Serlift

SERLIFT 50: Each film-coated tablet contains: Sertraline Hydrochloride USP Equivalent to Sertraline 50 mg.
SERLIFT TABLETS (sertraline hydrochloride) contains sertraline hydrochloride. Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It is chemically designated as (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. Its molecular formula is C₁₇H₁₇NCl₂HCl and molecular weight 342.7.

PHARMACOLOGY: Mechanism of action: The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significantly affinity for adrenergic (α₁, α₂, β) cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT_1A, 5HT_1B, 5HT₂) or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase.
Pharmacokinetics: 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 to 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 single-dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution.
The effects of food on the bioavailability of the sertraline tablet was studied in subjects administered a single dose with and without food. 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 radiolabelled 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 radiolabelled 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).
Special populations: Pediatrics: Sertraline pharmacokinetics were evaluated in a group of pediatric patients (aged 6-12 years, and 3-17 years) with a DSM-III-R diagnosis of major depressive disorder or obsessive-compulsive disorder. Patients included both males and females. 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 (male and 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 & ADMINISTRATION).
Elderly: Sertraline plasma clearance in a group of (male and 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.
Liver Disease: 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 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. 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 suggests 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 PRECAUTIONS and DOSAGE & ADMINISTRATION).
Renal Disease: Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min), moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment, the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment (see PRECAUTIONS).
Toxicology: Carcinogenicity/Mutagenicity/Impairment of fertility: 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).

SERLIFT TABLETS (sertraline hydrochloride) are indicated for the treatment of major depressive disorder, panic disorder, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and social anxiety disorder (social phobia) in adults.
SERLIFT TABLETS (sertraline hydrochloride) are also indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder (OCD).

Adults: Initial Treatment: Major Depressive Disorder and Obsessive-Compulsive Disorder: Sertraline hydrochloride should be administered at a dose of 50 mg once daily.
Panic Disorder, Posttraumatic Stress Disorder and Social Anxiety Disorder: 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 sertraline 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 sertraline, dose changes should not occur at intervals of less than 1 week.
Premenstrual Dysphonic Disorder: Sertraline hydrochloride treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.
While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle. 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.
SERLIFT TABLETS (sertraline hydrochloride) should be administered once daily, either in the morning or evening.
Maintenance/Continuation/Extended Treatment: Major Depressive Disorder: It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode. Systematic evaluation of sertraline 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 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.
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 sertraline 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 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.
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 sertraline 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 sertraline for periods of up to 28 weeks in patients with OCD and Panic Disorder who have responded while taking sertraline 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 sertraline 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 sertraline in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.
Switching Patients to or from a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with SERLIFT TABLETS (sertraline hydrochloride). In addition, at least 14 days should be allowed after stopping SERLIFT TABLETS (sertraline hydrochloride) before starting an MAOI.
Dosage for Pediatric Population (Children and Adolescents): Obsessive-Compulsive Disorder: Sertraline 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 sertraline 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 sertraline, dose changes should not occur at intervals of less than 1 week.
SERLIFT TABLETS (sertraline hydrochloride) should be administered once daily, either in the morning or evening.
Special Populations: Hepatic Impairments: 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 PRECAUTIONS).
Treatment of Pregnant Women during the Third Trimester: 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 SERLIFT TABLETS (sertraline hydrochloride) 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.
Discontinuation of Treatment with SERLIFT TABLETS (sertraline hydrochloride): 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.

Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths. Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor. The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and subsequently recovered. However, another patient who took 2.5 grams of sertraline hydrochloride alone experienced a fatal outcome. Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor and syncope.
Overdose Management: Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for sertraline are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose.

SERLIFT TABLETS (sertraline hydrochloride) are contraindicated in the following conditions: Patients with a hypersensitivity to sertraline or any of the inactive ingredients in formulations; Patients taking monoamine oxidase inhibitors (MAOIs); Patients taking pimozide.

Cases of serious sometimes fatal reactions have been reported in patients receiving sertraline, in combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability, and extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, sertraline should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping sertraline before starting an MAOI.
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. There has been a longstanding concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders.
Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied. The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive-compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults.
All pediatric patients being treated with antidepressants for any indication should be observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits.
Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior and the other symptoms described previously, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.
Prescriptions for sertraline should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described previously 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 is not approved for use in treating bipolar depression.
Use in Children: Suicidality in Children and Adolescents: Antidepressants increased risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of sertraline or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Sertraline is not approved for use in pediatric patients except for patients with obsessive-compulsive disorder (OCD) (See PRECAUTIONS).
Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive-compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

General: Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 0.4% of 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: Sertraline has not been evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarket testing. 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, sertraline should be introduced with care in patients with a seizure disorder.
Discontinuation of Treatment with sertraline: 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 & 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. 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.
Weak Uricosuric Effect: 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 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.
Sertraline is extensively metabolized by the liver. In patients with chronic mid 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.
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.
Hyponatremia: 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 the 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 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.
Use in Children: The efficacy of sertraline for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17. Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established. Two placebo controlled trials in pediatric patients with MDD have been conducted with sertraline, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of sertraline in a child or adolescent must balance the potential risks with the clinical need.
The safety of sertraline use in children and adolescents with OCD, aged 6-18 years, was evaluated in a 12-week, multicenter, placebo-controlled study with outpatients, aged 6-17 years, and in a flexible dose, 52 week open extension study of patients, aged 6-18 years, who had completed the initial 12 week, double-blind, placebo-controlled study. Sertraline 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, sertraline had an adverse event profile generally similar to that observed in adults.
Sertraline pharmacokinetics were evaluated in 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 sertraline in clinical trials, both controlled and uncontrolled. The adverse event profile observed in these patients was generally similar to that observed in adult studies with sertraline. As with other SSRIS, decreased appetite and weight loss have been observed in association with the use of sertraline. In a pooled analysis of two 10 week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major depressive disorder, 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) 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 sertraline treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label) 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 sertraline'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.
Use in the Elderly: U.S. geriatric clinical studies of sertraline in major depressive disorder included 663 sertraline-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 sertraline 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.
As with other SSRIs, sertraline has been associated with cases of clinically significant hyponatremia in elderly patients.

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. SERLIFT TABLETS (sertraline hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: 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. When treating a pregnant woman with sertraline during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE & ADMINISTRATION).
Labor and Delivery: The effect of sertraline on labor and delivery in humans is unknown.
Lactation: 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 SERLIFT TABLETS (sertraline hydrochloride) are administered to a nursing woman.

Side-effects which occurred significantly more frequently with sertraline than placebo in multiple dose studies were: nausea, diarrhea/loose stools, anorexia, dyspepsia, tremor, dizziness, insomnia, somnolence, increased sweating, dry mouth and sexual dysfunction (principally ejaculatory delay in males).
The side-effect profile commonly observed in double-blind, placebo-controlled studies in patients with OCD and PTSD was similar to that observed in patients with depression.
In pediatric OCD patients, side-effects which occurred significantly more frequently with sertraline than placebo were: headache, insomnia, agitation, anorexia, tremor. Most were of mild to moderate severity.
Post-marketing surveillance: Cardiovascular: Blood pressure disturbances including postural hypotension, tachycardia.
Eye disorders: Abnormal vision.
Gastro-intestinal: Vomiting, abdominal pain.
Nervous system: Amnesia, headache, drowsiness, movement disorders, paraesthesia, hypoaesthesia, depressive symptoms, hallucinations, aggressive reaction, agitation, anxiety, psychosis, depersonalisation, nervousness, panic reaction and signs and symptoms associated with serotonin syndrome which include fever, rigidity, confusion, agitation, diaphoresis, tachycardia, hypertension and diarrhea.
There have also been reports of manic reaction, although this phenomenon may be part of the underlying disease.
Convulsions (Seizures): Sertraline should be discontinued in any patient who develops seizures.
Musculoskeletal: Arthralgia, myalgia.
Hepatic/pancreatic: Rarely, pancreatitis and serious liver events (including hepatitis, jaundice and liver failure). Asymptomatic elevations in serum transaminases (SGOT and SGPT) have been reported in association with sertraline administration (0.8, 1.3%), with an increased risk associated with the 200 mg daily dose. The abnormalities usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.
Renal & urinary disorders: Urinary retention.
Reproductive: Hyperprolactinemia, galactorrhoea, menstrual irregularities, anorgasmy.
Skin and allergic reactions: Rash (including rare reports of erythema multiforme, photosensitivity), angioedema, ecchymoses, pruritus and anaphylactoid reactions.
Metabolic: Rare 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 reports were associated with older patients, and patients taking diuretics or other medications.
Haematologic: There have been rare reports of altered platelet function and/or abnormal clinical laboratory results in patients taking sertraline. While there have been reports of thrombocytopenia, abnormal bleeding or purpura in several patients taking sertraline, it is unclear whether sertraline had a causative role.
General: Malaise.
Other: Withdrawal reactions have been reported with sertraline. Common symptoms include dizziness, paraesthesia, headache, anxiety and nausea. Abrupt discontinuation of treatment with sertraline should be avoided. The majority of symptoms experienced on withdrawal of sertraline are non-serious and self-limiting.
In pediatric clinical trials in depression the following adverse events were reported at a frequency of at least 2% of patients and occurred at a rate of at least twice that of placebo: dry mouth (2.1% vs 0.5%), hyperkinesia (2.6% vs 0.5%), tremor (2.1% vs 0%), diarrhea (9.5% vs 1.6%), vomiting (4.2% vs 1.1%), agitation (6.3% vs 1.1%), anorexia (5.3% vs 1.1%) and urinary incontinence (2.1% vs 0%).
Suicidal thoughts and suicide attempts were mainly observed in clinical trials with Major Depressive Disorder.

Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins: Because sertraline is tightly bound to plasma protein, the administration of sertraline 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.
Cimetidine: 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.
CNS Active Drugs: 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 but did result in an increase in tremor compared with placebo. At this time, it is recommended that patients and 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).
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.
The effect of sertraline on methadone plasma levels in depressed methadone-maintained opiate addicts showed a significant mean increase in methadone plasma level/dose (P/D) ratio of 26%, while patients on placebo showed a significant mean decrease of 16% over the first 6 weeks of treatment. Depression and anxiety disorders are common in methadone-maintained patients. Clinicians treating depressed or anxious methadone patients with second-generation antidepressants should monitor for clinical signs of increased or decreased methadone levels and consider monitoring serum methadone levels.
Monoamine Oxidase Inhibitors: (See Contraindications and Warnings.)
Drugs Metabolized by P450 3A4: 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%).
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 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 co-administered drug may be required.
Sumatriptan: 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.
Tricyclic Antidepressant Drugs effective in the treatment of Major Depressive Disorder (TCAs): The extent to which SSRITCA 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.
Hypoglycemic Drugs: 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.
Atenolol: Sertraline (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.
Digoxin: In a placebo-controlled trial in normal volunteers, administration of sertraline for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.
Microsomal Enzyme Induction: Preclinical studies have shown sertraline 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.
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 sertraline.
Electroconvulsive Therapy: There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and sertraline.
Alcohol: 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.

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Antidepressants

N06AB06 - sertraline ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

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