Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3080
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Sertraline Hydrochloride (Tablet)
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Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The molecular formula CHNCl���HCl is represented by the following structural formula: Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol. Sertraline hydrochloride tablets are supplied for oral administration as scored tablets containing sertraline hydrochloride equivalent to 25 mg, 50 mg or 100 mg of sertraline and the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, D&C Yellow No. 10 Aluminum Lake, dibasic calcium phosphate (dihydrate), FD&C Blue No. 1 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and triacetin.
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Pharmacodynamics: 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 significant affinity for adrenergic (alpha, alpha, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT, 5HT, 5HT) 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.<br/>Pharmacokinetics:<br/>Systemic Bioavailability: In man, following oral once daily dosing over the range of 50 mg to 200 mg for 14 days, mean peak plasma concentrations (C) 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 Cand area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 mg to 200 mg. Consistent with the terminal elimination half-life, there is an approximately 2-fold accumulation, compared to a single-dose, of sertraline with repeated dosing over a 50 mg to 200 mg dose range. The single-dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution. In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean AUC and Cvalues were 114.8% and 120.6%, respectively. Ninety percent confidence intervals (CI) were within the range of 80% to 125% with the exception of the upper 90% CI limit for Cwhich was 126.5%. The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single-dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cwas 25% greater, while the time to reach peak plasma concentration (T) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Twas slightly prolonged from 5.9 hours to 7 hours with food.<br/>Metabolism: Sertraline undergoes extensive first-pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40% to 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% to 45% of the administered radioactivity was accounted for in feces, including 12% to 14% unchanged sertraline. Desmethylsertraline exhibits time related, dose dependent increases in AUC, Cand C, with about a 5-fold to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.<br/>Protein Binding: In vitro protein binding studies performed with radiolabeledH-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 .<br/>Pediatric Pharmacokinetics: Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to 12 years, 32 aged 13 to 17 years). Patients included both males (N = 28) and females (N = 33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6 to 12 year old group exhibited a mean sertraline AUCof 3107 ng-hr/mL, mean Cof 165 ng/mL, and mean half-life of 26.2 hr. The 13 to 17 year old group exhibited a mean sertraline AUCof 2296 ng-hr/mL, mean Cof 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6 to 12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUCof 2570 ng-hr/mL, mean Cof 142 ng/mL, and mean half-life of 27.2 hr. Relative to the adults, both the 6 to 12 year olds and the 13 to 17 year olds showed about 22% lower AUCand Cvalues 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 .<br/>Age: Sertraline plasma clearance in a group of 16 (eight male, eight 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 years old) 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.<br/>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 (N = 10, eight patients with Child-Pugh scores of 5 to 6 and two patients with Child-Pugh scores of 7 to 8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N = 10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used .<br/>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 (CL= 30 to 60 mL/min), moderate to severe (CL= 10 to 29 mL/min) or severe (receiving hemodialysis) renal impairment (N = 10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age matched volunteers (N = 12) with no renal impairment. Thus sertraline multiple-dose pharmacokinetics appear to be unaffected by renal impairment .<br/>Clinical Trials:<br/>Major Depressive Disorder: The efficacy of sertraline as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed dose study, including sertraline hydrochloride doses of 50, 100 and 200 mg/day. Overall, these studies demonstrated sertraline to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study2 was not readily interpretable regarding a dose response relationship for effectiveness. Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on sertraline hydrochloride 50 to 200 mg/day. These patients (N = 295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride 50 to 200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline comparedto those on placebo. The mean dose for completers was 70 mg/day. Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.
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Sertraline Hydrochloride Tablets are available with each tablet containing sertraline hydrochloride equivalent to 25 mg, 50 mg or 100 mg of sertraline. The 25 mg tablets are light-green film-coated, round, scored tablets debossed with M above the score and S1 below the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4186-93bottles of 30 tablets NDC 0378-4186-01bottles of 100 tablets NDC 0378-4186-05bottles of 500 tablets The 50 mg tablets are light-green film-coated, round, scored tablets debossed with M above the score and S2 below the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4187-93bottles of 30 tablets NDC 0378-4187-01bottles of 100 tablets NDC 0378-4187-05bottles of 500 tablets The 100 mg tablets are light-green film-coated, oval, scored tablets debossed with M to the left of the score and S3 to the right of the score on one side of the tablet and blank on the other side. They are available as follows: NDC 0378-4188-93bottles of 30 tablets NDC 0378-4188-01bottles of 100 tablets NDC 0378-4188-05bottles of 500 tablets Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription. Mylan Pharmaceuticals Inc.Morgantown, WV 26505 REVISED AUGUST 2008SERT:R6mc
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dailymed-ingredient:D&C_Yellow_No._10_Aluminum_Lake,
dailymed-ingredient:FD&C_Blue_No._1_Aluminum_Lake,
dailymed-ingredient:FD&C_Red_No._40_Aluminum_Lake,
dailymed-ingredient:anhydrous_lactose,
dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:dibasic_calcium_phosphate_(dihydrate),
dailymed-ingredient:hydroxypropyl_cellulose,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polydextrose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:sodium_lauryl_sulfate,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:triacetin
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General:<br/>Activation of Mania/Hypomania: During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline hydrochloride treated patients.<br/>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.<br/>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. No seizures were observed among approximately 3,000 patients treated with sertraline in the development program for major depressive disorder. However, four patients out of approximately 1,800 (220<18 years of age) exposed during the development program for another disorder experienced seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, sertraline should be introduced with care in patients with a seizure disorder.<br/>Discontinuation of Treatment with Sertraline: During marketing of sertraline hydrochloride tablets 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 hydrochloride. 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 .<br/>Abnormal Bleeding: SSRIs and SNRIs, including sertraline, may increase the risk of bleeding events. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis and petechiae to life threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of sertraline and NSAIDs, aspirin or other drugs that affect coagulation.<br/>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.<br/>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. Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 774 patients who received sertraline in double-blind trials were evaluated and the data indicate that sertraline is not associated with the development of significant ECG abnormalities. Sertraline administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or unstable angina requiring hospitalization. Exclusions from this trial included, among others, patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index event, severe or symptomatic bradycardia, nonatherosclerotic cause of angina, clinically significant renal impairment (creatinine>2.5 mg/dL), and clinically significant hepatic dysfunction. Sertraline treatment initiated during the acute phase of recovery (within 30 days post-MI or post hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia and changes in BP) and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke or angina). Sertraline hydrochloride is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cand 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 hydrochloride 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 .<br/>Interference with Cognitive and Motor Performance: In controlled studies, sertraline did not cause sedation and did not interfere with psychomotor performance. (See Information for Patients.)<br/>Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including sertraline. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of sertraline should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest and death.<br/>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.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families and their caregivers about the benefits and risks associated with treatment with sertraline and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and Other Serious Mental Illnesses and Suicidal Thoughts or Actions���is available for sertraline hydrochloride tablets. The prescriber or health professional should instruct patients, their families and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride tablets.<br/>Clinical Worsening and Suicide Risk: Patients, their families and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression and suicidal ideation, especially early during antidepressant treatment and when thedose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day to day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including sertraline hydrochloride, and triptans, tramadol or other serotonergic agents. Patients should be told that although sertraline has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely. Therefore, patients should be told that until they learn how they respond to sertraline they should be careful doing activities when they need to be alert, such as driving a car or operating machinery. Patients should be cautioned about the concomitant use of sertraline and NSAIDs, aspirin, warfarin or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Patients should be told that although sertraline has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of sertraline and alcohol is not advised. Patients should be told that while no adverse interaction of sertraline with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast-feeding an infant.<br/>Laboratory Tests: None.<br/>Drug Interactions:<br/>Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins: Because sertraline is tightly bound to plasma protein, the administration of sertraline hydrochloride to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline by other tightly bound drugs. In a study comparing prothrombin time AUCfollowing dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the sertraline group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline therapy is initiated or stopped.<br/>Cimetidine: In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline mean AUC (50%), C(24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.<br/>CNS Active Drugs: In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline hydrochloride (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 Tfor desmethyldiazepam in the sertraline group compared to a 20% decrease in the placebo group (p<0.03). The clinical significance of these changes is unknown. In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline did not significantly alter steady-state lithium levels or the renal clearance of lithium. Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of sertraline therapy with appropriate adjustments to the lithium dose. In a controlled study of a single-dose (2 mg) of pimozide, 200 mg sertraline (q.d.) coadministration to steady-state was associated with a mean increase in pimozide AUC and Cof 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 . Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multipleconcomitant medications. The effect of sertraline on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of sertraline therapy with appropriate adjustments to the valproate dose. The risk of using sertraline in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline and such drugs is required. There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder to sertraline hydrochloride. 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.<br/>Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS and WARNINGS.<br/>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 Cwere reduced by about 35%).<br/>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 coadministered drugs that are metabolized by P450 2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide. The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the coadministered drug. There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug metabolized by P450 2D6 with sertraline may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline is withdrawn from cotherapy, an increased dose of the coadministered drug may be required .<br/>Serotonergic Drugs: Based on the mechanism of action of SNRIs and SSRIs, including sertraline hydrochloride, and the potential for serotonin syndrome, caution is advised when SNRIs and SSRIs, including sertraline hydrochloride, are coadministered with other drugs that may affect the serotonergic neutrotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol or St. John's Wort . The concomitant use of sertraline hydrochloride with other SSRIs, SNRIs or tryptophan is not recommended .<br/>Triptans: There have been rare post-marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases .<br/>Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs): The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration 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 coadministered with sertraline .<br/>Hypoglycemic Drugs: In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride 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.<br/>Atenolol: Sertraline hydrochloride (100 mg) when administered to ten healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.<br/>Digoxin: In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.<br/>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.<br/>Drugs that Interfere with Hemostasis (Nonselective 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 use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when sertraline is initiated or discontinued.<br/>Electroconvulsive Therapy: There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and sertraline.<br/>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.<br/>Carcinogenesis: Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) on a mg/mbasis. There was a dose related increase of liver adenomas in male mice receiving sertraline at 10 to 40 mg/kg (0.25 to 1 times the MRHD on a mg/mbasis). 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/mbasis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10 to 40 mg/kg (0.5 to 2 times the MRHD on a mg/mbasis) compared to placebo controls, this effect was not clearly drug-related.<br/>Mutagenesis: Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.<br/>Impairment of Fertility: A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (4 times the maximum recommended human dose on a mg/mbasis).<br/>Pregnancy:<br/>Teratogenic Effects. 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/mbasis. 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/mbasis) in rats and 40 mg/kg (4 times the MRHD on a mg/mbasis) 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 4 days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/mbasis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/mbasis). 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. Sertraline hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>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 post-marketing 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 . Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk fordeveloping PPHN was approximately 6-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman with sertraline during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment . Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic in the context of antidepressant therapy at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery: The effect of sertraline on labor and delivery in humans is unknown.<br/>Nursing Mothers: It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sertraline is administered to a nursing woman.<br/>Pediatric Use: Safety and effectiveness in pediatric patients with major depressive disorder have not been established . Two placebo-controlled trials (n = 373) 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 hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need. Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of age and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight . Approximately 600 pediatric patients 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 mg to 200 mg) outpatient trials for major depressive disorder (N = 373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6 to 11) and adolescents (ages 12 to 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 kg for sertraline and 38.5 kg for placebo. At baseline the mean weight for adolescents was 61.4 kg forsertraline and 62.5 kg for placebo. There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents. For children, about 7% had a weight loss>7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss>7% of body weight compared to about 1% of the placebo patients. A subset of these patients who completed the randomized controlled trials (sertraline N = 99, placebo N = 122) were continued into a 24-week, flexible dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was seen during the first 8 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 8 weeks of the randomized controlled trials. The subjects continuing in the open-label study began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo-controlled trial + 24 weeks open-label, N = 68), had weight gain that was similar to that expected using data from age adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long-term. Safety and effectiveness in pediatric patients with major depressive disorder have not been established. The risks, if any, that may be associated with sertraline's use beyond one year in children and adolescents 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 .<br/>Geriatric Use: 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.<br/>Other Adverse Events in Geriatric Patients: In 354 geriatric subjects treated with sertraline 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 sertraline, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event .
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Human Experience: Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999). Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, eight 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 nonfatal 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.<br/>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. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference(PDR).
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sertraline hydrochloride
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Sertraline Hydrochloride (Tablet)
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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. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk ofsuicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD orother psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and 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. 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 above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare 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.<br/>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 above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. It should be noted that sertraline hydrochloride tablets are not approved for use in treating bipolar depression. Cases of serious sometimes fatal reactions have been reported in patients receiving sertraline hydrochloride, a selective serotonin reuptake inhibitor (SSRI), in combination with a monoamine oxidase inhibitor (MAOI). Symptoms of a drug interaction between an SSRI and an MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, 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. The concomitant use of sertraline hydrochloride with MAOIs intended to treat depression is contraindicated<br/>Serotonin Syndrome: The development of a potentially life threatening serotonin syndrome may occur in treatment with SNRIs and SSRIs, including sertraline hydrochloride, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases . The concomitant use of SNRIs and SSRIs, including sertraline hydrochloride, with serotonin precursors (such as tryptophan) is not recommended .
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Sertraline Hydrochloride
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