sertraline (as sertraline hydrochloride) 50 MG Oral Tablet
WARNINGS
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.
The risk differences (drug-placebo differences 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 (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.
Screening Patients for Bipolar Disorder 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.
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.
The concomitant use of sertraline hydrochloride with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and – Potential for Interaction with Monoamine Oxidase Inhibitors ).
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including sertraline hydrochloride treatment, but particularly with concomitant use of serotonergic drugs (including triptans and fentanyl) and with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists.
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.
Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
The concomitant use of sertraline hydrochloride with MAOIs intended to treat depression is contraindicated.
If concomitant treatment of sertraline hydrochloride, with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
The concomitant use of SNRIs and SSRIs, including serteraline hydrochloride, with serotonin precursors (such as tryptophan) is not recommended.
Treatment with sertraline hydrochloride and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Co-administration of sertraline hydrochloride with other drugs which enhance the effects of serotonergic neurotransmission, such as tryptophan, fenfluramine, fentanyl, 5-HT agonists, or the herbal medicine St.
John’s Wort (hypericum perforatum) should be undertaken with caution and avoided whenever possible due to the potential for pharmacodynamic interaction.
DRUG INTERACTIONS
Drug Interactions Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins Because sertraline is tightly bound to plasma protein, the administration of 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 sertraline hydrochloride 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 sertraline hydrochloride (50 to 200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline hydrochloride compared to a 1% decrease for placebo (p<0.02).
The normalization of prothrombin time for the sertraline hydrochloride group was delayed compared to the placebo group.
The clinical significance of this change is unknown.
Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped.
Cimetidine In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline hydrochloride mean AUC (50%), C max (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 sertraline hydrochloride (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride group compared to a 19% decrease relative to baseline for the placebo group (p<0.03).
There was a 23% increase in T max for desmethyldiazepam in the sertraline hydrochloride 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 sertraline hydrochloride 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 sertraline hydrochloride therapy with appropriate adjustments to the lithium dose.
In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and C max of about 40%, but was not associated with any changes in EKG.
Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known.
While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of sertraline hydrochloride and pimozide should be contraindicated (see CONTRAINDICATIONS ).
Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism.
Nonethless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of Sertraline Hydrochloride therapy with appropriate adjustments to the phenytoin dose, practiculary in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.
The effect of Sertraline Hydrochloride on valproate levels has not been evaluated in clinical trials.
In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the valproate dose.
The risk of using sertraline hydrochloride in combination with other CNS active drugs has not been systematically evaluated.
Consequently, caution is advised if the concomitant administration of sertraline hydrochloride and such drugs is required.
There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder to sertraline hydrochloride.
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 three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions.
The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride.
These data indicate that sertraline’s extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.
Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and C max were reduced by about 35%).
Drugs Metabolized by P450 2D6 Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder 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 antidepressant drugs effective in the treatment of major depressive disorder 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 drugs effective in the treatment of major depressive disorder 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 sertraline hydrochloride may require lower doses than usually prescribed for the other drug.
Furthermore, whenever sertraline hydrochloride is withdrawn from co-therapy, an increased dose of the co-administered drug may be required (see Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS ).
Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including sertraline hydrochloride, and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including sertraline hydrochloride, are coadministered with other drugs that may affect the serotonergic neutrotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.
John’s Wort (see WARNINGS-Serotonin Syndrome ).
The concomitant use of sertraline hydrochloride with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS – Drug Interactions ).
Triptans There have been rare post-marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan.
If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS – Serotonin Syndrome ).
Sumatriptan There have been rare post marketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan.
If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (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 sertraline hydrochloride, 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 sertraline (see Drugs Metabolized by P450 2D6 under PRECAUTIONS ).
Hypoglycemic Drugs In a placebo-controlled trial in normal volunteers; administration of sertraline hydrochloride 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.
Sertraline hydrochloride 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 Sertraline hydrochloride (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 sertraline hydrochloride 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 sertraline hydrochloride to induce hepatic microsomal enzymes.
In clinical studies, sertraline hydrochloride 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.
Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.) Serotonin release by platelets plays an important role in hemostasis.
Epidemiological studies of the case-control and cohort design that have demonstrated an association between the use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID, or aspirin potentiated the risk of bleeding.
These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin.
Patients receiving warfarin therapy should be carefully monitored when sertraline hydrochloride is initiated or discontinued.
Electroconvulsive Therapy There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and sertraline hydrochloride.
Alcohol Although sertraline hydrochloride did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of sertraline hydrochloride and alcohol is not recommended.
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 listed in the Physicians’ Desk Reference (PDR).
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 empirical formula C 17 H 17 NC l2 ∙HCl is represented by the following structural formula: Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.
Sertraline 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: D & C Yellow #10 aluminum lake (in 25 mg tablet), FD & C Blue #2 aluminum lake (in 25 mg & 50 mg tablets), magnesium stearate, microcrystalline cellulose, polyethylene glycolS, polyvinyl alcohol, povidone K30, sodium starch glycolate, talc, titanium dioxide & yellow iron oxide.
Chemical Structure
CLINICAL STUDIES
Clinical Trials Major Depressive Disorder The efficacy of sertraline as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder.
Study 1 was an 8-week study with flexible dosing of sertraline 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 sertraline doses of 50, 100, and 200 mg/day.
Overall, these studies demonstrated sertraline hydrochloride 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 sertraline 50-200 mg/day.
These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride 50-200 mg/day or placebo.
A statistically significantly lower relapse rate was observed for patients taking sertraline hydrochloride 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.
Premenstrual Dysphoric Disorder (PMDD) The effectiveness of sertraline for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles.
Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV.
Patients in Study 2 met DSM-IV criteria for PMDD.
Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses.
The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies.
Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown.
Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms.
Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
In Study 1, involving n=251 randomized patients, sertraline hydrochloride treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle.
In subsequent cycles, patients were dosed in the range of 50-150 mg/day on the basis of clinical response and toleration.
The mean dose for completers was 102 mg/day.
Sertraline hydrochloride administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.
In Study 2, involving n=281 randomized patients, sertraline hydrochloride treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses.
In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration.
Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle.
The mean sertraline hydrochloride dose for completers was 74 mg/day.
Sertraline hydrochloride administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.
There was insufficient information to determine the effect of race or age on outcome in these studies.
HOW SUPPLIED
Sertraline hydrochloride modified oval biconvex tablets, containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
Sertraline hydrochloride 25 mg Tablets: Light Green film coated, Modified oval biconvex tablets debossed with 5 on the left side of bisect and 8 on the right side of bisect on one side and “W” on other.
NDC 51138-585-30 Bottles of 30 Sertraline hydrochloride 50 mg Tablets: Light Blue film coated, Modified oval biconvex tablets debossed with 5 on the left side of bisect and 7 on the right side of bisect on one side and “W” on other.
NDC 51138-586-30 Bottles of 30 Sertraline hydrochloride 100 mg Tablets: Light Yellow film coated, Modified oval biconvex tablets debossed with 5 on the left side of bisect and 6 on the right side of bisect on one side and “W” on other.
NDC 51138-587-30 Bottles of 30 New Tablet ID Store at 20ºC to 25ºC (68ºF to 77ºF) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
GERIATRIC USE
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 elderly 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 2.
Urinary tract infection was the only adverse event not appearing in Table 2.
SSRIs and SNRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia ).
Diabetes/Loss of Glycemic Control Cases of new onset diabetes mellitus have been reported in patients receiving SSRIs including sertraline hydrochloride.
Loss of glycemic control including both hyperglycemia and hypoglycemia has also been reported in patients with and without preexisting diabetes.
Patients should therefore be monitored for signs and symptoms of glucose fluctuations.
Diabetic patients especially should have their glycemic control carefully monitored since their dosage of insulin and/or concomitant oral hypoglycemic drug may need to be adjusted.
INDICATIONS AND USAGE
Major Depressive Disorder Sertraline is 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 ).
Premenstrual Dysphoric Disorder (PMDD) Sertraline hydrochloride is indicated for the treatment of premenstrual dysphoric disorder (PMDD) in adults.
The efficacy of sertraline hydrochloride in the treatment of PMDD was established in 2 placebo-controlled trials of female adult outpatients treated for 3 menstrual cycles who met criteria for the DSM-III-R/IV category of PMDD (see Clinical Trials under CLINICAL PHARMACOLOGY ).
The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability.
Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control.
Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating and weight gain.
These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationships with others.
In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.
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.
Therefore, the physician who elects to use sertraline hydrochloride for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).
PEDIATRIC USE
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 hydrochloride, 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 hydrochloride (see ADVERSE REACTIONS ).
As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of sertraline hydrochloride.
In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 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 6-11) and adolescents (ages 12-17), 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 the 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 the 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 hydrochloride’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 10 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 ).
PREGNANCY
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 2 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 2 basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m 2 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 2 basis).
The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m 2 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.
NUSRING MOTHERS
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.
BOXED WARNING
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 is 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 )
INFORMATION FOR PATIENTS
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 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.
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 contents.
Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text 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.
Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including sertraline hydrochloride, and triptans, tramadol, or other serotonergic agents.
Patients should be told that although sertraline hydrochloride 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.
Therefore, patients should be told that until they learn how they respond to sertraline hydrochloride they should be careful doing activities when they need to be alert, such as driving a car or operating machinery.
Patients should be cautioned about the concomitant use of sertraline hydrochloride and non-selective NSAIDs (i.e., NSAIDs that inhibit both cycloxygenase isoenzymes COX1 and 2), aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Patients should be told that although sertraline hydrochloride 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 hydrochloride and alcohol is not advised.
Patients should be told that while no adverse interaction of sertraline hydrochloride 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.
DOSAGE AND ADMINISTRATION
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, 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.
Premenstrual Dysphoric 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 (see Clinical Trials under CLINICAL PHARMACOLOGY ).
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.
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) (see Clinical Trials under CLINICAL PHARMACOLOGY ).
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.
Premenstrual Dysphoric 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 Patients to or from a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with sertraline hydrochloride.
In addition, at least 14 days should be allowed after stopping sertraline hydrochloride before starting an MAOI (see CONTRAINDICATIONS and 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 (see CLINICAL PHARMACOLOGY and PRECAUTIONS ).
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 (see PRECAUTIONS ).
When treating pregnant women with sertraline hydrochloride during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
The physician may consider tapering sertraline hydrochloride in the third trimester.
Discontinuation of Treatment with Sertraline Symptoms associated with discontinuation of sertraline hydrochloride and other SSRIs and SNRIs, have been reported (see PRECAUTIONS ).
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.