Medicine Online
Any medical inquiries? Search MOL for answers:
MEDICAL DRUGS
Home > Medical Drugs > Drugs beginning with S > Sertraline Hydrochloride Tablets 25 mg, 50 mg and 100 mg
Medical References
Diseases & Conditions
Women's Health
Mental Health
Men's Health
Healthy Choice News
Site Map Links
Medical Tips
Attention, chocolate lovers: You may not be able to help yourselves. Swiss and British scientists have linked the widespread love of chocolate to a chemical "signature" that may be programmed into our metabolic systems.
Read more health news

Sertraline Hydrochloride Tablets 
25 mg, 50 mg and 100 mg

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of sertraline hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Sertraline hydrochloride tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)

DESCRIPTION

Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration. 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 molecular formula C17H17Cl2N·HCl is represented by the following structural formula:

Sertraline hydrochloride is a white to off-white crystalline powder that is sparingly soluble in methanol and in dimethyl formamide.

Each sertraline hydrochloride tablet, intended for oral administration, contains sertraline hydrochloride equivalent to 25 mg, 50 mg or 100 mg of sertraline. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, FD&C blue #1 aluminum lake 12% (in 25 mg tablet), FD&C blue #2 aluminum lake (in 50 mg tablet), yellow iron oxide (in 25 mg and 100 mg tablets), hydroxypropyl cellulose, hypromellose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics

The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to downregulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase.

Pharmacokinetics

Clinical Trials

INDICATIONS AND USAGE

Sertraline hydrochloride tablets are indicated for the treatment of major depressive disorder in adults.

The efficacy of sertraline hydrochloride in the treatment of a major depressive episode was established in six to eight week controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see Clinical Trials under CLINICAL PHARMACOLOGY).

A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.

The antidepressant action of sertraline hydrochloride in hospitalized depressed patients has not been adequately studied.

The efficacy of sertraline hydrochloride 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 sertraline hydrochloride for extended periods should be reevaluated periodically (see Clinical Trials under CLINICAL PHARMACOLOGY).

CONTRAINDICATIONS

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

Sertraline hydrochloride tablets are contraindicated in patients with a hypersensitivity to sertraline or any of the inactive ingredients in sertraline hydrochloride tablets.

WARNINGS

Cases of serious sometimes fatal reactions have been reported in patients receiving 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, sertraline hydrochloride 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 sertraline hydrochloride before starting an MAOI.

Clinical Worsening and Suicide Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1
Age Range Drug-Placebo Difference in
Number of Cases of Suicidality
per 1000 Patients Treated
Drug-Related Increases
<1814 additional cases
18-245 additional cases
Drug-Related Decreases
25-641 fewer case
≥656 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION - Discontinuation of Treatment with Sertraline Hydrochloride, for a description of the risks of discontinuation of sertraline hydrochloride.)

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for sertraline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

PRECAUTIONS

General

Discontinuation of Treatment with Sertraline Hydrochloride

During marketing of sertraline hydrochloride and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with sertraline hydrochloride. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).

Abnormal Bleeding

Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a non-selective nonsteroidal anti-inflammatory drug (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated the risk of bleeding (see DRUG INTERACTIONS). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of sertraline hydrochloride with non-selective NSAIDs (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2), aspirin, or other drugs that affect coagulation.

Information for Patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sertraline hydrochloride tablets and should counsel them in its appropriate use.  A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions" is available for sertraline hydrochloride tablets.  The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its spans.  Patients should be given the opportunity to discuss the spans of the Medication Guide and to obtain answers to any questions they may have.  The complete div of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride.

Laboratory Tests

None.

Drug Interactions

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 to 40 mg/kg (0.25 to 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 to 40 mg/kg (0.5 to 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. Sertraline hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy-Nonteratogenic Effects

Neonates exposed to sertraline hydrochloride and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS).

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1-2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

When treating a pregnant woman with sertraline hydrochloride during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic in the condiv of antidepressant therapy at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Labor and Delivery

The effect of sertraline hydrochloride 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 hydrochloride is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients with major depressive disorder have not been established (see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo controlled trials (n=373) in pediatric patients with MDD have been conducted with sertraline, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of sertraline hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need.

Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients between 6 and 17 years of age and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight (see Pharmacokinetics under CLINICAL PHARMACOLOGY).

Approximately 600 pediatric patients between 6 and 17 years of age have received sertraline in clinical trials, both controlled and uncontrolled. The adverse event profile observed in these patients was generally similar to that observed in adult studies with sertraline (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of sertraline. In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50 to 200 mg) outpatient trials for major depressive disorder (N=373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6 to 11) and adolescents (ages 12 to 17), in both cases representing a slight weight loss for sertraline compared to a slight gain for placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo. There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents. For children, about 7% had a weight loss >7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss >7% of body weight compared to about 1% of placebo patients. A subset of these patients who completed the randomized controlled trials (sertraline N=99, placebo N=122) were continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label, N=68), had weight gain that was similar to that expected using data from age-adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric patients with major depressive disorder have not been established.

The risks, if any, that may be associated with sertraline’s use beyond 1 year in children and adolescents have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 12 to 52 weeks in duration and from the extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use (see WARNINGS, Clinical Worsening and Suicide Risk).

Geriatric Use

U.S. geriatric clinical studies of sertraline hydrochloride in major depressive disorder included 663 sertraline hydrochloride-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects (see ADVERSE REACTIONS), and other reported experience has not identified differences in safety patterns between the geriatric and younger subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of sertraline hydrochloride in major depressive disorder. No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.

Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with sertraline hydrochloride in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Table 1. Urinary tract infection was the only adverse event not appearing in Table 1 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.

As with other SSRIs, sertraline hydrochloride has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).

ADVERSE REACTIONS

During its premarketing assessment, multiple doses of sertraline hydrochloride were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to sertraline hydrochloride varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder.

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 sertraline hydrochloride who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving sertraline hydrochloride. 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 2 enumerates the most common treatment-emergent adverse events associated with the use of sertraline hydrochloride (incidence of at least 5% for sertraline hydrochloride) for the treatment of adult patients with major depressive disorder/other* in placebo-controlled clinical trials. Most patients in major depressive disorder/other* studies received doses of 50 to 200 mg/day.

TABLE 2:  MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS FOR MAJOR DEPRESSIVE DISORDER/OTHER*
Percentage of Patients Reporting Event
Body System/Adverse EventSertraline Hydrochloride
(N=861)
Placebo
(N=853)
Autonomic Nervous System Disorders
  Ejaculation Failure **7<1
  Mouth Dry169
  Sweating Increased83
Centr. & Periph. Nerv. System Disorders
  Somnolence136
  Tremor11 3
  Dizziness127
General
  Fatigue118
  Pain12
  Malaise<11
Gastrointestinal Disorders
  Abdominal Pain22
  Anorexia3 2
  Constipation8 6
  Diarrhea/Loose Stools189
  Dyspepsia63
  Nausea2612
Psychiatric Disorders
  Agitation64
  Insomnia169
  Libido Decreased1<1

*Major depressive disorder and other premarketing controlled trials.
 
**Primarily ejaculatory delay.  Denominator used was for male patients only (N=271 sertraline hydrochloride major depressive disorder/other*; N=271 placebo  major depressive disorder/other*).

Associated with Discontinuation in Placebo-Controlled Clinical Trials

Table 3 uls the adverse events associated with discontinuation of sertraline hydrochloride treatment (incidence at least twice that for placebo and at least 1% for sertraline hydrochloride in clinical trials) in major depressive disorder/other*.

TABLE 3:  MOST COMMON ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS
Adverse EventMajor Depressive Disorder/OtherMajor depressive disorder and other premarketing controlled trials.
(N=861)
Abdominal Pain
Agitation1%
Anxiety
Diarrhea/ Loose Stools2%
Dizziness
Dry Mouth1%
Dyspepsia
Ejaculation FailurePrimarily ejaculatory delay. Denominator used was for male patients only (N=271 major depressive disorder/other*). 1%
Fatigue
Headache2%
Hot Flushes
Insomnia1%
Nausea4%
Nervousness
Palpitation
Somnolence1%
Tremor2%

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 sertraline hydrochloride in placebo-controlled trials.

TABLE 4
Adverse EventSertraline HydrochloridePlacebo
Ejaculation failureDenominator used was for male patients only (N=1118 Sertraline Hydrochloride; N=926 placebo)
(primarily delayed ejaculation)
14%1%
Decreased libidoDenominator used was for male and female patients (N=2799 Sertraline Hydrochloride; N=2394 placebo) 6%1%

There are no adequate and well-controlled studies examining sexual dysfunction with sertraline treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Other Adverse Events in Pediatric Patients

In over 600 pediatric patients treated with sertraline, the overall profile of adverse events was generally similar to that seen in adult studies. However, the following adverse events, from controlled trials, not appearing in Table 1, were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo rate (N=281 patients treated with sertraline); fever, hyperkinesias, urinary incontinence, aggressive reaction, sinusitis, epistaxis, and purpura.

Other Events Observed During the Premarketing Evaluation of Sertraline Hydrochloride

Following is a ul of treatment-emergent adverse events reported during premarketing assessment of sertraline hydrochloride in clinical trials (over 4000 adult subjects) except those already uled 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 sertraline hydrochloride who experienced an event of the type cited on at least one occasion while receiving sertraline hydrochloride. All events are included except those already uled 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 sertraline hydrochloride treatment seemed remote. It is important to emphasize that although the events reported occurred during treatment with sertraline hydrochloride, they were not necessarily caused by it.

Events are further categorized by body system and uled 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.

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 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.

Sertraline hydrochloride 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.

Other Events Observed During the Postmarketing Evaluation of Sertraline Hydrochloride

Reports of adverse events temporally associated with sertraline hydrochloride that have been received since market introduction, that are not uled above and that may have no causal relationship with the drug, include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia (including torsade de pointes-type arrhythmias), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, hyperglycemia, galactorrhea, hyperprolactinemia, neuroleptic malignant syndrome-like events, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical features (which in the majority of cases appeared to be reversible with discontinuation of sertraline hydrochloride) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

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 sertraline hydrochloride, alprazolam, and d-amphetamine in humans, sertraline hydrochloride 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 sertraline hydrochloride did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior. In animal studies sertraline hydrochloride 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 sertraline hydrochloride misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

OVERDOSAGE

Human Experience

Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999).

Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.

The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and subsequently recovered. However, another patient who took 2.5 grams of sertraline hydrochloride alone experienced a fatal outcome.

Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor and syncope.

Overdose Management

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered. Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for sertraline are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are uled in the Physicians' Desk Reference® (PDR®).

DOSAGE AND ADMINISTRATION

Initial Treatment

Dosage for Adults

Maintenance/Continuation/Extended Treatment

Special Populations

HOW SUPPLIED

Sertraline Hydrochloride Tablets 25 mg are available for oral administration as light green, oval shaped, scored, film coated tablets, imprinted “APO” on one side and “SE” bisect “25” on the other side. They are supplied as follows:

Bottles of 30 (NDC 60505-0180-3)
Bottles of 60 (NDC 60505-0180-6)
Bottles of 90 (NDC 60505-0180-9)
Bottles of 180 (NDC 60505-0180-2)
Bottles of 500 (NDC 60505-0180-7)
Bottles of 1000 (NDC 60505-0180-8)

Sertraline Hydrochloride Tablets 50 mg are available for oral administration as bluish purple, oval shaped, scored, film coated tablets, imprinted “APO” on one side and “SE” bisect “50” on the other side. They are supplied as follows:

Bottles of 30 (NDC 60505-0181-3)
Bottles of 60 (NDC 60505-0181-6)
Bottles of 90 (NDC 60505-0181-9)
Bottles of 180 (NDC 60505-0181-2)
Bottles of 500 (NDC 60505-0181-7)
Bottles of 1000 (NDC 60505-0181-8)

Sertraline Hydrochloride Tablets 100 mg are available for oral administration as yellow, oval shaped, scored, film coated tablets, imprinted “APO” on one side and “SER” bisect “100” on the other side. They are supplied as follows:

Bottles of 30 (NDC 60505-0182-3)
Bottles of 60 (NDC 60505-0182-6)
Bottles of 90 (NDC 60505-0182-9)
Bottles of 180 (NDC 60505-0182-2)
Bottles of 500 (NDC 60505-0182-7)
Bottles of 1000 (NDC 60505-0182-8)

Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86° F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container [see USP].

APOTEX INC.
SERTRALINE HYDROCHLORIDE TABLETS
25 mg, 50 mg and 100 mg

Manufactured by: Manufactured for:
Apotex Inc. Apotex Corp.
Toronto, Ontario Weston, Florida
Canada M9L 1T9 33326

Revised: May 2007

Rev. 7

MEDICATION GUIDE

Antidepressant Medicines, Depression and other Serious Mental Illnesses, and
                                    Suicidal Thoughts or Actions

Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:

  • all risks and benefits of treatment with antidepressant medicines
  • all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

  • Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults when the medicine is first started.
  • Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
  • How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
  • Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is first started or when the dose is changed.
  • Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
  • Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling very agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

  • Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
  • Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
  • Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
  • Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a ul of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
  • Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

Revised: May 2007