The mechanism of action of sertraline is presumed to be linked to its ability to inhibit the neuronal reuptake of serotonin. It has only very weak effects on norepinephrine and dopamine neuronal reuptake. At clinical doses, sertraline blocks the uptake of serotonin into human platelets.

Like most clinically effective antidepressants, sertraline downregulates brain norepinephrine and serotonin receptors in animals. In receptor binding studies, sertraline has no significant affinity for adrenergic (alpha₁, alpha₂ & beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5-HT1A, 5-HT1B, 5-HT2) or benzodiazepine binding sites.

In placebo-controlled studies in normal volunteers, ZOLOFT (sertraline hydrochloride) did not cause sedation and did not interfere with psychomotor performance.

Following multiple oral once-daily doses of 200 mg, the mean peak plasma concentration (C_max) of sertraline is 0.19 µg/mL occurring between 6 to 8 hours post-dose. The area under the plasma concentration time curve is 2.8 mg·hr/L. For desmethylsertraline, C_max is 0.14 μg/mL, the half-life 65 hours and the area under the curve 2.3 mg·hr/L. Following single or multiple oral once-daily doses of 50 to 400 mg/day the average terminal elimination half-life is approximately 26 hours. Linear dose proportionality has been demonstrated over the clinical dose range of 50 to 200 mg/day.

Food appears to increase the bioavailability by about 40%: it is recommended that ZOLOFT be administered with meals.

Sertraline is extensively metabolized to N-desmethylsertraline, which shows negligible pharmacological activity. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation and glucuronide conjugation. Biliary excretion of metabolites is significant. Approximately 98% of sertraline is plasma protein bound. The interactions between sertraline and other highly protein bound drugs have not been fully evaluated (see Precautions).

The pharmacokinetics of sertraline itself appear to be similar in young and elderly subjects. Plasma levels of N-desmethylsertraline show a 3-fold elevation in the elderly following multiple dosing, however, the clinical significance of this observation is not known.

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.

Liver and Renal Disease: The pharmacokinetics of sertraline in patients with significant hepatic or renal dysfunction have been determined (see Precautions and Dosage).

Panic Disorder: Four placebo-controlled clinical trials have been performed to investigate the efficacy of ZOLOFT in panic disorder: two flexible dose studies and two fixed dose studies. At the last week of treatment (week 10 or 12), both flexible dose studies and one of the fixed dose studies showed statistically significant differences from placebo in favour of ZOLOFT in terms of mean change from baseline in the total number of full panic attacks (last observation carried forward analysis). As the flexible dose studies were of identical protocol, data for these investigations can be pooled. The mean number of full panic attacks at baseline was 6.2/week (N=167) in the ZOLOFT group and 5.4/week in the placebo group (N=175). At week 10 (last observation carried forward analysis), the mean changes from baseline were −4.9/week and −2.5/week for the ZOLOFT and placebo groups, respectively. The proportion of patients having no panic attacks at the final evaluation was 57% in the placebo group and 69% in the ZOLOFT group. The mean daily dose administered at the last week of treatment was approximately 120 mg (range: 25-200 mg) in the flexible dose studies. No clear dose-dependency has been demonstrated over the 50 to 200 mg/day dose range investigated in the fixed dose studies.

Obsessive-Compulsive Disorder: Five placebo-controlled clinical trials, in adults, of 8 to 16 weeks in duration have been performed to investigate the efficacy of ZOLOFT in obsessive-compulsive disorder: four flexible dose studies (50-200 mg/day) and one fixed dose study (50, 100, & 200 mg/day). Results for three of the four flexible dose studies and the 50 and 200 mg dose groups of the fixed dose study were supportive of differences from placebo in favour of ZOLOFT in terms of mean change from baseline to endpoint on the Yale-Brown Obsessive-Compulsive Scale and/or the National Institute of Mental Health Obsessive-Compulsive Scale (last observation carried forward analysis). No clear dose-dependency was demonstrated over the 50 to 200 mg/day dose range investigated in the fixed dose studies. In the flexible dose studies, the mean daily dose administered at the last week of treatment ranged from 124-180 mg.

One placebo-controlled clinical trial of 12 weeks duration, was performed in children and adolescents aged 6-17 years, to investigate the efficacy of ZOLOFT in obsessive-compulsive disorder. The study used flexible dosing, starting with 25 mg/day in children 6-12 years old (ZOLOFT n=53, placebo n=54) and with 50 mg/day in adolescents 13-17 years old (ZOLOFT n=39, placebo n=41). In both age groups, ZOLOFT was titrated up to a maximum 200 mg/day, over 4 weeks, as tolerated. The mean dose for completers (74/92 ZOLOFT treated patients) was 178 mg/day. Results showed statistically significant differences from placebo in favour of ZOLOFT in terms of mean change from baseline to endpoint (last observation carried forward analysis) on the Children's Yale-Brown Obsessive Compulsive Scale (p=0.005), the National Institute of Mental Health Obsessive-Compulsive Scale (p=0.019) and the Clinical Global Impresssion Improvement Rating Scale (p=0.002).

The long term safety, including effects on growth and development, in patients under 18 years of age, has not been established.

ZOLOFT (sertraline hydrochloride) is indicated for the symptomatic relief of depressive illness. However, the antidepressant action of ZOLOFT in hospitalized depressed patients has not been adequately studied.

A placebo-controlled European study carried out over 44 weeks, in patients who were responders to ZOLOFT has indicated that ZOLOFT may be useful in continuation treatment, suppressing reemergence of depressive symptoms.

However, because of methodological limitations, these findings on continuation treatment have to be considered tentative at this time.

ZOLOFT is indicated for the symptomatic relief of panic disorder, with or without agoraphobia. The efficacy of ZOLOFT was established in 10-week and 12-week controlled trials of patients with panic disorder as defined according to DSM-III-R criteria.

The effectiveness of ZOLOFT in long-term use for the symptomatic relief of panic disorder (i.e., for more than 12 weeks) has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use ZOLOFT for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

ZOLOFT is indicated for the symptomatic relief of obsessive-compulsive disorder (OCD). The obsessions or compulsions must be experienced as intrusive, markedly distressing, time-consuming, or significantly interfering with the person's social or occupational functioning.

The effectiveness of ZOLOFT in long-term use for the symptomatic relief of OCD ( i.e., for more than 12 weeks) has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use ZOLOFT for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.

ZOLOFT (sertraline hydrochloride) is contraindicated in patients with known hypersensitivity to the drug.

Cases of serious, sometimes fatal, reactions have been reported in patients receiving ZOLOFT (sertraline hydrochloride) in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI, selegiline and the reversible MAOI (reversible inhibitor of monoamine oxidase-RIMA), moclobemide. Some cases presented with features resembling the serotonin syndrome. Similar cases, have been reported with other antidepressants during combined treatment with an MAOI and in patients who have recently discontinued an antidepressant and have been started on an 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. Therefore, ZOLOFT 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 elapse after discontinuing ZOLOFT treatment before starting an MAOI.

The concomitant use of ZOLOFT and pimozide is contraindicated as ZOLOFT has been shown to increase plasma pimozide levels. Elevation of pimozide blood concentration may result in QT interval prolongation and severe arrhythmias including torsades de pointes (see Precautions and Information for the Patient).

• Recent analyses of placebo-controlled clinical trial safety databases from SSRI and other newer antidepressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioral and emotional changes, including an increased risk of suicidal ideation and behavior over that of placebo.

  
  

• The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.

  
  

• There are clinical trial and post-marketing reports with SSRIs and other newer antidepressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type adverse events include: akathisia, agitation, disinhibition, emotional lability, hostility, aggression, depersonalization. In some cases, the events occurred within several weeks of starting treatment.

  
  

Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behavior is advised in patients of all ages. This include monitoring for agitation-type emotional and behavioral changes.

Patients currently taking ZOLOFT should not be discontinued abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer antidepressant drug, a gradual reduction in the dose rather than an abrupt cessation is recommended.

See Contraindications.

During clinical testing in depressed patients, hypomania or mania occurred in approximately 0.6% of ZOLOFT (sertraline hydrochloride) treated patients. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed antidepressants.

ZOLOFT has not been evaluated in patients with seizure disorders. These patients were excluded from clinical studies during the product's premarket testing. No seizures were observed among approximately 3000 patients treated with ZOLOFT in the development program for depression. However, 4 patients out of approximately 1800 (220 <18 years of age) exposed during the development program for obsessive-compulsive disorder experienced seizures representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, ZOLOFT should be introduced with care in patients with a seizure disorder.

The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Therefore, high risk patients should be closely supervised throughout therapy and consideration should be given to the possible need for hospitalization. It should be noted that a causal role for SSRIs and other antidepressants in inducing self-harm or harm to others has not been established. In order to minimize the opportunity for overdosage, prescriptions for ZOLOFT should be written for the smallest quantity of drug consistent with good patient management (see Warnings, Potential Association with Behavioral and Emotional Changes, Including Self-harm ).

Because of the well-established co-morbidity between both obsessive-compulsive disorder and depression and panic disorder and depression, the same precautions should be observed when treating patients with obsessive-compulsive disorder and panic disorder.

When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation (e.g. dizziness, abnormal dreams, sensory disturbances (including paresthesias and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting and sweating or other symptoms which may be of clinical significance (see Adverse Effects). A gradual reduction in the dosage over several weeks, rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see Adverse Effects and Dosage).

Any psychoactive drug may impair judgment, thinking, or motor skills, and patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that the drug treatment does not affect them adversely.

General: Clinical experience with ZOLOFT in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using ZOLOFT in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

ZOLOFT has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. However, the electrocardiograms of 1006 patients who received ZOLOFT in double-blind trials were evaluated and the data indicate that ZOLOFT is not associated with the development of clinically significant ECG abnormalities.

In placebo-controlled trials, the frequency of clinically noticeable changes (±15-20 mmHg) in blood pressure was similar in patients treated with either ZOLOFT or placebo.

Sertraline is extensively metabolized by the liver. A single dose pharmacokinetic study in subjects with mild, stable cirrhosis demonstrated a prolonged elimination half-life and increased AUC in comparison to normal subjects. The use of sertraline in patients with hepatic disease must be approached with caution. If sertraline is administered to patients with hepatic impairment, a lower or less frequent dose should be considered (see Pharmacology and Dosage).

ZOLOFT is extensively metabolized and excretion of unchanged drug in the urine is a minor route of elimination. In patients with mild to moderate renal impairment (creatinine clearance 30-60 mL/min) or moderate to severe renal impairment (creatinine clearance 10-29 mL/min), multiple-dose pharmacokinetic parameters (AUC_0-24 or C_max) were not significantly different compared with controls. Half-lives were similar and there were no differences in plasma protein binding in all groups studied. This study indicates that, as expected from the low renal excretion of sertraline, sertraline dosing does not have to be adjusted based on the degree of renal impairment.

In carcinogenicity studies in CD-1 mice, sertraline at doses up to 40 mg/kg produces a dose related increase in the incidence of liver adenomas in male mice. Liver adenomas have a very variable rate of spontaneous occurrence in the CD-1 mouse. The clinical significance of these findings is unknown.

The safety of ZOLOFT during pregnancy and lactation has not been established and therefore, it should not be used in women of childbearing potential or nursing mothers, unless, in the opinion of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus.

Post-marketing reports indicate that some neonates exposed to ZOLOFT, SSRIs (Selective Serotonin Reuptake Inhibitors), or newer antidepressants late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. 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 other newer antidepressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see Precautions, Monoamine Oxidase Inhibitors). When treating a pregnant woman with ZOLOFT during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. (See Dosage.)

See Pregnancy.

The effect of ZOLOFT on labor and delivery in humans is unknown.

The safety and effectiveness of ZOLOFT in children below the age of 18 have not been established.

462 elderly patients (≥65 years) with depressive illness have participated in multiple dose therapeutic studies with ZOLOFT. The pattern of adverse reactions in the elderly was comparable to that in younger patients.

Several cases of hyponatremia have been reported and appeared to be reversible when sertraline was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of these occurrences have been in elderly individuals, some in patients taking diuretics or who were otherwise volume depleted.

There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking ZOLOFT. While there have been reports of abnormal bleeding or purpura in several patients taking ZOLOFT, it is unclear whether ZOLOFT had a causative role.

CNS Active Drugs: ZOLOFT (200 mg daily) did not potentiate the effects of carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects, however the risk of using ZOLOFT in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of ZOLOFT and such drugs is required.

Pimozide: 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%. Although these increases were not identified in the trial as being associated with clinically important effects on QT intervals, the trial design was not optimal for the investigation of pharmacodynamic effects in the clinical setting. For ethical considerations, a trial with higher doses could not be done. Since the highest recommended pimozide dose (12 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 ZOLOFT and pimozide is contraindicated (see Contraindications and Information for the Patient).

Serotonergic Drugs: There is limited controlled experience regarding the optimal timing of switching from other antidepressants and antipanic agents to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) or Tricyclic Antidepressants (TCAs) etc. to another has not been established.

Co-administration with tryptophan, TCAs and other antidepressants may lead to a higher incidence of serotonin-associated side effects.

Rare postmarketing reports describe patients with weakness, hyperreflexia, and incoordination following the combined use of a selective serotonin reuptake inhibitor (SSRI) and 5-HT₁ agonists (triptans). If concomitant treatment with ZOLOFT and a triptan (e.g., almotriptan, sumatriptan, rizatriptan, naratriptan, zolmitriptan), tricyclic antidepressants, or other drugs with serotonergic activity (including but not limited to fenfluramine and tryptophan) is clinically warranted and appropriate observation of the patient for acute and long-term adverse events is advised.

St. John's Wort: In common with other SSRIs, pharmacodynamic interactions between ZOLOFT and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects.

Lithium: In placebo-controlled trials in normal volunteers, the co-administration of sertraline with lithium did not significantly alter lithium pharmacokinetics, but did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. When co-administering sertraline with medications, such as lithium, which may act via serotonergic mechanisms, patients should be appropriately monitored.

Phenytoin: It is recommended that plasma phenytoin concentrations be monitored following initiations of sertraline therapy, with appropriate adjustments to the phenytoin dose. The pharmacokinetic and pharmacodynamic effects have not been adequately characterized.

Monoamine Oxidase Inhibitors: See Contraindications.

Drugs Metabolized by P450 System: Drugs Metabolized by P450 3A4: In two separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine or carbamazepine, under steady-state conditions. The results of these studies demonstrated that sertraline co-administration did not increase plasma concentrations of terfenadine or carbamazepine. These data suggest that sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance.

Drugs Metabolized by P450 2D6: Many antidepressants, e.g., the SSRIs, including sertraline and most tricyclic antidepressants, inhibit the biochemical activity of the drug metabolizing isozyme, cytochrome P450 2D6 (debrisoquin hydroxylase), and thus may increase the plasma concentration of co-administered drugs that are metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressants and the type Ic antiarrhythmics, propafenone and flecainide. There is variability among the antidepressants in the extent of clinically important P450 2D6 inhibition. In two drug interaction clinical trials using desipramine and the recommended starting SSRI doses in normal volunteers, the effect of ZOLOFT was compared to two other SSRIs. In the first study, mean desipramine steady state AUC (24) increased by 23% and 380% during coadministration with ZOLOFT and the comparative SSRI, respectively. In a second study using a different comparative SSRI, mean desipramine steady state AUC (24) increased by 37% and 421% during coadministration with ZOLOFT and the comparative SSRI, respectively. These trial results indicate that the effect of ZOLOFT was significantly less pronounced than that of the two comparative SSRIs. Nevertheless, concomitant use of a drug metabolized by P450 2D6 with ZOLOFT, may require lower doses than are usually prescribed for the other drug. Furthermore, whenever ZOLOFT is withdrawn from co-therapy, an increased dose of the co-administered drug may be required.

Electroconvulsive Therapy: There are no clinical studies with the combined use of electroconvulsive therapy (ECT) and ZOLOFT.

Alcohol: Although ZOLOFT did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of ZOLOFT and alcohol in depressed, panic disorder or OCD patients has not been studied and is not recommended.

Hypoglycemic Drugs: There are no controlled clinical trials with ZOLOFT in diabetic patients treated with insulin or oral hypoglycemic drugs.

In a placebo-controlled trial in normal volunteers, the administration of ZOLOFT for 22 days (dose of ZOLOFT was 200 mg/day for the final 13 days), caused a statistically significant 16% decrease in the clearance of tolbutamide following an i.v. dose of 1000 mg. In a placebo-controlled study in normal volunteers, glibenclamide (5 mg) was given before and after administration of sertraline (200 mg/day final dose) to steady state or placebo. No significant changes were observed in the total plasma concentration of glibenclamide.

Hypoglycemia requiring dextrose infusion was observed in one patient treated with ZOLOFT, glibenclamide, haloperidol, bisacodyl, aspirin and flucloxacillin. The causal relationship to ZOLOFT treatment was not firmly established. Nevertheless, close monitoring of glycemia in patients treated with ZOLOFT and oral hypoglycemic drugs or insulin is recommended.

Digoxin: In a parallel placebo controlled trial in normal volunteers (10 subjects per group), the administration of ZOLOFT for 17 days (dose of ZOLOFT: 200 mg for the last 10 days) did not cause changes in the total plasma concentrations of digoxin except a decrease of T_max as compared to baseline.

Beta-Blockers: There is no experience with the use of ZOLOFT in hypertensive patients controlled by beta-blockers. In a placebo-controlled crossover study in normal volunteers, the effect of ZOLOFT on the β-adrenergic blocking activity of atenolol was assessed. The mean CD25's (the doses of isoproterenol required to increase heart rate by 25 bpm, the chronotropic dose 25 or CD25) and the average decreases in heart rate seen with atenolol during exercise test were not statistically different in the ZOLOFT versus the placebo group. These data suggest that ZOLOFT does not alter the β-blocking action of atenolol.

Cimetidine: In a placebo-controlled crossover study in normal volunteers, the potential of cimetidine to alter the disposition of a single 100 mg dose of ZOLOFT was assessed. The mean sertraline C_max and AUC were significantly higher in the cimetidine-treated group, as were the mean desmethylsertraline T_max and AUC. These data suggest that concomitant administration of cimetidine may inhibit the metabolism of sertraline and its metabolite, desmethylsertraline, and may result in a decrease in the clearance and first pass metabolism of sertraline, with a possible increase in drug-related side effects.

Diazepam: In a normal volunteer, double-blind, placebo-controlled study comparing the disposition of intravenously administered diazepam before and after administration of sertraline (200 mg/day final dose) to steady state or placebo, there was a statistically significant 13% decrease relative to baseline in diazepam clearance for the sertraline group over that of the placebo group. These changes are of unknown clinical significance.

Warfarin: In a placebo-controlled study in healthy men comparing prothrombin time AUC (0-120 hr) following single dosing with warfarin (0.75 mg/kg) before and after dosing to steady state with either sertraline (200 mg/day final dose) or placebo, there was a statistically significant mean increase in prothrombin time of 8% relative to baseline for sertraline compared to a 1% decrease for placebo. The normalization of prothrombin time for the sertraline group was delayed compared to the placebo group. The clinical significance of these changes are unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped in patients receiving warfarin.

Because sertraline is highly bound to plasma protein, the administration of ZOLOFT to a patient taking another drug which is tightly bound to protein may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely adverse effects may result from displacement of protein bound sertraline by other tightly bound drugs.

Microsomal Enzyme Induction: ZOLOFT was shown to induce hepatic enzymes as determined by the decrease of the antipyrine half-life. This degree of induction reflects a clinically insignificant change in hepatic metabolism.

In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of ZOLOFT, alprazolam, and d-amphetamine in humans, ZOLOFT 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 ZOLOFT did not reveal any drug-seeking behavior. In animal studies ZOLOFT 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 ZOLOFT misuse or abuse (e.g. development of tolerance, incrementation of dose, drug-seeking behavior).

In clinical development programs, ZOLOFT (sertraline hydrochloride) has been evaluated in 1902 subjects with depression. The most commonly observed adverse events associated with the use of ZOLOFT were: gastrointestinal complaints, including nausea, diarrhea/loose stools and dyspepsia; male sexual dysfunction (primarily ejaculatory delay); insomnia and somnolence; tremor; increased sweating and dry mouth; and dizziness. In the fixed dose placebo controlled study, the overall incidence of side effects was dose related with a majority occurring in the patients treated with 200 mg dose.

The discontinuation rate due to adverse events was 15% in 2710 subjects who received ZOLOFT in premarketing multiple dose clinical trials. The more common events (reported by at least 1% of subjects) associated with discontinuation included agitation, insomnia, male sexual dysfunction (primarily ejaculatory delay), somnolence, dizziness, headache, tremor, anorexia, diarrhea/loose stools, nausea and fatigue.

Table 1 enumerates adverse events that occurred at a frequency of 1% or more among ZOLOFT patients who participated in controlled trials comparing titrated ZOLOFT with placebo.

Table 1: ZOLOFT

Treatment-emergent Adverse Experience Incidence in Placebo-controlled Clinical Trials in Adults<sup>a

a.</sup> Events reported by at least 1% of patients treated with Zoloft are included.
^b. % based on male patients only: 271 ZOLOFT and 271 placebo patients. Male sexual dysfunction can be broken down into the categories of decreased libido, impotence and ejaculatory delay. In this data set, the percentages of males in the ZOLOFT group with these complaints are 4.8%, 4.8% and 8.9%, respectively. It should be noted that since some ZOLOFT patients reported more than one category of male sexual dysfunction, the incidence of each category of male sexual dysfunction combined is larger than the incidence for the general category of male sexual dysfunction, in which each patient is counted only once.
^c. % based on female patient only: 590 ZOLOFT and 582 placebo patients.

In placebo-controlled clinical trials, 430 patients with panic disorder were treated with ZOLOFT in doses of 25-200 mg/day. During treatment, most patients received doses of 50-200 mg/day. Adverse events observed at an incidence of at least 5% for ZOLOFT and at an incidence that was twice or more the incidence among placebo-treated patients included: diarrhea, ejaculation failure (primarily ejaculatory delay), anorexia, constipation, libido decreased, agitation, and tremor.

In the total safety data base for panic disorder, 14% of patients discontinued treatment due to an adverse event. The most common events leading to discontinuation were nausea (2.6%), insomnia (2.3%), somnolence (2.3%), and agitation (2.1%).

In placebo-controlled clinical trials for OCD, adverse events observed at an incidence of at least 5% for ZOLOFT and at an incidence that was twice or more the incidence among placebo-treated patients included: nausea, insomnia, diarrhea, decreased libido, anorexia, dyspepsia, ejaculation failure (primarily ejaculatory delay), tremor, and increased sweating.

In placebo-controlled clinical trials for OCD, 10% of patients treated with ZOLOFT discontinued treatment due to an adverse event. The most common events leading to discontinuation were nausea (2.8%), insomnia (2.6%), and diarrhea (2.1%).

Table 2 enumerates adverse events that occurred at a frequency of 2% or more among patients on ZOLOFT who participated in controlled trials comparing ZOLOFT with placebo in the treatment of panic disorder and obsessive-compulsive disorder. Only those adverse events which occurred at higher rate during ZOLOFT treatment than during placebo treatment are included.

Table 2: ZOLOFT

Treatment-emergent Adverse Experience Incidence in Placebo-controlled Clinical Trials for Panic and Obsessive-compulsive Disorder in Adults^a