SERTRALINE HCL
DESCRIPTION:
ZOSERT (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 is C17H17NCl2*HCl.
Sertraline hydrochloride is a white crystalline powder that is slightly soluble
in water and isopropyl alcohol, and sparingly soluble in ethanol.
ZOSERT 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.
ACTIONS/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 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 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. The elimination half-life
of sertraline was prolonged in a single dose study of patients with mild, stable
cirrhosis, with a mean of 52 hours compared to 22 hours seen in subjects without
liver disease. In hepatically impaired patients, it was observed that the Cmax
and AUC were increased by 1.7 and 4.4 fold, respectively, compared to healthy
subjects. This suggests that the use of sertraline in patients with liver
disease must be approached with caution. If sertraline is administered to
patients with liver disease, a lower or less frequent dose should be used (see
PRECAUTIONS and DOSAGE AND ADMINISTRATION).
RENAL DISEASE--The pharmacokinetics of sertraline in patients with significant
renal dysfunction have not been determined.
CLINICAL STUDIES:
CLINICAL TRIALS
DEPRESSION--The efficacy of ZOSERT 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 ZOSERT
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 ZOSERT doses of 50, 100, and
200 mg/day. Overall, these studies demonstrated ZOSERT 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 ZOSERT 50-200 mg/day. These patients
(N=295) were randomized to continuation for 44 weeks on double-blind ZOSERT 50-
200 mg/day or placebo. A statistically significantly lower relapse rate was
observed for patients taking ZOSERT 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 ZOSERT 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 ZOSERT in a range of 50 to
200 mg/day; the mean dose for completers was 186 mg/day. Patients receiving
ZOSERT 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 ZOSERT doses of 50, 100, and
200 mg/day. Patients receiving ZOSERT 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 ZOSERT in a range of 50 to
200 mg/day; the mean dose for completers was 185 mg/day. Patients receiving
ZOSERT 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 ZOSERT 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 ZOSERT 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. ZOSERT 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 ZOSERT doses
for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for
studies 1 and 2. In these studies, ZOSERT 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 ZOSERT 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 ZOSERT doses of 50, 100, and
200 mg/day. Patients receiving ZOSERT 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.
INDICATIONS AND USAGE:
DEPRESSION--ZOSERT (sertraline hydrochloride) is indicated for the treatment
of depression.
The efficacy of ZOSERT 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 STUDIES).
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 ZOSERT in hospitalized depressed patients has not
been adequately studied.
The efficacy of ZOSERT 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 ZOSERT for extended periods should be reevaluated
periodically (see Clinical Trials under CLINICAL STUDIES).
OBSESSIVE-COMPULSIVE DISORDER--ZOSERT 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 ZOSERT 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 STUDIES).
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 ZOSERT 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 ZOSERT for extended periods should
periodically reevaluate the long-term usefulness of the drug for the individual
patient (see DOSAGE AND ADMINISTRATION).
PANIC DISORDER--ZOSERT 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 ZOSERT 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 STUDIES).
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 ZOSERT (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 ZOSERT for extended periods
should periodically re-evaluate the long- term usefulness of the drug for the
individual patient (See DOSAGE AND ADMINISTRATION).
CONTRAINDICATIONS:
Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is
contraindicated (see WARNINGS).
WARNINGS:
CASES OF SERIOUS SOMETIMES FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS
RECEIVING ZOSERT (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, ZOSERT 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 ZOSERT
BEFORE STARTING AN MAOI.
PRECAUTIONS:
GENERAL
ACTIVATION OF MANIA/HYPOMANIA--During premarketing testing, hypomania or mania
occurred in approximately 0.4% of ZOSERT (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--ZOSERT 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 ZOSERT 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, ZOSERT 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 ZOSERT 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 both OCD and depression and
panic disorder and depression, the same precautions observed when treating
patients with depression should be observed when treating patients with OCD or
panic disorder.
WEAK URICOSURIC EFFECT--ZOSERT (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 ZOSERT.
USE IN PATIENTS WITH CONCOMITANT ILLNESS- -Clinical experience with ZOSERT in
patients with certain concomitant systemic illness is limited. Caution is
advisable in using ZOSERT in patients with diseases or conditions that could
affect metabolism or hemodynamic responses.
ZOSERT 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
ZOSERT in double-blind trials were evaluated and the data indicate that ZOSERT
is not associated with the development of significant ECG abnormalities.
ZOSERT is extensively metabolized by the liver. In subjects with mild, stable
cirrhosis of the liver, the clearance of sertraline was decreased, thus
increasing the elimination half-life. A lower or less frequent dose should be
used in patients with cirrhosis.
Since ZOSERT is extensively metabolized, excretion of unchanged drug in urine is
a minor route of elimination. However, until the pharmacokinetics of ZOSERT have
been studied in patients with renal impairment and until adequate numbers of
patients with severe renal impairment have been evaluated during chronic
treatment with ZOSERT, it should be used with caution in such patients.
INTERFERENCE WITH COGNITIVE AND MOTOR PERFORMANCE--In controlled studies, ZOSERT
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 ZOSERT 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 ZOSERT. While
there have been reports of abnormal bleeding or purpura in several patients
taking ZOSERT, it is unclear whether ZOSERT had a causative role.
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with patients for whom
they prescribe ZOSERT:
Patients should be told that although ZOSERT 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 ZOSERT has not been shown in experiments
with normal subjects to increase the mental and motor skill impairments caused
by alcohol, the concomitant use of ZOSERT and alcohol is not advised.
Patients should be told that while no adverse interaction of ZOSERT 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
ZOSERT (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 ZOSERT
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 ZOSERT (50-
200 mg/day) or placebo, there was a mean increase in prothrombin time of 8%
relative to baseline for ZOSERT compared to a 1% decrease for placebo (p<0.02).
The normalization of prothrombin time for the ZOSERT group was delayed compared
to the placebo group. The clinical significance of this change is unknown.
Accordingly, prothrombin time should be carefully monitored when ZOSERT therapy
is initiated or stopped.
CIMETIDINE--In a study assessing disposition of ZOSERT (100 mg) on the second of
8 days of cimetidine administration (800 mg daily), there were significant
increases in ZOSERT 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 ZOSERT (50
to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to
baseline in diazepam clearance for the ZOSERT 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 ZOSERT 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 ZOSERT 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 ZOSERT therapy with appropriate adjustments to
the lithium dose.
The risk of using ZOSERT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant
administration of ZOSERT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching
from other antidepressants to ZOSERT. 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 ZOSERT may
require lower doses than usually prescribed for the other drug. Furthermore,
whenever ZOSERT is withdrawn from co-therapy, an increased dose of the co-
administered drug may be required (see Tricyclic Antidepressants under
PRECAUTIONS).
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 ZOSERT, 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 ZOSERT (see Drugs
Metabolized by P450 2D6) under PRECAUTIONS).
HYPOGLYCEMIC DRUGS--In a placebo-controlled trial in normal volunteers,
administration of ZOSERT 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. ZOSERT
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--ZOSERT (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
ZOSERT 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 ZOSERT to induce
hepatic microsomal enzymes. In clinical studies, ZOSERT 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 ZOSERT.
ALCOHOL--Although ZOSERT did not potentiate the cognitive and psychomotor
effects of alcohol in experiments with normal subjects, the concomitant use of
ZOSERT 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/m(squared) 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/m(squared) 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/m(squared) 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/m(squared) 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/m(squared) 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/m(squared) basis) in rats and 40 mg/kg
(4 times the MRHD on a mg/m(squared)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/m(squared) basis). The no effect dose for rat pup
mortality was 10 mg/kg (0.5 times the MRHD on a mg/m(squared) 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. ZOSERT (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 ZOSERT 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 ZOSERT is administered to a
nursing woman.
PEDIATRIC USE--The efficacy of ZOSERT 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 STUDIES). The
effectiveness of ZOSERT 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 ACTIONS/CLINICAL PHARMACOLOGY).
More than 250 patients with depression or OCD between 6 and 17 years of age have
received ZOSERT in clinical trials. The adverse event profile observed in these
patients was generally similar to that observed in adult studies with ZOSERT
(see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and weight loss
have been observed in association with the use of ZOSERT. 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 ZOSERT. The pattern of adverse reactions in the elderly was similar
to that in younger patients.
DRUG INTERACTIONS:
POTENTIAL EFFECTS OF COADMINISTRATION OF DRUGS HIGHLY BOUND TO PLASMA PROTEINS--
Because sertraline is tightly bound to plasma protein, the administration of
ZOSERT (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 ZOSERT
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 ZOSERT (50-
200 mg/day) or placebo, there was a mean increase in prothrombin time of 8%
relative to baseline for ZOSERT compared to a 1% decrease for placebo (p<0.02).
The normalization of prothrombin time for the ZOSERT group was delayed compared
to the placebo group. The clinical significance of this change is unknown.
Accordingly, prothrombin time should be carefully monitored when ZOSERT therapy
is initiated or stopped.
CIMETIDINE--In a study assessing disposition of ZOSERT (100 mg) on the second of
8 days of cimetidine administration (800 mg daily), there were significant
increases in ZOSERT 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 ZOSERT (50
to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to
baseline in diazepam clearance for the ZOSERT 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 ZOSERT 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 ZOSERT 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 ZOSERT therapy with appropriate adjustments to
the lithium dose.
The risk of using ZOSERT in combination with other CNS active drugs has not been
systematically evaluated. Consequently, caution is advised if the concomitant
administration of ZOSERT and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching
from other antidepressants to ZOSERT. 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 ZOSERT may
require lower doses than usually prescribed for the other drug. Furthermore,
whenever ZOSERT is withdrawn from co-therapy, an increased dose of the co-
administered drug may be required (see Tricyclic Antidepressants under
PRECAUTIONS).
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 ZOSERT, 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 ZOSERT (see Drugs
Metabolized by P450 2D6) under PRECAUTIONS).
HYPOGLYCEMIC DRUGS--In a placebo-controlled trial in normal volunteers,
administration of ZOSERT 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. ZOSERT
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--ZOSERT (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
ZOSERT 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 ZOSERT to induce
hepatic microsomal enzymes. In clinical studies, ZOSERT 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.
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 ZOSERT.
ALCOHOL--Although ZOSERT did not potentiate the cognitive and psychomotor
effects of alcohol in experiments with normal subjects, the concomitant use of
ZOSERT and alcohol is not recommended.
(See Also PRECAUTIONS.)