WARNINGS
Cases of serious, sometimes fatal, reactions have
been reported in patients receiving sertraline HCl, 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, myocionus, 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, it is recommended
that sertraline HCl 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 sertraline HCl before starting an MAOI.
PRECAUTIONS
General
Activation of Mania/Hypomania: During
premarketing testing, hypomania or mania occurred in approximately
0.4% of sertraline HCl 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: Sertraline HCl 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 sertraline HCl 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, sertraline HCl 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
sertraline HCl 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: Sertraline HCl 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 sertraline HCl.
Use in Patients with Concomitant Illness:
Clinical experience with sertraline HCl in patients with
certain concomitant systemic illness is limited. Caution
is advisable in using sertraline HCl in patients with
diseases or conditions that could affect metabolism or
hemodynamic responses.
Sertraline HCl 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 sertraline HCl in double-blind
trials were evaluated and the data indicate that sertraline
HCl is not associated with the development of significant
ECG abnormalities.
Sertraline HCl 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 sertraline HCl 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 pharmacokinetics 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, sertraline HCl 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
sertraline HCl 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 sertraline
HCl. While there have been reports of abnormal bleeding
or purpura in several patients taking sertraline HCl,
it is unclear whether sertraline HCl had a causative role.
Information for Patients
Physicians are advised to discuss the following issues
with patients for whom they prescribe sertraline HCl:
Patients should be told that although sertraline HCl 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 sertraline HCl has
not been shown in experiments with normal subjects to
increase the mental and motor skill impairments caused
by alcohol, the concomitant use of sertraline HCl and
alcohol in depressed patients is not advised.
Patients should be told that while no adverse interaction
of sertraline HCl 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.
Sertraline HCl oral concentrate is contraindicated with
disulfuram (Antabuse) due to the alcohol content of the
concentrate.
Sertraline HCl contains 12% alcohol. Sertraline HCl oral
concentrate must be diluted before use. Just before taking,
use the dropper provided to remove the required amount
of sertraline HCl oral concentrate and mix with 4 oz (½
cup) of water, gingerale, lemon/lime soda, lemonade or
orange juice ONLY. Do not mix sertraline HCl oral concentrate
with anything other than the liquids listed. The dose
should be taken immediately after mixing. Do not mix in
advance. At times, a slight haze may appear after mixing;
this is normal. Note that caution should be exercised
for persons with latex sensitivity, as the dropper dispenser
contains dry natural rubber.
Laboratory Tests
None.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 in the incidence 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 MHRD 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
MHRD 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 wmarrow 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 human dose on a mg/kg basis and 4
times on a mg/m2 basis).
Pregnancy, Teratogenic Effects, 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 HCl 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 four
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 HCl. The clinical
significance of these effects is unknown. There are no
adequate and well controlled studies in pregnant women.
Sertraline HCl should be used during pregnancy only if
the potential benefit justifies the potential risk to
the fetus.
Labor and Delivery
The effect of sertraline HCl 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 sertraline HCl is administered
to a nursing woman.
Pediatric Use
The efficacy of sertraline HCl 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 STUDIES). The effectiveness
of sertraline HCl 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 CLINICAL PHARMACOLOGY, Pharmacokinetics).
More than 250 patients with depression or OCD between
6 and 17 years of age have received sertraline HCl in
clinical trials. The adverse event profile observed in
these patients was generally similar to that observed
in adult studies with sertraline HCl (see ADVERSE REACTIONS).
As with other SSRIs, decreased appetite and weight loss
have been observed in association with the use of sertraline
HCl. 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 be 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 sertraline HCl. The pattern of
adverse reactions in the elderly was similar to that in
younger patients.
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