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    Selective Serotonin Reuptake Inhibitor Antidepressants, SSRIs

    BOXED WARNING

    Children, growth inhibition, suicidal ideation

    Fluoxetine is approved for the treatment of depression in children 8 years of age and older, and for the treatment of obsessive-compulsive disorder (OCD) in children 7 years of age and older. The safety and effectiveness of fluoxetine in younger children have not been established. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n=4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis 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. Pooled analysis of short-term clinical trials during early phase treatment with SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. 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 at the time of dose increase or decrease. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with fluoxetine. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, 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. The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy. Monitor height and weight periodically while the patient is receiving fluoxetine. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving fluoxetine.

    DEA CLASS

    Rx

    DESCRIPTION

    Selective serotonin reuptake inhibitor (SSRI); longest half-life of all the SSRIs.
    FDA-approved for depression, OCD, panic disorder, bulimia nervosa, and PMDD in adults; approved for depression and OCD in pediatrics; primary off-label uses include premature ejaculation, hot flashes, posttraumatic stress disorder, and childhood anxiety disorders.
    Requires close monitoring in pediatrics and young adults due to increased risk of suicidality during the initial stages of treatment.

    COMMON BRAND NAMES

    Prozac, Prozac Weekly, Sarafem, Selfemra

    HOW SUPPLIED

    Fluoxetine/Fluoxetine Hydrochloride/Prozac Oral Sol: 5mL, 20mg
    Fluoxetine/Fluoxetine Hydrochloride/Prozac Weekly Oral Cap DR Pellets: 90mg
    Fluoxetine/Fluoxetine Hydrochloride/Prozac/Sarafem Oral Tab: 10mg, 20mg, 60mg
    Fluoxetine/Fluoxetine Hydrochloride/Prozac/Sarafem/Selfemra Oral Cap: 10mg, 20mg, 40mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    For the treatment of depression with a daily dosage formulation.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Adults

    20 mg/day PO initially. May increase dose after several weeks by 10 to 20 mg as needed and tolerated. A less frequent or lower dosage should be considered for geriatric adults. Doses above 20 mg/day may be administered once daily or divided into 2 doses administered in the morning and at noon. Max: 80 mg/day PO. Generally, acute episodes of depression require several months of sustained pharmacologic therapy. Periodically re-evaluate to determine the need for continued treatment. Whether the dose needed to induce remission is identical to that needed for maintenance is unknown

    .32127

    Children and Adolescents 8 years and older

    10 to 20 mg/day PO initially. If treatment is initiated at 10 mg/day, the dose is increased to the target dose of 20 mg/day PO after 1 week. Because higher plasma concentrations have been observed in lower weight children, an initial and target dose of 10 mg/day PO is suggested; however, if clinical improvement is not seen after several weeks, the dose may be increased to 20 mg/day PO. Treatment of an acute episode of major depression generally consists of several months or longer; however, it is not known if the dose needed to induce remission is equal to the dose needed to sustain euthymia. During prolonged use, patients should be periodically reassessed to determine the need for continued treatment.

    For the once-weekly maintenance treatment of depression.
    Oral dosage (delayed-release capsules e.g., Prozac Weekly)
    Adults

    90 mg PO once weekly, beginning 7 days after the last 20 mg daily dose. In one long-term maintenance study, both the 90 mg once-weekly fluoxetine dose and the 20 mg/day dose were superior to placebo in delaying the time to relapse of depressive symptoms; however, therapeutic equivalence of the regimens has not been established. If a satisfactory response is not maintained, consider re-establishing a daily dosing regimen. Periodically re-evaluate to determine the need for continued treatment.

    For acute treatment of treatment-resistant depression in combination with olanzapine.
    Oral dosage
    Adults

    Olanzapine 5 mg PO and fluoxetine 20 mg PO once daily in the evening initially. Adjust doses to efficacy and tolerability of individual components within the established effective range of olanzapine 5 to 20 mg/day and fluoxetine 20 to 50 mg/day PO. Max: olanzapine 18 mg with fluoxetine 75 mg per day. Monotherapy with fluoxetine only should not be used. Assess need for continued treatment periodically. APPROXIMATE CORRESPONDING DOSES FOR INDIVIDUAL DRUGS COMPARED TO FIXED DOSE COMBINATION PRODUCT (SYMBYAX): Symbyax 3 mg/25 mg = Olanzapine 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/25 mg = Olanzapine 5 mg with Fluoxetine 20 mg; Symbyax 12 mg/25 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/50 mg = Olanzapine 5 mg with Fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 40 mg + 10 mg.

    Geriatric and debilitated Adults, Adults at risk for hypotension, those with slowed drug metabolism (e.g., females, non-smokers), or those who might be pharmacodynamically sensitive to treatment

    Olanzapine 2.5 to 5 mg with fluoxetine 20 mg PO once daily in the evening initially. Adjust doses slowly to efficacy and tolerability within the established effective range of olanzapine 5 to 20 mg/day and fluoxetine 20 to 50 mg/day PO. Adult Max: olanzapine 18 mg with fluoxetine 75 mg per day. Monotherapy with fluoxetine only should not be used. Assess need for continued treatment periodically. APPROXIMATE CORRESPONDING DOSES FOR INDIVIDUAL DRUGS COMPARED TO FIXED DOSE COMBINATION PRODUCT (SYMBYAX): Symbyax 3 mg/25 mg = Olanzapine 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/25 mg = Olanzapine 5 mg with Fluoxetine 20 mg; Symbyax 12 mg/25 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/50 mg = Olanzapine 5 mg with Fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 40 mg + 10 mg.

    For acute treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in combination with olanzapine.
    Oral dosage
    Adults

    Olanzapine 5 mg PO and fluoxetine 20 mg PO once daily in the evening initially. Adjust doses to efficacy and tolerability of individual components within the established effective dose range of olanzapine 5 to 12.5 mg/day and fluoxetine 20 to 50 mg/day PO. Max: 18 mg olanzapine with 75 mg fluoxetine per day. Monotherapy with fluoxetine only should not be used. Assess need for continued treatment periodically. APPROXIMATE CORRESPONDING DOSES FOR INDIVIDUAL DRUGS COMPARED TO FIXED DOSE COMBINATION PRODUCT (SYMBYAX): Symbyax 3 mg/25 mg = Olanzapine 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/25 mg = Olanzapine 5 mg with Fluoxetine 20 mg; Symbyax 12 mg/25 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/50 mg = Olanzapine 5 mg with Fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 40 mg + 10 mg.

    Geriatric and debilitated Adults, Adults at risk for hypotension, those with slowed drug metabolism (e.g., females, non-smokers), or those who might be pharmacodynamically sensitive to treatment

    Olanzapine 2.5 to 5 mg with fluoxetine 20 mg PO once daily in the evening initially. Subsequently titrate dosage slowly with caution and close monitoring within the effective dose range of olanzapine 5 to 12.5 mg/day and fluoxetine 20 to 50 mg/day PO. Adult Max: 18 mg olanzapine with 75 mg fluoxetine per day. Monotherapy with fluoxetine only should not be used. Assess need for continued treatment periodically. APPROXIMATE CORRESPONDING DOSES FOR INDIVIDUAL DRUGS COMPARED TO FIXED DOSE COMBINATION PRODUCT (SYMBYAX): Symbyax 3 mg/25 mg = Olanzapine 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/25 mg = Olanzapine 5 mg with Fluoxetine 20 mg; Symbyax 12 mg/25 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/50 mg = Olanzapine 5 mg with Fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 40 mg + 10 mg.

    Children and Adolescents 10 years and older

    Initially, 2.5 mg of olanzapine with 20 mg of fluoxetine PO in the evening. Make dosage adjustments according to efficacy and tolerability. Efficective dose range: 3 mg to 12 mg/day PO olanzapine with 25 to 50 mg/day PO fluoxetine. Max: olanzapine 12 mg with fluoxetine 50 mg per day. Monotherapy with fluoxetine only should not be used. Assess need for continued treatment periodically. APPROXIMATE CORRESPONDING DOSES FOR INDIVIDUAL DRUGS COMPARED TO FIXED DOSE COMBINATION PRODUCT (SYMBYAX): Symbyax 3 mg/25 mg = Olanzapine 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/25 mg = Olanzapine 5 mg with Fluoxetine 20 mg; Symbyax 12 mg/25 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 20 mg; Symbyax 6 mg/50 mg = Olanzapine 5 mg with Fluoxetine 40 mg + 10 mg; and Symbyax 12 mg/50 mg = Olanzapine 10 mg + 2.5 mg with Fluoxetine 40 mg + 10 mg.

    For the treatment of obsessive-compulsive disorder (OCD).
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Adults

    20 mg/day PO initially. More than 85% of patients will not need an increase above 20 mg/day to achieve maximum benefit. May increase the dose every month by 10 to 20 mg if needed. A less frequent or lower dosage should be considered for geriatric adults. Max: 80 mg/day PO. May divide into 2 doses if dosage is 20 mg/day or more, given at morning and at noon.

    Children and Adolescents 7 years and older

    10 mg/day PO initially. In higher weight children and adolescents, increase to 20 mg/day after 2 weeks; may increase dosage after several more weeks if insufficient clinical improvement is observed. Target dosage (higher weight): 20 to 60 mg/day PO. In lower weight children, the initial 10 mg dosage may be increased after several weeks if insufficient clinical improvement is observed. Target dosage (lower weight): 20 to 30 mg/day PO.

    Children† 3 to 6 years

    Limited data are available. 5 mg/day PO initially, followed by gradual increases based on response to a range of 5 to 15 mg/day may be effective in preschool children with OCD resistant to nonpharmacologic treatment and symptoms and functional impairment that are severe. Behavioral disinhibition has occurred in some preschool children receiving doses of 15 to 20 mg/day PO. These adverse behavioral symptoms have resolved after dose reductions. Further study assessing safety and efficacy is necessary.

    For the treatment of panic disorder with or without agoraphobia.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Adults

    10 mg/day PO initially. After 1 week, increase to 20 mg/day PO. After several weeks, a further dose increase may be considered if clinical improvement is not observed. A less frequent or lower dosage should be considered for geriatric adults. Max: 60 mg/day PO suggested. Dosages above 60 mg/day have not been studied in panic disorder. In clinical trials, the most frequently administered dose was 20 mg/day. May divide into 2 doses for daily doses above 20 mg/day, given at morning and noon.

    Children† and Adolescents† 8 years and older

    Published data are extremely limited. In one open-label evaluation of 6 months, the mean dose of 9 patients receiving fluoxetine during the first 6 to 8 weeks was 34.4 mg/day PO, with a range of 20 to 60 mg/day PO. The median time to attain an improvement rating ("much to very much improved") was 7.5 weeks. A benzodiazepine was used in 67% of the patients while awaiting the clinical response to the SSRI.

    For the treatment of bulimia nervosa.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Adults

    In clinical trials, doses less than 60 mg/day were not effective in reducing binge eating and vomiting;; therefore, the recommended dose is 60 mg PO once daily, administered in the morning. For some patients, including geriatric adults, it may be necessary to titrate to this dosage over several days. Doses above 60 mg/day PO have not been systematically studied in patients with bulimia. Used for up to 52 weeks in clinical trials.

    Children and Adolescents 12 years and older

    20 mg/day PO initially, followed by titration by 20 mg/day every 3 days to a maximum dose of 60 mg/day PO. In one small study of 10 adolescent females with a diagnosis of bulimia nervosa (BN) or eating disorder not otherwise specified (EDNOS), this regimen combined with supportive psychotherapy was associated with a significant decrease in the core behavioral symptoms of BN (e.g., binging, purging). The CGI-improvement scores were much improved for 2 subjects, improved for 5 subjects, and slightly improved for 3 subjects. The most common side effects were headache, drowsiness, poor concentration, difficulty sitting still, decreased appetite, tremor, and difficulty with sleep induction or maintenance; however, no patient discontinued treatment due to side effects. Although further research is needed, the effective dose established in this study was consistent with the effective dose for bulimia in adults.

    For the treatment of premenstrual dysphoric disorder (PMDD).
    Oral dosage (e.g., Sarafem or other regular capsules, tablets or oral solution)
    Adult females

    20 mg PO once daily initially, given continuously or during the luteal phase only (i.e., starting a daily dose 14 days prior to the anticipated start of menses through the first full day of menses and repeating with each new cycle). In clinical trials, doses of 20 to 60 mg/day PO were effective, although the 60-mg dose did not provide additional benefit. Doses above 60 mg/day PO have not been evaluated in PMDD. Max: 80 mg/day PO.

    For the treatment of generalized anxiety disorder (GAD)†.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Adolescents and Children 7 years and older

    Limited data; dosage not established; further study needed. 10 mg/day PO initially, followed by titration. Limited data suggest that 20 mg/day PO may be an effective dose. In a randomized controlled trial of pediatric patients 7 years of age and older with a diagnosis of 1 or more anxiety disorders including GAD, fluoxetine-treated patients with GAD had a significantly better clinical response than placebo-treated patients (67% vs. 36%). Fluoxetine was initiated at 10 mg/day for the first week and, if tolerated, increased to 20 mg/day. Initial improvement seen at 4 weeks; improvement was sustained during the 1-year, open-label, follow-up study.

    For the treatment of social phobia (social anxiety disorder)†.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Children and Adolescents 7 years and older

    10 mg/day PO initially, followed by titration; a target dose of 20 to 40 mg/day PO may be effective for treating social phobia in children and adolescents. In one randomized, placebo-controlled trial comparing the effectiveness of fluoxetine to Social Effectiveness Therapy for Children (SET-C) in pediatric patients with a primary diagnosis of social phobia, fluoxetine was titrated as follows: 10 mg/day PO for 2 weeks, 20 mg/day for 2 weeks, 30 mg/day for 2 weeks, and 40 mg/day thereafter unless side effects necessitated a dose reduction. At study end, both SET-C and fluoxetine decreased social distress equally; however, SET-C was superior to fluoxetine in the percentage of treatment responders (100% vs. 61%), lack of post-treatment diagnosis (53% vs. 21.2%), and achievement of high end-state functioning (94% vs. 55.6%). SET-C was the only treatment superior to placebo in improving social skills, decreasing anxiety in specific social interactions, and enhancing social competence. In a separate study assessing fluoxetine treatment in various childhood anxiety disorders, 76% of patients with primary social phobia were assessed as much or very much improved compared to 21% of patients treated with placebo. In one study of 60 patients aged 15 to 77 years, the findings were less robust, and fluoxetine failed to show a significant difference from placebo.

    For the treatment of posttraumatic stress disorder (PTSD)†.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Adults

    Initially, 20 mg PO once daily. A range of 20 to 80 mg/day PO has been used; follow recommended dosage titration schedules. A lower or less frequent dose may be considered in the geriatric adult. Mean effective dosage in most trials has been 40 mg/day PO. Fluoxetine has been effective for a wide variety of traumatic stressors, including combat. Max: 80 mg/day PO. May divide daily dose into 2 doses, given morning and at noon, if the dosage is more than 20 mg/day.

    For the treatment of anorexia nervosa†.
    Oral dosage (regular capsules, tablets or oral solution)
    Adults

    Initially, 10 mg/day, gradually increased to a maximum of 60 mg/day (mean dose 40 mg/day), has been used.Fluoxetine treatment has yielded mixed results in both inpatient and outpatient settings. Fluoxetine has not been proven to add benefit to the acute phase treatment of patients with anorexia nervosa. However, when given after successful weight restoration and resolution of the psychological effects of malnutrition, fluoxetine may reduce the rate of relapse of anorexia nervosa.

    For the treatment of obesity†.
    Oral dosage (regular capsules, tablets or oral solution)
    Adults

    Studies have used doses of 60 mg/day PO after titration, but results are conflicting, and weight-loss effect does not appear to be sustained with long-term evaluation. Doses over 20 mg/day may be given in 2 divided doses given at morning and noon. In a 3-month study of obese non-diabetics, fluoxetine (dose unclear) was not superior to placebo however, in a 12-month study of obese non-diabetics, fluoxetine 60 mg/day PO produced significantly greater weight loss than placebo at week 28 but no difference was seen at week 52. Fluoxetine 60 mg/day PO was superior to placebo in obese diabetics in another 12-month study. More study is needed.

    For the treatment of borderline personality disorder†.
    Oral dosage (regular capsules, tablets or oral solution)
    Adults

    Initially, 20 mg PO once daily. May increase every month by 20 mg as needed and tolerated.Doses over 20 mg/day may be given in 2 divided doses given at morning and noon. Max: 80 mg/day PO. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed, but have little benefit over placebo as monotherapy in randomized, controlled trials, and fluoxetine is usually combined with olanzapine or other effective treatment for borderline personality disorder. An SSRI can be helpful if comorbid depression is present.

    For the treatment of autistic disorder†.
    Oral dosage (regular capsules, tablets or oral solution)
    Adults

    Although data are limited, fluoxetine may be useful for autistic patients with coexisting OCD or depressive symptoms. Initially, 20 mg PO once daily or 20 mg every other day PO titrated to a maximum of 80 mg/day has been recommended. Usual dose ranges 20 to 40 mg/day PO.

    Children and Adolescents 2 years and older

    2.5 mg/day PO initially, titrated based on weight and tolerability to a maximum target dose of 0.8 mg/kg/day PO in older children and adolescents by week 4 has been used. Weight-based dosing of 0.15 to 0.5 mg/kg/day has also been used in younger children. One 8-week controlled trial of children (5 years and older) and adolescents (n = 45 total) indicated that fluoxetine treatment was associated with a significant reduction in repetitive behaviors. In a long-term study (duration: 5 to 76 months) of children aged 2 to 8 years (n = 129), 17% of patients had an excellent response, 52% a good response, 8% fair, and 23% poor. Forty percent of good/excellent responders had optimal daily doses over 12 mg/day (with weight-based dosing not exceeding 40 mg/day PO). Improvement with fluoxetine had a strong correlation with familial major affective disorders. Behavioral hyperactivity may limit treatment in some patients.

    For the treatment of separation anxiety disorder†.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Adolescents

    5 mg/day PO initially, with titration to effective doses. Adolescents (n = 11) were titrated from an initial dose of 5 mg/day up to 20 mg/day by week 3, with subsequent increases to a maximum of 80 mg/day PO if clinically indicated. The mean daily dose for adolescents was 40 mg/day PO. In this open-label study of 16 pediatric patients with one or more anxiety disorders, 10 out of 10 patients with separation anxiety disorder showed clinical improvement (4 rated as improved and 6 rated as much improved); the patients improved over 6 to 9 weeks (mean of 5 weeks). Youth with only 1 diagnosis responded to lower doses than those with 2 or more diagnoses. After treatment with fluoxetine, 7 of 10 patients with separation anxiety disorder no longer met diagnosis criteria. However, in a separate study of mixed anxiety disorders, clinical response to fluoxetine was similar to placebo, although patients with SCARED-C (Screen for Child Anxiety Related Emotional Disorders, child version) scores of at least 30 at intake showed a trend toward better response to fluoxetine than placebo. Further study is needed to evaluate the safety and efficacy in treating separation anxiety disorder.

    Children 9 years and older

    5 mg/day PO initially, with titration to effective doses. Children (n = 5) were titrated from an initial dose of 5 mg/day up to 20 mg/day in week 4, with subsequent increases to a maximum of 40 mg/day PO if clinically indicated. The mean daily dose for children was 24 mg/day PO. In this open-label study of 16 pediatric patients with one or more anxiety disorders, 10 out of 10 patients with separation anxiety disorder showed clinical improvement (4 rated as improved and 6 rated as much improved); the patients improved over 6 to 9 weeks (mean of 5 weeks). Youth with only 1 diagnosis responded to lower doses than those with 2 or more diagnoses. After treatment with fluoxetine, 7 of 10 patients with separation anxiety disorder no longer met diagnosis criteria. However, in a separate study of mixed anxiety disorders, clinical response to fluoxetine was similar to placebo, although patients with SCARED-C (Screen for Child Anxiety Related Emotional Disorders, child version) scores of at least 30 at intake showed a trend toward better response to fluoxetine than placebo. Further study is needed to evaluate the safety and efficacy in treating separation anxiety disorder.

    For the treatment of fibromyalgia†.
    Oral dosage (immediate-release capsules, tablets or oral solution)
    Adults

    Initially, 20 mg PO once daily and gradually titrate to response as tolerated. Max: 80 mg/day PO. Response to antidepressants should be expected within 2 to 4 weeks once an effective dosage is achieved. Because the evidence of efficacy with fluoxetine is not as robust as some other medications, the drug is considered a second-line treatment option; optimal dosing is not yet established. In one flexible-dose trial, the mean total daily fluoxetine dose was 55 mg +/- 25 mg for patients completing the 12-week study. In this trial, fluoxetine significantly improved the Fibromyalgia Impact Questionnaire total score compared to placebo and also significantly improved the Fibromyalgia Impact Questionnaire pain subscore compared to placebo as the second primary outcome. In a fixed-dose study of fluoxetine 20 mg/day PO versus placebo, fluoxetine was not found to be effective in treating fibromyalgia symptoms. One meta-analysis found strong evidence for fluoxetine in reducing pain, but a small effect in reducing depression and health-related quality of life, and no effect on fatigue.

    For the treatment of neurogenic orthostatic hypotension†.
    Oral dosage (regular capsules, tablets or oral solution)
    Adults

    In a case report, 5 patients with symptomatic orthostatic hypotension received 20 mg PO once daily for 6 to 8 weeks; 4 patients experienced a complete or partial reduction of symptoms.

    For the treatment of premature ejaculation†.
    Oral dosage (regular capsules, tablets or oral solution)
    Adult males

    5 mg to 20 mg/day PO has been shown to increase ejaculatory latency and is suggested per treatment guidelines. In one study, men with lifelong rapid ejaculation (1 minute or less) received fluoxetine 20 mg/day PO, another SSRI (fluvoxamine, paroxetine, sertraline), or placebo for 6 weeks. Mean intravaginal ejaculation latency time (IELT) with placebo was 20 seconds; the IELT in men treated with fluoxetine increased to about 110 seconds. According to guidelines, a regimen in which the dose is increased from 20 mg/day PO to 40 or 60 mg/day PO after 1 week has also been used with success.

    For the treatment of hot flashes† in women with breast cancer experiencing symptoms of menopause†.
    Oral dosage (regular capsules, tablets or oral solution)
    Adult females

    One phase III study reported that 20 mg/day PO reduced the weekly incidence and severity of hot flashes 50% compared to 36% in the placebo in women with a history of breast cancer or a concern regarding the use of estrogen (because of breast cancer risk); some women were taking tamoxifen or raloxifene therapy. The modest improvement noted with fluoxetine was statistically significant p = 0.02).

    For migraine prophylaxis†.
    Oral dosage
    Adults

    20 mg to 40 mg PO daily after titration. The American Academy of Neurology does not support or refute the use of fluoxetine for migraine prophylaxis due to inadequate or conflicting data.

    For the treatment of selective mutism† in children who have failed an adequate trial of psychotherapy.
    Oral dosage (regular capsules, tablets or oral solution e.g., Prozac)
    Children and Adolescents 4 years and older

    Pharmacotherapy for selective mutism is not well-studied. Various dosage titrations have been used. Target doses range from 8 mg/day PO to 60 mg/day PO; lower weight children usually receive lower target doses. Weight based dosing of 0.3 mg/kg/day PO up to 0.6 mg/kg/day PO has also been used. The majority of data use an initial dose of 20 mg/day PO with gradual titration; with a maximum of 60 mg/day PO. One case report documented an initial dose of 4 mg/day PO and a final dose of 8 mg/day in a 4-year old child, with some improvement noted within 5 days. In another study, the mean dose at study end was 28.1 mg/day PO (range: 10 to 60 mg/day PO). Significant improvement may not occur for 6 to 12 weeks, and individual response is variable. The most frequently reported adverse effects include excitement or behavioral disinhibition, insomnia, jitteriness, and headache. Further study is needed to evaluate safety and efficacy.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    80 mg/day PO (immediate-release daily dose forms); 90 mg/week PO for once weekly formulation.

    Geriatric

    80 mg/day PO (immediate-release daily dose forms); 90 mg/week PO for once weekly formulation.

    Adolescents

    60 mg/day PO of conventional oral dosage forms; safety and efficacy not established for the once-weekly dosage form.

    Children

    7 to 12 years: 30 mg/day PO for lower weight children and 60 mg/day for higher weight children with OCD. Doses up to 0.8 mg/kg/day PO (Max: 60 mg/day) have been used off-label for various psychiatric conditions. Do not use the once-weekly dosage form.
    4 to 6 years: Safety and efficacy have not been established. Doses up to 0.6 mg/kg/day PO (Max: 60 mg/day) have been used off-label in children with selective mutism. Do not use the once-weekly dosage form.
    2 to 3 years: Safety and efficacy have not been established. Doses up to 0.5 mg/kg/day PO (Max: 40 mg/day) have been used off-label in children with autism. Do not use the once-weekly dosage form.
    1 to 2 years: Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    A lower or less frequent dose should be used in patients with liver disease; however, quantitative guidelines are not available.

    Renal Impairment

    CrCl < 10 mL/min: Higher concentrations of the metabolites of fluoxetine (e.g., norfluoxetine) may be present in patients with severe renal impairment; however, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.
     
    Intermittent hemodialysis:
    In a study of adult patients on hemodialysis, the steady-state plasma concentrations of fluoxetine and its active metabolite norfluoxetine were comparable to those of patients with normal renal function during use of dosages of 20 mg/day PO for 2 months; there are no routine dosage adjustments recommended for patients receiving dialysis.

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.
    Immediate-release dosage forms: In most patients, the initial daily dose should be given in the morning. However, a small number of patients (5—10%) experience sedation. In these individuals, give the dose at bedtime. If the first few doses are not well tolerated, consider restarting with a lower dose, then titrating to effective dose. Doses > 20 mg/day PO may be administered as one daily dose or divided into two doses. When the daily dose is divided, administration in the morning and at noon may minimize insomnia.

    Oral Solid Formulations

    Prozac Weekly: The delayed-release capsule contains enteric-coated pellets. Swallow whole, do not crush, cut, or chew.

    Oral Liquid Formulations

    Oral solution: To ensure accurate dosing, measure dosage with an oral syringe or other calibrated measuring device.

    STORAGE

    Generic:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Prozac:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Prozac Weekly:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Sarafem:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Selfemra :
    - Protect from light
    - Store between 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Fluoxetine is contraindicated in those patients with fluoxetine hypersensitivity or hypersensitivity to any of the formulation components.

    Abrupt discontinuation

    Avoid abrupt discontinuation of any SSRI if possible. Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of potential withdrawal symptoms. However, withdrawal symptoms have been reported less frequently with long-acting SSRIs such as fluoxetine than short-acting SSRIs such as paroxetine. Symptoms associated with abrupt withdrawal of fluoxetine have included dysphoric mood, irritability, agitation, dizziness, paresthesias, and headache.

    Electroconvulsive therapy (ECT), seizure disorder

    Fluoxetine should be used with caution in patients with a seizure disorder. Seizures have been reported rarely in patients taking fluoxetine; however, they have occurred primarily in cases of fluoxetine overdose. Fluoxetine's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date. Some clinicians have reported that in rare instances ECT-induced seizures were prolonged in patients taking fluoxetine. A possible mechanism of seizure prolongation may be a lowering of the seizure threshold caused by high concentrations of fluoxetine or its active metabolite norfluoxetine.

    Children, growth inhibition, suicidal ideation

    Fluoxetine is approved for the treatment of depression in children 8 years of age and older, and for the treatment of obsessive-compulsive disorder (OCD) in children 7 years of age and older. The safety and effectiveness of fluoxetine in younger children have not been established. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n=4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis 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. Pooled analysis of short-term clinical trials during early phase treatment with SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. 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 at the time of dose increase or decrease. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with fluoxetine. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, 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. The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy. Monitor height and weight periodically while the patient is receiving fluoxetine. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving fluoxetine.

    MAOI therapy

    Fluoxetine is contraindicated for concomitant use in patients receiving MAOI therapy. At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders. Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue, which also have MAOI activity, is also contraindicated because of an increased risk of serotonin syndrome. Other medications when combined with fluoxetine may increase the risk for serotonin syndrome. Serotonin syndrome has been reported with SSRIs, including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents including serotonin agonists (triptans), tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort. If such symptoms occur, discontinue fluoxetine and initiate supportive treatment. The prolonged half-life of fluoxetine should be taken into account when treating such reactions.

    Bipolar disorder, mania

    All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, fluoxetine 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. It should be noted that fluoxetine is not approved for use in treating bipolar depression. Analysis of short-term studies in older patients aged >= 65 years showed a decline in the risk of suicidal thinking and behavior during early phase treatment with SSRIs and other antidepressants, contrary to the data obtained in children and young adults.

    Hepatic disease

    Fluoxetine should be used cautiously in patients with hepatic disease or dysfunction. In patients with cirrhosis, the elimination half-lives of fluoxetine and norfluoxetine are significantly prolonged. In addition, because fluoxetine treatment has been associated with prolongation of the QTc interval and significant arrhythmias, caution is advisable when using fluoxetine in patients with conditions that predispose to increased fluoxetine exposure such as hepatic impairment. If fluoxetine is administered to a patient with hepatic impairment, a lower dose or less frequent dosing interval should be used.

    Alcoholism, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diarrhea, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, malnutrition, myocardial infarction, poor metabolizers, QT prolongation, thyroid disease, ventricular arrhythmias

    QT prolongation and ventricular arrhythmias, including torsade de pointes, have been reported in patients treated with fluoxetine. Use fluoxetine with caution in patients with congenital long QT syndrome, a previous history of QT prolongation, or a family history of long QT syndrome or sudden cardiac death. Also use fluoxetine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic impairment may also be at increased risk for QT prolongation. In addition, conditions that predispose patients to increased fluoxetine exposure (e.g., overdose, hepatic impairment, CYP2D6 poor metabolizers, concomitant use of CYP2D6 inhibitors or highly protein-bound drugs) may put patients at risk. Electrolyte imbalances should be corrected prior to initiating treatment with fluoxetine. Caution is recommended when treating patients at risk for a significant electrolyte imbalance (e.g., diuretic therapy, diarrhea). Consider obtaining a baseline ECG in addition to periodic ECG monitoring if initiating fluoxetine treatment in a patient with risk factors for QT prolongation and TdP. Discontinue fluoxetine and obtain prompt cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

    Dehydration, hyponatremia, hypovolemia

    Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, have been associated with cases of clinically significant 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. Should adverse reactions requiring drug discontinuation occur, the long half-life of fluoxetine and its major metabolite must be kept in mind.

    Anticoagulant therapy, bleeding, thrombolytic therapy

    Monitor patients taking an SSRI, like fluoxetine, 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 should be instructed to promptly report any bleeding events to the practitioner.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing fluoxetine 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.

    Driving or operating machinery, ethanol ingestion

    Fluoxetine may impair judgment, thinking, or motor skills. Patients should use caution when driving or operating machinery, until they are reasonably certain that fluoxetine does not affect them adversely. As with other psychotropic medications, patients should be advised to avoid ethanol ingestion while taking fluoxetine.

    Diabetes mellitus

    In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.

    Akathisia

    The use of fluvoxamine 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. It is generally recommended to 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 fluoxetine to patients with anorexia nervosa or other conditions where weight loss is undesirable.

    Bone fractures, osteoporosis

    Use selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, 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 SSRI-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.

    Neonates, pregnancy

    Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It should be noted that the diagnosis of premenstrual dysphoric disorder (PMDD) does exist during pregnancy; fluoxetine should not be used for this purpose during pregnancy. Animal teratology studies with fluoxetine have failed to show an increased risk of fetal malformations. A prospective cohort study reported an increased risk of cardiovascular malformations in newborns born to women exposed to fluoxetine during the first trimester compared to women not exposed to fluoxetine; however, several epidemiological studies have not demonstrated an increased risk of congenital malformations. Animal studies have 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 applicability of these animal findings to human gestation is unknown; some human epidemiologic studies have suggested that the cognitive and behavioral development of infants prenatally exposed to fluoxetine does not differ from controls. Neonates exposed to SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding 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 either serotonin syndrome or, possibly, a drug discontinuation syndrome. Women who are pregnant, or are planning a pregnancy, and currently taking fluoxetine 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 prior to delivery may be considered. In a prospective study, 228 women taking fluoxetine during pregnancy were evaluated against a control group; the rates of spontaneous abortion were similar in both groups. Rates of major structural anomalies in the neonates prenatally exposed to fluoxetine were also not significantly different from controls. However, the fluoxetine group reported the presence of 3 or more minor anomalies more frequently. In an analysis based on use during a specific trimester, neonates exposed to fluoxetine during the last trimester had higher rate of neonatal prematurity, low-birth weight at term, and poor neonatal adaptation. A prospective, human cohort study was conducted to evaluate the outcome of neonates born to 267 women who took an SSRI during pregnancy; the SSRI-exposed newborns had similar rates of major malformation, spontaneous and elective abortion, and stillbirth when compared to neonatal controls. Mean birth weight and gestational age were also similar among the 2 groups of neonates. Increasing evidence suggests an association between antidepressant use during pregnancy and a subsequent diagnosis of autism spectrum disorder (ASD) in the offspring. In 2 separate population based case-control studies, an approximate 2-fold increased risk of autism spectrum disorder 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. Epidemiologic reports suggest an association between maternal use of SSRIs after 20 weeks gestation and the development of persistent pulmonary hypertension of the newborn (PPHN). More recent retrospective studies have not shown an increased risk of PPHN with SSRI exposure. In December 2011, the FDA issued a safety announcement stating that based on conflicting data, an increased risk of PPHN from SSRI exposure cannot be determined. The FDA advises that healthcare professionals should not alter their current practice of treating depression in pregnancy at this time. A prospective study of pregnant women receiving antidepressant treatment found that only 26% of those maintained on their antidepressant had relapsed versus 68% of those who had discontinued their medication. 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

    The FDA has generally recommended against fluoxetine use during lactation. Because fluoxetine and its active metabolite are eliminated slowly, consideration should be given to the possible presence of the drug in breast milk for a prolonged period after discontinuation of therapy. Fluoxetine should be used with caution in breast-feeding mothers because of the excretion of the drug into breast milk. SSRI concentrations in breast milk are typically similar to those of maternal serum. Patients should advise their physician of their intention to breast-feed. Fluoxetine has been observed to cause increased irritability, colic, vomiting, and decreased sleep in infants. A 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, and breast-feeding should be avoided at times of peak serum concentrations. Consider the benefits of breast-feeding, the risk of potential drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding baby experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    In clinical trials of fluoxetine, no overall differences in safety were observed between geriatric and younger adults, and other reported clinical experience has not identified differences in responses, but greater sensitivity of some older adults 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 fluoxetine 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 / 2.0-2.0
    tardive dyskinesia / Delayed / 0.1-1.0
    suicidal ideation / Delayed / 0.1-1.0
    arrhythmia exacerbation / Early / 0.1-1.0
    heart failure / Delayed / 0.1-1.0
    myocardial infarction / Delayed / 0.1-1.0
    proteinuria / Delayed / 0.1-1.0
    seizures / Delayed / 0-0.2
    peptic ulcer / Delayed / 0-0.1
    hematemesis / Delayed / 0-0.1
    GI bleeding / Delayed / 0-0.1
    pancreatitis / Delayed / 0-0.1
    cholecystitis / Delayed / 0-0.1
    esophageal ulceration / Delayed / 0-0.1
    GI obstruction / Delayed / 0-0.1
    muscle paralysis / Delayed / 0-0.1
    pulmonary hypertension / Delayed / 0-0.1
    thrombosis / Delayed / 0-0.1
    ventricular fibrillation / Early / 0-0.1
    coronary vasospasm / Early / 0-0.1
    stroke / Early / 0-0.1
    atrial fibrillation / Early / 0-0.1
    cardiac arrest / Early / 0-0.1
    bradycardia / Rapid / 0-0.1
    pneumothorax / Early / 0-0.1
    apnea / Delayed / 0-0.1
    pulmonary edema / Early / 0-0.1
    laryngeal edema / Rapid / 0-0.1
    ocular hypertension / Delayed / 0-0.1
    hearing loss / Delayed / 0-0.1
    oliguria / Early / 0-0.1
    diabetic ketoacidosis / Delayed / 0-0.1
    hyperkalemia / Delayed / 0-0.1
    torticollis / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    erythema nodosum / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    laryngospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    eosinophilic pneumonia / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    optic neuritis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatic necrosis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    serotonin syndrome / Delayed / Incidence not known
    persistent pulmonary hypertension of the newborn / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known

    Moderate

    impotence (erectile dysfunction) / Delayed / 1.0-7.0
    ejaculation dysfunction / Delayed / 2.0-7.0
    constipation / Delayed / 5.0-5.0
    oral ulceration / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    esophagitis / Delayed / 0.1-1.0
    cholelithiasis / Delayed / 0.1-1.0
    dysphagia / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    gastritis / Delayed / 0.1-1.0
    colitis / Delayed / 0.1-1.0
    stomatitis / Delayed / 0.1-1.0
    neuropathic pain / Delayed / 0.1-1.0
    myoclonia / Delayed / 0.1-1.0
    teeth grinding (bruxism) / Delayed / 0.1-1.0
    migraine / Early / 0.1-1.0
    akathisia / Delayed / 0.1-1.0
    ataxia / Delayed / 0.1-1.0
    hypertonia / Delayed / 0.1-1.0
    hostility / Early / 0.1-1.0
    psychosis / Early / 0.1-1.0
    euphoria / Early / 0.1-1.0
    depression / Delayed / 0.1-1.0
    anemia / Delayed / 0.1-1.0
    hypotension / Rapid / 0.1-1.0
    angina / Early / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    peripheral edema / Delayed / 0.1-1.0
    edema / Delayed / 0.1-1.0
    vaginal bleeding / Delayed / 0.1-1.0
    atopic dermatitis / Delayed / 0.1-1.0
    skin ulcer / Delayed / 0.1-1.0
    photophobia / Early / 0.1-1.0
    conjunctivitis / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    cystitis / Delayed / 0.1-1.0
    dysuria / Early / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    urinary incontinence / Early / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    hypothyroidism / Delayed / 0.1-1.0
    hypercholesterolemia / Delayed / 0.1-1.0
    dehydration / Delayed / 0.1-1.0
    hypokalemia / Delayed / 0.1-1.0
    hyperlipidemia / Delayed / 0.1-1.0
    gout / Delayed / 0.1-1.0
    bone pain / Delayed / 0.1-1.0
    synovitis / Delayed / 0.1-1.0
    mania / Early / 0.7-0.7
    abdominal pain / Early / 0-0.1
    fecal incontinence / Early / 0-0.1
    neuritis / Delayed / 0-0.1
    hallucinations / Early / 0-0.1
    EEG changes / Delayed / 0-0.1
    dysarthria / Delayed / 0-0.1
    hyperesthesia / Delayed / 0-0.1
    dystonic reaction / Delayed / 0-0.1
    lymphocytosis / Delayed / 0-0.1
    thrombocytopenia / Delayed / 0-0.1
    leukopenia / Delayed / 0-0.1
    phlebitis / Rapid / 0-0.1
    priapism / Early / 0-0.1
    psoriasis / Delayed / 0-0.1
    furunculosis / Delayed / 0-0.1
    hypoxia / Early / 0-0.1
    hypoventilation / Rapid / 0-0.1
    hemoptysis / Delayed / 0-0.1
    blepharitis / Early / 0-0.1
    iritis / Delayed / 0-0.1
    exophthalmos / Delayed / 0-0.1
    hyperacusis / Delayed / 0-0.1
    hepatitis / Delayed / 0-0.1
    flank pain / Delayed / 0-0.1
    glycosuria / Early / 0-0.1
    hyperglycemia / Delayed / 0-0.1
    diabetes mellitus / Delayed / 0-0.1
    hypocalcemia / Delayed / 0-0.1
    hyperuricemia / Delayed / 0-0.1
    myasthenia / Delayed / 0-0.1
    myopathy / Delayed / 0-0.1
    osteoporosis / Delayed / 0-0.1
    confusion / Early / 1.0
    amnesia / Delayed / 1.0
    QT prolongation / Rapid / 1.0
    hypertension / Early / 1.0
    palpitations / Early / 1.0
    chest pain (unspecified) / Early / 1.0
    dyskinesia / Delayed / Incidence not known
    memory impairment / Delayed / Incidence not known
    impulse control symptoms / Delayed / Incidence not known
    hematoma / Early / Incidence not known
    bleeding / Early / Incidence not known
    platelet dysfunction / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    cataracts / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    osteopenia / Delayed / Incidence not known
    withdrawal / Early / Incidence not known
    growth inhibition / Delayed / Incidence not known

    Mild

    insomnia / Early / 10.0-33.0
    nausea / Early / 12.0-29.0
    headache / Early / 21.0-21.0
    asthenia / Delayed / 7.0-21.0
    diarrhea / Early / 8.0-18.0
    anorexia / Delayed / 4.0-17.0
    drowsiness / Early / 5.0-17.0
    anxiety / Delayed / 6.0-15.0
    tremor / Early / 3.0-13.0
    xerostomia / Early / 4.0-12.0
    yawning / Early / 1.0-11.0
    libido decrease / Delayed / 1.0-11.0
    dyspepsia / Early / 6.0-10.0
    pharyngitis / Delayed / 3.0-10.0
    dizziness / Early / 9.0-9.0
    hyperhidrosis / Delayed / 2.0-8.0
    urticaria / Rapid / 7.0-7.0
    rash (unspecified) / Early / 2.0-7.0
    sinusitis / Delayed / 1.0-6.0
    abnormal dreams / Early / 1.0-5.0
    flushing / Rapid / 1.0-5.0
    flatulence / Early / 3.0-3.0
    vomiting / Early / 3.0-3.0
    pruritus / Rapid / 3.0-3.0
    weight loss / Delayed / 2.0-2.0
    epistaxis / Delayed / 1.0-2.0
    fever / Early / 2.0-2.0
    hypersalivation / Early / 0.1-1.0
    polydipsia / Early / 0.1-1.0
    eructation / Early / 0.1-1.0
    paranoia / Early / 0.1-1.0
    vertigo / Early / 0.1-1.0
    hypoesthesia / Delayed / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    syncope / Early / 0.1-1.0
    breast enlargement / Delayed / 0.1-1.0
    orgasm dysfunction / Delayed / 0.1-1.0
    mastalgia / Delayed / 0.1-1.0
    menorrhagia / Delayed / 0.1-1.0
    libido increase / Delayed / 0.1-1.0
    breast discharge / Delayed / 0.1-1.0
    amenorrhea / Delayed / 0.1-1.0
    leukorrhea / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    skin discoloration / Delayed / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    alopecia / Delayed / 0.1-1.0
    malaise / Early / 0.1-1.0
    hyperventilation / Early / 0.1-1.0
    hiccups / Early / 0.1-1.0
    mydriasis / Early / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    nocturia / Early / 0.1-1.0
    polyuria / Early / 0.1-1.0
    urinary urgency / Early / 0.1-1.0
    arthralgia / Delayed / 0.1-1.0
    pelvic pain / Delayed / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    paresthesias / Delayed / 0-0.1
    hyporeflexia / Delayed / 0-0.1
    petechiae / Delayed / 0-0.1
    purpura / Delayed / 0-0.1
    pallor / Early / 0-0.1
    hirsutism / Delayed / 0-0.1
    seborrhea / Delayed / 0-0.1
    parosmia / Delayed / 0-0.1
    diplopia / Early / 0-0.1
    appetite stimulation / Delayed / 1.0
    weight gain / Delayed / 1.0
    dysgeusia / Early / 1.0
    emotional lability / Early / 1.0
    hyperkinesis / Delayed / 2.0
    agitation / Early / 1.0
    hypothermia / Delayed / 1.0
    chills / Rapid / 1.0
    otalgia / Early / 1.0
    tinnitus / Delayed / 1.0
    increased urinary frequency / Early / 1.0
    gynecomastia / Delayed / Incidence not known
    influenza / 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.
    Acarbose: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    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: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Minor) Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Acetaminophen; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    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 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 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. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions
    Acetaminophen; Propoxyphene: (Major) Fluoxetine may inhibit the metabolism of propoxyphene. Clinicians should be alert for an exaggerated opiate response if propoxyphene is given with fluoxetine.
    Acetaminophen; Tramadol: (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 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 a SSRI. Concomitant use of tramadol also increases the seizure risk in patients taking selective serotonin reuptake inhibitors (SSRIs). Post-marketing reports implicate the concurrent use of SSRIs with tramadol in some cases of seizures. Lastly, SSRIs such as fluoxetine may inhibit the formation of the active M1 metabolite of tramadol by inhibiting CYP2D6. 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. Patients receiving tramadol in combination with an SSRI should be monitored for the emergence of serotonin syndrome, neuroleptic malignant syndrome-like reactions, or other adverse effects.
    Albiglutide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Albuterol: (Minor) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Albuterol; Ipratropium: (Minor) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Alfentanil: (Moderate) Alfentanil is metabolized by the cytochrome P450 3A4 isoenzyme present in the liver. Inhibitors of CYP3A4, such as fluoxetine, may decrease systemic clearance of alfentanil leading to increased or prolonged effects. Close monitoring for oversedation and respiratory depression is warranted if a CYP3A4 inhibitor is used with alfentanil.
    Alfuzosin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include alfuzosin.
    Aliskiren; Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored. (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine 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. Co-administration of almotriptan and fluoxetine (60 mg daily for 8 days), a potent inhibitor of CYP2D6, had no effect on almotriptan clearance, but maximal concentrations of almotriptan were increased 18%. The difference is not considered clinically significant.
    Alogliptin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Alogliptin; Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Alogliptin; Pioglitazone: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Alpha-glucosidase Inhibitors: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Alprazolam: (Moderate) Clinical study results suggest that the interaction between alprazolam, a CYP3A4 substrate fluoxetine, a CYP3A4 inhibitor may be of clinical significance, and caution is recommended during co-administration. Concurrent use of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased the half-life by 17%, and decreased measured psychomotor performance. Monitor patients closely for excessive alprazolam-related side effects.
    Alteplase, tPA: (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 fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Amiodarone: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include amiodarone. In addition, amiodarone inhibits CYP2D6 and may theoretically increase concentrations of other drugs metabolized by this enzyme, such as fluoxetine.
    Amitriptyline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    Amitriptyline; Chlordiazepoxide: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Amlodipine: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Atorvastatin: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Benazepril: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored. (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored. (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Amlodipine; Olmesartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Telmisartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Amlodipine; Valsartan: (Moderate) Administering amlodipine with CYP3A4 inhibitors, such as fluoxetine, may increase the plasma concentration of amlodipine; this effect might lead to hypotension in some individuals. Caution should be used when fluoxetine is coadministered with amlodipine; therapeutic response should be monitored.
    Amoxapine: (Moderate) Selective serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6, the isoenzyme partially responsible for the metabolism of amoxapine. CYP2D6 is inhibited most by fluoxetine and least by citalopram and escitalopram. Norfluoxetine, the metabolite of fluoxetine, is also an inhibitor of CYP2D6. In several cases, symptoms of toxicity, including seizures, have been reported when the structurally related tricyclic antidepressants were 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 an SSRI is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7 to 9 days).
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include clarithromycin.
    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 fluoxetine and amphetamines. 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. The MAOI activity of amphetamines may also be of concern with the use of drugs that have serotonergic activity. All serotonergic agents should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. In addition, amphetamines and amphetamine derivatives are metabolized to some degree by CYP2D6 and a kinetic interaction is possible with strong CYP2D6 inhibitors, such as fluoxetine. Increased systemic exposure to amphetamines from CYP2D6 inhibition may result in high blood pressure, tachycardia, anxiety, irritability, insomnia, or other amphetamine-related adverse effects. Patients receiving fluoxetine and an amphetamine should be monitored for the emergence of serotonin syndrome or other adverse effects, particularly during treatment initiation and during dosage increases.
    Anagrelide: (Major) Coadministration may increase the risk of QT prolongation and torsade de pointes (TdP). TdP and ventricular tachycardia have been reported with both anagrelide and fluoxetine. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients for cardiovascular effects and evaluate as necessary. In addition, platelet aggregation may be impaired by 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. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include apomorphine.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if fluoxetine and aprepitant are used concurrently and monitor for an increase in fluoxetine-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Fluoxetine is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important. Fluoxetine is also a weak CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Aripiprazole: (Major) Because both fluoxetine and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. Also, fluoxetine is a potent inhibitor of CYP2D6, which may decrease the clearance of CYP2D6 substrates including aripiprazole. The manufacturer recommends that the oral aripiprazole dose be reduced by one-half when co-administered with potent inhibitors of CYP2D6. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if a potent CYP2D6 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP2D6 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. 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.
    Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as fluoxetine are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Arsenic Trioxide: (Major) Avoid coadministration of fluoxetine and arsenic trioxide. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide.
    Artemether; Lumefantrine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including artemether; lumefantrine. In addition, artemether is a substrate and fluoxetine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Lumefantrine is an inhibitor and fluoxetine is a substrate/inhibitor of the CYP2D6 isoenzyme; therefore, coadministration may lead to increased fluoxetine concentrations. Additionally, lumefantrine is a substrate and fluoxetine is an inhibitor of the CYP3A4 isoenzyme; therefore, concomitant use may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects.
    Asenapine: (Major) According to the manufacturer of asenapine, the drug should not be used with other drugs known to cause QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported during post-marketing use of fluoxetine. In addition, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of CYP2D6 and CYP3A4 substrates including asenapine. However, because asenapine is a primary substrate for CYP1A2, a clinically significant pharmacokinetic interaction is less likely to occur. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    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: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine. (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: (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. (Minor) Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    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. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine. (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. (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    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 fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and fluoxetine are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, atomoxetine is primarily metabolized by CYP2D6 and fluoxetine is a strong inhibitor of CYP2D6. In extensive metabolizers (EMs) taking atomoxetine who are treated concurrently with fluoxetine, the atomoxetine AUC is roughly 6-8 fold and Cmax 3-4 fold greater than if atomoxetine is given alone. In children and adolescents up to 70 kg receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), atomoxetine should be initiated at 0.5 mg/kg/day and only increased to the usual target dose of 1.2 mg/kg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. In children and adolescents over 70 kg and adults receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers, atomoxetine should be initiated at 40 mg/day and only increased to the usual target dose of 80 mg/day if symptoms fail to improve after 4 weeks and the initial dose is well tolerated. If concurrent use is necessary, monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation) during concurrent use.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine 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 fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine 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 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine 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.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with fluoxetine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with fluoxetine can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Axitinib: (Moderate) Use caution if coadministration of axitinib with fluoxetine is necessary, due to the risk of increased axitinib-related adverse reactions. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. According to the manufacturer, the inhibition of CYP3A4 by fluoxetine is not clinically significant; reported in vivo studies have been single-dose. However, active metabolite norfluoxetine is a moderate inhibitor of CYP3A4, and the possibility of clinically relevant drug interactions cannot be excluded. Fluoxetine is also a CYP2C19 inhibitor. Coadministration with a strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. The manufacturer of axitinib recommends a dose reduction in patients receiving strong CYP3A4 inhibitors, but recommendations are not available for moderate or weak CYP3A4 inhibitors.
    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    Azilsartan; Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Azithromycin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include azithromycin.
    Bedaquiline: (Major) 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. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with bedaquiline include fluoxetine.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Belladonna; Opium: (Major) Fluoxetine may inhibit the metabolism of opium. Clinicians should be alert for an exaggerated opiate response if opium is given with fluoxetine.
    Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Bendroflumethiazide; Nadolol: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine 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 fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine 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 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine 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: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including bepridil, via inhibition of CYP3A4 metabolism.
    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.
    Bicalutamide: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as fluoxetine, decrease the metabolism of bicalutamide and increase bicalutamide concentrations. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluoxetine.
    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) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluoxetine. (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 fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering fluoxetine with boceprevir due to an increased potential for boceprevir-related adverse events. If fluoxetine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of fluoxetine and boceprevir. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may be elevated.
    Bortezomib: (Minor) Agents that inhibit cytochrome P450 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with fluoxetine is not known.
    Bosentan: (Moderate) Bosentan is metabolized by CYP2C9 and CYP3A4. Fluoxetine may inhibit both of these isoenzymes and thereby increase the plasma concentrations of bosentan. It is prudent to monitor for potential adverse effects of bosentan during coadministration with fluoxetine; excessive dosage may result in hypotension or elevated hepatic enzymes.
    Brexpiprazole: (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving a strong CYP2D6 inhibitor and one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. It should be noted that no dosage adjustment is needed in patients taking a strong CYP2D6 inhibitor who are receiving brexpiprazole as adjunct treatment for major depressive disorder because CYP2D6 considerations are already factored into general dosing recommendations.
    Brimonidine; Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could theoretically impair timolol metabolism; the clinical significance of such interactions is unknown.
    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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Brompheniramine; Guaifenesin; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Budesonide: (Moderate) Avoid coadministration of oral budesonide and fluoxetine due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluoxetine a weak CYP3A4 inhibitor and the active metabolite norfluoxetine is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
    Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and fluoxetine due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; fluoxetine a weak CYP3A4 inhibitor and the active metabolite norfluoxetine is a moderate CYP3A4 inhibitor. In the presence of a strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Bumetanide: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine: (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4. (Minor) Bupivacaine is metabolized by CYP3A4 isoenzymes. Known inhibitors of CYP3A4, such as fluoxetine, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity.
    Buprenorphine: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Fluoxetine also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels 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 fluoxetine, 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 buprenorphine if serotonin syndrome is suspected. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as fluoxetine may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation, cautious use and close monitoring are advisable if concurrent use of fluoxetine and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). Fluoxetine also has a possible risk for QT prolongation and TdP. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels 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 fluoxetine, 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 buprenorphine if serotonin syndrome is suspected. In addition, since the metabolism of buprenorphine is mediated by CYP3A4, co-administration of a CYP3A4 inhibitor such as fluoxetine may decrease the clearance of buprenorphine resulting in prolonged or increased opioid effects. If co-administration is necessary, monitor patients for respiratory depression and sedation at frequent intervals and consider dose adjustments until stable drug effects are achieved. The effect of CYP3A4 inhibitors on buprenorphine implants has not been studied, and the effect may be dependent on the route of administration.
    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 fluoxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added.
    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 fluoxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added.
    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 fluoxetine. 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, buspirone is a primary CYP3A4 substrate and concurrent use with an inhibitor of CYP3A4, such as fluoxetine, may decrease systemic clearance of buspirone leading to increased or prolonged effects. If buspirone is administered with fluoxetine, a low initial dose of buspirone is advisable with subsequent dosage adjustments based on clinical response. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or other adverse effects. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
    Cabazitaxel: (Moderate) Fluoxetine is a mild CYP3A4 inhibitor. Cabazitaxel is a CYP3A4 substrate. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if cabazitaxel is coadministered with a mild or moderate CYP3A4 inhibitor; closely monitor patients for cabazitaxel-related toxicities.
    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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Canagliflozin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Canagliflozin; Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine 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 fluoxetine is necessary, and monitor for an increase in fluoxetine-related adverse reactions. Fluoxetine is a CYP2C9 substrate; 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 fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Carbamazepine: (Moderate) Carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Fluoxetine inhibits CYP3A4 and may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations.
    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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Cariprazine: (Major) The metabolite of fluoxetine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as cariprazine. Decreased metabolism of cariprazine may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as fluoxetine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Carvedilol: (Minor) Inhibitors of the hepatic CYP450 isozyme CYP 2D6, such as fluoxetine, may inhibit the hepatic oxidative metabolism of carvedilol.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and fluoxetine; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine.
    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.
    Chlordiazepoxide: (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Chlordiazepoxide; Clidinium: (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as fluoxetine, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    Chlorothiazide: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Chlorpheniramine; Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Minor) Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Minor) Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Chlorpromazine: (Major) Fluoxetine is associated with a possible risk of QT prolongation and torsade de pointes (TdP) and chlorpromazine also has an established risk of QT prolongation and TdP. Combination therapy with these agents should be avoided if possible. Fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum phenothiazine concentrations, which may lead to phenothiazine-related side effects such as cardiac side effects, hypotension, CNS sedation, or extrapyramidal symptoms. 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.
    Chlorthalidone: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Chlorthalidone; Clonidine: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine 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: (Major) Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to have pharmacokinetic interactions with many medications that are potent inhibitors of CYP3A4, including fluoxetine. These agents have been shown to increase both cilostazol AUC and Cmax when administered concurrently. When significant CYP3A4 inhibitors, such as fluoxetine, are administered concomitantly with cilostazol, the manufacturer recommends that the cilostazol dosage be reduced by 50%.
    Cimetidine: (Moderate) Although no clinical data are available, it is possible that inhibitors of hepatic enzymes such as cimetidine may decrease the metabolism of fluoxetine. Until more data are available, cimetidine should be used cautiously in patients receiving fluoxetine.
    Cinacalcet: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as fluoxetine.
    Ciprofloxacin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ciprofloxacin.
    Cisapride: (Severe) Cisapride is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit, and may inhibit the clearance of and potentiate the toxicity of cisapride. QT prolongation and ventricular arrhythmias, including torsade de pointes and death, have been reported when inhibitors of CYP3A4 are coadministered with cisapride. Due to the serious nature of cisapride toxicity, fluoxetine should be avoided in these patients.
    Citalopram: (Severe) Due to the similarity in pharmacology of fluoxetine and citalopram 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 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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include clarithromycin.
    Clobazam: (Moderate) A dosage reduction of clobazam and/or fluoxetine may be necessary during co-administration of clobazam and fluoxetine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and fluoxetine is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated. In addition, fluoxetine is a substrate of CYP2D6 and limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. A dosage reduction of CYP2D6 substrates may be necessary during co-administration of clobazam. It should be noted that because fluoxetine is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance.
    Clomipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    Clonazepam: (Moderate) Fluoxetine may inhibit CYP3A4 metabolism of oxidized benzodiazepines, including clonazepam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Clopidogrel: (Major) Use clopidogrel and fluoxetine together with caution and monitor for reduced clopidogrel effectiveness. Consider alternative therapy to fluoxetine, if possible. Fluoxetine may reduce the antiplatelet activity of clopidogrel through potent inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite. In a large cohort study of clopidogrel and concomitant CYP2C19-inhibiting selective serotonin reuptake inhibitors (SSRIs) (n = 9,281) vs. non-inhibiting SSRIs (n = 44,278), patients receiving concurrent CYP2C19-inhibiting SSRIs, such as fluoxetine, had an increased risk of composite ischemic events. This risk was more pronounced in patients 65 years and older. Additionally, because SSRIs affect platelet activation, concomitant use with clopidogrel may increase the risk of bleeding. In this study, bleeding events did occur in both groups; however, there were no meaningful differences in bleeding events between groups. Monitor for signs and symptoms of bleeding.
    Clorazepate: (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including clorazepate. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Clozapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Clozapine is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of CYP2D6 and CYP3A4 substrates including clozapine. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Decreased metabolism of clozapine may lead to clinically important adverse reactions such as seizures or orthostatic hypotension. According to the manufacturer of clozapine, concomitant use of clozapine and substrates or inhibitors of CYP2D6 may require lower doses of either drug. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    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.
    Cobimetinib: (Major) If concurrent use of cobimetinib and fluoxetine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and fluoxetine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Codeine: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    Codeine; Guaifenesin: (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    Codeine; Phenylephrine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine. (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    Codeine; Promethazine: (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine. (Moderate) The activity of codeine is due to its conversion to morphine via the CYP2D6 hepatic isoenzyme and therefore its analgesic effectiveness may vary greatly when combined with drugs that potently inhibit CYP2D6, such as fluoxetine.
    Conjugated Estrogens: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Bazedoxifene: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Conjugated Estrogens; Medroxyprogesterone: (Moderate) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Crizotinib: (Major) Monitor for an increase in crizotinib-related adverse reactions (e.g., vision disorders, diarrhea, increased transaminases, and neuropathy) if coadministration with fluoxetine is necessary; also monitor ECGs for QT prolongation and electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if the QTc interval is prolonged 500 msec or more or greater than 60 msec change from baseline. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Crizotinib has also been associated with QT prolongation. Additionally, crizotinib is primarily metabolized by CYP3A4/5; fluoxetine is a weak CYP3A4 inhibitor, while its metabolite norfluoxetine is a moderate inhibitor of CYP3A4. Coadministration with a strong CYP3A4 inhibitor increased the AUC and Cmax of crizotinib (single dose) by 3.2-fold and 1.4-fold, respectively; weak CYP3A4 inhibitors may also increase crizotinib exposure. The effect of CYP3A4 inhibitors on steady-state crizotinib exposure has not been evaluated.
    Cyclobenzaprine: (Major) Cyclobenzaprine is structurally similar to tricyclic antidepressants, which have been reported to prolong the QT interval, especially when given in excessive doses (or in overdosage). Because QT prolongation has been reported with both cyclobenzaprine and fluoxetine, concurrent use should be approached with caution. In addition, serotonin syndrome has been reported during concurrent use of cyclobenzaprine and SSRIs (e.g., fluoxetine) due to the serotonin-enhancing properties of both drugs. 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. Because of the potential risk and severity of serotonin syndrome, cautious use is recommended, particularly during initiation of treatment and dose increases. If serotonin syndrome occurs, cyclobenzaprine and fluoxetine should be discontinued immediately and supportive symptomatic treatment should be initiated.
    Cyclosporine: (Moderate) Fluoxetine is a CYP3A4 inhibitor and may decrease the clearance of cyclosporine, with the potential to cause cyclosporine toxicity, including nephrotoxicity or seizures, or require the downward dosage adjustment of 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.
    Dapagliflozin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Dapagliflozin; Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Dapagliflozin; Saxagliptin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Darifenacin: (Moderate) Fluoxetine inhibits CYP2D6 and CYP3A4. Serum concentrations of darifenacin, a CYP2D6 and CYP3A4 substrate, may increase when used in combination with fluoxetine. Patients should be monitored for increased anticholinergic effects if these drugs are coadministered.
    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.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Because both ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring for adverse effects is prudent. (Major) Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration. (Major) Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration.
    Dasatinib: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include dasatinib.
    Daunorubicin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Degarelix: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include degarelix.
    Delavirdine: (Minor) Delavirdine is metabolized by CYP2D6 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This interaction can result in substantial increases in the trough levels of delavirdine, up to a 50% increase.
    Desflurane: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
    Desipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    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. If serotonin syndrome is suspected, desvenlafaxine and concurrent serotonergic agents should be discontinued. Dosage adjustments of fluoxetine may be necessary during concurrent use of desvenlafaxine; the dose of CYP2D6 substrates should be reduced by up to one-half if co-administered with desvenlafaxine 400 mg/day.
    Deutetrabenazine: (Major) Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if must use concurrently with a strong CYP2D6 inhibitor, such as fluoxetine. For patients taking a deutetrabenazine dosage more than 24 mg/day with fluoxetine, assess the QTc interval before and after increasing the dosage of either medication. Fluoxetine is a strong CYP2D6 inhibitor, and the metabolites of deutetrabenazine, alpha- and beta-HTBZ, are CYP2D6 substrates. The systemic exposure of alpha- and beta-HTBZ may be increased resulting in an increase in deutetrabenazine-related adverse reactions, like QT prolongation and drowsiness. Clinically relevant QTc prolongation may occur with deutetrabenazine. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. 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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented. (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine.
    Dextromethorphan; Quinidine: (Severe) Concurrent use of either quinidine or dextromethorphan; quinidine and fluoxetine is considered a contraindication. Quinidine and dextromethorphan; quinidine are contraindicated for use in patients taking drugs that prolong the QT interval and are metabolized by CYP2D6. Fluoxetine is a primary substrate of CYP2D6, and is associated with a risk of QT prolongation and torsade de pointes (TdP). (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 fluoxetine. 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, fluoxetine has been shown to interfere with dextromethorphan metabolism leading to clinical toxicity that resembles serotonin syndrome. If serotonin syndrome occurs, all serotonergic agents should be discontinued and appropriate medical treatment should be implemented.
    Diazepam: (Moderate) Diazepam is metabolized by CYP2C19 and CYP3A4. Fluoxetine impairs both of these pathways at therapeutic doses. This can result in substantial increases in the half-life of diazepam, and the psychomotor and physiological response may be altered.
    Dienogest; Estradiol valerate: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Diethylpropion: (Major) Phentermine and diethylpropion have a similar mechanism of action. When phentermine was given with fluoxetine, adrenergic excess and dyskinesia were observed. Thus, diethylpropion may interact with fluoxetine similarly. It is unclear, however, if all SSRIs would be affected as fluoxetine has the longest half-life of the group.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Minor) Concomitant use of a potent CYP2D6 inhibitor like fluoxetine with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Dihydroergotamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Diltiazem: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers via inhibition of CYP3A4 metabolism.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including disopyramide. In addition, CYP3A4 inhibitors, such as fluoxetine may increase serum plasma concentrations of disopyramide, a CYP3A4 substrate. Monitor clinical response and serum disopyramide concentrations.
    Diuretics: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Docetaxel: (Minor) Docetaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of docetaxel.
    Dofetilide: (Severe) QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Because of the potential for TdP, use of fluoxetine with dofetilide is contraindicated.
    Dolasetron: (Major) Taking these drugs together may increases the risk for serotonin syndrome. If serotonin syndrome is suspected, discontinue dolasetron 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include dolasetron.
    Donepezil: (Major) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
    Donepezil; Memantine: (Major) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
    Dorzolamide; Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could theoretically impair timolol metabolism; the clinical significance of such interactions is unknown.
    Doxepin: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    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.
    Doxorubicin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Dronabinol, THC: (Moderate) Use caution if coadministration of dronabinol with fluoxetine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; fluoxetine is a weak inhibitor of CYP2C9 and 3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. A hypomanic episode was reported in a 21 year old female with depression and bulimia receiving fluoxetine 20 mg per day for 4 weeks after smoking marijuana. Her symptoms resolved in 4 days. Because dronabinol, THC is a synthetic analog of a naturally occurring substance found in marijuana, interactions with fluoxetine may also occur with dronabinol.
    Dronedarone: (Severe) QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Dronedarone administration is associated with a dose-related increase in the QTc interval. The concomitant use of dronedarone with fluoxetine may induce TdP and is contraindicated.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with droperidol include fluoxetine.
    Drospirenone; Estradiol: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    Dulaglutide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    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: (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of fluoxetine. Tamsulosin is extensively metabolized by CYP2D6 and CYP3A4 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Therefore, concomitant use with drugs that inhibit both CYP2D6 and CYP3A4, such as fluoxetine, should be avoided.
    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) Coadministration of efavirenz and fluoxetine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Fluoxetine administration is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz. Efavirenz is a CYP3A4 substrate, while fluoxetine is a mild CYP3A4 inhibitor.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of efavirenz and fluoxetine may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Fluoxetine administration is associated with QT prolongation and TdP. In addition, concurrent use may increase the systemic concentration of efavirenz. Efavirenz is a CYP3A4 substrate, while fluoxetine is a mild CYP3A4 inhibitor.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with fluoxetine may cause the plasma concentrations of elbasvir and grazoprevir to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Fluoxetine is a mild inhibitor of CYP3A; both elbasvir and grazoprevir are metabolized by CYP3A. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Eletriptan: (Major) The use of fluoxetine with eletriptan might increase eletriptan exposure. Eletriptan is metabolized by CYP3A4 and fluoxetine is a CYP3A4 inhibitor. 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) In poor CYP2D6 metabolizers (PMs), coadministration of fluoxetine and eliglustat is not recommended. In extensive or intermediate CYP2D6 metabolizers (EMs or IMs), concurrent use of these agents requires dosage reduction of eliglustat to 84 mg PO once daily; monitor patients closely and consider reducing the dosage of fluoxetine and titrating to clinical effect. Coadministration of eliglustat with both fluoxetine and a strong or moderate CYP3A inhibitor is contraindicated in all patients. Fluoxetine is a substrate and strong inhibitor of CYP2D6 and a weak inhibitor of CYP3A that is independently associated with QT prolongation and torsade de pointes (TdP). Eliglustat is a substrate and inhibitor of CYP2D6 and a CYP3A substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of fluoxetine and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of one or both drugs, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with even weak CYP3A inhibitors, such as fluoxetine, in this population may significantly increase eliglustat exposure and, hence, concurrent use is not recommended.
    Empagliflozin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Empagliflozin; Linagliptin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin.
    Empagliflozin; Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Fluoxetine may help to normalize blood glucose and increase insulin sensitivity. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including rilpivirine. In addition, close clinical monitoring is advised when administering fluoxetine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including rilpivirine. In addition, close clinical monitoring is advised when administering fluoxetine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Fluoxetine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
    Enalapril; Felodipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism.
    Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Encainide: (Moderate) Fluoxetine is a potent inhibitor of the hepatic CYP2D6 isoenzyme. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including encainide. Increased plasma antiarrhythmic drug concentrations may increase the risk of proarrhythmias.
    Enflurane: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
    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.
    Epirubicin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine 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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergonovine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergot alkaloids: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Ergotamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Eribulin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include eribulin.
    Erlotinib: (Moderate) Use caution if coadministration of erlotinib with fluoxetine is necessary due to the risk of increased erlotinib-related adverse reactions, and avoid coadministration with erlotinib if the patient is additionally taking a CYP1A2 inhibitor. If the patient is taking both fluoxetine and a CYP1A2 inhibitor and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements; the manufacturer of erlotinib makes the same recommendations for toxicity-related dose reductions in patients taking strong CYP3A4 inhibitors without concomitant CYP1A2 inhibitors. Fluoxetine is a weak CYP3A4 inhibitor, but its active metabolite, norfluoxetine, is a moderate inhibitor of CYP3A4. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Coadministration of erlotinib with ketoconazole, a strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. Coadministration of erlotinib with ciprofloxacin, a moderate inhibitor of CYP3A4 and CYP1A2, increased the erlotinib AUC by 39% and the Cmax by 17%; coadministration with fluoxetine may also increase erlotinib exposure.
    Erythromycin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include erythromycin.
    Erythromycin; Sulfisoxazole: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include erythromycin.
    Escitalopram: (Severe) Due to the similarity in pharmacology of fluoxetine 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 fluoxetine 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: (Minor) Fluoxetine may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
    Esomeprazole; Naproxen: (Minor) Fluoxetine may inhibit the CYP2C19 isoenzyme, leading to increased plasma levels of drugs that are substrates for the CYP2C19 isoenzyme, such as esomeprazole.
    Esterified Estrogens: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Esterified Estrogens; Methyltestosterone: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Estradiol Cypionate; Medroxyprogesterone: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Levonorgestrel: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norethindrone: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estradiol; Norgestimate: (Minor) As fluoxetine inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when coadministered with either estrogens or combined hormonal contraceptives.
    Estropipate: (Minor) Estrogens are partially metabolized by CYP3A4. Drugs that inhibit CYP3A4 such as fluoxetine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness. Patients receiving estrogens should be monitored for an increase in adverse events.
    Eszopiclone: (Moderate) Patients should be advised of the potential for next-day psychomotor and/or memory impairment during co-administration of eszopiclone and CYP3A4 inhibitors, such as fluoxetine or fluvoxamine. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
    Ethacrynic Acid: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    Etoposide, VP-16: (Minor) Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with fluoxetine. Fluoxetine is a weak inhibitor of CYP3A4 and etoposide, VP-16 is a CYP3A4 substrate. Coadministration may increase etoposide concentrations. This also applies to combination products containing fluoxetine, such as fluoxetine; olanzapine.
    Everolimus: (Major) Everolimus is a substrate of CYP3A4. Coadministration with weak inhibitors of CYP3A4, such as fluoxetine, is not recommended. Patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. In addition, everolimus is a mixed inhibitor of CYP2D6. The effect of everolimus on a CYP2D6 substrate, such as fluoxetine, has not been established.
    Exenatide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Ezogabine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ezogabine.
    Felodipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism.
    Fenofibric Acid: (Minor) As fenofibric acid is a mild-to-moderate inhibitor of CYP2C9 and CYP2C19; while fluoxetine is a substrate of both. Although not formally studied, co-administration may lead to increased fluoxetine plasma concentrations and toxicity. Monitor the therapeutic effect of fluoxetine 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. In addition, fentanyl is metabolized by CYP3A4 and concurrent use of inhibitors of this isoenzyme, such as fluoxetine, may increase the bioavailability of fentanyl leading to increased or prolonged effects such as respiratory depression. Careful monitoring is recommended during co-administration of fentanyl and SSRIs for signs and symptoms of serotonin syndrome or other serious effects.
    Fesoterodine: (Minor) Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. Although not studied, the weak CYP3A4 inhibitory effects of fluoxetine, in theory, may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. Of note, the manufacturer does not recommend dosage adjustments of fesoterodine during concurrent use of moderate CYP3A4 inhibitors.
    Fingolimod: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include fingolimod.
    Flecainide: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Flecainide is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine is a potent CYP2D6 inhibitor, and increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including flecainide, can occur. Increased plasma antiarrhythmic drug concentrations may increase the risk of proarrhythmias.
    Flibanserin: (Major) The concomitant use of flibanserin and a strong CYP2C19 inhibitor or multiple weak CYP3A4 inhibitors, including fluoxetine, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fluconazole: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include fluconazole.
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Olanzapine has a possible risk of QT prolongation and TdP; however, fluoxetine and olanzapine are commonly used together in a commercially available combination product for treating certain mood disorders. Fluoxetine, a CYP2D6 inhibitor, minimally increases the systemic exposure to olanzapine, a CYP2D6 substrate (mean increase in maximum olanzapine concentration of 16% and mean decrease in olanzapine clearance of 16%). Dose modifications are not required based upon this kinetic interaction.
    Fluphenazine: (Moderate) Because fluphenazine and some SSRIs including 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. In addition, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum phenothiazine concentrations, leading to side effects. 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.
    Flurazepam: (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including flurazepam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Fluticasone; Salmeterol: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Fluvastatin: (Moderate) In theory, concurrent use CYP2C9 inhibitors, such as fluoxetine, and fluvastatin, a CYP2C9 substrate, may result in reduced metabolism of fluvastatin and potential for toxicity including myopathy and rhabdomyolysis.
    Fluvoxamine: (Severe) Due to the similarity in pharmacology of fluoxetine 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 fluoxetine 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.
    Folic Acid, Vitamin B9: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    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.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with fluoxetine. Fluoxetine is an inhibitor of CYP2C9 and CYP3A4, two isoenzymes responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with fluoxetine the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Formoterol; Mometasone: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as fluoxetine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have also been reported in patients treated with fluoxetine. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Fosphenytoin: (Major) Cytochrome CYP2C19 is one of two pathways by which hydantoins are metabolized, and fluoxetine inhibits this pathway. Hydantoin toxicity has been described in several patients after the addition of fluoxetine.
    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 fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Galantamine: (Moderate) A population pharmacokinetic analysis showed that the clearance of galantamine was decreased by 25% to 33% during coadministration of certain CYP2D6 inhibitors including fluoxetine (n = 48). The CYP2D6 isoenzyme is partially involved in the metabolism of galantamine. The clinical relevance of this interaction is unknown; however, increased galantamine concentrations could potentially result in dose-related toxicity.
    Gemifloxacin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include gemifloxacin.
    Gemtuzumab Ozogamicin: (Major) Avoid coadministration of gemtuzumab ozogamicin with fluoxetine due to the potential for additive QT interval prolongation and risk of torsade de Use gemtuzumab ozogamicin and fluoxetine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    Glipizide; Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Glyburide; Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Glycopyrrolate; Formoterol: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Goserelin: (Major) Fluoxetine should be used cautiously and with close monitoring with goserelin. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. 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) Because of the potential risk and severity of serotonin syndrome, use caution when administering granisetron with other drugs that have serotonergic properties such as fluoxetine. If serotonin syndrome is suspected, discontinue granisetron 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include granisetron.
    Guaifenesin; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, such as fluoxetine, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically
    Halogenated Anesthetics: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
    Haloperidol: (Major) Fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of antipsychotics that are CYP2D6 and CYP3A4 substrates including haloperidol. Decrease metabolism of haloperidol can result in adverse effects associated with haloperidol use including dizziness, impaired psychomotor performance, and extrapyramidal symptoms. In addition, haloperidol is associated with a risk for QT prolongation and TdP, and should be used cautiously with potent CYP2D6 inhibitors such as fluoxetine. Because symptoms consistent with elevated haloperidol levels have been observed during co-administration of SSRIs, patients receiving these combinations should be carefully monitored for adverse effects. The effects of fluoxetine on hepatic metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    Halothane: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
    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.
    Homatropine; Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Losartan: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia. (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) Coadministration of metoprolol, a primary substrate of CYP2D6, and fluoxetine, a potent CYP2D6 inhibitor, may result in significantly increased metoprolol serum concentrations. Monitor for bradycardia, reduced blood pressure, and increased side effects of metoprolol if coadministered with fluoxetine. An increase in metoprolol serum concentrations would decrease the cardioselectivity of metoprolol. One report noted an interaction between fluoxetine and metoprolol in which bradycardia occurred in a patient receiving metoprolol after fluoxetine was added. The patient had not previously experienced this reaction while on either drug alone. The authors postulated that fluoxetine may have inhibited hepatic metabolism of metoprolol. (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia. (Moderate) Propranolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as fluoxetine, could impair propranolol metabolism. Bradycardia has occurred in a patient receiving propranolol after fluoxetine was added. Monitor for decreased blood pressure, reduced heart rate, or for other propranolol-induced side effects if these drugs are coadministered.
    Hydrochlorothiazide, HCTZ; Quinapril: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Triamterene: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrochlorothiazide, HCTZ; Valsartan: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Hydrocodone: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Ibuprofen: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Phenylephrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydrocodone; Pseudoephedrine: (Minor) The metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as fluoxetine, may result in a reduction in the analgesic effect of hydrocodone.
    Hydromorphone: (Major) Fluoxetine may inhibit the metabolism of hydromorphone. Clinicians should be alert for an exaggerated opiate response if hydromorphone is given with fluoxetine.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and fluoxetine. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include fluoxetine.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine 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 fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine 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 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine 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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include ibutilide.
    Idarubicin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
    Iloperidone: (Major) Fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate CYP3A4 inhibitor, which may result in decreased clearance of atypical antipsychotics that are CYP2D6 and CYP3A4 substrates including iloperidone. Decreased metabolism of iloperidone may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. In addition, iloperidone is associated with a risk for QT prolongation and TdP, and should be used cautiously with potent CYP2D6 inhibitors such as fluoxetine. In one study, concurrent use of fluoxetine (20 mg twice daily for 21 days) and iloperidone (3 mg single dose) in CYP2D6 extensive metabolizers increased the AUC of iloperidone and its metabolite P88 by 2- to 3-fold, and decreased the AUC of its metabolite P95 by one-half. The manufacturer of iloperidone recommends that the iloperidone dose be reduced by one-half during concurrent use of a potent CYP2D6 inhibitor such as fluoxetine. If fluoxetine is subsequently withdrawn, the iloperidone dose should be returned to the previous amount. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    Imatinib: (Moderate) Agents that inhibit cytochrome P450 3A4, such as fluoxetine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
    Imipramine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering fluoxetine 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. In addition, because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. Pharmacokinetic interactions between fluoxetine and TCAs may also occur. Various combinations of CYP2D6 with other hepatic isoenzymes, such as CYP2C19, CYP1A2, CYP3A4, and CYP2C9, are involved in the metabolism of TCAs. Fluoxetine is a potent inhibitor of CYP2D6, and may also cause clinically relevant inhibition of CYP3A4 and CYP2C19. At least one case report exists of a death thought to be due to impaired clearance of amitriptyline by fluoxetine. Patients receiving a tricyclic antidepressant should be monitored closely for toxicity if fluoxetine is added. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    Incretin Mimetics: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Indacaterol: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Indapamide: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with fluoxetine due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    Insulin Degludec; Liraglutide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Insulin Glargine; Lixisenatide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Insulins: (Moderate) Monitor patients receiving fluoxetine concomitantly with insulin for changes in glycemic control. Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents.
    Irinotecan Liposomal: (Moderate) Use caution if irinotecan liposomal is coadministered with fluoxetine, a weak CYP3A4 inhibitor, due to a possible increased risk of irinotecan-related toxicity. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
    Irinotecan: (Moderate) Fluoxetine is a mild inhibitor of CYP3A4; irinotecan is a CYP3A4 substrate. Coadministration may result in increased irinotecan exposure. Use caution if concomitant use is necessary and monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with fluoxetine may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; fluoxetine is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include halogenated anesthetics.
    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 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. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Isoniazid, INH; Pyrazinamide, PZA; 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 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. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Isoniazid, INH; 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 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. If combination therapy is necessary, patients should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions.
    Isradipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including isradipine, via inhibition of CYP3A4 metabolism.
    Itraconazole: (Major) Itraconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with itraconazole include fluoxetine.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and fluoxetine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; norfluoxetine, the active metabolite of fluoxetine, inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
    Ixabepilone: (Moderate) Fluoxetine is a mild CYP3A4 inhibitor. Ixabepilone is a CYP3A4 substrate, and concomitant use of ixabepilone with mild or moderate CYP3A4 inhibitors has not been studied. Alternative therapies that do not inhibit the CYP3A4 isoenzyme should be considered. Caution is recommended if ixabepilone is coadministered with fluoxetine; closely monitor patients for ixabepilone-related toxicities.
    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) Ketoconazole has been associated with prolongation of the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include fluoxetine.
    Lapatinib: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include lapatinib.
    Lenvatinib: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Lesinurad: (Moderate) Use lesinurad and fluoxetine together with caution; fluoxetine may increase the systemic exposure of lesinurad. Fluoxetine is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Lesinurad; Allopurinol: (Moderate) Use lesinurad and fluoxetine together with caution; fluoxetine may increase the systemic exposure of lesinurad. Fluoxetine is a mild inhibitor of CYP2C9, and lesinurad is a CYP2C9 substrate.
    Leuprolide: (Major) 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include fluoxetine.
    Leuprolide; Norethindrone: (Major) 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. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include fluoxetine.
    Levalbuterol: (Minor) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Levofloxacin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include levofloxacin.
    Levomefolate: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    Levomefolate; Mecobalamin; Pyridoxal-5-phosphate: (Minor) Levomefolate and fluoxetine should be used together cautiously. Fluoxetine is a noncompetitive inhibitor of levomefolate active transport in the intestines. Monitor patients for decreased efficacy of levomefolate if these agents are used together.
    Levomethadyl: (Major) Fluoxetine may inhibit the metabolism of levomethadyl via cytochrome P450 CYP3A4. Increased concentrations of levomethadyl may predispose patients to the development of serious arrhythmias.
    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.
    Levorphanol: (Major) Fluoxetine may inhibit the metabolism of levorphanol. Clinicians should be alert for an exaggerated opiate response if levorphanol is given with fluoxetine.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and fluoxetine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; fluoxetine inhibits CYP3A4.
    Linagliptin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin.
    Linagliptin; Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of insulin and other antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents, such as linagliptin.
    Linezolid: (Severe) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with linezolid, fluoxetine 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 five weeks or until 24 hours after the last dose of linezolid, whichever comes first. Fluoxetine 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 fluoxetine 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.
    Liraglutide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Lithium: (Major) Lithium is an effective augmenting agent to antidepressants in treatment-resistant depression; however, lithium has been associated with QT prolongation and should be used cautiously and with close monitoring with other drugs having the potential to prolong the QT interval such as fluoxetine. In addition, lithium has been reported to have central serotonin-enhancing effects and may interact pharmacodynamically with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine 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, fluoxetine and lithium should be discontinued and symptomatic treatment should be initiated. Fluoxetine has been reported to increase or decrease lithium concentrations. 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.
    Lixisenatide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of incretin mimetics. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Lomitapide: (Major) Concomitant use of lomitapide and fluoxetine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Fluoxetine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Long-acting beta-agonists: (Moderate) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Loperamide: (Major) Loperamide should be used cautiously and with close monitoring with fluoxetine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). In addition, the plasma concentrations of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with fluoxetine, a CYP3A4 and 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 effects.
    Loperamide; Simethicone: (Major) Loperamide should be used cautiously and with close monitoring with fluoxetine. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). In addition, the plasma concentrations of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with fluoxetine, a CYP3A4 and 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 effects.
    Lopinavir; Ritonavir: (Major) Because both ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring for adverse effects is prudent. (Major) Because lopinavir; ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring of SSRI therapeutic and adverse effects is prudent.
    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.
    Losartan: (Minor) Inhibitors of the hepatic CYP2C9 isoenzyme, such as fluoxetine, have potential to inhibit the conversion of losartan to its active metabolite. Monitor therapeutic response to individualize losartan dosage.
    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: (Minor) Although an interaction between ivacaftor and fluoxetine is possible, the clinical impact of this interaction has not yet been determined. Increased monitoring is recommended if ivacaftor is administered concurrently with CYP2C9 substrates. Fluoxetine is partially metabolized by CYP2C9, but it is also a substrate for at least 2 other enzymes. In vitro studies showed ivacaftor to be a weak inhibitor of CYP2C9. Co-administration may possibly lead to increased exposure to fluoxetine; however, because fluoxetine has multiple metabolic pathways, the clinical impact of this inhibition is not clear. In addition, ivacaftor is a CYP3A substrate, and fluoxetine is a mild CYP3A inhibitor. Co-administration may lead to increased ivacaftor exposure.
    Lumacaftor; Ivacaftor: (Minor) Concomitant use of fluoxetine and lumacaftor; ivacaftor may alter fluoxetine exposure; caution and close monitoring are advised if these drugs are used together. Fluoxetine is a substrate of CYP2C9 and CYP2C19. In vitro data suggest that lumacaftor; ivacaftor may induce CYP2C19 and induce and/or inhibit CYP2C9. Although induction of fluoxetine through the CYP2C19 pathway could potentially lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on CYP2C9-mediated metabolism is not clear. Monitor the patient for decreased fluoxetine efficacy or increased or prolonged therapeutic effects and adverse events. Of note, norfluoxetine, the active metabolite of fluoxetine, is a moderate CYP3A inhibitor. Although lumacaftor; ivacaftor is a primary substrate of CYP3A, lumacaftor; ivacaftor dosage adjustment is not required.
    Lurasidone: (Major) The metabolite of fluoxetine is a moderate CYP3A4 inhibitor and may decrease the clearance of CYP3A4 substrates such as lurasidone. Decreased metabolism of lurasidone may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity. The effects of fluoxetine on the metabolism of interacting drugs may persist for several weeks after discontinuation of fluoxetine because of its long elimination half-life.
    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) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including maprotiline. In addition, clinicians should be alert for pharmacokinetic or pharmacodynamic interactions between cyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants. The SSRIs are known to inhibit CYP2D6 and/or CYP3A4, the isozymes responsible for metabolism of many of the cyclic antidepressants. CYP2D6 is impaired most by fluoxetine and is the isozyme most responsible for metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. Patients receiving maprotiline should be monitored closely for toxicity if a SSRI-type drug is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7-9 days).
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with fluoxetine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and fluoxetine is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Meclizine: (Moderate) Meclizine is metabolized by CYP2D6, fluoxetine is a CYP2D6 inhibitor. Concomitant use may increase meclizine plasma concentrations which may intensify its sedative and anticholinergic effects.
    Mefloquine: (Major) Mefloquine is metabolized by CYP3A4. Inhibitors of this enzyme, such as fluoxetine, may decrease the clearance of mefloquine and increase mefloquine systemic exposure. Fluoxetine has also been reported to prolong the QT 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. This interaction is also relevant to combination drugs containing fluoxetine, such as fluoxetine; olanzapine. Olanzapine may also increase the QT interval.
    Meglitinides: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Melatonin: (Moderate) It is unknown if melatonin would interact with psychotropic medications. One limited 4-week study in depressed patients with insomnia noted no interactions when melatonin was added to fluoxetine therapy. However, one case report of excessive melatonin ingestion in combination with fluoxetine therapy resulted in a case of acute psychosis that resolved within 24 hours of melatonin ingestion. The possibility of pharmacodynamic or pharmacokinetic interaction between fluoxetine and melatonin should be considered in this case.
    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. (Major) Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include fluoxetine.
    Mesoridazine: (Severe) Fluoxetine is contraindicated for use with some phenothiazine antipsychotics including thioridazine and mesoridazine. Mesoridazine has an established risk of QT prolongation and torsade de pointes (TdP), and post-marketing reports suggest a possible risk of QT prolongation and TdP with fluoxetine. In addition, the phenothiazine metabolism may be decreased during use of CYP2D6 inhibitors such as fluoxetine. Due to the long half-life of fluoxetine and its active metabolite, mesoridazine should not be initiated within 5 weeks after discontinuing fluoxetine. Decreased metabolism of these CYP2D6 substrates by fluoxetine may also lead to arrhythmias or other clinically important adverse reactions such as extrapyramidal symptoms.
    Metaproterenol: (Minor) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include beta-agonists.
    Metformin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Metformin; Pioglitazone: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Metformin; Repaglinide: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Metformin; Rosiglitazone: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Metformin; Saxagliptin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents. (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Metformin; Sitagliptin: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    Methadone: (Major) QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine; therefore, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Methadone is associated with a possible risk of QT prolongation and TdP. In addition, fluoxetine may inhibit the metabolism of methadone via CYP3A4 or CYP2D6. In patients treated with methadone and fluoxetine, the plasma concentration of methadone increased. Interestingly in patients treated with methadone, the R-enantiomer (the active moiety) was increased by the addition of fluoxetine. Patients may experience increases in CNS depressive effects or respiratory depression. Thus, methadone-treated patients receiving SSRIs should be carefully monitored and dosage adjustment should be undertaken if warranted.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine 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 fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine 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 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine 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 fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Methylene Blue: (Severe) According to the manufacturer of fluoxetine, treatment initiation with fluoxetine 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 fluoxetine (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving fluoxetine and requiring urgent treatment with IV methylene blue, fluoxetine 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 5 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Fluoxetine 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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    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: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering SSRIs with other drugs that have serotonergic properties such as ergot alkaloids (e.g., ergotamine or dihydroergotamine). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. In addition, fluoxetine and fluvoxamine may reduce the metabolism of ergotamine, dihydroergotamine or methysergide via inhibition of the hepatic CYP3A4 isoenzyme, potentially increasing the risk of ergot-related side effects. Administration of fluoxetine or fluvoxamine with other ergot alkaloids, like ergonovine or methylergonovine, may also need to be approached with caution. Avoid coadministration of ergot alkaloids with fluoxetine or when possible; be alert for excessive serotonergic effects or ergotism when co-use is not avoidable.
    Metoclopramide: (Major) Metoclopramide is a substrate of CYP2D6 and fluoxetine is a strong CYP2D6 inhibitor; due to the risk of increased metoclopramide plasma concentrations and extrapyramidal adverse reactions, dose adjustments of oral metoclopramide are recommended when administered in combination with strong CYP2D6 inhibitors. In addition, 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 patients with gastroesophageal reflux receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily or 10 mg PO three times daily. In patients with diabetic gastroparesis receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily times daily. Healthy patients given 20 mg of metoclopramide and 60 mg of fluoxetine for 8 days had a 40% and 90% increase in metoclopramide Cmax and AUC, respectively, compared to patients who received metoclopramide alone.
    Metolazone: (Moderate) Patients receiving a diuretic during treatment with fluoxetine 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 fluoxetine should be considered in patients who develop symptomatic hyponatremia.
    Metoprolol: (Moderate) Coadministration of metoprolol, a primary substrate of CYP2D6, and fluoxetine, a potent CYP2D6 inhibitor, may result in significantly increased metoprolol serum concentrations. Monitor for bradycardia, reduced blood pressure, and increased side effects of metoprolol if coadministered with fluoxetine. An increase in metoprolol serum concentrations would decrease the cardioselectivity of metoprolol. One report noted an interaction between fluoxetine and metoprolol in which bradycardia occurred in a patient receiving metoprolol after fluoxetine was added. The patient had not previously experienced this reaction while on either drug alone. The authors postulated that fluoxetine may have inhibited hepatic metabolism of metoprolol.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include fluoxetine.
    Mexiletine: (Moderate) Fluoxetine is a potent inhibitor of the hepatic CYP2D6 isoenzyme. Inhibition of CYP2D6 can result in increased concentrations of antiarrhythmic drugs metabolized via the same pathway, including mexiletine. Increased plasma concentrations may increase the risk of proarrhythmias.
    Midazolam: (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including midazolam. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
    Midostaurin: (Major) The concomitant use of midostaurin and fluoxetine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. Electrolyte imbalances should be corrected prior to initiating treatment with fluoxetine. Discontinue fluoxetine and obtain prompt cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation and ventricular arrhythmias, including torsade de pointes, have been reported in patients treated with fluoxetine.
    Mifepristone, RU-486: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include mifepristone, RU-486.
    Miglitol: (Moderate) Fluoxetine may enhance the hypoglycemic effects of antidiabetic agents. Serum glucose should be monitored closely when fluoxetine is added to any regimen containing antidiabetic agents.
    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 isoenzymes such as fluoxetine may be increased when co-administered with mirabegron. Fluoxetine is primarily metabolized by CYP2D6. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) Concomitant use of mirtazapine and fluoxetine may increase the risk of serotonin syndrome, QT prolongation, and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. 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 fluoxetine 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.
    Modafinil: (Moderate) Although no clinical data are available, fluoxetine may inhibit the clearance and potentiate the actions of modafinil. Modafinil is metabolized by CYP3A4 isozyme, a pathway that fluoxetine is known to inhibit.
    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 fluoxetine, 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 fluoxetine 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 fluoxetine, 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 fluoxetine should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated.
    Moxifloxacin: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP include moxifloxacin.
    Nabilone: (Minor) A hypomanic episode was reported in a 21 year old female with depression and bulimia receiving fluoxetine 20 mg/day for 4 weeks after smoking marijuana. Her symptoms resolved in 4 days. This interaction may also occur with nabilone which is a synthetic analog of a naturally occurring substance found in marijuana.
    Nanoparticle Albumin-Bound Paclitaxel: (Minor) Paciltaxel is metabolized by cytochrome P450 3A enzymes. Drugs that inhibit the CYP3A enzymes, such as fluoxetine, can significantly reduce the metabolism of paclitaxel.
    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: (Major) Avoid the concomitant use of nebivolol and fluoxetine. Nebivolol is metabolized by CYP2D6; fluoxetine inhibits CYP2D6. An 8-fold increase in the AUC and a 3-fold increase in Cmax for d-nebivolol was seen when a daily dose of fluoxetine 20 mg was administered to healthy volunteers for 21 days prior to the administration of a single 10 mg dose of nebivolol. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nebivolol; Valsartan: (Major) Avoid the concomitant use of nebivolol and fluoxetine. Nebivolol is metabolized by CYP2D6; fluoxetine inhibits CYP2D6. An 8-fold increase in the AUC and a 3-fold increase in Cmax for d-nebivolol was seen when a daily dose of fluoxetine 20 mg was administered to healthy volunteers for 21 days prior to the administration of a single 10 mg dose of nebivolol. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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 fluoxetine. 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; 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 fluoxetine. 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.
    Nicardipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nicardipine, via inhibition of CYP3A4 metabolism.
    Nifedipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nifedipine, via inhibition of CYP3A4 metabolism.
    Nilotinib: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including nilotinib. In addition, nilotinib may inhibit CYP2D6 and may theoretically increase serum concentrations of fluoxetine. Patients should be monitored for toxicity if nilotinib is administered with CYP2D6 substrates such as fluoxetine.
    Nimodipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including nimodipine, via inhibition of CYP3A4 metabolism.
    Nintedanib: (Moderate) Fluoxetine is a mild inhibitor of CYP3A4 and nintedanib is a minor CYP3A4 substrate. Coadministration may increase the concentration and clinical effect of nintedanib. If concomitant use of fluoxetine and nintedanib is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity, elevated liver enzymes, and hypertension. A d