ZOLOFT
 Source: FDA

(sertraline hydrochloride)
Tablets and Oral Concentrate

CONTRAINDICATIONS

All Dosage Forms of ZOLOFT:

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

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

Oral Concentrate:

ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

WARNINGS

Cases of serious sometimes fatal reactions have been reported in patients receiving ZOLOFT
 (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, 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 be allowed after stopping ZOLOFT before starting an MAOI.

Clinical Worsening and Suicide Risk

Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.

Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.

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, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

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

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 ZOLOFT, for a description of the risks of discontinuation of ZOLOFT).

It should be noted that ZOLOFT is approved in the pediatric population only for obsessive compulsive 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 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 ZOLOFT is not approved for use in treating bipolar depression.

PRECAUTIONS

General

Activation of Mania/Hypomania–During premarketing testing, hypomania or mania occurred in approximately 0.4% of ZOLOFT
 (sertraline hydrochloride) treated patients.

Weight Loss–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.

Seizure –ZOLOFT 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 ZOLOFT 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 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.

Discontinuation of Treatment with Zoloft

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

Abnormal Bleeding

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

Weak Uricosuric Effect–ZOLOFT
 (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.

Use in Patients with Concomitant Illness–Clinical experience with ZOLOFT in patients with certain concomitant systemic illness is limited. Caution is advisable in using ZOLOFT 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 ZOLOFT in double-blind trials were evaluated and the data indicate that ZOLOFT is not associated with the development of significant ECG abnormalities.

ZOLOFT administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was evaluated in a post-marketing, 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. ZOLOFT 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).
 

ZOLOFT is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cmax 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 PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Since ZOLOFT 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).

Interference with Cognitive and Motor Performance–In controlled studies, ZOLOFT did not cause sedation and did not interfere with psychomotor performance. (See Information for Patients.)

Hyponatremia–Several cases of hyponatremia have been reported and appeared to be reversible when ZOLOFT 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.

Platelet Function–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.

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe ZOLOFT:

Patients should be told that although ZOLOFT 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 ZOLOFT 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 ZOLOFT 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 ZOLOFT has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of ZOLOFT and alcohol is not advised.

Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

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

ZOLOFT oral concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

ZOLOFT Oral Concentrate contains 20 mg/mL of sertraline (as the hydrochloride) as the active ingredient and 12% alcohol. ZOLOFT Oral Concentrate must be diluted before use. Just before taking, use the dropper provided to remove the required amount of ZOLOFT Oral Concentrate and mix with 4 oz (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix ZOLOFT Oral Concentrate with anything other than the liquids listed. The dose should be taken immediately after mixing. Do not mix in advance. At times, a slight haze may appear after mixing; this is normal. Note that caution should be exercised for persons with latex sensitivity, as the dropper dispenser contains dry natural rubber.

Laboratory Tests None.

Drug Interactions

Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins–Because sertraline is tightly bound to plasma protein, the administration of ZOLOFT
 (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 ZOLOFT 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 ZOLOFT (50-200 mg/day) or placebo,

there was a mean increase in prothrombin time of 8% relative to baseline for ZOLOFT compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the ZOLOFT group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when ZOLOFT therapy is initiated or stopped.

Cimetidine–In a study assessing disposition of ZOLOFT (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in ZOLOFT mean AUC (50%), Cmax (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 ZOLOFT (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the ZOLOFT group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in Tmax for desmethyldiazepam in the ZOLOFT 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 ZOLOFT 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 ZOLOFT 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 Cmax 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 ZOLOFT and pimozide should be contraindicated (see CONTRAINDICATIONS).

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.

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 ZOLOFT. 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 (S SRI) 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 Cmax 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 ZOLOFT may require lower doses than 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 (see Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder under PRECAUTIONS).

Sumatriptan–There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor

(S SRI) 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 ZOLOFT, 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 ZOLOFT (see Drugs Metabolized by P450 2D6 under PRECAUTIONS).

Hypoglycemic Drugs–In a placebo-controlled trial in normal volunteers, administration of ZOLOFT 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. ZOLOFT 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–ZOLOFT (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 ZOLOFT 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 ZOLOFT to induce hepatic microsomal enzymes. In clinical studies, ZOLOFT 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 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 ZOLOFT.

Electroconvulsive Therapy–There are no clinical studies establishing the risks or benefits of 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 is not recommended.

Carcinogenesis–Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) on a mg/m² basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 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.

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

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

Pregnancy–Pregnancy Category C–Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/m² basis. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m² basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m² basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m² basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m² basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown. There are no adequate and well-controlled studies in pregnant women. ZOLOFT
 (sertraline hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy-Nonteratogenic Effects–Neonates exposed to Zoloft 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).

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 AND ADMINISTRATION).

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

Nursing Mothers–It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZOLOFT is administered to a nursing woman.

Pediatric Use–The efficacy of ZOLOFT for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17 (see Clinical Trials under CLINICAL PHARMACOLOGY). The efficacy of ZOLOFT in pediatric patients with major depressive disorder, panic disorder, PTSD, PMDD or social anxiety disorder has not been established.

The safety of ZOLOFT use in children and adolescents with OCD, ages 6-18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-week, double-blind, placebo-controlled study. ZOLOFT was administered at doses of either 25

mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week pediatric study and in the 52 week study, ZOLOFT had an adverse event profile generally similar to that observed in adults.

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

Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of age have received ZOLOFT 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 ZOLOFT (see ADVERSE REACTIONS). As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of ZOLOFT. 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 mean weight loss observed among sertralinetreated 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 below the age of 6 have not been established.

The risks, if any, that may be associated with ZOLOFT’s use beyond 1 year in children and adolescents with OCD or major depressive disorder 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).

Geriatric Use–U.S. geriatric clinical studies of ZOLOFT in major depressive disorder included 663 ZOLOFT-treated subjects ³ 65 years of age, of those, 180 were ³ 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 ZOLOFT 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 ZOLOFT in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 1 and 2. Urinary tract infection was the only adverse event not appearing in Tables 1 and 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, ZOLOFT has been associated with cases of clinically significant hyponatremia in elderly patients (see Hyponatremia under PRECAUTIONS).

ADVERSE REACTIONS

During its premarketing assessment, multiple doses of ZOLOFT were administered to over

4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to ZOLOFT

varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.

Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of ZOLOFT who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving ZOLOFT. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Incidence in Placebo-Controlled Trials–Table 1 enumerates the most common treatment-emergent adverse events associated with the use of ZOLOFT (incidence of at least 5% for ZOLOFT and at least twice that for placebo within at least one of the indications) for the treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 2 enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients treated with ZOLOFT and with incidence greater than placebo who participated in controlled clinical trials comparing ZOLOFT with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 2 provides combined data for the pool of studies that are provided separately by indication in Table 1.

TABLE 1
MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN
PLACEBO-CONTROLLED CLINICAL TRIALS