Sertraline Hydrochloride - Cobalt Pharmaceuticals

In man, following oral once-daily dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (C_max) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the C_max and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg dose range.

The effects of food on the bioavailability of the sertraline tablet were studied in subjects administered in a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the C_max was 25% greater, while the time to reach peak plasma concentration (T_max) decreased from 8 hours post-dosing to 5.5 hours.

Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40 - 45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40 - 45% of the administered radioactivity was accounted for in feces, including 12 - 14% unchanged sertraline.

Desmethylsertraline exhibits time-related, dose dependent increases in AUC_{(0-24 hour)}, C_max and C_min, with about a 5 - 9 fold increase in these pharmacokinetic parameters between day 1 and day 14.

In vitro protein binding studies performed with radiolabeled ³H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, viz., warfarin and propranolol (see PRECAUTIONS).

Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to 12 years, 32 aged 13 to 17 years). Patients included both males (N = 28) and females (N = 33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6 - 12 year old group exhibited a mean sertraline AUC_{(0-24 hr)} of 3107 ng-hr/mL, mean C_max of 165 ng/mL, and mean half-life of 26.2 hr. The 13 - 17 year old group exhibited a mean sertraline AUC_{(0-24 hr)} of 2296 ng-hr/mL, mean C_max of 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6 - 12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC_{(0-24 hr)} of 2570 ng-hr/mL, mean C_max of 142 ng/mL, and mean half-life of 27.2 hr. Relative to the adults, both the 6 - 12 year olds and the 13 - 17 year olds showed about 22% lower AUC_{(0-24 hr)} and C_max values when plasma concentration was adjusted for weight. These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights, especially in very young patients, in order to avoid excessive plasma levels (see DOSAGE AND ADMINISTRATION).

Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for 14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females.

As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of sertraline. In patients with chronic mild liver impairment (N = 10, 8 patients with Child-Pugh scores of 5 - 6 and 2 patients with Child-Pugh scores of 7 - 8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N = 10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see PRECAUTIONSand DOSAGE AND ADMINISTRATION).

Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CL_cr = 30 - 60 mL/min), moderate to severe (CL_cr = 10 - 29 mL/min) or severe (receiving hemodialysis) renal impairment (N = 10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N = 12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment (see PRECAUTIONS).

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 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 to 200 mg/day. These patients (N = 295) were randomized to continuation for 44 weeks on double-blind sertraline 50 to 200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline 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.

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.

During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline hydrochloride treated patients.

Significant weight loss may be an undesirable result of treatment with sertraline for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss.

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

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

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

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

Sertraline hydrochloride is associated with a mean decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.

Clinical experience with sertraline in patients with certain concomitant systemic illness is limited. Caution is advisable in using sertraline in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 774 patients who received sertraline in double-blind trials were evaluated and the data indicate that sertraline is not associated with the development of significant ECG abnormalities.

Sertraline administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was evaluated in a postmarketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or unstable angina requiring hospitalization. Exclusions from this trial included, among others, patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina, clinically significant renal impairment (creatinine > 2.5 mg/dL), and clinically significant hepatic dysfunction. Sertraline treatment initiated during the acute phase of recovery (within 30 days post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke, or angina).

Sertraline is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, C_max and elimination half-life. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used (see CLINICAL PHARMACOLOGYand DOSAGE AND ADMINISTRATION).

Since sertraline is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment (see CLINICAL PHARMACOLOGY).

In controlled studies, sertraline did not cause sedation and did not interfere with psychomotor performance. (See Information for 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 sertraline. While there have been reports of abnormal bleeding or purpura in several patients taking sertraline, it is unclear whether sertraline had a causative role.

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 told that although sertraline 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 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 and non-selective NSAIDs (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 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 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 and alcohol is not advised.

Patients should be told that while no adverse interaction of sertraline 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.

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 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 (50 to 200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline compared to a 1% decrease for placebo (p < 0.02). The normalization of prothrombin time for the sertraline 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.

In a study assessing disposition of sertraline (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline mean AUC (50%), C_max (24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.

In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline 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 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 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 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.) coadministration 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 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. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.

The effect of sertraline 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 therapy with appropriate adjustments to the valproate dose.

The risk of using sertraline in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline 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, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to sertraline. 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.

See CONTRAINDICATIONSand WARNINGS.

In three separate in vivo interaction studies, sertraline was coadministered 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%).

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 coadministered 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 coadministered 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 may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from co-therapy, an increased dose of the coadministered drug may be required (see Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs)under PRECAUTIONS).

There have been rare postmarketing 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.

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, 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).

In a placebo-controlled trial in normal volunteers, administration of sertraline 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 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.

Sertraline (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.

In a placebo-controlled trial in normal volunteers, administration of sertraline for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.

Preclinical studies have shown sertraline to induce hepatic microsomal enzymes. In clinical studies, sertraline 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.

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 a non-selective NSAID (i.e., NSAIDs that inhibit both cyclooxygenase isoenzymes, COX 1 and 2) or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with sertraline.

There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and sertraline.

Although sertraline did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of sertraline and alcohol is not recommended.

Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) on a mg/m² basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10 - 40 mg/kg (0.25 - 1.0 times the MRHD on a mg/m² basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m² basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10 - 40 mg/kg (0.5 - 2.0 times the MRHD on a mg/m² basis) compared to placebo controls, this effect was not clearly drug related.

Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays; bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (4 times the maximum recommended human dose on a mg/m² basis).

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

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

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

In 354 geriatric subjects treated with sertraline 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 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.

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

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 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 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.

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with sertraline. In addition, at least 14 days should be allowed after stopping sertraline before starting an MAOI (see CONTRAINDICATIONSand WARNINGS).

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 PHARMACOLOGYand PRECAUTIONS).

Neonates exposed to sertraline 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 during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering sertraline in the third trimester.

Symptoms associated with discontinuation of sertraline 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.