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  • CLASSES

    Selective Serotonin Reuptake Inhibitor Antidepressants, SSRIs

    BOXED WARNING

    Children, growth inhibition, suicidal ideation

    The safety and efficacy of sertraline have been established in the treatment of obsessive compulsive disorder in children and adolescents 6 to 17 years of age. Two placebo-controlled trials were conducted in pediatric patients with major depression, but the data were not sufficient to support an indication for use. There is a causal relationship between the use of antidepressants, such as sertraline, and the risk of suicidal ideation and behavior in children, adolescents, and young adults (ages 18 to 24 years). Pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Risk for suicidality does not appear to differ among individual antidepressant agents. However, data from a cohort of 36,842 children (age range: 6 to 18 years) suggested those who use multiple antidepressants may have a higher risk of suicide behavior, most likely a result of increased severity of depression rather than drug effect. Suicidal ideation appears to be more prevalent in children with or at high risk for bipolar affective disorder on antidepressants. In a study of 52 patients (mean age: 15 years; range: 7 to 22 years) with bipolar affective disorder or subthreshold manic symptoms, 25.5% had new onset suicidal ideation within the first 3 months of antidepressant use. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or after dose changes. It is unknown if the suicidality risk extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with primary depressive symptoms or symptoms secondary to another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with sertraline. In patients who exhibit a worsening of depression or emerging suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased appetite and weight loss have been observed with the use of SSRIs. Monitor for potential growth inhibition (e.g., weight and height) in pediatric patients treated with an SSRI.

    DEA CLASS

    Rx

    DESCRIPTION

    Selective serotonin reuptake inhibitor (SSRI).
    Approved for depression, OCD, panic disorder, PTSD, premenstrual-dysphoric disorder (PMDD), and social anxiety disorder in adults; approved for OCD in pediatrics; primary off-label uses include premature ejaculation, hot flashes, and generalized anxiety disorder.
    Requires close monitoring in pediatrics and young adults due to increased risk of suicidality during the initial stages of treatment.

    COMMON BRAND NAMES

    Zoloft

    HOW SUPPLIED

    Sertraline/Sertraline Hydrochloride/Zoloft Oral Sol: 1mL, 20mg
    Sertraline/Sertraline Hydrochloride/Zoloft Oral Tab: 25mg, 50mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    For the treatment of major depression in adults.
    Oral dosage
    Adults

    50 mg PO once daily. A lower initial dose may be used (e.g., 25 mg PO once daily) to minimize adverse effects. If necessary, increase at intervals of not less than 1 week. Max: 200 mg/day PO. Continuation of medication for 6 to 12 months after symptom remission is recommended; periodically reassess to determine the need for ongoing treatment.

    For the treatment of major depression† in pediatric patients.
    Oral dosage
    Children and Adolescents 12 to 17 years†

    25 to 50 mg/day PO initially. Clinical guidelines recommend to start with a low dose and titrate gradually at 4-week intervals until clinical response is achieved ; some studies report titration in 25 mg to 50 mg/day increments as often as every 1 to 2 weeks. A dose of 50 mg/day PO is considered effective. A mean final dose of 110 (+/- 50) mg/day PO, which was approximately 2 (+/- 0.85) mg/kg/day, was reported in an open study of 13 hospitalized adolescents. In another analysis, the mean dosage range was approximately 121 to 134 mg/day PO. Max: 200 mg/day PO. Patients with minimal or no response after 8 weeks of treatment will likely need alternative treatment. Continuation of medication for 6 to 12 months after symptom remission is recommended; periodically reassess to determine the need for ongoing treatment.

    Children 6 to 11 years†

    12.5 mg to 25 mg/day PO initially. Clinical guidelines recommend to start with a low dose and titrate gradually at 4-week intervals until clinical response is achieved ; some studies report titration in 25 mg to 50 mg/day increments as often as every 1 to 2 weeks. A dose of 50 mg/day PO is considered effective ; a mean final dose of 100 (+/- 53) mg/day PO, which was approximately 1.6 (+/- 0.7) mg/kg/day based on available weights, was reported in a retrospective review of 21 children (age range: 8 to 18 years). Max: 200 mg/day PO. Patients with minimal or no response after 8 weeks of treatment will likely need alternative treatment. Continuation of medication for 6 to 12 months after symptom remission is recommended; periodically reassess to determine the need for ongoing treatment.

    For the treatment of social phobia (social anxiety disorder).
    Oral dosage
    Adults

    Initial dose of 25 mg PO once daily. After one week, increase dose to 50 mg PO once daily. If necessary, increase by 50 mg/day at intervals of not less than 1 week up to 200 mg/day. In a double-blind crossover study, a statistically significant improvement in scores on the Liebowitz Social Anxiety Scale was found with sertraline after 10 weeks but not with placebo. In a 20-week study, a relative response rate of 24% was achieved (ranked as 'much improved' or 'very much improved' on the Clinical Global Impression scale) versus placebo. In a follow-up 24-week study to assess relapse rates, 4% of patients in the sertraline group experienced a relapse versus 36% of those switched to placebo.

    Children† and Adolescents† 7 years and older

    25 mg/day PO initially, followed by flexible dosing titration based upon response and tolerability, up to 200 mg/day. One large placebo-controlled trial assessed 488 pediatric patients with a primary diagnosis of social phobia (10%), separation anxiety disorder (1.4%), generalized anxiety (7.1%), or a combination of these anxiety disorders (81.5%). Nearly 81% of patients receiving sertraline + cognitive behavior therapy (CBT) were rated as very much or much improved compared to 54.9% of those receiving sertraline alone, 59.7% of those receiving CBT alone, and 23.7% of those receiving placebo. At the final visit, the mean dose of sertraline in treated patients was 133.7 mg/day or 146 mg/day. Periodically reassess to determine the need for ongoing maintenance treatment. Further study is needed to evaluate the long-term safety and efficacy of SSRIs in treating childhood anxiety disorders.

    For the treatment of obsessive-compulsive disorder (OCD).
    Oral dosage
    Adults

    50 mg PO once daily initially. Doses of 50 to 200 mg/day PO were effective during clinical trials. Max: 200 mg/day PO. It is generally agreed that pharmacologic therapy is necessary for several months or longer; however, it is not known if the dose needed during the maintenance phase is equal to the dose needed to achieve an initial response. Periodically reassess the need for maintenance treatment.

    Adolescents

    50 mg/day PO initially, administered in the morning or evening. Although a dose-effect relationship has not been established, patients not responding to the initial dose may benefit from dose increases. Max: 200 mg/day PO. Due to the long elimination half-life of sertraline, dose adjust only at intervals of 1 week or more. Maintenance treatment is generally needed; however, it is not known if the maintenance dose is equal to the dose needed to achieve the initial response. Periodically reassess the need for maintenance treatment.

    Children 6 to 12 years

    25 mg/day PO initially, administered in the morning or evening. Although a dose-effect relationship has not been established, patients not responding to the initial dose may benefit from dose increases at intervals of not less than 1 week. Max: 200 mg/day. Maintenance treatment is generally needed; however, it is not known if the maintenance dose is equal to the dose needed to achieve the initial response. Periodically reassess the need for continued treatment.

    For the treatment of posttraumatic stress disorder (PTSD).
    Oral dosage
    Adults

    25 mg PO once daily initially. After 1 week, increase dose to 50 mg PO once daily. If necessary, increase by 50 mg/day at intervals of not less than 1 week. Max: 200 mg/day. In the treatment of PTSD, sertraline has been effective for a wide variety of traumatic stressors, including combat.

    For the treatment of panic disorder.
    Oral dosage
    Adults

    25 mg PO once daily initially. After 1 week, increase dose to 50 mg PO once daily. If necessary, increase by 50 mg/day at intervals of not less than 1 week up to 200 mg/day.

    Children† and Adolescents† 8 years and older

    The effective dose range has not been established; published data are extremely limited. A usual starting dose is 25 mg/day PO with flexible dosing titration based upon response and tolerability. Max: 200 mg/day PO based on data for other pediatric conditions. In a 6-month, open-label pilot study of 12 children and adolescents with panic disorder and some with comorbid mood or other anxiety disorders, 75% were classified as showing much to very much improvement at a median duration of 7.5 weeks of treatment with sertraline, fluoxetine, or paroxetine. Eleven patients showed some improvement, except 1 patient receiving fluoxetine who showed no change in symptomatology. The sertraline-treated patient received a dose of 125 mg/day PO during the acute treatment phase and 150 mg/day during the follow-up phase. A benzodiazepine was used in 67% of the patients while awaiting the clinical response to the SSRI. Periodically reassess to determine the need for ongoing maintenance treatment. Evaluation of the long-term safety and efficacy of sertraline in the treatment of childhood panic disorder is needed.

    For the treatment of premenstrual dysphoric disorder (PMDD).
    Oral dosage
    Adult females

    50 mg/day PO initially, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on provider assessment. 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 using 100 mg/day with luteal phase dosing, a 50 mg/day titration step for three days should be implemented at the beginning of each luteal phase dosing period. In one study, 62% of women receiving sertraline had at least 30% improvement from baseline versus only 34% of women receiving placebo. The mean effective dosage was 100 mg/day.

    For the treatment of generalized anxiety disorder (GAD)†.
    Oral dosage
    Adults

    25 mg PO once daily initially. After 1 week, increase dose to 50 mg PO once daily. If necessary, increase by 50 mg/day at intervals of not less than 1 week up to 200 mg/day.

    Children and Adolescents 7 years and older

    25 mg/day PO initially, followed by flexible dosing titration based upon response and tolerability, up to 200 mg/day. One large placebo-controlled trial assessed 488 pediatric patients with a primary diagnosis of generalized anxiety disorder (7.1%), separation anxiety disorder (1.4%), social phobia (10%), or a combination of these anxiety disorders (81.5%). Nearly 81% of patients receiving sertraline + cognitive behavior therapy (CBT)were very much or much improved compared to 54.9% of those receiving sertraline alone, 59.7% of those receiving CBT alone, and 23.7% of those receiving placebo. At the final visit (12 weeks), the mean sertraline dose in treated groups was 133.7 mg/day or 146 mg/day. Periodically reassess to determine need for continued treatment. Evaluation of the long-term safety and efficacy of sertraline in the treatment of childhood GAD is needed.

    For the treatment of separation anxiety disorder†.
    Oral dosage
    Children and Adolescents 7 years and older

    25 mg/day PO initially, followed by flexible dosing titration based upon response and tolerability, up to 200 mg/day has been used. One large placebo-controlled trial assessed 488 pediatric patients with a primary diagnosis of separation anxiety disorder (1.4%), generalized anxiety disorder (7.1%), social phobia (10%), or a combination of these anxiety disorders (81.5%). Nearly 81% of patients receiving cognitive behavior therapy (CBT) + sertraline were rated as very much or much improved compared to 54.9% of those receiving sertraline alone, 59.7% of those receiving CBT alone, and 23.7% of those receiving placebo. At the final visit, the mean dose of sertraline in the CBT-sertraline group was 133.7 mg/day and the mean dose in the sertraline group was 146 mg/day. Patients should be periodically reassessed to determine the need for ongoing maintenance treatment. Further study is needed to evaluate the long-term safety and efficacy of SSRIs in treating childhood anxiety disorders.

    For the treatment of hot flashes† due to menopause† or in women who have been treated for breast cancer.
    For women experiencing hot flashes† as a symptom of menopause†.
    Oral dosage
    Adult females

    Initial dosage has been 50 mg PO once daily, titrated to doses as high as 100 mg/day PO. Because efficacy data from clinical trials are statistically inconsistent, sertraline has been suggested as a second-line SSRI treatment for hot flashes; there is a trend toward clinical improvement. The American College of Obstetricians and Gynecologists (ACOG) guidelines and The North American Menopause Society (NAMS) Guidelines for non-hormonal therapy identify SSRIs as alternatives to hormonal therapy, particularly when hormonal replacement is not acceptable or is contraindicated; the data for sertraline are not as robust as with some other agents in the class. In a double-blind, cross-over design randomized, controlled trial (RCT) of 102 women over 9 weeks, women reported five fewer hot flashes per week while taking sertraline 50 mg/day PO than while taking placebo (p = 0.002). The range of hot flashes at baseline was large: average of 45.6 episodes per week (range: 2 to 148 episodes); overall clinical treatment benefit on frequency relative to placebo was relatively small; the overall severity of hot flashes did not differ between the groups; a post-hoc analysis of the same trial data determined that women reporting the greatest benefit from sertraline were more likely to have a higher frequency and severity of hot flashes at baseline. A third study comparing sertraline 50 mg/day PO to placebo found no benefit; however, the 38% placebo response may have influenced study outcomes; there was a 39% response rate to sertraline. Fixed dosing did not allow titration to efficacy. Another study found sertraline 50 mg/day PO more effective than placebo; a higher percentage of patients (p = 0.01) showed a symptomatic improvement of climacteric symptoms (e.g., 35.3% placebo and 81.3% sertraline).

    For hot flashes† in women treated for breast cancer or for an increased risk of breast cancer.
    Oral dosage
    Adult females

    Clinical trial data regarding efficacy are inconsistent in the dose range of 50 mg/day to 100 mg/day PO. In a 12-week cross-over design, randomized controlled trial (RCT), women taking tamoxifen received placebo or sertraline for 6 weeks, followed by 6 weeks of the other treatment. Compared to baseline, hot flash frequency decreased by 50% in 36% of women taking sertraline vs. 27% of women taking placebo (p = 0.7, NS); additionally, women who crossed over to sertraline after taking placebo experienced a reduction of 0.9 and 1.7 in hot flash frequency and index, respectively, and those who took placebo after sertraline experienced an increase 1.5 and 3.4 in hot flash frequency and index, respectively (p = 0.03 for comparison of both frequency and index between groups). Another RCT compared sertraline 100 mg/day PO to placebo; no significant differences were noted in either the frequency or severity score for hot flashes between the groups.

    For the treatment of premature ejaculation†.
    Oral dosage
    Adult males

    Titrate from an initial low dosage (e.g., 25 to 50 mg PO once daily) based on response and tolerability. A dose range of 25 to 200 mg/day PO has been shown to increase ejaculatory latency and is suggested, among some other SSRIs, in the American Urological Association (AUA) treatment guidelines and the guidelines of the International Society for Sexual Medicine; use lowest effective dose; the benefit of higher doses may be outweighed by increased frequency of erectile dysfunction and decreased libido. In one study, men with lifelong rapid ejaculation (i.e., an intravaginal ejaculation latency time of 1 minute or less) received sertraline, another SSRI (fluoxetine, fluvoxamine, paroxetine), or placebo for 6 weeks. Mean intravaginal ejaculation latency time (IELT) with placebo was 20 seconds; the IELT in men treated with sertraline 50 mg/day PO increased to approximately 110 seconds. Other studies provide similar support for the use of sertraline or other SSRIs.
         Alternatively, 50 mg PO as a single dose 4 to 8 hours prior to intercourse has demonstrated efficacy and is suggested per the AUA treatment guidelines. It is unclear if daily or situational dosing is more effective. Likewise, the optimal interval for situational dosing before intercourse is not well defined. The choice of regimen is ultimately defined by clinical judgement and patient preference in light of the frequency of sexual activity.

    For the treatment of pruritus† due to cholestatic liver disease.
    Oral dosage
    Adults

    Patients treated with sertraline at doses of 50 to 100 mg PO once daily (median dose = 75 mg) reported a significant improvement in itching and decrease in the number of other medications used to treat pruritus (e.g., cholestyramine, antihistamines, phenobarbital).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    200 mg/day PO.

    Geriatric

    200 mg/day PO; however, lower dosages may be effective/better tolerated.

    Adolescents

    200 mg/day PO.

    Children

    6 to 12 years: 200 mg/day PO.
    1 to 5 years: Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Dosage adjustments are recommended.
    Mild hepatic impairment (Child Pugh A, score 5 or 6): The recommended initial dose and therapeutic range dosing is 50% of the normal daily dosage.
    Moderate to severe hepatic impairment (Child Pugh B, score 7 to 9 or Child Pugh C, score 10 to 15): Use of sertraline is not recommended.

    Renal Impairment

    No dosage adjustments are needed.
     
    Intermittent hemodialysis
    No dosage adjustments are needed. Sertraline is unlikely to be significantly removed by hemodialysis given its large volume of distribution.

    ADMINISTRATION

    Oral Administration

    May take without regard to meals in the morning or evening.

    Oral Liquid Formulations

    Oral solution:
    Must be diluted before use.
    Use the supplied calibrated dropper to measure the correct dose.
    Mix the measured dose with 4 ounces (120 mL) of water, ginger ale, lemon-lime soda, lemonade, or orange juice ONLY.
    After mixing, a slight haze may appear; this is normal.
    Consume the dose immediately after mixing; do not prepare in advance.
    The dropper contains dry natural rubber; use with caution in patients with a latex sensitivity.

    STORAGE

    Zoloft:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Sertraline is contraindicated in patients with a hypersensitivity to sertraline or any of the formulation components.
     
    Some reports suggest that a false positive urine drug screen may occur for benzodiazepines in patients who have received sertraline. False positive results may occur for several days following discontinuation of sertraline. Caution should be exercised when interpreting positive urine drug screens for these medications, and confirmation by alternative tests such as gas chromatography/mass spectrometry should be considered.

    Abrupt discontinuation

    Avoid abrupt discontinuation of any SSRI if possible. Gradual tapering is recommended during discontinuation of sertraline to decrease or prevent the occurrence of potential discontinuation symptoms. The most frequent SSRI discontinuation symptoms include dizziness, vertigo, nausea, vomiting, flu-like symptoms, sensory disturbances (e.g., paresthesias, electric shock sensation), sleep disturbances, irritability, anxiety, and/or agitation. Discontinuation symptoms are most likely to occur after withdrawal of SSRIs with a short half-life (e.g., paroxetine, fluvoxamine).

    Children, growth inhibition, suicidal ideation

    The safety and efficacy of sertraline have been established in the treatment of obsessive compulsive disorder in children and adolescents 6 to 17 years of age. Two placebo-controlled trials were conducted in pediatric patients with major depression, but the data were not sufficient to support an indication for use. There is a causal relationship between the use of antidepressants, such as sertraline, and the risk of suicidal ideation and behavior in children, adolescents, and young adults (ages 18 to 24 years). Pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Risk for suicidality does not appear to differ among individual antidepressant agents. However, data from a cohort of 36,842 children (age range: 6 to 18 years) suggested those who use multiple antidepressants may have a higher risk of suicide behavior, most likely a result of increased severity of depression rather than drug effect. Suicidal ideation appears to be more prevalent in children with or at high risk for bipolar affective disorder on antidepressants. In a study of 52 patients (mean age: 15 years; range: 7 to 22 years) with bipolar affective disorder or subthreshold manic symptoms, 25.5% had new onset suicidal ideation within the first 3 months of antidepressant use. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or after dose changes. It is unknown if the suicidality risk extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with primary depressive symptoms or symptoms secondary to another primary disorder such as OCD. All patients with a history of suicidal ideation or behaviors prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with sertraline. In patients who exhibit a worsening of depression or emerging suicidality, a decision should be made to change or discontinue treatment. If discontinuing, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased appetite and weight loss have been observed with the use of SSRIs. Monitor for potential growth inhibition (e.g., weight and height) in pediatric patients treated with an SSRI.

    Bipolar disorder, mania

    The use of antidepressants has been associated with the precipitation of mania or hypomania in susceptible individuals. If a patient develops manic symptoms, sertraline should be withheld, and appropriate therapy initiated to treat the manic symptoms. Depression may also be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or emergence of suicidality.

    MAOI therapy

    Concomitant use of MAOI therapy with sertraline or within 14 days of stopping treatment with sertraline is contraindicated because of an increased risk of serotonin syndrome. The use of sertraline within 14 days of stopping MAOI therapy is also contraindicated. Starting sertraline in a patient who is being treated with linezolid or intravenous methylene blue, both of which inhibit monoamine oxidase, is also contraindicated because of an increased risk of serotonin syndrome. Starting sertraline in a patient being treated with an MAOI such as linezolid or methylene blue is also contraindicated; however, there may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or methylene blue in a patient taking sertraline. If acceptable alternatives are not available and benefits are judged to outweigh the risks of serotonin syndrome, sertraline should be promptly discontinued before initiating treatment with the MAOI. Monitor the patient closely for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of MAOI, whichever comes first. The development of a potentially life-threatening serotonin syndrome has been reported with the use of SSRIs such as sertraline alone, but particularly with concomitant use of other serotonergic drugs. If concomitant use of sertraline with certain other serotonergic drugs (i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort) is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with sertraline and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Sertraline oral concentrate is contraindicated in patients receiving disulfiram due to the alcohol content of the sertraline concentrate.

    Electroconvulsive therapy (ECT), seizure disorder

    Sertraline should be used with caution in patients with a history of seizure disorder. Patients with a history of seizures were excluded from clinical studies with sertraline. Seizures have been reported rarely in patients taking SSRIs. The risks or benefits of using sertraline during electroconvulsive therapy (ECT) have not been established in clinical studies. Some clinicians have reported that in rare instances the ECT-induced seizure was prolonged in the presence of an antidepressant.

    Dehydration, hyponatremia, hypovolemia

    Selective serotonin reuptake inhibitors (SSRIs) such as sertraline may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Elderly patients, those receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of the SSRI, as well as implementation of the appropriate medical interventions.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Cases of QT prolongation and torsade de pointes (TdP) have been reported during postmarketing use of sertraline. Therefore, sertraline should be used with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. The manufacturer recommends against coadministration of sertraline and other medications known to prolong the QTc interval. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic impairment may also be at increased risk for QT prolongation.

    Hepatic disease

    Dosage adjustments of sertraline are recommended in patients with hepatic disease. In studies of patients with chronic mild hepatic disease, sertraline clearance was reduced. For patients with mild hepatic impairment (Child Pugh scores 5 or 6), the recommended initial dose and therapeutic range dosing is 50% of the normal daily dosage. The use of sertraline in patients with moderate (Child Pugh scores 7 to 9) or severe hepatic impairment (Child Pugh scores 10 to 15) is not recommended.

    Anticoagulant therapy, bleeding, thrombolytic therapy

    Monitor patients taking an SSRI for signs and symptoms of bleeding. Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). Concurrent use of aspirin, NSAIDs, anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking sertraline should be instructed to promptly report any bleeding events to the practitioner.

    Bone fractures, osteoporosis

    Use selective serotonin reuptake inhibitors (SSRIs), including sertraline, with caution in patients with osteoporosis. Epidemiological studies on bone fracture risk following exposure to SSRIs have reported an association between SSRI treatment and bone fractures. It is unknown to what extent fracture risk is directly attributable to SSRI treatment. If a sertraline-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising, consider the possibility of a fragility fracture. Patients at risk for osteoporosis, such as postmenopausal females, may benefit from more frequent monitoring of bone density during long-term use of an SSRI.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing sertraline to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

    Akathisia

    The use of sertraline or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. Discontinue treatment with the SSRI if akathisia occurs.

    Anorexia nervosa

    Decreased appetite and weight loss have been observed during administration of SSRIs. Therefore, caution is advisable when administering sertraline to patients with anorexia nervosa or other conditions where weight loss is undesirable.

    Driving or operating machinery, ethanol ingestion

    Because any psychoactive drug may impair judgment, thinking, or motor skills, patients should use caution when driving or operating machinery, until they are reasonably certain that sertraline does not affect them adversely. Although sertraline has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid ethanol ingestion while taking sertraline.

    Neonates, pregnancy

    Sertraline oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy. Use other sertraline formulations during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. The majority of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no increase in major birth defect risk. Epidemiologic studies showing an increased risk of congenital cardiac defects (e.g., septal defects) did not control for confounders that may have affected the study results. Neonates exposed to SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms 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 serotonin syndrome or, possibly, a drug discontinuation syndrome. Although available data are conflicting, some epidemiologic reports suggest an association between maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension of the newborn (PPHN). Because PPHN is associated with significant morbidity and mortality, it is important that practitioners are aware of antidepressant exposure to avoid delays in diagnosis and treatment. In a meta-analysis of 7 studies, there was a small but significant association between SSRI exposure in late pregnancy and PPHN (OR 2.5, 95% CI 1.32 to 4.73; p = 0.005). Effects were not significant for other moderator variables examined (e.g., study design, congenital malformations, meconium aspiration). Effects of caesarian delivery, maternal body mass index, and preterm delivery were not assessed. PPHN occurs in approximately 1.9 of 1,000 live births in the general population and is a relatively uncommon event; based on this analysis it is estimated that an average of 1 associated case of PPHN would result from 286 to 351 women being treated with an SSRI during late gestation. The FDA advises that healthcare professionals should not alter their current practice of treating depression in pregnancy at this time. Women who are pregnant, or are planning a pregnancy, and currently taking sertraline should consult with their physician about whether to continue taking it. Carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the half-life into consideration, tapering of the serotonergic agent, such as sertraline, prior to delivery may be considered. A prospective study of pregnant women receiving antidepressant treatment found that only 26% of women maintained on their antidepressant had relapsed versus 68% of those who had discontinued their medication. Increasing evidence suggests an association between antidepressant use during pregnancy and a subsequent diagnosis of autism spectrum disorder (ASD) in the offspring. In two separate population based case-control studies, an approximate 2-fold increased risk of ASD was observed. One study found the increased risk was associated only with SSRI use, while the other study found an increased risk associated with use of SSRIs and tricyclic antidepressants. Animal teratology studies with sertraline have failed to show an increased risk of fetal malformations; however, an increase in stillbirths and pup deaths during the first few days after birth has been noted in animal studies where sertraline was initiated in the last trimester of gestation. In other animal studies where sertraline was administered during the period of organogenesis, delayed ossification was observed in fetuses at doses of 0.4 to 3.1 times the maximum recommended human dose (MRHD). A decrease in fertility was seen in 1 of 2 rat studies at a dose of 4 times the MRHD. Animal studies have also shown that SSRIs downregulate serotonin receptors in the fetal cortex and that these changes can be present for a period of time after birth; the effect on neurological development is unknown and the applicability of any of these findings to humans is also unknown. The effect of SSRIs on labor and delivery in humans is unknown. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388.

    Breast-feeding

    Available data from published literature demonstrate low levels of sertraline and its metabolites in human milk. In a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. No adverse reactions were observed in these infants. There are no data on the effects of sertraline on milk production. Because of its slow elimination, consideration should be given to the possible presence of the drug for a prolonged periods after discontinuation of therapy. Other SSRIs have been observed to cause increased irritability, colic, vomiting, and decreased sleep in infants. The pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum and, therefore, may be the preferred antidepressants in breast-feeding mothers. If breast-feeding is continued, the infant should be observed for evidence of adverse effects. Consider the developmental and health benefits of breast-feeding, along with the mother’s clinical need for sertraline therapy and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Clinical studies of sertraline in major depressive disorder included 663 subjects 65 years of age and older. Of those, 180 patients were 75 years of age and older. The pattern of adverse reactions observed in geriatric subjects relative to younger adults was similar in clinical trials and in reported clinical experience; however, greater sensitivity of some older individuals cannot be ruled out. According to the Beers Criteria, SSRIs are considered potentially inappropriate medications (PIMs) in elderly patients with a history of falls or fractures and should be avoided, unless safer alternatives are not available, since SSRIs can produce ataxia, impaired psychomotor function, syncope, and additional falls; if sertraline must be used, consider reducing use of other CNS-active medications that increase the risk of falls and fractures and implement other strategies to reduce fall risk. In addition, the Beers expert panel recommends caution when using SSRIs in older adults because SSRIs can cause or exacerbate hyponatremia and SIADH and the elderly are at increased risk of developing these conditions. Sodium levels should be closely monitored when starting or changing dosages in older adults. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Concurrent use of two or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    ADVERSE REACTIONS

    Severe

    visual impairment / Early / 4.0-4.0
    coma / Early / 0-2.0
    seizures / Delayed / 0-2.0
    anaphylactoid reactions / Rapid / 0-2.0
    bronchospasm / Rapid / 0-2.0
    ocular hypertension / Delayed / 0-0.1
    suicidal ideation / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    AV block / Early / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    vasculitis / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    pulmonary hypertension / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known
    persistent pulmonary hypertension of the newborn / Delayed / Incidence not known

    Moderate

    ejaculation dysfunction / Delayed / 3.0-8.0
    constipation / Delayed / 6.0-6.0
    palpitations / Early / 4.0-4.0
    impotence (erectile dysfunction) / Delayed / 4.0-4.0
    melena / Delayed / 0-2.0
    ataxia / Delayed / 0-2.0
    euphoria / Early / 0-2.0
    teeth grinding (bruxism) / Delayed / 0-2.0
    hallucinations / Early / 0-2.0
    confusion / Early / 0-2.0
    hypertension / Early / 0-2.0
    sinus tachycardia / Rapid / 0-2.0
    peripheral vasodilation / Rapid / 0-2.0
    hypercholesterolemia / Delayed / 0-2.0
    bullous rash / Early / 0-2.0
    blurred vision / Early / 0-2.0
    elevated hepatic enzymes / Delayed / 0-2.0
    edema / Delayed / 0-2.0
    hematuria / Delayed / 0-2.0
    vaginal bleeding / Delayed / 0-2.0
    priapism / Early / 0-2.0
    hypothyroidism / Delayed / 0-2.0
    hyperglycemia / Delayed / 0-2.0
    galactorrhea / Delayed / 0-2.0
    hypoglycemia / Early / 0-2.0
    diabetes mellitus / Delayed / 0-2.0
    dystonic reaction / Delayed / Incidence not known
    akathisia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    impulse control symptoms / Delayed / Incidence not known
    hostility / Early / Incidence not known
    psychosis / Early / Incidence not known
    mania / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    bleeding / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    trismus / Delayed / Incidence not known
    cataracts / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    osteopenia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    growth inhibition / Delayed / Incidence not known

    Mild

    nausea / Early / 26.0-26.0
    diarrhea / Early / 20.0-20.0
    insomnia / Early / 20.0-20.0
    xerostomia / Early / 14.0-14.0
    dizziness / Early / 12.0-12.0
    fatigue / Early / 12.0-12.0
    drowsiness / Early / 11.0-11.0
    tremor / Early / 9.0-9.0
    dyspepsia / Early / 8.0-8.0
    agitation / Early / 8.0-8.0
    hyperhidrosis / Delayed / 7.0-7.0
    libido decrease / Delayed / 4.0-7.0
    vomiting / Early / 4.0-4.0
    appetite stimulation / Delayed / 0-2.0
    lethargy / Early / 0-2.0
    hypoesthesia / Delayed / 0-2.0
    hyperactivity / Early / 0-2.0
    syncope / Early / 0-2.0
    irritability / Delayed / 0-2.0
    purpura / Delayed / 0-2.0
    epistaxis / Delayed / 0-2.0
    maculopapular rash / Early / 0-2.0
    alopecia / Delayed / 0-2.0
    pruritus / Rapid / 0-2.0
    urticaria / Rapid / 0-2.0
    muscle cramps / Delayed / 0-2.0
    arthralgia / Delayed / 0-2.0
    tinnitus / Delayed / 0-2.0
    mydriasis / Early / 0-2.0
    yawning / Early / 0-2.0
    fever / Early / 0-2.0
    orgasm dysfunction / Delayed / 1.0-2.0
    hyperkinesis / Delayed / Incidence not known
    headache / Early / Incidence not known
    nightmares / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    petechiae / Delayed / Incidence not known
    ecchymosis / Delayed / Incidence not known
    photosensitivity / Delayed / Incidence not known
    malaise / Early / Incidence not known
    nocturia / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    menstrual irregularity / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving abciximab. Monitor closely for signs and symptoms of bleeding.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Acetaminophen; Caffeine; Dihydrocodeine: (Major) Because of the potential risk and severity of serotonin syndrome and a potential for additive CNS effects, caution should be observed when coadministering drugs that have additive properties such as sertraline and dihydrocodeine. In addition, sertraline has the potential for clinically relevant CYP2D6 inhibition and may decrease the metabolism of dihydrocodeine to dihydromorphine, increasing the risk of dihydrocodeine-related adverse effects such as CNS or respiratory depression. Inhibition of CYP2D6 by sertraline may also result in reduced effectiveness of dihydrocodeine by inhibiting the conversion of dihydrocodeine to dihydromorphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue the serotonergic agents, and institute appropriate treatment.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Acetaminophen; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Doxylamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Acetaminophen; Oxycodone: (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Acetaminophen; Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy.
    Acetaminophen; Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sertraline with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures. Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. SSRIs that are CYP2D6 inhibitors, including sertraline, can prevent the formation of the active M1 metabolite of tramadol. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
    Alfuzosin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Almotriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Alprazolam: (Minor) The manufacturer of alprazolam states that in vitro studies suggest sertraline may inhibit the metabolism of alprazolam via inhibition of CYP3A4. The potential for clinical interaction is uncertain. Be alert for any change in psychomotor performance or other benzodiazepine-related side effects when sertraline is combined with alprazolam.
    Alteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Amiloride: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Amiodarone: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval, including amiodarone. If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Amitriptyline; Chlordiazepoxide: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Amoxapine: (Moderate) Sertraline is a mild to moderate inhibitor of CYP2D6, the isoenzyme partially responsible for the metabolism of amoxapine. In several cases, symptoms of toxicity, including seizures, have been reported when the structurally related tricyclic antidepressants have been co-administered with an SSRI. At least one case report exists of a death thought to be due to impaired clearance of the tricyclic antidepressant amitriptyline by fluoxetine. Patients receiving amoxapine should be monitored closely for toxicity if sertraline is added.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Amphetamines: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as amphetamines and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, the MAOI activity of amphetamines may be of concern with the use of drugs that have serotonergic activity. Patients receiving sertraline and an amphetamine should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. All serotonergic agents should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Anagrelide: (Major) Coadministration of sertraline and anagrelide should be avoided if possible due to the potential for QT prolongation and torsade de pointes (TdP). There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. TdP and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary.
    Antithrombin III: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like antithrombin III. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Apixaban: (Major) The concomitant use of selective serotonin reuptake inhibitors (SSRIs) and apixaban can increase the risk of bleeding. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
    Apomorphine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Ardeparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Arformoterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Aripiprazole: (Major) There have been postmarketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation has been reported during therapeutic use of aripiprazole and following overdose. In addition, because aripiprazole is partially metabolized by CYP2D6, increased aripiprazole plasma concentrations may occur during concurrent use of inhibitors of CYP2D6 such as sertraline. If these agents must be used together, the patient should be carefully monitored for aripiprazole-related adverse reactions. Dose adjustments are required if aripiprazole is also used with a CYP3A4 inhibitor along with a CYP2D6 inhibitor such as sertraline. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.
    Arsenic Trioxide: (Major) Avoid coadministration of sertraline and arsenic trioxide. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. In addition, TdP, QT prolongation, and complete atrioventricular block have been reported with arsenic trioxide use. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide.
    Artemether; Lumefantrine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Artemether; lumefantrine is associated with QT prolongation and should be avoided in combination with other QT prolonging drugs. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Artemether; lumefantrine is associated with QT prolongation and should be avoided in combination with other QT prolonging drugs. Consider ECG monitoring if other QT prolonging drugs must be used with or after artemether; lumefantrine treatment. In addition, lumefantrine is a CYP2D6 inhibitor and sertraline is a CYP2D6 substrate; therefore, coadministration may lead to increased sertraline concentrations.
    Asenapine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Asenapine has also been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect.
    Aspirin, ASA: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Major) Because of the potential risk and severity of serotonin syndrome and a potential for additive CNS effects, caution should be observed when coadministering drugs that have additive properties such as sertraline and dihydrocodeine. In addition, sertraline has the potential for clinically relevant CYP2D6 inhibition and may decrease the metabolism of dihydrocodeine to dihydromorphine, increasing the risk of dihydrocodeine-related adverse effects such as CNS or respiratory depression. Inhibition of CYP2D6 by sertraline may also result in reduced effectiveness of dihydrocodeine by inhibiting the conversion of dihydrocodeine to dihydromorphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue the serotonergic agents, and institute appropriate treatment. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Carisoprodol: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Carisoprodol; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Omeprazole: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Oxycodone: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Aspirin, ASA; Pravastatin: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Atazanavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Atenolol; Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Atomoxetine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. In addition, because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as sertraline may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation) if coadministration is necessary.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of sertraline, treatment initiation with sertraline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than sertraline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving sertraline and requiring urgent treatment with IV methylene blue, sertraline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Sertraline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
    Azilsartan; Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Azithromycin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation and TdP have been spontaneously reported during azithromycin postmarketing surveillance.
    Barbiturates: (Moderate) Sertraline is a substrate for CYP3A4 and CYP2C19. Drugs that induce hepatic isoenzymes, such as barbiturates could decrease sertraline plasma concentrations, potentially causing decreased effectiveness of this SSRI.
    Bedaquiline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Bendroflumethiazide; Nadolol: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of sertraline, treatment initiation with sertraline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than sertraline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving sertraline and requiring urgent treatment with IV methylene blue, sertraline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Sertraline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
    Bepridil: (Severe) Bepridil inhibits the cardiac conduction system, and may slow conduction through the AV node, increasing the duration of the refractory refractory period of the action potential. Bepridil administration has Class I antiarrhythmic properties and is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Patients receiving other drugs which have the potential for QT prolongation have an increased risk of developing proarrhythmias during bepridil therapy. There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, the manufacturer advises caution when using sertraline in patients with risk factors for QT prolongation, including use of other drugs that prolong the QTc interval. Because of the potential for TdP, use of bepridil with sertraline is considered contraindicated.
    Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and selective serotonin reuptake inhibitors (SSRIs) are used concomitantly. Coadministration of betrixaban and SSRIs may increase the risk of bleeding.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Potential QT prolongation has been reported in limited case reports with metronidazole. In addition, medications with alcohol content, such as sertraline oral solution, should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of sertraline contain a high-percentage of alcohol and although infrequent, may cause disulfiram-like reactions in patients taking metronidazole concurrently.
    Bismuth Subsalicylate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Potential QT prolongation has been reported in limited case reports with metronidazole. In addition, medications with alcohol content, such as sertraline oral solution, should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of sertraline contain a high-percentage of alcohol and although infrequent, may cause disulfiram-like reactions in patients taking metronidazole concurrently. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Bosentan: (Moderate) Sertraline is a substrate for CYP3A4 and CYP2C19. Drugs that induce these hepatic isoenzymes, such as bosentan, could decrease sertraline concentrations, potentially causing decreased effectiveness of this SSRI. Case reports have described the appearance of antidepressant discontinuation symptoms when sertraline was combined with certain inducers. Monitor for a reduced antidepressant or mood effect or antidepressant discontinuation symptoms
    Bretylium: (Severe) The use of bretylium in conjunction with drugs associated with QT prolongation should be used with extreme caution due to the potential risk for ventricular tachycardia, including torsade de pointes (TdP); in most cases, the co-use of such agents would be considered contraindicated. There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, the manufacturer advises caution when using sertraline in patients with risk factors for QT prolongation.
    Brexpiprazole: (Moderate) Because brexpiprazole is partially metabolized by CYP2D6, increased brexpiprazole plasma concentrations may occur during concurrent use of inhibitors of CYP2D6. Sertraline is generally considered a weak inhibitor of CYP2D6, but has the potential for clinically important interactions with CYP2D6 substrates, particularly those with a narrow therapeutic index. Decreased metabolism of brexpiprazole may lead to clinically important adverse reactions such as sedation or extrapyramidal symptoms.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Brompheniramine; Guaifenesin; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Budesonide; Formoterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Bumetanide: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Buprenorphine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue all serotonergic agents if serotonin syndrome occurs.
    Buprenorphine; Naloxone: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Buprenorphine has been associated with QT prolongation and has a possible risk of TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with any drug that has the potential to prolong the QT interval. In addition, concurrent use of opioids with other drugs that modulate serotonergic function, such as SSRIs, has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue all serotonergic agents if serotonin syndrome occurs.
    Bupropion: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including sertraline. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that sertraline inhibits the hydroxylation of bupropion.
    Bupropion; Naltrexone: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including sertraline. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that sertraline inhibits the hydroxylation of bupropion.
    Buspirone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as buspirone and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Cabergoline: (Moderate) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as cabergoline. Patients receiving cabergoline with an SSRI should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Caffeine; Ergotamine: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Cangrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymosis, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cangrelor). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Capecitabine: (Moderate) Use caution if coadministration of capecitabine with sertraline is necessary, and monitor for an increase in sertraline-related adverse reactions. Sertraline is a CYP2C9 substrate in vitro; capecitabine and/or its metabolites are thought to be inhibitors of CYP2C9. In a drug interaction study, the mean AUC of another CYP2C9 substrate, S-warfarin (single dose), significantly increased after coadministration with capecitabine; the maximum observed INR value also increased by 91%.
    Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Carbamazepine: (Moderate) Sertraline is a substrate for CYP3A4 and CYP2C19. Drugs that induce hepatic isoenzymes, such as carbamazepine could decrease sertraline plasma concentrations, potentially causing decreased effectiveness of sertraline.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Ceritinib: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Ceritinib causes concentration-dependent prolongation of the QT interval. If concurrent use is required, conduct periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients taking medications known to prolong the QTc interval. Hold ceritinib therapy in patients who develop a QTc greater than 500 milliseconds on at least 2 separate ECGs; additionally, a ceritinib dosage adjustment and/or therapy discontinuation may be necessary. Permanently discontinue ceritinib therapy in patients who develop QT prolongation with TdP, polymorphic ventricular tachycardia, or other serious arrhythmias.
    Cevimeline: (Moderate) Cevimeline is metabolized by cytochrome P450 3A4 and CYP2D6. Inhibitors of either of these isoenzymes, such as the SSRIs, would be expected to lead to an increase in cevimeline plasma concentrations.
    Chloroquine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Chloroquine is associated with an increased risk of QT prolongation and TdP; fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses.
    Chlorothiazide: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Chlorpheniramine; Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Chlorpheniramine; Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome and a potential for additive CNS effects, caution should be observed when coadministering drugs that have additive properties such as sertraline and dihydrocodeine. In addition, sertraline has the potential for clinically relevant CYP2D6 inhibition and may decrease the metabolism of dihydrocodeine to dihydromorphine, increasing the risk of dihydrocodeine-related adverse effects such as CNS or respiratory depression. Inhibition of CYP2D6 by sertraline may also result in reduced effectiveness of dihydrocodeine by inhibiting the conversion of dihydrocodeine to dihydromorphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue the serotonergic agents, and institute appropriate treatment.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome and a potential for additive CNS effects, caution should be observed when coadministering drugs that have additive properties such as sertraline and dihydrocodeine. In addition, sertraline has the potential for clinically relevant CYP2D6 inhibition and may decrease the metabolism of dihydrocodeine to dihydromorphine, increasing the risk of dihydrocodeine-related adverse effects such as CNS or respiratory depression. Inhibition of CYP2D6 by sertraline may also result in reduced effectiveness of dihydrocodeine by inhibiting the conversion of dihydrocodeine to dihydromorphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue the serotonergic agents, and institute appropriate treatment.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Chlorpheniramine; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Chlorpromazine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Chlorpromazine, a phenothiazine, is associated with an established risk of QT prolongation and TdP. In addition, sertraline is a CYP2D6 inhibitor and chlorpromazine is a CYP2D6 substrate. Decreased metabolism of chlorpromazine may lead to adverse effects such as arrhythmias, orthostatic hypotension, excessive sedation, or extrapyramidal symptoms.
    Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Chlorthalidone; Clonidine: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Choline Salicylate; Magnesium Salicylate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Cilostazol: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Ciprofloxacin: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance.
    Cisapride: (Severe) Coadministration of sertraline and cisapride is contraindicated due to the risk of QT prolongation. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. There have been postmarketing reports of QT prolongation and torsade de pointes TdP during treatment with sertraline.
    Citalopram: (Severe) Due to the similarity in pharmacology of sertraline and citalopram and the potential for serious adverse reactions, including serotonin syndrome, QT prolongation, and torsade de pointes (TdP), these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both sertraline and citalopram have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Clarithromycin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Clarithromycin is associated with an established risk for QT prolongation and TdP.
    Class IC Antiarrhythmics: (Major) Because both sertraline and Class IC Antiarrhythmics are associated with a possible risk of QT prolongation and Torsade de Pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, sertraline is a mild to moderate inhibitor of CYP2D6, and inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including flecainide and propafenone.
    Clomipramine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Clopidogrel: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving clopidogrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Clozapine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Treatment with clozapine has been associated with QT prolongation, TdP, cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. In addition, concurrent use of clozapine, a CYP2D6 substrate, with a CYP2D6 inhibitor, such as sertraline, can increase clozapine plasma concentrations and lead to adverse effects, such as seizures or orthostatic hypotension. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of sertraline. A case denoting sudden cardiac death has been described in the literature when clozapine was combined with sertraline, but causality was not established.
    Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Cocaine: (Major) Concomitant use of cocaine with drugs that have CNS serotonergic properties, such as SSRIs, could potentiate serotonin neurotransmission, and result in the serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions. Additionally, citalopram causes dose-dependent QT interval prolongation. Local anesthetics (e.g., cocaine) are associated with a possible risk for QT prolongation and according to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Codeine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Codeine; Guaifenesin: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Codeine; Phenylephrine; Promethazine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, sertraline is a CYP2D6 inhibitor and might increase promethazine concentrations, leading to sedation or other antihistaminic side effects.
    Codeine; Promethazine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and sertraline because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of sertraline could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If sertraline is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, sertraline is a CYP2D6 inhibitor and might increase promethazine concentrations, leading to sedation or other antihistaminic side effects.
    Conivaptan: (Major) Avoid coadministration of conivaptan, a CYP3A4/P-glycoprotein (P-gp) inhibitor and sertraline, a CYP3A4 substrate. Concurrent use may result in increased serum concentrations of sertraline. According to the manufacturer of conivaptan, concomitant use of conivaptan and CYP3A substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with sertraline.
    Crizotinib: (Major) Avoid coadministration of crizotinib with sertraline due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. There have also been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Cyclobenzaprine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of cyclobenzaprine with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
    Cyclosporine: (Moderate) Although a causal relationship has not been established, the combination of cyclosporine and sertraline is suspected of causing serotonin syndrome in a renal transplant patient. Sertraline serum concentrations may have increased due to possible CYP3A4 inhibition by cyclosporine.
    Cyproheptadine: (Moderate) Cyproheptadine is a serotonin antagonist in the CNS and can oppose the pharmacologic actions of selective serotonin reuptake inhibitors (SSRIs). Cyproheptadine has been used for the management of orgasm dysfunction caused by the SSRIs and for the adjunctive treatment of SSRI overdose (i.e., serotonin syndrome) in emergency situations; however, a reversal of antidepressant effects may occur when cyproheptadine is given in a routine manner along with the SSRIs due to the serotonin antagonistic effects of cyproheptadine. Cyproheptadine reportedly has interfered with the antidepressant and anti-bulimia actions of fluoxetine but more data are needed to confirm a direct drug-drug interaction.
    Dabigatran: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Dalteparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Danaparoid: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like danaparoid. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Darifenacin: (Moderate) Sertraline, an inhibitor of CYP3A4, may decrease the metabolism of darifenacin and increase serum concentrations. Patients should be monitored for increased anticholinergic effects if these drugs are used concomitantly; dosage adjustments of darifenacin may be necessary.
    Darunavir: (Moderate) Use caution when coadministering darunavir with sertraline, as decreased SSRI concentrations may be seen. If sertraline is coadministered with darunavir, carefully titrate the dose of sertraline based on a clinical assessment of antidepressant response.
    Darunavir; Cobicistat: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Moderate) Use caution when coadministering darunavir with sertraline, as decreased SSRI concentrations may be seen. If sertraline is coadministered with darunavir, carefully titrate the dose of sertraline based on a clinical assessment of antidepressant response.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Moderate) Use caution when coadministering darunavir with sertraline, as decreased SSRI concentrations may be seen. If sertraline is coadministered with darunavir, carefully titrate the dose of sertraline based on a clinical assessment of antidepressant response.
    Dasatinib: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. In vitro studies have shown that dasatinib has the potential to prolong the QT interval. Caution is advised if coadministration is required.
    Degarelix: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QTc prolongation has been reported with the use of degarelix.
    Delavirdine: (Moderate) Delavirdine is a potent inhibitor of cytochrome P450 2D6 and 3A4 and might decrease sertraline metabolism leading to increased adverse reactions.
    Desflurane: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Halogenated anesthetics can prolong the QT interval.
    Desipramine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Desmopressin: (Major) Additive hyponatremic effects may be seen in patients treated with desmopressin and drugs associated with water intoxication, hyponatremia, or SIADH including SSRIs. Use combination with caution, and monitor patients for signs and symptoms of hyponatremia.
    Desvenlafaxine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors like desvenlafaxine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Discontinuation symptoms have been reported when switching from other antidepressants to desvenlafaxine. It may be advisable to taper the previous antidepressant to minimize discontinuation symptoms.
    Deutetrabenazine: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Clinically relevant QTc prolongation may occur with deutetrabenazine. For patients taking a deutetrabenazine dosage more than 24 mg/day and other medications known to prolong the QTc interval, assess the QTc interval before and after increasing the deutetrabenazine dosage or other medications that prolong the QTc interval.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dexmethylphenidate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dexmethylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate, a racemic compound containing dexmethylphenidate. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Dextromethorphan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Dextromethorphan; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, sertraline is a CYP2D6 inhibitor and might increase promethazine concentrations, leading to sedation or other antihistaminic side effects.
    Dextromethorphan; Quinidine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as dextromethorphan and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. (Major) The manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Quinidine also inhibits CYP2D6; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6. Sertraline is partially metabolized by CYP2D6; however, because sertraline is metabolized by various CYP450 enzymes, inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Because of the potential risk and severity of serotonin syndrome and a potential for additive CNS effects, caution should be observed when coadministering drugs that have additive properties such as sertraline and dihydrocodeine. In addition, sertraline has the potential for clinically relevant CYP2D6 inhibition and may decrease the metabolism of dihydrocodeine to dihydromorphine, increasing the risk of dihydrocodeine-related adverse effects such as CNS or respiratory depression. Inhibition of CYP2D6 by sertraline may also result in reduced effectiveness of dihydrocodeine by inhibiting the conversion of dihydrocodeine to dihydromorphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue the serotonergic agents, and institute appropriate treatment.
    Dihydroergotamine: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Disopyramide: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Disopyramide has been associated with QT prolongation and TdP.
    Disulfiram: (Major) The ingestion of ethanol by patients receiving disulfiram causes an extremely unpleasant reaction that can last from 30 minutes to several hours. Oral sertraline solution contains a high percentage of alcohol (12%) and should not be co-administered with disulfiram. A disulfiram-like reaction is not expected with formulations of sertraline that do not contain alcohol.
    Diuretics: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Dofetilide: (Severe) Because of the potential for torsade de pointes (TdP), use of sertraline with dofetilide is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Dolasetron: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. In addition, taking these drugs together may increase the risk for serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If concurrent use is required and serotonin syndrome occurs, discontinue all serotonergic agents and initiate appropriate medical treatment.
    Dolutegravir; Rilpivirine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; additive effects may occur when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Donepezil: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Donepezil; Memantine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Doxepin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Doxercalciferol: (Moderate) Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including selective serotonin reuptake inhibitors (SSRIs), may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if SSRIs are coadministered with doxercalciferol.
    Dronedarone: (Severe) The concomitant use of dronedarone with other drugs that prolong the QTc may induce torsade de pointes (TdP) and is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Droperidol: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Droperidol administration is associated with an established risk for QT prolongation and TdP. Droperidol should not be used in combination with any drug known to have potential to prolong the QT interval, such as sertraline. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal.
    Duloxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should generally not be administered with serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, desvenlafaxine, duloxetine, and milnacipran. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as sertraline. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Edoxaban: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with edoxaban; however, the absolute risk is not known. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Efavirenz: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation has been observed with use of efavirenz. Also, sertraline is a substrate of CYP2C9, CYP2C19, and CYP3A4; efavirenz is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Coadministration results in decreased sertraline Cmax (29%), AUC (39%), and Cmin (46%).
    Efavirenz; Emtricitabine; Tenofovir: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation has been observed with use of efavirenz. Also, sertraline is a substrate of CYP2C9, CYP2C19, and CYP3A4; efavirenz is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Coadministration results in decreased sertraline Cmax (29%), AUC (39%), and Cmin (46%).
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation has been observed with use of efavirenz. Also, sertraline is a substrate of CYP2C9, CYP2C19, and CYP3A4; efavirenz is an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. Coadministration results in decreased sertraline Cmax (29%), AUC (39%), and Cmin (46%).
    Elbasvir; Grazoprevir: (Moderate) Administering sertraline with elbasvir; grazoprevir may result in elevated sertraline plasma concentrations. Sertraline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., eletriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Eliglustat: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; additive effects may occur when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; additive effects may occur when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Encorafenib: (Major) Avoid coadministration of encorafenib and sertraline due to the potential for additive QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Enflurane: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Halogenated anesthetics can prolong the QT interval.
    Enoxaparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Eptifibatide: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Ergoloid Mesylates: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Ergonovine: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Ergot alkaloids: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Ergotamine: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Eribulin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT prolongation.
    Erythromycin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Erythromycin is associated with QT prolongation and TdP.
    Erythromycin; Sulfisoxazole: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Erythromycin is associated with QT prolongation and TdP.
    Escitalopram: (Severe) Due to the similarity in pharmacology of sertraline and escitalopram and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both sertraline and escitalopram have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Esomeprazole: (Moderate) In one study using a small number of subjects taking sertraline relative to the other SSRIs studied, sertraline concentrations were increased by approximately 38.5% during coadministration with esomeprazole, a CYP2C19 inhibitor. However, the clinical significance of the interaction is not proven, as sertraline is metabolized by multiple CYP enzymes, not just CYP2C19, and inhibition by one pathway does not usually influence sertraline pharmacokinetics.
    Esomeprazole; Naproxen: (Moderate) In one study using a small number of subjects taking sertraline relative to the other SSRIs studied, sertraline concentrations were increased by approximately 38.5% during coadministration with esomeprazole, a CYP2C19 inhibitor. However, the clinical significance of the interaction is not proven, as sertraline is metabolized by multiple CYP enzymes, not just CYP2C19, and inhibition by one pathway does not usually influence sertraline pharmacokinetics.
    Ethacrynic Acid: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Ezogabine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Ezogabine has been associated with QT prolongation. The manufacturer of ezogabine recommends caution during concurrent use of medications known to increase the QT interval.
    Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as sertraline, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of sertraline during coadministration with fenofibric acid.
    Fentanyl: (Major) Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as fentanyl. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
    Fingolimod: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of TdP. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Fluconazole: (Major) The manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Fluconazole is an azole antifungal that has a possible risk of QT prolongation. Postmarketing reports indicate that sertraline has a possible risk of QT prolongation and torsade de pointes (TdP). Fluconazole is a moderate CYP3A4 inhibitor and sertraline is a partial CYP3A4 substrate, However, sertraline is metabolized by various CYP450 enzymes, and inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations.
    Fluoxetine: (Severe) Due to the similarity in pharmacology of fluoxetine and sertraline and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both fluoxetine and sertraline have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Fluoxetine; Olanzapine: (Severe) Due to the similarity in pharmacology of fluoxetine and sertraline and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both fluoxetine and sertraline have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI. (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Minor) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Fluphenazine is associated with a possible risk of QT prolongation. In addition, CYP2D6 substrates such as fluphenazine may require lower doses during concurrent use with sertraline, due to CYP2D6 inhibition by sertraline and the potential for arrhythmias or other adverse reactions associated with antipsychotics such as extrapyramidal symptoms.
    Fluticasone; Salmeterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Fluvoxamine: (Severe) Due to the similarity in pharmacology of sertraline and fluvoxamine and the potential for serious adverse reactions, including serotonin syndrome, these selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Also, both sertraline and fluvoxamine have been associated with QT prolongation and torsade de pointes (TdP), which could theoretically result in additive effects on the QT interval. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Fondaparinux: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like fondaparinux. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Formoterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Foscarnet: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Both QT prolongation and TdP have been reported during postmarketing use of foscarnet. Because of these reports, avoid the use of foscarnet with other drugs known to prolong the QT interval. If these drugs must be coadministered, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Fosphenytoin: (Moderate) Monitor phenytoin levels when initiating or titrating sertraline; a reduction in the fosphenytoin dose may be necessary. Clinical trial data suggest that sertraline increases the plasma concentration of phenytoin.
    Frovatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., frovatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Furosemide: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Gemifloxacin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Gemifloxacin may prolong the QT interval in some patients.The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. If these agents must be coadministered, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment.
    Gilteritinib: (Major) Avoid coadministration of sertraline with gilteritinib if possible due to the potential for decreased response to sertraline. Gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like sertraline that target these receptors.
    Glasdegib: (Major) Avoid coadministration of glasdegib with sertraline due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Glycopyrrolate; Formoterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Goserelin: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Granisetron: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Granisetron has been associated with QT prolongation. In addition, taking these drugs together may increase the risk for serotinin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue serotonergic agents and initiate appropriate medical treatment.
    Grapefruit juice: (Minor) Advise patients to not significantly alter their intake of grapefruit juice while taking sertraline until more data are available. Grapefruit juice has been reported to inhibit the metabolism of sertraline, elevating sertraline trough concentrations. It is not clear if the interaction is clinically significant for patients. The theorized mechanism is the inhibition of sertraline metabolism via CYP3A4; however, sertraline is known to be metabolized by many CYP enzymes, and inhibition of one enzyme is not likely to significantly affect sertraline pharmacokinetics.
    Guaifenesin; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Halogenated Anesthetics: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Halogenated anesthetics can prolong the QT interval.
    Haloperidol: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation and TdP have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. According to the manufacturer of haloperidol, caution is advisable when prescribing the drug concurrently with medications known to prolong the QT interval. In addition, sertraline is a CYP2D6 inhibitor and pharmacokinetic interactions are possible with CYP2D6 substrates including haloperidol.
    Halothane: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Halogenated anesthetics can prolong the QT interval.
    Heparin: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Histrelin: (Moderate) Consider periodic monitoring of EGCs for QT prolongation and monitor electrolytes if coadministration of histrelin and sertraline is necessary; correct any electrolyte abnormalities. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline. Androgen deprivation therapy (e.g., histrelin) also prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Homatropine; Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Hydrocodone: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Ibuprofen: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Phenylephrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydrocodone; Pseudoephedrine: (Major) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and sertraline because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. Concomitant use of hydrocodone with sertraline may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of sertraline could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If sertraline is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Sertraline is a weak inhibitor of CYP2D6. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Hydroxychloroquine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Hydroxychloroquine prolongs the QT interval and should not be administered with other drugs known to prolong the QT interval.
    Hydroxyzine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) According to the manufacturer of sertraline, treatment initiation with sertraline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than sertraline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving sertraline and requiring urgent treatment with IV methylene blue, sertraline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Sertraline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin.
    Ibuprofen; Oxycodone: (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Ibutilide: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Ibutilide administration can cause QT prolongation and TdP; proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with sertraline, a CYP3A substrate, as sertraline toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Iloperidone has been associated with QT prolongation and the manufacturer of iloperidone recommends avoiding concurrent use of other agents also known to have this effect.
    Imatinib: (Major) Sertraline is a substrate for the CYP isoenzymes 3A4, 2D6 and 2C19. Imatinib is a potent inhibitor of cytochrome P450 2D6 and 3A4 and might decrease sertraline metabolism leading to increased adverse reactions.
    Imipramine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Indacaterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Indapamide: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with sertraline due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Inotuzumab has been associated with QT prolongation. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment.
    Isocarboxazid: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Isoflurane: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Halogenated anesthetics can prolong the QT interval.
    Isoniazid, INH: (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Coadministration may result in a decrease in sertraline plasma concentrations, potentially decreasing the effectiveness of sertraline or causing antidepressant discontinuation symptoms. Sertraline is a substrate of CYP3A4 and CYP2C19. Rifampin is a potent CYP3A4 inducer, and also induces CYP2C19. Case reports have described a reduced antidepressant effect or antidepressant discontinuation symptoms when sertraline was combined with certain inducers, including rifampin. (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome.
    Isoniazid, INH; Rifampin: (Major) Coadministration may result in a decrease in sertraline plasma concentrations, potentially decreasing the effectiveness of sertraline or causing antidepressant discontinuation symptoms. Sertraline is a substrate of CYP3A4 and CYP2C19. Rifampin is a potent CYP3A4 inducer, and also induces CYP2C19. Case reports have described a reduced antidepressant effect or antidepressant discontinuation symptoms when sertraline was combined with certain inducers, including rifampin. (Major) Concurrent use of isoniazid and selective serotonin reuptake inhibitors (SSRIs) should be avoided if possible. Isoniazid is chemically related to iproniazid, a drug that was known to possess MAO inhibiting activity. Although isoniazid does not inhibit mitochondrial MAO, it does appear to inhibit plasma MAO. Isoniazid may possess enough MAO inhibiting activity to produce clinical symptoms consistent with serotonergic excess when combined with SSRIs. Concurrent use of SSRIs and MAOIs may lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome.
    Itraconazole: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Itraconazole has been associated with QT prolongation. Itraconazole is a potent CYP3A4 inhibitor and sertraline is a partial CYP3A4 substrate. However, sertraline is metabolized by various CYP450 enzymes, and inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations.
    Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sertraline. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sertraline is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sertraline, can theoretically increase sertraline exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with sertraline due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Kava Kava, Piper methysticum: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including SSRIs, may interact with the phytomedicinal kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Ketoconazole: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Ketoconazole has been associated with QT prolongation. Ketoconazole is a potent CYP3A4 inhibitor and sertraline is a partial CYP3A4 substratre. However, sertraline is metabolized by various CYP450 enzymes, and inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations.
    Lapatinib: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and TdP have been reported in postmarketing experience. Correct hypokalemia or hypomagnesemia prior to lapatinib administration. Consider ECG and electrolyte monitoring if concurrent use is required.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with sertraline due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Leuprolide: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levofloxacin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing use of levofloxacin.
    Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of levomilnacipran with other drugs that have serotonergic properties, such as selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, levomilnacipran and concurrent serotonergic agents should be discontinued.
    Linezolid: (Severe) According to the manufacturer of sertraline, treatment initiation with sertraline is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than sertraline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving sertraline and requiring urgent treatment with linezolid, sertraline should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid, whichever comes first. Sertraline may be re-initiated 24 hours after the last dose of linezolid. Linezolid is an antibiotic that is also a non-selective monoamine oxidase (MAO) inhibitor. Since monoamine oxidase type A deaminates serotonin, administration of a non-selective MAO inhibitor concurrently with sertraline can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid.
    Lithium: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has been associated with QT prolongation. In addition, lithium has been reported to have central serotonin-enhancing effects and may interact pharmacodynamically with selective serotonin reuptake inhibitors (SSRIs) such as sertraline to cause serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients should be informed of the possible increased risk of serotonin syndrome. If serotonin syndrome occurs, sertraline and lithium should be discontinued and symptomatic treatment should be initiated. One systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression found no difference in discontinuation rate due to adverse events between the lithium and placebo groups. However, there are case reports of neurotoxicity (e.g., confusion, ataxia) as well as fever and seizures when SSRIs have been used with lithium. Neurotoxicity may be more likely to occur in the elderly.
    Lofexidine: (Moderate) Monitor the ECG for QT prolongation during concurrent use of lofexidine and sertraline. Lofexidine may prolong the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. QT prolongation and torsade de pointes have been reported in postmarketing surveillance of sertraline.
    Long-acting beta-agonists: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Loperamide: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with sertraline, a CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS depression.
    Loperamide; Simethicone: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. In addition, the plasma concentrations of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with sertraline, a CYP2D6 inhibitor, further increasing the risk of toxicity. If these drugs are used together, monitor for cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, TdP, cardiac arrest) and other loperamide-associated adverse reactions, such as CNS depression.
    Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, selective serotonin reuptake inhibitors (SSRIs). Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
    Low Molecular Weight Heparins: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of sertraline by decreasing its systemic exposure. If used together, a higher dose of sertraline may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dose. In vitro, sertraline is a substrate of CYP2C19, CYP3A4, CYP2C9, CYP2D6, and CYP2B6. Lumacaftor; ivacaftor is a strong inducer of CYP3A. In vitro studies suggest lumacaftor has the potential to induce CYP2C19, CYP2C9, and CYP2B6; inhibition of CYP2C9 has also been observed. (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sertraline. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sertraline is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sertraline, can theoretically increase sertraline exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of sertraline by decreasing its systemic exposure. If used together, a higher dose of sertraline may be required to obtain the desired therapeutic effect. Do not exceed the recommended maximum dose. In vitro, sertraline is a substrate of CYP2C19, CYP3A4, CYP2C9, CYP2D6, and CYP2B6. Lumacaftor; ivacaftor is a strong inducer of CYP3A. In vitro studies suggest lumacaftor has the potential to induce CYP2C19, CYP2C9, and CYP2B6; inhibition of CYP2C9 has also been observed.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as sertraline. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Magnesium Salicylate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Maprotiline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with elevated serum concentrations. Cases of long QT syndrome and TdP have been described with maprotiline use, but rarely occur when the drug is used alone in usually prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mefloquine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval.
    Meperidine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. A 42-year-old man became agitated, restless, diaphoretic, tachycardic, and hypertensive immediately after receipt of meperidine 50 mg intravenously. Two weeks before the incident, the patient had stopped a regimen of the SSRI, fluoxetine. Serotonin syndrome was suspected, as fluoxetine and norfluoxetine have long half-lives, and previous meperidine receipt during a time when the patient had not been taking fluoxetine was uneventful. If serotonin syndrome is suspected, the SSRI and concurrent serotonergic agents should be discontinued.
    Meperidine; Promethazine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as meperidine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. A 42-year-old man became agitated, restless, diaphoretic, tachycardic, and hypertensive immediately after receipt of meperidine 50 mg intravenously. Two weeks before the incident, the patient had stopped a regimen of the SSRI, fluoxetine. Serotonin syndrome was suspected, as fluoxetine and norfluoxetine have long half-lives, and previous meperidine receipt during a time when the patient had not been taking fluoxetine was uneventful. If serotonin syndrome is suspected, the SSRI and concurrent serotonergic agents should be discontinued. (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, sertraline is a CYP2D6 inhibitor and might increase promethazine concentrations, leading to sedation or other antihistaminic side effects.
    Mesoridazine: (Severe) Mesoridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Mesoridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, such as sertraline. In addition, many phenothiazines are CYP2D6 substrates and use with a CYP2D6 inhibitor such as sertraline may increase systemic exposure to the phenothiazine, leading to an increased potential for arrhythmias.
    Methadone: (Major) Coadministration should be avoided if possible to due the potential risk of serotonin syndrome, QT prolongation or torsade de pointes (TdP), or opioid-related side effects. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. The need to coadminister methadone with drugs known to prolong the QT interval should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is associated with an increased risk for QT prolongation and TdP, especially at higher doses (greater than 200 mg/day but averaging approximately 400 mg/day in adult patients). Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. In addition, both sertraline and methadone have central serotonergic properties and serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Lastly, sertraline is a CYP2D6 inhibitor and methadone is partially metabolized by CYP2D6, which may increase the risk of CNS depressive effects, respiratory depression, QT prolongation, or other adverse effects.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) According to the manufacturer of sertraline, treatment initiation with sertraline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than sertraline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving sertraline and requiring urgent treatment with IV methylene blue, sertraline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Sertraline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
    Methyclothiazide: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Methylene Blue: (Severe) According to the manufacturer of sertraline, treatment initiation with sertraline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than sertraline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving sertraline and requiring urgent treatment with IV methylene blue, sertraline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Sertraline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin; therefore, concurrent use of an MAO-A inhibitor with a serotonergic agent may result in a clinically significant interaction. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving SSRIs, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. One case describes a patient receiving citalopram who experienced agitation, restlessness, pupil dilation with sluggish response to light, myoclonic movements of the lower limbs, and brisk reflexes following an infusion of methylene blue, while another patient receiving paroxetine developed tachycardia, agitation, dystonia and abnormal eye movements. During a retrospective study of 193 surgical patients who had received a methylene blue injection, it was found that all 12 of the patients who experienced postoperative neurological sequelae had been taking a serotonin reuptake inhibitor preoperatively. One of the 12 patients experienced cardiopulmonary arrest and died. Of the remaining 181 patients who did not experience neurological sequelae, 8.8% were taking a serotonin reuptake inhibitor. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
    Methylergonovine: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Methylphenidate: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as methylphenidate and selective serotonin reuptake inhibitors (SSRIs). There are rare reports of serotonin syndrome occurring during use of an SSRI and methylphenidate. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving this combination should be monitored for the emergence of serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical management should be implemented.
    Methysergide: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Metoclopramide: (Major) A few published case reports have documented possible interactions between metoclopramide and SSRIs that have resulted in either serotonin syndrome-type events and/or movement disorders (e.g., dystonia). The mechanism of the interactions is unknown but is thought to be a pharmacodynamic interaction; the interactions do not appear common. In most of the cases reported, a single drug effect was not ruled out; however, the time course of the events are enough to raise suspicion that a drug interaction might be possible. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving sertraline and metoclopramide should be monitored for the emergence of serotonin syndrome or other adverse effects.
    Metolazone: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Metronidazole: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Potential QT prolongation has been reported in limited case reports with metronidazole. In addition, medications with alcohol content, such as sertraline oral solution, should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of sertraline contain a high-percentage of alcohol and although infrequent, may cause disulfiram-like reactions in patients taking metronidazole concurrently.
    Mexiletine: (Moderate) Some SSRIs may interact with certain antiarrhythmics. Sertraline is a mild to moderate inhibitor of CYP2D6. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including encainide and mexiletine. Clinical data are not always available to document interactions. Increased plasma concentrations may increase the risk of proarrhythmia.
    Midostaurin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation was reported in patients who received midostaurin in clinical trials. Consider obtaining electrocardiograms to monitor the QT interval if coadministration is required.
    Mifepristone: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Mifepristone is associated with dose-dependent prolongation of the QT interval; to minimize the risk of QT prolongation, the lowest effective dose should always be used.
    Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of milnacipran with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as sertraline may be increased when co-administered with mirabegron. Sertraline has been shown to be a CYP2D6 substrate and a mild to moderate inhibitor of CYP2D6 in vitro. Mirabegron exposure may also increase. Appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) Concomitant use of mirtazapine and sertraline may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during use of mirtazapine, primarily after overdose or in patients with risk factors for QT prolongation (e.g., concurrent use of other medications associated with QT prolongation). Both mirtazapine and sertraline have central serotonin-enhancing effects, and case reports suggest that serotonin syndrome is possible. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Mitotane: (Moderate) Use caution if mitotane and sertraline are used concomitantly, and monitor for decreased efficacy of sertraline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and sertraline is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of sertraline.
    Modafinil: (Moderate) Dose adjustments of sertraline, a substrate for CYP2C19, may be necessary when used concomitantly with modafinil. Elimination of sertraline may be prolonged by modafinil via inhibition of CYP2C19, with resultant higher systemic exposure. Monitor for adverse effects, such as serotonin excess, and reduce the sertraline dosage if needed.
    Monoamine oxidase inhibitors: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as sertraline, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and sertraline should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when administering selective serotonin reuptake inhibitors (SSRIs), such as sertraline, with other drugs that have serotonergic properties such as morphine. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and sertraline should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Moxifloxacin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of moxifloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Naproxen; Sumatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Naratriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., naratriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with sertraline. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as sertraline, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with sertraline. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as sertraline, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nefazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as nefazodone and sertraline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least one case report of serotonin syndrome from the concurrent use of nefazodone and a selective serotonin reuptake inhibitor (i.e., paroxetine) has been published. Additionally, when a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient serotonin-related adverse events. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Netupitant, Fosnetupitant; Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as sertraline. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Nevirapine: (Moderate) Nevirapine is an inducer of the cytochrome P4503A enzyme. Concomitant administration of nevirapine with drugs that are extensively metabolized by this enzyme, such as sertraline, may require dosage adjustments.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib and sertraline; significant prolongation of the QT interval may occur. Sudden death and QT prolongation have occurred in patients who received nilotinib therapy. QT prolongation and torsade de pointes have been reported in postmarketing surveillance of sertraline.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
    Nonsteroidal antiinflammatory drugs: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal antiinflammatory drugs (NSAIDs) may increase the risk of bleeding, including an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of NSAIDs. Additionally, NSAIDs impair the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in more than 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with NSAIDs, the risk was increased by more than 12.2-fold. The absolute risk of GI bleed from concomitant therapy with NSAIDs and a SSRI was low (17/4107 patients).
    Norfloxacin: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Quinolones have been associated with a risk of QT prolongation. Although extremely rare, TdP has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Major) Because both sertraline and tricyclic antidepressants are associated with a possible risk of QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sertraline with other drugs that have serotonergic properties such as tricyclic antidepressants. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Clinicians should also be alert for pharmacokinetic interactions between tricyclic antidepressants and SSRIs. Sertraline is a weak to moderate inhibitor of CYP2D6, the isozyme responsible for metabolism of many of the tricyclic antidepressants. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if an SSRI is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Octreotide: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for the development of TdP, the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval.
    Ofloxacin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Ondansetron: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of TdP. In addition, taking these drugs together may increase the risk for serotinin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, discontinue all serotonergic agents and initiate appropriate medical treatment.
    Oritavancin: (Moderate) Coadministration of oritavancin and sertraline may result in increases or decreases in sertraline exposure and may increase side effects or decrease efficacy of sertraline. Sertraline is metabolized by CYP3A4, CYP2D6, CYP2C9, and CYP2C19. Oritavancin weakly induces CYP3A4 and CYP2D6, while weakly inhibiting CYP2C9 and CYP2C19. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
    Osimertinib: (Major) Avoid coadministration of sertraline with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline.
    Oxaliplatin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation and ventricular arrhythmias including fatal TdP have been reported during postmarketing use of oxaliplatin. Monitor ECGs and electrolytes in patients receiving oxaliplatin concomitantly with other drugs known to prolong the QT interval; correct electrolyte abnormalities prior to administration of oxaliplatin.
    Oxycodone: (Moderate) The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue the suspected drugs if serotonin syndrome is suspected and manage cliinically. There has been a case report of possible serotonin syndrome caused by the combination of oxycodone and selective serotonin reuptake inhbitors (SSRIs).
    Paliperidone: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Paliperidone has been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer of paliperidone, the drug should be avoided in combination with other agents also known to have this effect. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Palonosetron: (Major) Because of the potential risk and severity of serotonin syndrome, use caution when administering palonosetron with other drugs that have serotonergic properties such as sertraline. If serotonin syndrome is suspected, discontinue palonosetron and concurrent serotonergic agents and initiate appropriate medical treatment. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Panobinostat: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation has been reported with panobinostat therapy; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to 480 milliseconds or higher during therapy; permanently discontinue if QT prolongation does not resolve.
    Paroxetine: (Severe) Due to the similarity in pharmacology of sertraline and paroxetine and the potential for serious adverse reactions, including serotonin syndrome, selective serotonin reuptake inhibitors (SSRIs) should not be administered together. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. In addition, because sertraline is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. It is advisable to monitor for signs and symptoms of serotonin syndrome during an overlapping transition from one SSRI to another SSRI.
    Pasireotide: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Pazopanib has been reported to prolong the QT interval. Coadministration of pazopanib and other drugs that prolong the QT interval is not advised. If concurrent use is required, closely monitor the patient for QT interval prolongation.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to sertraline if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while sertraline is partially metabolized by the CYP2D6 isoenzyme.
    Pentamidine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Systemic pentamidine has been associated with QT prolongation.
    Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy.
    Pentazocine; Naloxone: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy.
    Pentosan: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants, like pentosan. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Pergolide: (Moderate) Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., sertraline), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Perphenazine: (Minor) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Perphenazine is associated with a possible risk of QT prolongation. In addition, CYP2D6 substrates such as perphenazine may require lower doses during concurrent use with sertraline, due to CYP2D6 inhibition by sertraline and the potential for arrhythmias or other adverse reactions associated with antipsychotics such as extrapyramidal symptoms.
    Perphenazine; Amitriptyline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children. (Minor) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Perphenazine is associated with a possible risk of QT prolongation. In addition, CYP2D6 substrates such as perphenazine may require lower doses during concurrent use with sertraline, due to CYP2D6 inhibition by sertraline and the potential for arrhythmias or other adverse reactions associated with antipsychotics such as extrapyramidal symptoms.
    Phenelzine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Phentermine: (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like topiramate may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation. (Moderate) Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine's effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.
    Phenylephrine; Promethazine: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, sertraline is a CYP2D6 inhibitor and might increase promethazine concentrations, leading to sedation or other antihistaminic side effects.
    Phenytoin: (Moderate) Monitor phenytoin levels when initiating or titrating sertraline; a reduction in the phenytoin dose may be necessary. Clinical trial data suggest that sertraline increases the plasma concentration of phenytoin.
    Pimavanserin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval.
    Pimozide: (Severe) Pimozide is contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). Pimozide is thought to be primarily metabolized through CYP3A4, and to a lesser extent, CYP1A2 and CYP2D6. Elevated plasma concentrations of pimozide occurring through inhibition of one or more of these isoenzymes can lead to QT prolongation, ventricular arrhythmias, and sudden death. Concurrent use of pimozide and CYP3A4 inhibitors or potent CYP2D6 inhibitors is contraindicated by the manufacturer of pimozide. Because citalopram is associated with a dose-dependent QT prolongation and pimozide has an established association with QT prolongation and torsade de pointes (TdP), concurrent use of pimozide and citalopram is contraindicated. In a controlled study, the mean QTc values increased about 10 msec in the group receiving a combination of a single dose of pimozide 2 mg and citalopram 40 mg daily for 11 days compared to the pimozide monotherapy group. The mean AUC and Cmax of pimozide were not altered. Concurrent use of pimozide with fluvoxamine, a CYP1A2 and CYP3A4 inhibitor, or fluoxetine, a CYP2D6 and CYP3A4 inhibitor, may result in elevated pimozide concentrations. Sertraline, a CYP2D6 inhibitor, has been noted to increase the AUC of pimozide by roughly 40%. Paroxetine, a potent CYP2D6 inhibitor, has been associated with mean increases in pimozide AUC of 151% and increases in pimozide Cmax of 62%. The modest CYP2D6 inhibitory effects of escitalopram may result in increased concentrations of drugs metabolized via the same pathway such as pimozide.
    Posaconazole: (Major) The manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Concurrent use of posaconazole with sertraline may cause an increased risk for QT prolongation. Posaconazole is an azole antifungal that has a risk of QT prolongation. Postmarketing reports indicate that sertraline has a possible risk of QT prolongation and torsade de pointes (TdP). Posaconazole is a potent CYP3A4 inhibitor and sertraline is a partial CYP3A4 substrate, However, sertraline is metabolized by various CYP450 enzymes, and inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations.
    Prasugrel: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Primaquine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Primaquine has the potential for QT interval prolongation.
    Procainamide: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Procainamide is associated with a well-established risk of QT prolongation and TdP.
    Procarbazine: (Major) Procarbazine is a weak monoamine oxidase inhibitor (MAOI). Although procarbazine appears to be less likely than other MAOIs to produce serious drug interactions, clinicians should avoid the use of selective serotonin reuptake inhibitors (SSRIs) in patients receiving MAOIs. Fatalities have been reported when fluoxetine was administered to patients receiving MAOIs. Confusion, seizures, severe hypertension, and other, less severe symptoms have also been reported with this drug combination. Non-selective MAOIs inhibit both MAO types A and B. Since serotonin is metabolized by MAO type A, it is thought that this drug interaction may lead to serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between the discontinuation of MAOI therapy and the start of therapy with an SSRI except fluoxetine. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and commencement of MAOI therapy. This 5-week period is needed because of the long half-lives of fluoxetine and its principle metabolite norfluoxetine.
    Prochlorperazine: (Minor) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, sertraline is a CYP2D6 inhibitor and might increase promethazine concentrations, leading to sedation or other antihistaminic side effects.
    Protriptyline: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Quetiapine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. According to the manufacturer, use of quetiapine should be avoided in combination with drugs known to increase the QT interval.
    Quinidine: (Major) The manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Quinidine administration is associated with QT prolongation and torsade de pointes (TdP). Quinidine also inhibits CYP2D6; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6. Sertraline is partially metabolized by CYP2D6; however, because sertraline is metabolized by various CYP450 enzymes, inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations.
    Quinine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Quinine has been associated with QT prolongation and rare cases of TdP. Avoid concurrent use of quinine with other drugs that may cause QT prolongation and TdP.
    Ranolazine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. In addition, sertraline and ranolazine are partially metabolized by CYP2D6 and both agents are inhibitors of CYP2D6. Increased plasma concentrations of either drug are possible, which may increase the risk of QT prolongation.
    Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including selective serotonin reuptake inhibitors (SSRIs). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During post-marketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any SSRI. Conversely, when discontinuing an SSRI, it is advisable to wait the length of 4 to 5 half-lives of the individual agent being discontinued prior to initiation with rasagiline. At least 5 weeks should elapse between the discontinuation of fluoxetine therapy and initiation of rasagiline; this 5-week period is needed because of the long half-lives of fluoxetine and its active metabolite norfluoxetine. Fluvoxamine is a strong CYP1A2 inhibitor, and rasagiline plasma concentrations may increase up to 2-fold during concurrent use, resulting in the potential for increased adverse events from rasagiline.
    Remifentanil: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected.
    Reteplase, r-PA: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Ribociclib: (Major) Avoid coadministration of ribociclib with sertraline due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with sertraline due to an increased risk for QT prolongation and torsade de pointes (TdP). Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Rifabutin: (Moderate) Sertraline is a substrate for CYP3A4 and CYP2C19. Drugs that induce hepatic isoenzymes, such as rifabutin, could decrease sertraline plasma concentrations, potentially causing decreased effectiveness of this SSRI.
    Rifampin: (Major) Coadministration may result in a decrease in sertraline plasma concentrations, potentially decreasing the effectiveness of sertraline or causing antidepressant discontinuation symptoms. Sertraline is a substrate of CYP3A4 and CYP2C19. Rifampin is a potent CYP3A4 inducer, and also induces CYP2C19. Case reports have described a reduced antidepressant effect or antidepressant discontinuation symptoms when sertraline was combined with certain inducers, including rifampin.
    Rifapentine: (Moderate) Sertraline is a substrate for CYP3A4 and CYP2C19. Drugs that induce hepatic isoenzymes, such as rifapentine, could decrease sertraline plasma concentrations, potentially causing decreased effectiveness of this SSRI.
    Rilpivirine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; additive effects may occur when administering rilpivirine with other drugs that may prolong the QT or PR interval.
    Risperidone: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Risperidone has been associated with a possible risk for QT prolongation and/or torsade de pointes. Reports of QT prolongation and TdP during risperidone therapy are noted by the manufacturer, primarily in the overdosage setting. Sertraline and Risperidone are commonly used together in clinical practice; however, if the patient has risk factors for cardiac disease or arrhythmias, close monitoring is recommended.
    Rivaroxaban: (Major) Selective serotonin reuptake inhibitors (SSRIs) can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding with rivaroxaban; however, the absolute risk is not known. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner.
    Rizatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., rizatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Rolapitant: (Major) Use caution if sertraline and rolapitant are used concurrently, and monitor for sertraline-related adverse effects. Sertraline is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Romidepsin has been reported to prolong the QT interval. If romidepsin must be coadministered with another drug that prolongs the QT interval, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Safinamide: (Major) The concurrent use of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) is generally avoided; however, the manufacturer of safinamide recommends monitoring for serotonin syndrome and using the lowest effective dose of the SSRI during concurrent use. During clinical trial evaluation of safinamide, 1 case of serotonin syndrome occurred during co-administration with an SSRI. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
    Salmeterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Salsalate: (Moderate) The combined use of selective serotonin reuptake inhibitors (SSRIs) and aspirin, ASA or other salicylates which affect hemostasis may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. A cohort study in > 26,000 patients found that SSRI use alone increased the risk for serious GI bleed by 3.6-fold; when an SSRI was combined with aspirin the risk was increased by > 5-fold. The absolute risk of GI bleed from concomitant therapy with aspirin and a SSRI was low (20/2640 patients) in this cohort study and the clinician may determine that the combined use of these drugs is appropriate.
    Saquinavir: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Avoid administering saquinavir boosted with ritonavir concurrently with other drugs that may prolong the QT interval. If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations.
    Selegiline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Sevoflurane: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Halogenated anesthetics can prolong the QT interval.
    Short-acting beta-agonists: (Minor) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists versus short-acting beta-agonists such as albuterol or levalbuterol.
    Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Because of the potential risk and severity of serotonin syndrome or neuroleptic malignant syndrome-like reactions, caution should be observed when administering sibutramine with other drugs that have serotonergic properties such as selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, in vitro studies indicate that metabolism of sibutramine is mediated through CYP3A4. Theoretically, the metabolism of sibutramine may be decreased as a result of CYP3A4 inhibition by fluoxetine or fluvoxamine. Patients receiving sibutramine in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of sertraline, which is a CYP3A4 substrate. Monitor patients for adverse effects of sertraline, such as QT prolongation and CNS and GI effects.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Moderate) Use caution when prescribing sodium picosulfate; magnesium oxide; anhydrous citric acid in patients taking concomitant medications that are known to induce Antidiuretic Hormone Secretion (SIADH), such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics and carbamazepine, as these drugs may increase the risk of water retention and/or electrolyte imbalance.
    Solifenacin: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Solifenacin has been associated dose-dependent prolongation of the QT interval. TdP has been reported with postmarketing use, although causality was not determined.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with sertraline is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Sotalol: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Sotalol administration is associated with QT prolongation and TdP. Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment.
    Spironolactone: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    St. John's Wort, Hypericum perforatum: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combinations of St. John's wort, Hypericum perforatum with selective serotonin reuptake inhibitors (SSRIs). Interactions between SSRIs and serotonergic agents can lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome reactions have been documented when SSRIs were used concurrently with St. John's wort. A single case report is noted of a 50 year old woman with depression who experienced excessive sedation after ingesting paroxetine with St. John's wort. After discontinuing her conventional paroxetine treatment for 10 days, she started St. John's wort powder at a dose of 600 mg per day. The woman experienced no adverse events related to the change in therapy. She decided to take paroxetine 20 mg one evening due to an episode of insomnia. The next day she was found in an arousable but lethargic and incoherent state. After 2 hours, she complained of weakness, fatigue, and nausea. The patient recovered completely within 48 hours.
    Streptokinase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Sumatriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Sunitinib: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Sunitinib can prolong the QT interval.
    Tacrolimus: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tacrolimus causes QT prolongation.
    Tamoxifen: (Moderate) Use caution if coadministration of sertraline with tamoxifen is necessary due to the risk of QT prolongation. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have been described when tamoxifen is used at lower doses. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a moderate CYP2D6 inhibitor such as sertraline. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure; interactions with moderate CYP2D6 inhibitors have not been evaluated. If concomitant use in necessary, monitor patient closely for increased side effects.
    Tapentadol: (Major) Caution is advised when tapentadol is coadministered with selective serotonin reuptake inhibitors (SSRIs) as this combination may increase the potential for serotonin syndrome development. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage adjustments (increases) of either agent.
    Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and selective serotonin reuptake inhibitors (SSRIs) due to the theoretical risk of serotonin syndrome. Animal studies did not predict serotonergic effects; however, patients on concurrent SSRIs were excluded from clinical trials. Addtionally, tedizolid is an antibiotic that is also a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome has been reported in patients receiving either citalopram, escitalopram, fluoxetine, or paroxetine in combination with linezolid, which is structurally similar to tedizolid.
    Telavancin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Telavancin has been associated with QT prolongation.
    Telithromycin: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Telithromycin is associated with QT prolongation and torsade de pointes.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and sertraline is necessary, as the systemic exposure of sertraline may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of sertraline; consider increasing the dose of sertraline if necessary. Sertraline is a CYP3A4 substrate in vitro. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Tenecteplase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Terbinafine: (Moderate) Systemic terbinafine inhibits hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as selective serotonin reuptake inhibitors (SSRIs). The clinical relevance of the interaction is not known. Topical forms of terbinafine do not interact.
    Tetrabenazine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong the QTc.
    Tezacaftor; Ivacaftor: (Minor) Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates, such as sertraline. Ivacaftor is an inhibitor of CYP3A and a weak inhibitor of CYP2C9; sertraline is metabolized by CYP3A and CYP2C9. Co-administration of ivacaftor with CYP3A and CYP2C9 substrates, such as sertraline, can theoretically increase sertraline exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that may prolong the QT interval and increase the risk of TdP, such as sertraline. In addition, thioridazine is a CYP2D6 substrate and use with a CYP2D6 inhibitor such as sertraline may lead to arrhythmias.
    Thrombin Inhibitors: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombin inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an anticoagulant medication.
    Thrombolytic Agents: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Ticagrelor: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Ticlopidine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Tinidazole: (Severe) Alcoholic beverages and preparations containing ethanol, such as sertraline oral solution, should be avoided during tinidazole therapy and for three days after stopping therapy. Formulations containing a high-percentage of alcohol, although infrequent, may cause disulfiram-like reactions in patients taking tinidazole concurrently. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of sertraline.
    Tinzaparin: (Major) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving low molecular weight heparins. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with molecular weight heparins.
    Tiotropium; Olodaterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Tipranavir: (Moderate) Use caution when coadministering sertraline with a combination of tipranavir plus ritonavir because increased sertraline concentrations may occur. Tipranavir and ritonavir are potent CYP3A4 inhibitors and sertraline is a substrate of CYP3A4. Patients should be monitored for sertraline-induced adverse effects, including nausea, vomiting, diarrhea, and QT prolongation.
    Tirofiban: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
    Tolterodine: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as selective serotonin reuptake inhibitors (SSRIs) like topiramate may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2 to 3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Toremifene: (Major) Avoid coadministration of sertraline and toremifene due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Torsemide: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Tramadol: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering sertraline with other drugs that have serotonergic properties such as tramadol. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Several cases of serotonin syndrome have been reported after the administration of tramadol with an SSRI. The combination of SSRIs and tramadol has also been associated with an increased risk of seizures. Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. SSRIs that are CYP2D6 inhibitors, including sertraline, can prevent the formation of the active M1 metabolite of tramadol. The inhibition of this metabolite may decrease the analgesic effectiveness of tramadol but increase the level of the parent compound, which has more serotonergic activity than the metabolite. If serotonin syndrome is suspected, sertraline and concurrent serotonergic agents should be discontinued.
    Tranylcypromine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with selective serotonin reuptake inhibitors (SSRIs). MAOIs should not be used within 5 weeks of discontinuing treatment with fluoxetine or within 14 days of discontinuing treatment with other SSRIs. Conversely, SSRIs should not be initiated within 14 days of stopping an MAOI. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Trazodone: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Trazodone can prolong the QT/QTc interval at therapeutic doses and there are postmarketing reports of TdP. Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. In addition, because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering drugs that have serotonergic properties such as sertraline and trazodone. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Triamterene: (Moderate) Patients receiving a diuretic during treatment with sertraline may be at greater risk of developing syndrome of inappropriate antidiuretic hormone secretion (SIADH). Hyponatremia due to SIADH has been reported during therapy with SSRIs. Cases involving serum sodium levels lower than 110 mmol/l have occurred. Hyponatremia may be potentiated by agents which can cause sodium depletion such as diuretics. Discontinuation of sertraline should be considered in patients who develop symptomatic hyponatremia.
    Trifluoperazine: (Minor) Because trifluoperazine and SSRIs including citalopram, escitalopram, and fluoxetine are associated with a possible risk of QT prolongation and torsade de pointes (TdP), combination therapy should be used cautiously and with close monitoring. According to the manufacturer of citalopram, ECG monitoring is recommended in patients receiving concurrent drugs that prolong the QT interval. In addition, fluoxetine and paroxetine are potent inhibitors of CYP2D6 and may result in increases in serum phenothiazine concentrations, leading to side effects. Mild CYP2D6 inhibitors, including citalopram, escitalopram, and sertraline also have the potential to interact with phenothiazines. The effects of fluoxetine on hepatic metabolism of interacting drugs may persist for a time after discontinuation of fluoxetine because of its long elimination half-life.
    Trimipramine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, serotonin syndrome is possible when coadministering drugs that have serotonergic properties such as sertraline and TCAs. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Lastly, sertraline is a CYP2D6 inhibitor, one of the isoenzymes responsible for the metabolism of TCAs. During a study evaluating the effects of concurrent use of sertraline and low-dose doxepin (6 mg) in healthy subjects, the doxepin mean AUC and Cmax estimates were about 21% and 32% higher, respectively, during concomitant sertraline administration than in those receiving doxepin alone. Measurements of psychomotor function showed more impairment in the combination group than the group receiving doxepin alone; however, subjective measures of alertness were similar between the two groups. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if sertraline is added. The American Heart Association has published guidelines regarding cardiovascular monitoring of certain psychotropic drug combinations in children.
    Triptorelin: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Umeclidinium; Vilanterol: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists than short-acting beta-agonists.
    Urokinase: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving thrombolytic agents. Patients should be closely monitored for signs and symptoms of bleeding when a thrombolytic agent is administered with an SSRI.
    Valerian, Valeriana officinalis: (Moderate) Substances that act on the CNS, including psychoactive drugs, may theoretically interact with valerian, Valeriana officinalis. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Persons taking medications such as SSRIs should discuss the use of herbal supplements with their health care professional prior to consuming these herbs. Patients should not abruptly stop taking their prescribed psychoactive medication.
    Vandetanib: (Major) Avoid coadministration of vandetanib with sertraline due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. There have also been postmarketing reports of QT prolongation and TdP during treatment with sertraline.
    Vardenafil: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug that is associated with a possible risk for QT prolongation and TdP must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Venlafaxine: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Venlafaxine administration is associated with a possible risk of QT prolongation, and TdP has been reported with postmarketing use. In addition, serotonin syndrome is possible when combining drugs with central serotonergic properties. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Vilazodone: (Major) Due to possible additive effects on serotonin concentrations, it is advisable to avoid combining selective serotonin reuptake inhibitors (SSRIs) with vilazodone. Interactions between vilazodone and serotonergic agents can lead to serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Patients receiving vilazodone and sertraline should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and sertraline should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as selective serotonin reuptake inhibitors (SSRIs). Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion. In addition, fluoxetine and fluvoxamine are CYP3A4 inhibitors and coadministration with vorapaxar, a CYP3A4 substrate, may result in increased serum concentrations of vorapaxar. Increased exposure to vorapaxar may increase the risk of bleeding complications. Patients should be instructed to monitor for signs and symptoms of bleeding while taking a SSRI with vorapaxar and to promptly report any bleeding events.
    Voriconazole: (Major) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Voriconazole has been associated with QT prolongation and rare cases of TdP. Voriconazole is a CYP3A4 inhibitor and sertraline is a partial CYP3A4 substrate. However, sertraline is metabolized by various CYP450 enzymes, and inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations.
    Vorinostat: (Moderate) There have been postmarketing reports of QT prolongation and torsade de pointes (TdP) during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval. Vorinostat therapy is associated with a risk of QT prolongation.
    Vortioxetine: (Major) Due to similarity of pharmacology and the potential for additive adverse effects, including serotonin syndrome, vortioxetine should generally not be co-administered with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Warfarin: (Major) Caution is advised during concurrent use of warfarin with sertraline. If these drugs are administered together, instruct patients to monitor for signs and symptoms of bleeding, and to promptly report any bleeding events to their practitioner. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if sertraline is added to or removed from the regimen of a patient stabilized on warfarin. In one study of healthy volunteers, the mean hypoprothrombinemic response to warfarin was slightly affected by sertraline (prothrombin time prolonged by 8%). The mechanism of this interaction is uncertain. Pharmacokinetic studies did not find any displacement of warfarin from protein binding sites by the highly protein bound sertraline. SSRIs like sertraline can inhibit serotonin uptake by platelets, thus causing platelet dysfunction and increasing the risk for bleeding; however, the absolute risk is not known.
    Ziprasidone: (Major) Concomitant use of ziprasidone and sertraline should be avoided due to a potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. There have been postmarketing reports of QT prolongation and TdP during treatment with sertraline and the manufacturer of sertraline recommends avoiding concurrent use with drugs known to prolong the QTc interval.
    Zolmitriptan: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., zolmatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen.
    Zolpidem: (Moderate) Disorientation, delusions, or hallucinations have been reported rarely during co-administration of zolpidem and SSRIs including sertraline. The duration of the visual hallucinations ranged from 30 minutes to 7 hours. Data from a clinical study in which SSRI-treated patients were given immediate-release zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n = 95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction. The mechanism for the interaction is thought to be pharmacodynamic in nature. In one study with sertraline, inhibition of zolpidem metabolism occurred when sertraline was chronically coadministered; zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%).

    PREGNANCY AND LACTATION

    Pregnancy

    Sertraline oral solution contains 12% alcohol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy. Use other sertraline formulations during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. The majority of evidence from epidemiologic studies of pregnant women exposed to sertraline in the first trimester suggest no increase in major birth defect risk. Epidemiologic studies showing an increased risk of congenital cardiac defects (e.g., septal defects) did not control for confounders that may have affected the study results. Neonates exposed to SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms 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 serotonin syndrome or, possibly, a drug discontinuation syndrome. Although available data are conflicting, some epidemiologic reports suggest an association between maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension of the newborn (PPHN). Because PPHN is associated with significant morbidity and mortality, it is important that practitioners are aware of antidepressant exposure to avoid delays in diagnosis and treatment. In a meta-analysis of 7 studies, there was a small but significant association between SSRI exposure in late pregnancy and PPHN (OR 2.5, 95% CI 1.32 to 4.73; p = 0.005). Effects were not significant for other moderator variables examined (e.g., study design, congenital malformations, meconium aspiration). Effects of caesarian delivery, maternal body mass index, and preterm delivery were not assessed. PPHN occurs in approximately 1.9 of 1,000 live births in the general population and is a relatively uncommon event; based on this analysis it is estimated that an average of 1 associated case of PPHN would result from 286 to 351 women being treated with an SSRI during late gestation. The FDA advises that healthcare professionals should not alter their current practice of treating depression in pregnancy at this time. Women who are pregnant, or are planning a pregnancy, and currently taking sertraline should consult with their physician about whether to continue taking it. Carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the half-life into consideration, tapering of the serotonergic agent, such as sertraline, prior to delivery may be considered. A prospective study of pregnant women receiving antidepressant treatment found that only 26% of women maintained on their antidepressant had relapsed versus 68% of those who had discontinued their medication. Increasing evidence suggests an association between antidepressant use during pregnancy and a subsequent diagnosis of autism spectrum disorder (ASD) in the offspring. In two separate population based case-control studies, an approximate 2-fold increased risk of ASD was observed. One study found the increased risk was associated only with SSRI use, while the other study found an increased risk associated with use of SSRIs and tricyclic antidepressants. Animal teratology studies with sertraline have failed to show an increased risk of fetal malformations; however, an increase in stillbirths and pup deaths during the first few days after birth has been noted in animal studies where sertraline was initiated in the last trimester of gestation. In other animal studies where sertraline was administered during the period of organogenesis, delayed ossification was observed in fetuses at doses of 0.4 to 3.1 times the maximum recommended human dose (MRHD). A decrease in fertility was seen in 1 of 2 rat studies at a dose of 4 times the MRHD. Animal studies have also shown that SSRIs downregulate serotonin receptors in the fetal cortex and that these changes can be present for a period of time after birth; the effect on neurological development is unknown and the applicability of any of these findings to humans is also unknown. The effect of SSRIs on labor and delivery in humans is unknown. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388.

    MECHANISM OF ACTION

    The precise antidepressant effect of SSRIs is not fully understood, but involves selective serotonin reuptake blockade at the neuronal membrane, which enhances the actions of serotonin (5-HT). Initially, SSRIs increase availability of serotonin in the somatodendritic area through serotonin reuptake blockade at the serotonin transport pump. During long-term administration of SSRIs, serotonin autoreceptors are down-regulated and desensitized, allowing the neuron to increase serotonin release in the axon terminal synapses and increase its neuronal impulses. Because of the delay in therapeutic response to SSRIs, it is theorized that the change in the balance of serotonin receptors over time is an important mechanism of effect. The therapeutic action of SSRIs in treating anxiety disorders is thought to occur from potent central serotonin reuptake blockade although the exact mechanism is unknown. SSRIs have less sedative, anticholinergic, and cardiovascular effects than do tricyclic antidepressants due to dramatically decreased binding to histaminergic, muscarinic, and alpha-adrenergic receptors.

    PHARMACOKINETICS

    Sertraline is administered orally. In young adults, steady-state concentrations are achieved after about 1 week. Sertraline appears to be highly protein-bound (98%), but it does not compete with warfarin or propranolol for binding sites, possibly because its presumed binding site is alpha1-acid glycoprotein and not albumin. Sertraline undergoes extensive first pass metabolism. In vitro data suggest sertraline is a substrate of many hepatic CYP450 enzymes. One study noted that multiple enzymes catalyzed sertraline N-demethylation, with CYP2B6 contributing the greatest extent, and lesser contributions from CYP2C19, CYP2C9, CYP3A4, and CYP2D6. The primary metabolite of N-demethylation is N-desmethylsertraline, which is substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. For deamination, data support a role for CYP3A4 and CYP2C19. The average elimination half-life of sertraline is approximately 26 hours. N-desmethylsertraline has an elimination half-life of 62 to 104 hours. Unchanged sertraline is not detected in the urine; however, 12% to 14% of unchanged sertraline is recovered in feces.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6
    Because sertraline is metabolized by various CYP450 enzymes, inhibition of one enzyme by another drug is not likely to significantly affect sertraline concentrations. Sertraline inhibits CYP2D6 in vivo; it may be necessary to reduce the dosage of concomitantly administered drugs metabolized by CYP2D6. Sertraline appears to have little effect, if any, on the metabolic capacity of other CYP450 hepatic isoenzymes. Sertraline and N-desmethylsertraline have a high in vitro affinity for P-gp; the clinical significance of this finding is unknown.

    Oral Route

    After oral administration of sertraline for 14 days in adults, the mean peak plasma concentration (Cmax) occurs between 4.5 to 8.4 hours. The single dose bioavailability of the tablets is approximately equal to an equivalent dose of oral solution. Administration with food causes a small increase in Cmax and exposure (AUC). Steady-state concentrations are achieved after 1 week of once daily dosing.