SERVAL

Sertraline is a popular antidepressant medication commonly known as a selective serotonin reuptake inhibitor (SSRI), and is similar to drugs such as Citalopram and Fluoxetine.

Despite marked structural differences between compounds in this drug class, SSRIs exert similar pharmacological effects.

Several weeks of therapy with sertraline may be required before beneficial effects are noticed.

Sertraline displays enhanced safety or tolerability than other classes of antidepressants, which frequently cause high levels of drowsiness, dizziness, blurred vision, and other undesirable effects. 6, 10, 19.

Sertraline is indicated for the management of major depressive disorder (MDD), post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), panic disorder (PD), premenstrual dysphoric disorder (PMDD), and social anxiety disorder (SAD).

Common off-label uses for sertraline include the prevention of post stroke depression 11, generalized anxiety disorder (GAD), fibromyalgia, premature ejaculation, migraine prophylaxis, diabetic neuropathy, and neurocardiogenic syncope.

Sertraline improves or relieves the symptoms of depression, OCD, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder via the inhibition of serotonin reuptake. 10, 21 Clinical studies have shown that it improves cognition in depressed patients.

It has less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs because it does not exert significant anticholinergic, antihistamine, or adrenergic (alpha1, alpha2, beta) blocking activity.

The onset of action and beneficial effects are usually noticed after 4-6 weeks, for reasons that are not fully understood and currently under investigation. 17, 27.

Following once-daily administration of 50-200 mg for two weeks, the mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5-8.4 hours after administration, and measured at 20-55 μg/L. 6, 21 Steady-state concentrations are reached after 1 week following once-daily administration, and vary greatly depending on the patient. 7, 21 Bioavailability has been estimated to be above 44%.

The area under the curve in healthy volunteers after a 100 mg dose of sertraline was 456 μg × h/mL in one study.

Effects of food on absorption

The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects given a single dose with and without food.

For the tablet, AUC was slightly increased when sertraline was administered with food, the Cmax was 25% greater, and the time to peak plasma concentration was shortened by about 2.5 hours.

For the oral concentrate preparation of sertraline, peak concentration was prolonged by approximately 1 hour with the ingestion of food.

Sertraline is widely distributed, and its volume of distribution is estimated to be more than 20 L/kg.

Post-mortem studies in humans have measured liver tissue concentrations of 3.9–20 mg/kg for sertraline and between 1.4-11 mg/kg for its active metabolite, N-desmethyl-sertraline (DMS).

Studies have also determined sertraline distributes into the brain, plasma, and serum.

Sertraline is heavily metabolized in the liver and has one major active metabolite.

It undergoes N-demethylation to form

N-desmethylsertraline, which is much less potent in its pharmacological activity than sertraline.

In addition to

N-demethylation, sertraline metabolism involves N-hydroxylation, oxidative deamination, and finally, glucuronidation.

The metabolism of sertraline is mainly catalyzed by CYP3A4 and CYP2B6, with some activity accounted for by CYP2C19 and CYP2D6. 6, 22 Hover over products below to view reaction partners Sertraline norsertraline α-Hydroxy sertraline ketone glucuronide α-Hydroxy sertraline ketone Sertraline carbamoyl-O-glucuronide.

Since sertraline is extensively metabolized, excretion of unchanged drug in the urine is a minor route of elimination, with 12-14% of unchanged sertraline excreted in the feces. 6, 7, 21.

The elimination half-life of sertraline is approximately 26 hours. 6, 21 One reference mentions an elimination half-life ranging from 22-36 hours.

In pharmacokinetic studies, the clearance of a 200 mg dose of sertraline in studies of both young and elderly patients ranged between 1.09 ± 0.38 L/h/kg.

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LD50 of sertraline is >2000 mg/kg in rats according to the FDA label.

One other references indicates an oral

LD50 of in mice and rats of 419-548 mg/kg and 1327-1591 mg/kg, respectively.

The most common signs and symptoms associated with a non-fatal sertraline overdose are somnolence, vomiting, tachycardia, nausea, dizziness, agitation, and tremor.

No cases of fatal overdose with only sertraline have been reported.

Most fatal cases are associated with the ingestion of sertraline with other drugs.

Consequences of a sertraline overdose may include serotonin syndrome, hypertension, hypotension, syncope, stupor, coma, bradycardia, bundle branch block, QT-prolongation, torsade de pointes, delirium, hallucinations, and pancreatitis.

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 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 Increases Compared to placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to placebo 25-64 1 fewer case >65 6 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.

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.

A major depressive episode may be the initial presentation of bipolar disorder.

It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder.

Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

It should be noted that sertraline hydrochloride is not approved for use in treating bipolar depression.

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Sertraline hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms(e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of sertraline hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated.

Sertraline hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking sertraline hydrochloride.

Sertraline hydrochloride should be discontinued before initiating treatment with the MAOI See CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION.

If concomitant use of sertraline hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St.

John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with

Sertraline hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

The pupillary dilation that occurs following use of many antidepressant drugs including sertraline may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

The use of MAOIs intended to treat psychiatric disorders with Sertraline hydrochloride or within 14 days of stopping treatment with Sertraline hydrochloride is contraindicated because of an because of an increased risk if serotonin syndrome.

The use of

Sertraline hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated See WARNINGS and DOSAGE AND ADMINISTRATION.

Sertraline hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methyelene blue is also contraindicated because of an increased risk of serotonin syndrome See WARNINGS and DOSAGE AND ADMINISTRATION.

Concomitant use in patients taking pimozide is contraindicated.

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

Initial Treatment Dosage for Adults Major Depressive Disorder –Sertraline hydrochloride treatment should be administered at a dose of 50 mg once daily.

While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of Sertraline hydrochloride for the treatment of this indication.

Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose.

Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.

Disorder – Sertraline hydrochloride treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.

While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle.

Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/ menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle.

If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period.

Sertraline hydrochloride should be administered once daily, either in the morning or evening.

Population (Children and Adolescents) Obsessive-Compulsive Disorder – Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).

While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of Sertraline hydrochloride for pediatric patients (6-17 years) with OCD.

Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing.

Given the 24 hour elimination half-life of Sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.

Maintenance/Continuation/Extended Treatment Major Depressive Disorder –It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode.

Systematic evaluation of sertraline hydrochloride has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50-200 mg/day (mean dose of 70 mg/day) .

It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response.

Patients should be periodically reassessed to determine the need for maintenance treatment.

Disorder –It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of

Sertraline hydrochloride has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day.

It is not known whether the dose of Sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response.

Disorder –Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Sertraline hydrochloride has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200 mg/day.

Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.

Disorder –It is generally agreed that OCD and Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment.

Systematic evaluation of continuing

Sertraline hydrochloride for periods of up to 28 weeks in patients with OCD and Panic Disorder who have responded while taking Sertraline hydrochloride during initial treatment phases of to 52 weeks of treatment at a dose range of 50-200 mg/day has demonstrated a benefit of such maintenance treatment.

Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Disorder –The effectiveness of sertraline hydrochloride in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials.

However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient.

Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric.

Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Sertraline hydrochloride.

Conversely, at least 14 days should be allowed after stopping Sertraline hydrochloride before starting an MAOI intended to treat psychiatric disorders See CONTRAINDICATIONS.

Use of Sertraline Hydrochloride With Other MAOIs Such as Linezolid or Methylene Blue: Do not start Sertraline hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered See CONTRAINDICATIONS.

In some cases, a patient already receiving Sertraline hydrochloride therapy may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Sertraline hydrochloride should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with

Sertraline hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue See WARNINGS.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Sertraline hydrochloride is unclear.

The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use See WARNINGS.

Special Populations Dosage for Hepatically Impaired

Patients –The use of sertraline in patients with liver disease should be approached with caution.

The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied.

If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used.

Treatment of Pregnant Women During the Third Trimester –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.

When treating pregnant women with

Sertraline hydrochloride during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Discontinuation of Treatment with Sertraline hydrochloride

Symptoms associated with discontinuation of Sertraline hydrochloride and other SSRIs and SNRIs, have been reported.

Patients should be monitored for these symptoms when discontinuing treatment.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Sertraline tablets, USP are available with each tablet containing sertraline hydrochloride, USP equivalent to 25 mg, 50 mg and 100 mg of sertraline.

Sertraline 25 mg Tablets: Light Green film coated Modified oval biconvex tablets debossed with I on the left Side of bisect and G on the right Side of bisect on one Side and "212" on other NDC 63187-859-30 Bottles of 30 NDC 63187-859-60 Bottles of 60 NDC 63187-859-90 Bottles of 90 Store at 20°C to 25°C (68°F to 77°F) .

Revised: 07/2016.