Studies 1 and 2
were 10-week flexible dose studies. ZOLOFT was initiated at 25 mg/day
for the first week, and then patients were dosed in a range of 50-200
mg/day on the basis of clinical response and toleration. The mean ZOLOFT
doses for completers to 10 weeks were 131 mg/day and 144 mg/day,
respectively, for Studies 1 and 2. In these studies, ZOLOFT was shown to
be
significantly more effective than placebo on change from baseline in
panic attack frequency and on
the Clinical Global Impression Severity of Illness and Global
Improvement scores. The difference between ZOLOFT and placebo in
reduction from baseline in the number of full panic attacks was
approximately 2 panic attacks per week in both studies.
Study 3 was a
12-week fixed-dose study, including ZOLOFT doses of 50, 100, and 200
mg/day.
Patients receiving ZOLOFT experienced a significantly greater reduction
in panic attack frequency
than patients receiving placebo. Study 3 was not readily interpretable
regarding a dose response relationship for effectiveness.
Subgroup analyses
did not indicate that there were any differences in treatment outcomes
as a
function of age, race, or gender.
In a longer-term
study, patients meeting DSM-III-R criteria for Panic Disorder who had
responded
during a 52-week open trial on ZOLOFT 50-200 mg/day (n=1 83) were
randomized to continuation
of ZOLOFT
or to substitution of placebo for up to 28 weeks of observation for
discontinuation due
to relapse or insufficient clinical response. Response during the open
phase was defined as a CGI?I score of 1(very much improved) or 2 (much
improved). Relapse during the double-blind phase
was defined as the
following conditions being met on three consecutive visits: (1) CGI-I
?
3; (2) meets
DSM-III-R criteria for Panic Disorder; (3) number of panic attacks
greater than at baseline. Insufficient clinical response indicated a
worsening of the patient?s condition that resulted in study
discontinuation, as assessed by the investigator. Patients receiving
continued ZOLOFT treatment experienced a significantly lower rate of
discontinuation due to relapse or insufficient clinical response over
the subsequent 28 weeks compared to those receiving placebo. This
pattern was demonstrated in male and female subjects.
Posttraumatic
Stress Disorder (PTSD)?The
effectiveness of ZOLOFT in the treatment of PTSD
was established in two multicenter placebo-controlled studies (Studies
1-2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean
duration of PTSD for these patients was 12 years (Studies 1 and 2
combined) and 44% of patients (169 of the 385 patients treated) had
secondary depressive disorder.
Studies 1 and 2
were 12-week flexible dose studies. ZOLOFT was initiated at 25 mg/day
for the first week, and patients were then dosed in the range of 50-200
mg/day on the basis of clinical
response and
toleration. The mean ZOLOFT dose for completers was 146 mg/day and 151
mg/day,
respectively for Studies 1 and 2. Study outcome was assessed by the
Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item
instrument that measures the three PTSD diagnostic symptom clusters of
reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as
the patient-rated Impact of Event Scale (IES) which measures intrusion
and avoidance symptoms. ZOLOFT was shown to be significantly more
effective than placebo on change from baseline to endpoint on the CAPS,
IES and on the Clinical Global Impressions (CGI) Severity of Illness and
Global Improvement scores. In two additional placebo-controlled PTSD
trials, the difference in response to treatment between patients
receiving ZOLOFT and patients receiving placebo was not statistically
significant. One of these additional studies was conducted in patients
similar to those recruited for Studies 1 and 2, while the second
additional study was conducted in predominantly male veterans.
As PTSD is a more
common disorder in women than men, the majority (76%) of patients in
these
trials were women (152 and 139 women on sertraline and placebo versus 39
and 55 men on sertraline and placebo; Studies 1 and 2 combined). Post
hoc exploratory analyses revealed a significant difference between
ZOLOFT and placebo on the CAPS, IES and CGI in women, regardless of
baseline diagnosis of comorbid major depressive disorder, but
essentially no effect
in the relatively
smaller number of men in these studies. The clinical significance of
this apparent
gender interaction is unknown at this time. There was insufficient
information to determine the effect of race or age on outcome.
In a
longer-term study, patients meeting DSM-III-R criteria for PTSD who had
responded during a
24-week open trial on ZOLOFT 5 0-200 mg/day (n=96) were randomized to
continuation of ZOLOFT or to substitution of placebo for up to 28 weeks
of observation for relapse. Response during the open phase was defined
as a CGI-I of 1 (very much improved) or 2 (much improved), and a
decrease in the CAPS-2 score of > 30% compared to baseline. Relapse
during the double-blind phase was defined as the following conditions
being met on two consecutive visits: (1) CGI?I
?
3; (2) CAPS-2
score increased by ?
30% and by
?
15 points
relative to baseline; and (3) worsening of the patient's condition in
the investigator's judgment. Patients receiving continued ZOLOFT
treatment experienced significantly lower relapse rates over the
subsequent 28 weeks compared to those receiving placebo. This pattern
was demonstrated in male and female subjects.
Premenstrual
Dysphoric Disorder (PMDD) ?
The effectiveness
of ZOLOFT for the treatment of
PMDD was established in two double-blind, parallel group,
placebo-controlled flexible dose trials (Studies 1 and 2) conducted over
3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late
Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now
referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV.
Patients in Study 2 met DSM-IV criteria
for PMDD. Study 1
utilized daily dosing throughout the study, while Study 2 utilized
luteal phase
dosing for the 2 weeks prior to the onset of menses. The mean duration
of PMDD symptoms for these patients was approximately 10.5 years in both
studies. Patients on oral contraceptives were excluded from these
trials; therefore, the efficacy of sertraline in combination with oral
contraceptives for the treatment of PMDD is unknown.
Efficacy was
assessed with the Daily Record of Severity of Problems (DRSP), a
patient-rated
instrument that
mirrors the diagnostic criteria for PMDD as identified in the DSM-IV,
and includes
assessments for mood, physical symptoms, and other symptoms. Other
efficacy assessments included the Hamilton Depression Rating Scale
(HAMD-17), and the Clinical Global Impression Severity of Illness
(CGI-S) and Improvement (CGI-I) scores.
In Study 1,
involving n=25 1 randomized patients, ZOLOFT treatment was initiated at
50 mg/day
and
administered daily throughout the menstrual cycle. In subsequent cycles,
patients were dosed
in the range
of 50-150 mg/day on the basis of clinical response and toleration. The
mean dose for
completers was 102 mg/day. ZOLOFT administered daily throughout the
menstrual cycle was
significantly more
effective than placebo on change from baseline to endpoint on the DRSP
total score,
the HAMD- 17 total score, and the CGI-S score, as well as the CGI-I
score at endpoint.
In Study 2,
involving n=281 randomized patients, ZOLOFT treatment was initiated at
50 mg/day in
the late luteal phase (last 2 weeks) of each menstrual cycle and then
discontinued at the onset of menses. In subsequent cycles, patients were
dosed in the range of 50-100 mg/day in the luteal
phase of each
cycle, on the basis of clinical response and toleration. Patients who
were titrated to
100 mg/day
received 50 mg/day for the first 3 days of the cycle, then 100 mg/day
for the remainder
of the cycle. The mean ZOLOFT dose for completers was 74 mg/day. ZOLOFT
administered in
the late luteal
phase of the menstrual cycle was significantly more effective than
placebo on change
from
baseline to endpoint on the DRSP total score and the CGI-S score, as
well as the CGI-I score
at endpoint.
There
was insufficient information to determine the effect of race or age on
outcome in these
studies.
Social Anxiety
Disorder ?
The effectiveness of ZOLOFT in the treatment of social anxiety disorder
(also known as social phobia) was established in two multicenter
placebo-controlled
studies (Study 1
and 2) of adult outpatients who met DSM-IV criteria for social anxiety
disorder.
Study 1 was a
12-week, multicenter, flexible dose study comparing ZOLOFT (50-200
mg/day) to
placebo, in which ZOLOFT was initiated at 25 mg/day for the first week.
Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale
(LSAS), a 24-item clinician administered
instrument that
measures fear, anxiety and avoidance of social and performance
situations, and by
(b) the proportion of responders as defined by the Clinical Global
Impression of Improvement (CGI-I) criterion of CGI-I
?
2 (very much
or much improved). ZOLOFT was statistically significantly more effective
than placebo as measured by the LSAS and the percentage of responders.
Study 2 was a
20-week, multicenter, flexible dose study that compared ZOLOFT (5 0-200
mg/day)
to placebo. Study outcome was assessed by the (a) Duke Brief Social
Phobia Scale (BSPS), a multi-item clinician-rated instrument that
measures fear, avoidance and physiologic response to social or
performance situations, (b) the Marks Fear Questionnaire Social Phobia
Subscale (FQ?SPS),
a 5-item patient-rated instrument that measures change in the severity
of phobic avoidance
and distress, and (c) the CGI-I responder criterion of
?
2. ZOLOFT was shown
to be statistically
significantly more
effective than placebo as measured by the BSPS total score and fear,
avoidance
and physiologic factor scores, as well as the FQ-SPS total score, and to
have significantly more responders than placebo as defined by the CGI-I.
Subgroup analyses
did not suggest differences in treatment outcome on the basis of gender.
There was
insufficient information to determine the effect of race or age on
outcome.
In a longer-term
study, patients meeting DSM-IV criteria for social anxiety disorder who
had responded while assigned to ZOLOFT (CGI-I of 1 or 2) during a
20-week placebo-controlled trial on ZOLOFT 50-200 mg/day were randomized
to continuation of ZOLOFT or to substitution of placebo for up to 24
weeks of observation for relapse. Relapse was defined as
?
2 point increase in the Clinical Global
Impression ? Severity of Illness (CGI- S) score compared to baseline or
study discontinuation due to lack of efficacy. Patients receiving ZOLOFT
continuation treatment experienced a statistically significantly lower
relapse rate over this 24-week study than patients randomized to placebo
substitution.
INDICATIONS AND USAGE
Major Depressive
Disorder?ZOLOFT
(sertraline
hydrochloride) is indicated for the treatment of major depressive
disorder in adults.
The efficacy of ZOLOFT in the treatment of a major
depressive episode was established in six to eight week controlled
trials of adult outpatients whose diagnoses corresponded most closely to
the DSM-III category of major depressive disorder (see Clinical Trials
under CLINICAL PHARMACOLOGY).
A major depressive
episode implies a prominent and relatively persistent depressed or
dysphoric mood that usually interferes with daily functioning (nearly
every day for at least 2 weeks); it should include at least 4 of the
following 8 symptoms: change in appetite, change in sleep, psychomotor
agitation or retardation, loss of interest in usual activities or
decrease in sexual drive, increased fatigue, feelings of guilt or
worthlessness, slowed thinking or impaired concentration, and a suicide
attempt or suicidal ideation.
The antidepressant
action of ZOLOFT in hospitalized depressed patients has not been
adequately
studied.
The efficacy of ZOLOFT in maintaining an
antidepressant response for up to 44 weeks following 8 weeks of
open-label acute treatment (52 weeks total) was demonstrated in a
placebo-controlled trial. The usefulness of the drug in patients
receiving ZOLOFT for extended periods should be reevaluated periodically
(see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder?ZOLOFT
is indicated for the treatment of
obsessions and compulsions in patients with obsessive-compulsive
disorder (OCD), as defined in the DSM-III-R; i.e., the obsessions or
compulsions cause marked distress, are time-consuming, or significantly
interfere with social or occupational functioning.
The efficacy of
ZOLOFT was established in 12-week trials with obsessive-compulsive
outpatients
having diagnoses of obsessive-compulsive disorder as defined according
to DSM-III or DSM-III-R criteria (see Clinical Trials under CLINICAL
PHARMACOLOGY).
Obsessive-compulsive disorder is characterized by recurrent and
persistent ideas, thoughts, impulses, or images (obsessions) that are
ego -dystonic and/or repetitive, purposeful, and
intentional behaviors (compulsions) that are
recognized by the person as excessive or unreasonable.
The efficacy of
ZOLOFT in maintaining a response, in patients with OCD who responded
during a
52-week treatment phase while taking ZOLOFT and were then observed for
relapse during a period of up to 28 weeks, was demonstrated in a
placebo-controlled trial (see Clinical Trials under CLINICAL
PHARMACOLOGY). Nevertheless, the physician who elects to use ZOLOFT for
extended periods should periodically re-evaluate the long-term
usefulness of the drug for the individual patient (see DOSAGE AND
ADMINISTRATION).
Panic Disorder?ZOLOFT
is indicated for the treatment of panic
disorder in adults, with or without agoraphobia, as defined in DSM-IV.
Panic disorder is characterized by the occurrence of
unexpected panic
attacks and associated concern about having additional attacks, worry
about the
implications or consequences of the attacks, and/or a significant change
in behavior related to the attacks.
The efficacy of
ZOLOFT was established in three 10-12 week trials in adult panic
disorder
patients whose diagnoses corresponded to the DSM-III-R category of panic
disorder (see Clinical
Trials under CLINICAL PHARMACOLOGY).
Panic disorder
(DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a
discrete period of intense fear or discomfort in which four (or more) of
the following symptoms develop abruptly and reach a peak within 10
minutes: (1) palpitations, pounding heart, or accelerated heart
rate; (2)
sweating; (3) trembling or shaking; (4) sensations of shortness of
breath or smothering; (5)
feeling of choking; (6) chest pain or discomfort; (7) nausea or
abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint;
(9) derealization (feelings of unreality) or depersonalization (being
detached from oneself); (10) fear of losing control; (11) fear of dying;
(12) paresthesias (numbness or tingling sensations); (13) chills or hot
flushes.
The efficacy of
ZOLOFT in maintaining a response, in adult patients with panic disorder
who responded during a 52-week treatment phase while taking ZOLOFT and
were then observed for relapse during a period of up to 28 weeks, was
demonstrated in a placebo-controlled trial (see
Clinical Trials
under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to
use ZOLOFT
for extended periods should periodically re-evaluate the long-term
usefulness of the
drug for the individual patient (see DOSAGE AND ADMINISTRATION).
Posttraumatic
Stress Disorder (PTSD)?ZOLOFT
(sertraline hydrochloride) is indicated for the treatment of
posttraumatic stress disorder in adults.
The efficacy of ZOLOFT in the treatment of PTSD was
established in two 12-week placebo-controlled trials of adult
outpatients whose diagnosis met criteria for the DSM-III-R category of
PTSD (see Clinical Trials under CLINICAL PHARMACOLOGY).
PTSD, as defined
by DSM-III-R/IV, requires exposure to a traumatic event that involved
actual or
threatened death or serious injury, or threat to the physical integrity
of self or others, and a response which involves intense fear,
helplessness, or horror. Symptoms that occur as a result of exposure to
the traumatic event include reexperiencing of the event in the form of
intrusive thoughts, flashbacks or dreams, and intense psychological
distress and physiological reactivity on exposure to cues to the event;
avoidance of situations reminiscent of the traumatic event, inability to
recall details of the event, and/or numbing of general responsiveness
manifested as diminished interest in significant activities,
estrangement from others, restricted range of affect, or sense of
foreshortened future; and symptoms of autonomic arousal including
hypervigilance, exaggerated startle response, sleep disturbance,
impaired concentration, and irritability or outbursts of anger. A PTSD
diagnosis requires that the symptoms are present for at least a month
and that they cause clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
The efficacy of
ZOLOFT in maintaining a response in adult patients with PTSD for up to
28 weeks
following 24 weeks of open-label treatment was demonstrated in a
placebo-controlled trial. Nevertheless, the physician who elects to use
ZOLOFT for extended periods should periodically re-evaluate the
long-term usefulness of the drug for the individual patient (see DOSAGE
AND ADMINISTRATION).
Premenstrual
Dysphoric Disorder (PMDD) ?
ZOLOFT is
indicated for the treatment of
premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of ZOLOFT in the
treatment of PMDD was established in 2 placebo-controlled trials of
female adult outpatients treated for 3 menstrual cycles who met criteria
for the DSM-III-R/IV category of PMDD (see Clinical Trials under
CLINICAL PHARMACOLOGY).
The essential features of PMDD include markedly
depressed mood, anxiety or tension, affective lability, and persistent
anger or irritability. Other features include decreased interest in
activities, difficulty concentrating, lack of energy, change in appetite
or sleep, and feeling out of control. Physical symptoms associated with
PMDD include breast tenderness, headache, joint and muscle pain,
bloating and weight gain. These symptoms occur regularly during the
luteal phase and remit within a few days following onset of menses; the
disturbance markedly interferes with work or school or with usual social
activities and relationships with others. In making the diagnosis, care
should be taken to rule out other cyclical mood disorders that may be
exacerbated by treatment with an antidepressant.
The effectiveness of ZOLOFT in long-term use, that
is, for more than 3 menstrual cycles, has not been systematically
evaluated in controlled trials. Therefore, the physician who elects to
use ZOLOFT for extended periods should periodically re-evaluate the
long-term usefulness of the drug for the individual patient (see DOSAGE
AND ADMINISTRATION).
Social Anxiety
Disorder ?
ZOLOFT (sertraline hydrochloride) is indicated for the treatment of
social anxiety disorder, also known as social phobia in adults.
The efficacy of ZOLOFT in the treatment of social
anxiety disorder was established in two placebo-controlled trials of
adult outpatients with a diagnosis of social anxiety disorder as defined
by DSM-IV criteria (see Clinical Trials under CLINICAL PHARMACOLOGY).
Social anxiety disorder, as defined by DSM-IV, is
characterized by marked and persistent fear of social or performance
situations involving exposure to unfamiliar people or possible scrutiny
by others and by fears of acting in a humiliating or embarrassing way.
Exposure to the feared social situation almost always provokes anxiety
and feared social or performance situations are avoided or else are
endured with intense anxiety or distress. In addition, patients
recognize that the fear is excessive or unreasonable and the avoidance
and anticipatory anxiety of the feared situation is associated with
functional impairment or marked distress.
The efficacy of ZOLOFT in maintaining a response in
adult patients with social anxiety disorder for up to 24 weeks following
20 weeks of ZOLOFT treatment was demonstrated in a placebo-controlled
trial. Physicians who prescribe ZOLOFT for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the
individual patient (see Clinical Trials under CLINICAL PHARMACOLOGY).
HOW SUPPLIED
ZOLOFT
(sertraline hydrochloride)
capsular-shaped scored tablets, containing sertraline hydrochloride
equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
ZOLOFT
25 mg Tablets: light green film coated
tablets engraved on one side with ZOLOFT and on the other side scored and
engraved with 25 mg.
NDC 0049-4960-50 Bottles of 50
ZOLOFT
50 mg Tablets: light blue film coated tablets engraved on one side with
ZOLOFT and on
the other side scored and engraved with 50 mg.
NDC 0049-4900-66 Bottles of 100
NDC 0049-4900-73 Bottles of 500
NDC 0049-4900-94 Bottles of 5000
NDC 0049-4900-4 1 Unit Dose Packages of 100
ZOLOFT
100 mg Tablets: light yellow film
coated tablets engraved on one side with ZOLOFT and on the other side scored
and engraved with 100 mg.
NDC 0049-4910-66 Bottles of 100
NDC 0049-4910-73 Bottles of 500
NDC 0049-4910-94 Bottles of 5000
NDC 0049-4910-41 Unit Dose Packages of 100
Store at 25?C
(77?F);
excursions permitted to 15?
- 30?C (59?
- 86?F)[see USP
Controlled Room Temperature].
ZOLOFT?
Oral Concentrate: ZOLOFT Oral Concentrate is a clear, colorless solution
with a
menthol scent containing sertraline hydrochloride equivalent to 20 mg of
sertraline per mL and
12% alcohol. It is supplied as a 60 mL bottle with an accompanying
calibrated dropper.
NDC 0049-4940-2 3
Bottles of 60 mL
Store at 25?C
(77?F);
excursions permitted to 15?
- 30?C (59? -
86?F) [see USP Controlled Room Temperature].
Rx only
?004 Pfizer Inc
LAB-0218-5.2.1
Revised July 2004
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A Note From James Harper, Founder, The Road Back
1. The Road Back Basics
2. The Four Simple Steps
3. "Nutritionals" Used on The Road Back Program
4. Medication Side Effects
5. Things to Be Aware of
6. General Pre-Tapering and Tapering Instructions
7. Daily Journal
8. Graph Your Success
9. Pre-Taper for Benzodiazepines, Anti-Anxiety, Anticonvulsants and Sleep Medication
10. Pre-Taper For Antidepressants, Antipsychotics, and ADHD Medication
11. How to Taper Off Benzodiazepines, Anti-Anxiety, Anticonvulsants and Sleep Medications
12. How to Taper Off Antidepressants, Antipychotics and ADHD Medication
13. Once Off Medication
14. What to Do If You Have Already Started to Taper Off Your Medication or Quit Cold Turkey
15. How to Taper Off Multiple Medication
16. What Can be Done if You Have Never Taken Psychiatric Medication
17. The Science Behind The Road Back
Copyright Notice, Patent Pending
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