Setral

Setral hydrochloride (Setral) 50 mg tablet: Each tablet contains Sertraline hydrochloride equivalent to 50 mg Setral.

Setral hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Setral hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C₁₇H₁₇NCl₂·HCl.

Setral hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.

Setral is supplied for oral administration as tablets containing Setral hydrochloride.

Setral is indicated for the treatment of symptoms of depression, including depression accompanied by symptoms of anxiety, in patients with or without a history of mania. Following satisfactory response, continuation with Setral therapy is effective in preventing relapse of the initial episode of depression or recurrence of further depressive episodes.

Setral is indicated for the treatment of obsessive-compulsive disorder (OCD). Following satisfactory response, continuation with Setral therapy is effective in preventing relapse of the initial episode of OCD.

Setral is indicated for the treatment of pediatric patients with OCD.

Setral is indicated for the treatment of panic disorder, with or without agoraphobia. Following satisfactory response, continuation with Setral therapy is effective in preventing relapse of the initial episode of panic disorder.

Setral is indicated for the treatment of post-traumatic stress disorder (PTSD). Following satisfactory response, continuation with Setral therapy is effective in preventing relapse of the initial episode of PTSD.

Setral is indicated for the treatment of social phobia (social anxiety disorder). Following satisfactory response, continuation with Setral therapy is effective in preventing relapse of the initial episode of social phobia.

Pre-menstrual Dysphoric Disorder (PMDD): Setral hydrochloride (Setral) is indicated for the treatment of pre-menstrual dysphoric disorder (PMDD).

The efficacy of Setral hydrochloride (Setral) in the treatment of PMDD was established in two placebo-controlled trials of female outpatients treated for 3 menstrual cycles who met criteria for the DSM-III R/IV category of PMDD.

The essential features of PMDD include markedly depressed mood, anxiety or tension, affective lability, and persistent anger or irritability. Other features include decreased interest in activities, difficulty concentrating, lack of energy, change in appetite or sleep, and feeling out of control. Physical symptoms associated with PMDD include breast tenderness, headache, joint and muscle pain, bloating, and weight gain. These symptoms occur regularly during the luteal phase and remit within a few days following onset of menses; the disturbance markedly interferes with work or school or with usual social activities and relationship with others. In making the diagnosis, care should be taken to rule out other cyclical mood disorders that may be exacerbated by treatment with an antidepressant.

The effectiveness of Setral hydrochloride (Setral) in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. Therefore the physician who elects to use Setral hydrochloride (Setral) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Setral is used to treat depression, obsessive-compulsive disorder (OCD), panic disorder, premenstrual dysphoric disorder (PMDD), posttraumatic stress disorder (PTSD), and social anxiety disorder (SAD).

Setral belongs to a group of medicines known as selective serotonin reuptake inhibitors (SSRIs). It works by increasing the activity of a chemical called serotonin in the brain.

Setral is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, Setral is used in certain patients with the following medical conditions:

• Premature ejaculation.

Initial Treatment

Dosage for Adults

Major Depressive Disorder and Obsessive-Compulsive Disorder

Setral treatment should be administered at a dose of 50 mg once daily.

Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder

Setral treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.

While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of Setral for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of Setral, dose changes should not occur at intervals of less than 1 week.

Premenstrual Dysphoric Disorder

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

While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle. Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period. Setral should be administered once daily, either in the morning or evening.

Dosage for Pediatric Population (Children and Adolescents)

Obsessive-Compulsive Disorder

Setral treatment should be initiated with a dose of 25 mg once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).

While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of Setral for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour elimination half-life of Setral, dose changes should not occur at intervals of less than 1 week.

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

Maintenance/Continuation/Extended Treatment

Major Depressive Disorder

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode. Systematic evaluation of Setral has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50-200 mg/day (mean dose of 70 mg/day). It is not known whether the dose of Setral 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.

Posttraumatic Stress Disorder

It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of Setral has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day. It is not known whether the dose of Setral 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.

Social Anxiety Disorder

Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of Setral has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200 mg/day. Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.

Obsessive-Compulsive Disorder and Panic Disorder

It is generally agreed that OCD and Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of continuing Setral for periods of up to 28 weeks in patients with OCD and Panic Disorder who have responded while taking Setral during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day has demonstrated a benefit of such maintenance treatment. It is not known whether the dose of Setral needed for maintenance treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Premenstrual Dysphoric Disorder

The effectiveness of Setral in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.

Switching A Patient To Or From A Monoamine Oxidase Inhibitor (MAOI) Intended To Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Setral. Conversely, at least 14 days should be allowed after stopping Setral before starting an MAOI intended to treat psychiatric disorders.

Use Of Setral With Other MAOIs Such As Linezolid Or Methylene Blue

Do not start Setral in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Setral therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Setral should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Setral may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Setral is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

Special Populations

Dosage for Hepatically Impaired Patients

The use of Setral in patients with liver disease should be approached with caution. The effects of Setral in patients with moderate and severe hepatic impairment have not been studied. If Setral is administered to patients with liver impairment, a lower or less frequent dose should be used.

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to Setral and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. When treating pregnant women with Setral during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

Discontinuation Of Treatment With Setral

Symptoms associated with discontinuation of Setral and other SSRIs and SNRIs, have been reported. Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Setral

Oral Concentrate

Setral

Oral Concentrate contains 20 mg/mL of Setral (as the hydrochloride) as the active ingredient and 12% alcohol. Setral

Oral Concentrate must be diluted before use. Just before taking, use the dropper provided to remove the required amount of Setral

Oral Concentrate and mix with 4 oz (½ cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix Setral

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 patients with latex sensitivity, as the dropper dispenser contains dry natural rubber.

Setral

Oral Concentrate is contraindicated with ANTABUSE (disulfiram) due to the alcohol content of the concentrate.

How supplied

Setral (Setral hydrochloride) capsular-shaped scored tablets, containing Setral hydrochloride equivalent to 25, 50 and 100 mg of Setral, are packaged in bottles.

Setral 25 mg Tablets: light green film coated tablets engraved on one side with Setral and on the other side scored and engraved with 25 mg.

NDC 0049-4960- 30 Bottles of 30

NDC 0049-4960- 50 Bottles of 50

Setral 50 mg Tablets: light blue film coated tablets engraved on one side with Setral and on the other side scored and engraved with 50 mg.

NDC 0049-4900- 30 Bottles of 30

NDC 0049-4900- 66 Bottles of 100

NDC 0049-4900- 73 Bottles of 500

NDC 0049-4900- 94 Bottles of 5000

NDC 0049-4900- 41 Unit Dose Packages of 100

Setral 100 mg Tablets: light yellow film coated tablets engraved on one side with Setral and on the other side scored and engraved with 100 mg.

NDC 0049-4910- 30 Bottles of 30

NDC 0049-4910- 66 Bottles of 100

NDC 0049-4910- 73 Bottles of 500

NDC 0049-4910- 94 Bottles of 5000

NDC 0049-4910- 41 Unit Dose Packages of 100

Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).

Setral

Oral Concentrate

Oral Concentrate is a clear, colorless solution with a menthol scent containing Setral hydrochloride equivalent to 20 mg of Setral per mL and 12% alcohol. It is supplied as a 60 mL bottle with an accompanying calibrated dropper.

NDC 0049-4940- 23 Bottles of 60 mL

Store at 25°C (77°F); excursions permitted to 15° - 30°C (59° - 86°F).

Distributed by: Roerig, Division of Pfizer Inc., NY, NY 10017. Revised: Aug 2014

See also:
What is the most important information I should know about Setral?

Neonates exposed to Setral and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), 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 SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

Infants exposed to SSRIs in 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. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Setral) in pregnancy and PPHN. Other studies do not show a significant statistical association.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

When treating a pregnant woman with Setral, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis.

Labor and Delivery

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

Nursing Mothers

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

Pediatric Use

The efficacy of Setral for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6 to 17. Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established. Two placebo controlled trials (n=373) in pediatric patients with MDD have been conducted with Setral, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Setral in a child or adolescent must balance the potential risks with the clinical need.

The safety of Setral use in children and adolescents with OCD, ages 6 to 18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6 to 17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6 to 18, who had completed the initial 12-week, double-blind, placebo-controlled study. Setral was administered at doses of either 25 mg/day (children, ages 6 to 12) or 50 mg/day (adolescents, ages 13 to 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, Setral had an adverse event profile generally similar to that observed in adults.

Setral 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.

Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of age have received Setral 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 Setral. As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of Setral. In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50 to 200 mg) outpatient trials for major depressive disorder (n=373), there was a difference in weight change between Setral and placebo of roughly 1 kilogram, for both children (ages 6 to 11) and adolescents (ages 12 to 17), in both cases representing a slight weight loss for Setral compared to a slight gain for placebo. At baseline the mean weight for children was 39 kg for Setral and 38.5 kg for placebo. At baseline the mean weight for adolescents was 61.4 kg for Setral and 62.5 kg for placebo. There was a bigger difference between Setral 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 (Setral 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 Setral during the open-label extension study, similar to mean weight loss observed among Setral treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of Setral treatment. Those subjects who completed 34 weeks of Setral 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 Setral'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 Setral 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 Setral use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that Setral 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 Setral to have adverse effects in chronic use.

Geriatric Use

U.S. geriatric clinical studies of Setral in major depressive disorder included 663 Setral-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects, 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 Setral 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 Setral in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.

SSRIS and SNRIs, including Setral, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.

Use Setral concentrate as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Setral concentrate comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Setral concentrate refilled.
• Take Setral concentrate by mouth with or without food.
• Use the dropper that comes with Setral concentrate to measure your dose. Ask your pharmacist for help if you are unsure of how to measure your dose.
• Setral concentrate must be diluted before you take it. Mix the prescribed amount with 4 oz (120 mL) of water, ginger ale, lemon/lime soda, lemonade, or orange juice. Do not mix it with any other kind of liquid.
• This mixture may become slightly hazy. This is normal.
• Drink the dose immediately after mixing. Do not store mixed medicine for use at a later time.
• Taking Setral concentrate at the same time each day will help you remember to take it.
• Continue to take Setral concentrate even if you feel well. Do not miss any doses.
• Do not suddenly stop taking Setral concentrate without checking with your doctor. Side effects may occur. They may include mental or mood changes, numbness or tingling of the skin, dizziness, confusion, headache, trouble sleeping, or unusual tiredness. If you need to stop Setral concentrate, your doctor may need to gradually lower your dose.
• If you miss a dose of Setral concentrate, take it as soon as possible. If it almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Setral concentrate.

Use: Labeled Indications

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder (MDD) in adults.

Obsessive-compulsive disorder: Treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD).

Panic disorder: Treatment of panic disorder in adults with or without agoraphobia.

Posttraumatic stress disorder: Treatment of posttraumatic stress disorder (PTSD) in adults.

Premenstrual dysphoric disorder: Treatment of premenstrual dysphoric disorder (PMDD) in adults.

Social anxiety disorder: Treatment of social anxiety disorder (social phobia) in adults.

Off Label Uses

Binge eating disorder

Data from two small, double-blind, randomized, controlled trials support the use of Setral to improve weight loss, binge frequency, and binge behaviors in patients with binge eating disorder.

According to the International Society for Sexual Medicine guidelines, Setral is effective and recommended in the management of premature ejaculation; however, paroxetine may have a more robust effect.

See also:
What other drugs will affect Setral?

MAOIs: See Contraindications and Precautions.

Pimozide: Increased pimozide levels have been demonstrated in a study of a single low dose pimozide (2 mg) with Setral co-administration. These increased levels were not associated with any changes in EKG. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide, concomitant administration of Setral and pimozide is contraindicated.

CNS Depressants and Alcohol: The co-administration of Setral 200 mg daily did not potentiate the effects of alcohol, carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects; however, the concomitant use of Setral and alcohol is not recommended.

Lithium: In placebo-controlled trials in normal volunteers, the co-administration of Setral 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 Setral with medications eg, lithium, which may act via serotonergic mechanisms, patients should be appropriately monitored.

Phenytoin: Placebo-controlled trials in normal volunteers suggest that chronic administration of Setral 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, it is recommended that plasma phenytoin concentrations be monitored following initiation of Setral therapy, with appropriate adjustments to the phenytoin dose. In addition, co-administration of phenytoin may cause a reduction of Setral plasma levels.

Sumatriptan: There have been rare post-marketing reports describing patients with weakness, hyperreflexia, incoordination, confusion, anxiety and agitation following the use of Setral and sumatriptan. If concomitant treatment with Setral and sumatriptan is clinically warranted, appropriate observation of the patient is advised.

Other Serotonergic Drugs: See Precautions.

Protein-Bound Drugs: Since Setral is bound to plasma proteins, the potential of Setral to interact with other plasma protein-bound drugs should be borne in mind. However, in 3 formal interaction studies with diazepam, tolbutamide and warfarin, respectively, Setral was not shown to have significant effects on the protein binding of the substrate.

Warfarin: Co-administration of Setral 200 mg daily with warfarin resulted in a small but statistically significant increase in prothrombin time, the clinical significance of which is unknown. Accordingly, prothrombin time should be carefully monitored when Setral therapy is initiated or stopped.

Other Drug Interactions: Formal drug interaction studies have been performed with Setral. Co-administration of Setral 200 mg daily with diazepam or tolbutamide resulted in small, statistically significant changes in some pharmacokinetic parameters. Co-administration with cimetidine caused a substantial decrease in Setral clearance. The clinical significance of these changes is unknown. Setral had no effect on the β-adrenergic-blocking ability of atenolol. No interaction of Setral 200 mg daily was observed with glibenclamide or digoxin.

Electroconvulsive Therapy (ECT): There are no clinical studies establishing the risks or benefits of the combined use of ECT and Setral.

Drugs Metabolized by Cytochrome P-450 (CYP)2D6: There is variability among antidepressants in the extent to which they inhibit the activity of isozyme CYP 2D6. The clinical significance of this depends on the extent of the inhibition and the therapeutic index of the co-administered drug. CYP 2D6 substrates with a narrow theapeutic index include TCAs and class 1C antiarrhythmics eg, propafenone and flecainide. In formal interaction studies, chronic dosing with Setral 50 mg daily showed minimal elevation (mean 23-37%) of steady-state desipramine plasma levels (a marker of CYP 2D6 isoenzyme activity).

Drugs Metabolized by Other CYP Enzymes (CYP 3A3/4, CYP 2C9, CYP 2C19, CYP 1A2) CYP 3A3/4: In vivo interaction studies have demonstrated that chronic administration of Setral 200 mg daily does not inhibit the CYP 3A3/4-mediated 6-β hydroxylation of endogenous cortisol or the metabolism of carbamazepine or terfenadine. In addition, the chronic administration of Setral 50 mg daily does not inhibit the CYP 3A3/4-mediated metabolism of alprazolam. The data suggest that Setral is not a clinically relevant inhibitor of CYP 3A3/4.

CYP 2C9: The apparent lack of clinically significant effects of the chronic administration of Setral 200 mg daily on plasma concentrations of tolbutamide, phenytoin and warfarin suggests that Setral is not a clinically relevant inhibitor of CYP 2C9.

CYP 2C19: The apparent lack of clinically significant effects of the chronic administration of Setral 200 mg daily on plasma concentrations of diazepam suggests that Setral is not a clinically relevant inhibitor of CYP 2C19.

CYP 1A2: In vitro studies indicate that Setral has little or no potential to inhibit CYP 1A2.

See also:
What are the possible side effects of Setral?

During its premarketing assessment, multiple doses of Setral were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to Setral 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 Setral who experienced a treatment emergent adverse event of the type cited on at least one occasion while receiving Setral. 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 non-drug factors to the side effect incidence rate in the population studied.

Incidence In Placebo-Controlled Trials

Table 2 enumerates the most common treatment-emergent adverse events associated with the use of Setral (incidence of at least 5% for Setral 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 3 enumerates treatment emergent adverse events that occurred in 2% or more of adult patients treated with Setral and with incidence greater than placebo who participated in controlled clinical trials comparing Setral with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.

TABLE 2 : MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS

TABLE 3 : TREATMENT-EMERGENT ADVERSE EVENTS: INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS Percentage of Patients Reporting Event Major Depressive Disorder/Other*, OCD, Panic Disorder, PTSD, PMDD and Social Anxiety Disorder combined

Associated With Discontinuation In Placebo-Controlled Clinical Trials

Table 4 lists the adverse events associated with discontinuation of Setral (Setral hydrochloride) treatment (incidence at least twice that for placebo and at least 1% for Setral in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.

TABLE 4 : MOST COMMON ADVERSE EVENTS ASSOCIATED WITH DISCONTINUATION IN PLACEBO-CONTROLLED CLINICAL TRIALS

Male And Female Sexual Dysfunction With SSRIs

Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.

Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients taking Setral in placebo-controlled trials.

TABLE 5

There are no adequate and well-controlled studies examining sexual dysfunction with Setral treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Other Adverse Events In Pediatric Patients

In over 600 pediatric patients treated with Setral, the overall profile of adverse events was generally similar to that seen in adult studies. However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3, were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo rate (N=281 patients treated with Setral): fever, hyperkinesia, urinary incontinence, aggressive reaction, sinusitis, epistaxis and purpura.

Other Events Observed During The Premarketing Evaluation Of Setral (Setral hydrochloride)

Following is a list of treatment-emergent adverse events reported during premarketing assessment of Setral in clinical trials (over 4000 adult subjects) except those already listed in the previous tables or elsewhere in labeling.

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 Setral who experienced an event of the type cited on at least one occasion while receiving Setral. All events are included except those already listed in the previous tables or elsewhere in labeling and those reported in terms so general as to be uninformative and those for which a causal relationship to Setral treatment seemed remote. It is important to emphasize that although the events reported occurred during treatment with Setral, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section.

Autonomic Nervous System Disorders -Frequent: impotence; Infrequent: flushing, increased saliva, cold clammy skin, mydriasis; Rare: pallor, angle-closure glaucoma, priapism, vasodilation.

Body as a Whole-General Disorders -Rare: allergic reaction, allergy.

Cardiovascular-Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia, postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension, peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.

Central and Peripheral Nervous System Disorders -Frequent: hypertonia, hypoesthesia; Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination, hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma, dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.

Disorders of Skin and Appendages -Infrequent: pruritus, acne, urticaria, alopecia, dry skin, erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema, dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.

Endocrine Disorders -Rare: exophthalmos, gynecomastia.

Gastrointestinal Disorders -Frequent: appetite increased; Infrequent: dysphagia, tooth caries aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia, hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue ulceration.

General-Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors, generalized edema; Rare: face edema, aphthous stomatitis.

Hearing and Vestibular Disorders -Rare: hyperacusis, labyrinthine disorder.

Hematopoietic and Lymphatic-Rare: anemia, anterior chamber eye hemorrhage.

Liver and Biliary System Disorders -Rare: abnormal hepatic function.

Metabolic and Nutritional Disorders -Infrequent: thirst; Rare: hypoglycemia, hypoglycemia reaction.

Musculoskeletal System Disorders -Frequent: myalgia; Infrequent: arthralgia, dystonia, arthrosis, muscle cramps, muscle weakness.

Psychiatric Disorders -Frequent: yawning, other male sexual dysfunction, other female sexual dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased, somnambulism, illusion.

Reproductive-Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis, breast enlargement, atrophic vaginitis, acute female mastitis.

Respiratory System Disorders -Frequent: rhinitis; Infrequent: coughing, dyspnea, upper respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea, stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.

Special Senses -Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma, visual field defect.

Urinary System Disorders -Infrequent: micturition frequency, polyuria, urinary retention, dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury.

Laboratory Tests

In man, asymptomatic elevations in serum transaminases (SGOT [or AST] and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with Setral (Setral hydrochloride) administration. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.

Setral therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance.

The safety profile observed with Setral treatment in patients with major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.

Other Events Observed During The Post marketing Evaluation Of Setral

Reports of adverse events temporally associated with Setral that have been received since market introduction, that are not listed above and that may have no causal relationship with the drug, include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia (including Torsade de Pointes arrhythmias), cerebrovascular spasm (including reversible cerebral vasconstriction syndrome and Call-Fleming syndrome), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, diabetes mellitus, hyperglycemia, galactorrhea, hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events - clinical features (which in the majority of cases appeared to be reversible with discontinuation of Setral) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.

Drug Abuse And Dependence

Controlled Substance Class

Setral (Setral hydrochloride) is not a controlled substance.

Physical And Psychological Dependence

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