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ZOLOFT® |
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ZOLOFT® (sertraline hydrochloride)
is a selective serotonin reuptake inhibitor (SSRI) for oral administration.
It is chemically unrelated to other SSRIs, tricyclic, tetracyclic, or
other available antidepressant agents. It has a molecular weight of 342.7.
Sertraline hydrochloride has the following chemical name: (1S-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,
hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose,
polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic
yellow iron oxide (in 100 mg tablet), and titanium dioxide.
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 clinically effective antidepressants. 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.
The effects of food on the bioavailability
of sertraline were studied in subjects administered a single dose with
and without food. AUC was slightly increased when drug was administered
with food but the Cmax was 25% greater, while the time to reach peak plasma
concentration decreased from 8 hours post-dosing to 5.5 hours.
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 (98%) 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 depression 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 years 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
Depression-The efficacy
of ZOLOFT as a treatment for depression was established in two placebo-controlled
studies in adult outpatients meeting DSM-III criteria for major depression.
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, parallel group
study in a pediatric outpatient population (children and adolescents,
ages 6-17). Patients 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.
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.
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 depression, 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.
Depression-ZOLOFT®
(sertraline hydrochloride) is indicated for the treatment of depression.
The efficacy of ZOLOFT in the treatment
of a major depressive episode was established in six to eight week controlled
trials of 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 effectiveness of ZOLOFT in long-term
use for OCD, i.e., for more than 12 weeks, has not been systematically
evaluated in placebo-controlled trials. Therefore, the physician who elects
to use ZOLOFT for extended periods should periodically reevaluate 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, 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 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 effectiveness of ZOLOFT®
(sertraline hydrochloride) in long-term use, that is, for more than 12 weeks,
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).
Posttraumatic Stress Disorder (PTSD)-ZOLOFT
(sertraline hydrochloride) is indicated for the treatment of posttraumatic
stress disorder.
The efficacy of ZOLOFT in the treatment
of PTSD was established in two 12-week placebo-controlled trials of 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 effectiveness of ZOLOFT in long-term
use for PTSD, i.e., for more than 12 weeks, has not been systematically
evaluated in placebo-controlled trials; therefore, the physician who elects
to use ZOLOFT for extended periods should periodically reevaluate the
long-term usefulness of the drug for the individual patient (see DOSAGE
AND ADMINISTRATION).
Concomitant use in patients taking monoamine
oxidase inhibitors (MAOIs) is contraindicated (see 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.
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 depression. 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.
Suicide-The possibility of a suicide
attempt is inherent in depression and may persist until significant remission
occurs. Close supervision of high risk patients should accompany initial
drug therapy. 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.
Because of the well-established comorbidity
between OCD and depression, panic disorder and depression, and PTSD and
depression, the same precautions observed when treating patients with
depression should be observed when treating patients with OCD, panic disorder
or PTSD.
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, and there have been no reports of acute
renal failure with ZOLOFT.
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.
ZOLOFT has not been evaluated or used to
any appreciable extent in patients with a recent history of myocardial
infarction or unstable heart disease. Patients with these diagnoses were
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 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.
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:
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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.
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 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.
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.
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 antidepressants 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 (SSRI) to another has not been established.
Monoamine Oxidase Inhibitors-See
CONTRAINDICATIONS and WARNINGS.
Drugs Metabolized by P450 3A4-In
two separate in vivo interaction studies, sertraline was co-administered
with cytochrome P450 3A4 substrates, terfenadine or carbamazepine, under
steady-state conditions. The results of these studies demonstrated that
sertraline co-administration did not increase plasma concentrations of
terfenadine or carbamazepine. These data suggest that sertraline’s extent
of inhibition of P450 3A4 activity is not likely to be of clinical significance.
Drugs Metabolized by P450 2D6-Many
antidepressants, e.g., the SSRIs, including sertraline, and most tricyclic
antidepressants 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 antidepressants 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 antidepressants 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
Antidepressants 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 (SSRI) 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 Antidepressants (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.
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.
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 effectiveness
of ZOLOFT in pediatric patients with depression or panic disorder has
not been systematically evaluated.
Sertraline pharmacokinetics were evaluated
in 61 pediatric patients between 6 and 17 years of age with
depression or OCD and revealed similar drug exposures to those of adults
when plasma concentration was adjusted for weight (see Pharmacokinetics
under CLINICAL PHARMACOLOGY).
More than 250 patients with depression
or OCD between 6 and 17 years of age have received ZOLOFT in clinical
trials. 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. Consequently, regular monitoring
of weight and growth is recommended if treatment of a child 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 sertraline’s extended use in children and adolescents with OCD 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 relatively short-term clinical studies
and from 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.
Geriatric Use-Several hundred elderly
patients have participated in clinical studies with ZOLOFT. The pattern
of adverse reactions in the elderly was similar to that in younger patients.
During its premarketing assessment, multiple
doses of ZOLOFT were administered to over 4000 adult subjects as
of February 26, 1998. 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 depression, OCD,
panic disorder and PTSD.
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 depression/other*, OCD, panic disorder
and PTSD in placebo-controlled clinical trials. Most patients received
doses of 50 to 200 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 depression/other*,
OCD, panic disorder and PTSD. 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 |
||||||||
|
Depression/Other* |
OCD |
Panic Disorder |
PTSD |
|||||
|
Body System/Adverse Event |
ZOLOFT (N=861) |
Placebo (N=853) |
ZOLOFT (N=533) |
Placebo (N=373) |
ZOLOFT (N=430) |
Placebo (N=275) |
ZOLOFT (N=374) |
Placebo (N=376) |
|
Autonomic Nervous System Disorders |
||||||||
|
Ejaculation |
7 |
<1 |
17 |
2 |
19 |
1 |
11 |
1 |
|
Mouth Dry |
16 |
9 |
14 |
9 |
15 |
10 |
11 |
6 |
|
Sweating |
8 |
3 |
6 |
1 |
5 |
1 |
4 |
2 |
|
Centr. & Periph. Nerv. System |
||||||||
|
Somnolence |
13 |
6 |
15 |
8 |
15 |
9 |
13 |
9 |
|
Tremor |
11 |
3 |
8 |
1 |
5 |
1 |
5 |
1 |
|
General |
|
|
|
|
|
|
|
|
|
Fatigue |
11 |
8 |
14 |
10 |
11 |
6 |
10 |
5 |
|
Gastrointestinal Disorders |
||||||||
|
Anorexia |
3 |
2 |
11 |
2 |
7 |
2 |
8 |
2 |
|
Constipation |
8 |
6 |
6 |
4 |
7 |
3 |
3 |
3 |
|
Diarrhea/Loose |
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 |
1 |
<1 |
11 |
2 |
7 |
1 |
7 |
2 |
(1)Primarily ejaculatory delay.
Denominator used was for male patients only (N=271 ZOLOFT depression/other*;
N=271 placebo depression/other*; N=296 ZOLOFT OCD; N=219 placebo OCD;
N=216 ZOLOFT panic disorder; N=134 placebo panic disorder; N=130 ZOLOFT
PTSD; N=149 placebo PTSD).
*Depression and other premarketing controlled
trials.
TABLE 2
TREATMENT-EMERGENT ADVERSE
EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL
TRIALS
Percentage of Patients Reporting
Event
Depression/Other*, OCD, Panic
Disorder and PTSD combined
|
Body System/Adverse Event** |
ZOLOFT |
Placebo |
|
Autonomic Nervous System Disorders |
||
|
Ejaculation Failure(1) |
14 |
1 |
|
Mouth Dry |
15 |
9 |
|
Sweating Increased |
6 |
2 |
|
Centr. & Periph. Nerv. System |
|
|
|
Somnolence |
14 |
7 |
|
Dizziness |
12 |
7 |
|
Headache |
26 |
24 |
|
Paresthesia |
3 |
2 |
|
Tremor |
8 |
2 |
|
Disorders of Skin and Appendages |
||
|
Rash |
3 |
2 |
|
Gastrointestinal Disorders |
||
|
Anorexia |
6 |
2 |
|
Constipation |
7 |
5 |
|
Diarrhea/Loose Stools |
21 |
11 |
|
Dyspepsia |
8 |
4 |
|
Flatulence |
4 |
3 |
|
Nausea |
27 |
13 |
|
Vomiting |
4 |
2 |
|
General |
||
|
Fatigue |
11 |
7 |
|
Hot Flushes |
2 |
1 |
|
Psychiatric Disorders |
||
|
Agitation |
6 |
4 |
|
Anxiety |
4 |
3 |
|
Insomnia |
22 |
11 |
|
Libido Decreased |
6 |
1 |
|
Nervousness |
6 |
4 |
|
Special Senses |
||
|
Vision Abnormal |
4 |
2 |
(1)Primarily ejaculatory delay.
Denominator used was for male patients only (N=913 ZOLOFT; N=773 placebo).
*Depression 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 and
pharyngitis.
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 depression/other*, OCD,
panic disorder and PTSD.
TABLE 3
MOST COMMON ADVERSE EVENTS
ASSOCIATED WITH
DISCONTINUATION IN PLACEBO-CONTROLLED
CLINICAL TRIALS
|
Adverse Event |
Depression/Other*, |
Depression/Other* |
OCD |
Panic Disorder |
PTSD |
|
Agitation |
1% |
1% |
– |
2% |
– |
|
Diarrhea |
2% |
2% |
2% |
1% |
– |
|
Dizziness |
1% |
– |
1% |
– |
– |
|
Dry Mouth |
– |
1% |
– |
– |
– |
|
Dyspepsia |
– |
– |
– |
1% |
– |
|
Ejaculation Failure(1) |
1% |
1% |
1% |
2% |
– |
|
Headache |
1% |
2% |
– |
– |
1% |
|
Insomnia |
2% |
1% |
3% |
2% |
– |
|
Nausea |
3% |
4% |
3% |
3% |
2% |
|
Nervousness |
– |
– |
– |
2% |
– |
|
Somnolence |
2% |
1% |
2% |
2% |
– |
|
Tremor |
– |
2% |
– |
– |
– |
(1)Primarily ejaculatory delay.
Denominator used was for male patients only (N=271 depression/other*;
N=296 OCD; N=216 panic disorder; N=130 PTSD).
*Depression 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
|
Treatment |
Ejaculation failure |
Decreased libido |
||
|
N (males only) |
Incidence |
N (males and females) |
Incidence |
|
|
ZOLOFT |
913 |
14% |
2198 |
6% |
|
Placebo |
773 |
1% |
1877 |
1% |
There are no adequate and well-controlled studies examining sexual dysfunction
with sertraline treatment.
Priaprism 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
approximately n=250 pediatric patients treated with ZOLOFT, the overall
profile of adverse events was generally similar to that seen in adult
studies, as shown in Tables 1 and 2. However, the following adverse events,
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 in a controlled
trial (n=187): hyperkinesia, twitching, fever, malaise, purpura, weight
decrease, concentration impaired, manic reaction, emotional lability,
thinking abnormal, and epistaxis.
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 depression, OCD, panic disorder and PTSD 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: increased coagulation times, bradycardia, AV block,
atrial arrhythmias, hypothyroidism, leukopenia, thrombocytopenia, hyperglycemia,
priapism, galactorrhea, hyperprolactinemia, neuroleptic malignant syndrome-like
events, psychosis, 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.
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).
Human Experience-As of November 1992,
there were 79 reports of non-fatal acute overdoses involving ZOLOFT,
of which 28 were overdoses of ZOLOFT alone and the remainder involved
a combination of other drugs and/or alcohol in addition to ZOLOFT. In
those cases of overdose involving only ZOLOFT, the reported doses ranged
from 500 mg to 6000 mg. In a subset of 18 of these patients
in whom ZOLOFT blood levels were determined, plasma concentrations ranged
from <5 ng/mL to 554 ng/mL. Symptoms of overdose with ZOLOFT
alone included somnolence, nausea, vomiting, tachycardia, ECG changes,
anxiety and dilated pupils. Treatment was primarily supportive and included
monitoring and use of activated charcoal, gastric lavage or cathartics
and hydration. Although there were no reports of death when ZOLOFT was
taken alone, there were 4 deaths involving overdoses of ZOLOFT in
combination with other drugs and/or alcohol. Therefore, any overdosage
should be treated aggressively.
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®).
Initial Treatment
Dosage for Adults
Depression and Obsessive-Compulsive
Disorder-ZOLOFT treatment should be administered at a dose of 50 mg
once daily.
Panic Disorder and Posttraumatic Stress
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 depression, OCD, panic disorder or PTSD ,
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 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.
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.
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).
Maintenance/Continuation/Extended Treatment
Depression-It is generally
agreed that acute episodes of depression require several months
or longer of sustained pharmacologic therapy. Whether the dose of antidepressant
needed to induce remission is identical to the dose needed to maintain
and/or sustain euthymia is unknown. Systematic evaluation of ZOLOFT has
shown that its antidepressant efficacy is maintained for periods of up
to 44 weeks following 8 weeks of open-label acute treatment
(52 weeks total) at a dose of 50-200 mg/day (mean dose of 70 mg/day)
(see Clinical Trials under CLINICAL PHARMACOLOGY).
Obsessive-Compulsive Disorder, Panic
Disorder and Posttraumatic Stress Disorder-Although the efficacy of
ZOLOFT beyond 10-12 weeks of dosing for OCD, panic disorder and PTSD
has not been documented in controlled trials, all are chronic conditions,
and it is reasonable to consider continuation of a responding patient.
Dosage adjustments 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).
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 0049-4900-41 | 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 controlled room temperature, 59°
to 86°F (15° to 30°C).
| Rx only |
©1999 Pfizer
Inc |
| 69-4721-00-5 | Revised December 1999 |