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  • CLASSES

    Selective Serotonin Reuptake Inhibitor Antidepressants, SSRIs

    BOXED WARNING

    Children, growth inhibition, suicidal ideation

    Fluoxetine is indicated for the treatment of major depressive disorder (MDD) in adolescents and children 8 years of age and older and for the treatment of obsessive-compulsive disorder (OCD) in pediatric patients 7 years of age and older. The safety and effectiveness of fluoxetine in children less than 7 years of age have not been established. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of fluoxetine may be necessary in patients with emerging suicidality or worsening depression. 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

    Oral selective serotonin reuptake inhibitor (SSRI) antidepressant
    Indicated for depression, obsessive-compulsive disorder (OCD), panic disorder, bulimia nervosa, and premenstrual dysphoric disorder in adults; used for depression and OCD in pediatric patients
    Increased risk of suicidality in pediatrics and young adults during treatment initiation

    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 (immediate-release 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. Max: 80 mg/day PO. May divide daily dose into 2 doses (e.g., morning and noon) if the dosage is 20 mg/day or more. Generally, acute episodes of depression require several months of sustained pharmacologic therapy. Periodically reassess the need for continued treatment. Guidance on the appropriate length of treatment is available through the American Psychiatric Association treatment guidelines for patients with major depressive disorder.

    Children and Adolescents 8 to 17 years

    10 to 20 mg PO once daily. An initial dose of 10 mg/day may be appropriate in lower weight children; increase to 20 mg/day after 1 week. Usual effective dose: 10 to 20 mg/day. Increase dose by 10 to 20 mg increments if clinical improvement is not sufficient; full effect may take 4 weeks or longer. Max: 60 mg/day. May divide daily dose into 2 doses (e.g., morning and noon) if the dosage is 20 mg/day or more. Periodically reassess 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 reassess the need for continued treatment. Guidance on the appropriate length of treatment is available through the American Psychiatric Association treatment guidelines for patients with major depressive disorder.

    For treatment-resistant depression in combination with olanzapine.
    Oral dosage (immediate-release capsules, tablets, or oral solution)
    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. Periodically reassess the need for continued treatment. 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. Periodically reassess the need for continued treatment. 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 (immediate-release capsules, tablets, or oral solution; e.g., Prozac)
    Adults

    20 mg PO once daily initially. Consider a dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer.  The recommended range is 20 to 60 mg/day. A less frequent or lower dosage should be considered for geriatric adults. Max: 80 mg/day PO. May divide into 2 doses (e.g., morning and noon), for daily dosages greater than 20 mg/day.

    Children and Adolescents 7 years and older

    10 mg/day PO initially. In higher weight pediatric patients, increase to 20 mg/day after 2 weeks; may increase the dosage after several more weeks if insufficient response. 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 response 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, may increase further  if clinical improvement is not observed. A less frequent or lower dosage should be considered for geriatric adults. Max: 60 mg/day; higher doses have not been studied in panic disorder. In clinical trials, the most common dose was 20 mg/day. May divide into 2 doses (morning and noon) for daily doses above 20 mg/day.

    Children and Adolescents 8 years and older†

    Usual starting dose is 10 mg/day PO, followed by titration after several weeks. Published data are extremely limited. In one open-label evaluation (n = 9) the mean dose 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 improvement ("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 (immediate-release capsules, tablets, or oral solution; e.g., Prozac)
    Adults

    The initial and recommended dose is 60 mg PO once daily, administered in the morning. In clinical trials, doses less than 60 mg/day were not effective in reducing binge eating and vomiting. For some patients, including geriatric adults, it may be necessary to titrate up to this dosage over several days. Doses above 60 mg/day PO have not been systematically studied in patients with bulimia. Following a short-term, placebo-controlled trial, patients enrolled in the 52-week relapse prevention continuation phase receiving fluoxetine 60mg/day experienced a significantly longer time to relapse than those receiving placebo.

    Children and Adolescents 12 years and older†

    Data are limited. 20 mg/day PO initially, then titrated by 20 mg/day every 3 days to a maximum dose of 60 mg/day PO is a suggested dose. In one small study of 10 adolescent females with a diagnosis of bulimia nervosa (BN) or eating disorder not otherwise specified (EDNOS), this regimen was associated with a significant decrease in the core behavioral symptoms of BN (e.g., binging, purging) and was used along with supportive psychotherapy. Although further research is needed, the study was consistent with the known effective dose for BN 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

    Dosage not established. 20 to 40 mg PO once daily has been studied. Clinical practice guidelines classify fluoxetine as having inadequate or conflicting data to support or refute use for migraine prophylaxis.

    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: 60 mg/day PO. 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 year: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    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.

    Oral Solid Formulations

    Immediate-release capsules or tablets: Initially, administer in the morning. Doses greater than 20 mg/day may be taken as one daily dose or divided into two doses (e.g., in the morning and at noon).
     
    Delayed-Release Capsules (e.g., Prozac Weekly): Administer on the same day of the week each week. Patients should swallow the capsule whole; do not crush, cut, or chew.

    Oral Liquid Formulations

    Oral solution: To ensure accurate dosing, measure dosage with a calibrated measuring device. Initially, administer in the morning. Doses greater than 20 mg/day may be taken as one daily dose or divided into two doses (e.g., in the morning and at noon).

    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 indicated for the treatment of major depressive disorder (MDD) in adolescents and children 8 years of age and older and for the treatment of obsessive-compulsive disorder (OCD) in pediatric patients 7 years of age and older. The safety and effectiveness of fluoxetine in children less than 7 years of age have not been established. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of fluoxetine may be necessary in patients with emerging suicidality or worsening depression. 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.

    Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, diarrhea, electrolyte imbalance, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypothermia, hypothyroidism, long QT syndrome, myocardial infarction, pheochromocytoma, poor metabolizers, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, stroke, systemic lupus erythematosus (SLE), ventricular arrhythmias

    QT prolongation and ventricular arrhythmias, including torsade de pointes, have been reported in patients treated with fluoxetine. 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. 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. Use fluoxetine with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to prolong the QT interval. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) 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. Use fluoxetine with caution in patients with conditions that may increase the risk of QT prolongation including hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances; correct electrolyte imbalances prior to initiating treatment. Caution is recommended when treating patients at risk for a significant electrolyte imbalance (e.g., diuretic therapy, diarrhea).

    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.

    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 after careful consideration of the maternal benefits and fetal risks. The diagnosis of premenstrual dysphoric disorder (PMDD) does exist during pregnancy and fluoxetine should not be used for this purpose during pregnancy. There are risks to the mother associated with untreated depression (e.g., relapse), and potential risks of persistent pulmonary hypertension of the newborn (PPHN) and poor neonatal adaptation after in utero exposure to SSRIs. Although SSRIs can cross the placenta, available data over several decades have not established an increased risk of major birth defects or miscarriage. Some observational studies have reported an increased incidence of cardiovascular malformations in newborns with first-trimester exposure to fluoxetine; however, these data have methodological limitations and causality to fluoxetine has not been established; however, a drug-associated risk cannot be excluded. 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 direct SSRI toxicity, serotonin syndrome, or a drug discontinuation syndrome. Some 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. The effect of SSRIs on labor and delivery in humans is unknown. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Health care providers are encouraged to register patients by visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ or by phone at 1-844-405-6185.

    Breast-feeding

    The developmental and health benefits of breast-feeding should be considered along with the need of the mother for fluoxetine and any potential adverse effects on the breastfed child from the drug or the underlying maternal condition. SSRI concentrations in breast milk are typically similar to those of maternal serum. A study of 19 nursing mothers on fluoxetine daily doses of 10 mg to 60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL) and the active metabolite norfluoxetine was found in 85% (range: less than 1 ng/mL up to 265 ng/mL). Because fluoxetine and norfluoxetine 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. Irritability, agitation, poor weight gain, and poor feeding have been reported in infants exposed to fluoxetine through breast milk. Some experts recommend that fluoxetine not be used during breast-feeding and that alternatives be considered. A pooled analysis found that maternal use of sertraline, 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.[44058] [32127] [45642]

    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.[32127] [44058] Selective serotonin reuptake inhibitors (SSRIs) may cause hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH); elderly patients appear to be at greater risk.[32127] [44058] Despite these cautions, the selective serotonin reuptake inhibitors (SSRIs) are often a preferred antidepressant group for treatment of depression or other behavioral symptoms in the elderly, including patients with dementia.  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. SSRIs can produce ataxia, impaired psychomotor function, syncope, and additional falls. If an SSRI must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures, and implement other strategies to reduce fall risk. Also, 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.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities; treatment duration should follow recommendations of pertinent literature and clinical practice guidelines for the condition treated. Monitor treated patients closely for worsening of depression and suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause a variety of adverse effects; some side effects can increase the risk of falls. Before discontinuation, many antidepressants, such as the SSRIs, may need a taper to avoid a withdrawal syndrome. At least quarterly, the facility should review the continued need of the antidepressant and document 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.[60742]

    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
    erythema nodosum / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    serum sickness / Delayed / Incidence not known
    vasculitis / Delayed / Incidence not known
    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    laryngospasm / Rapid / Incidence not known
    toxic epidermal necrolysis / 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
    urinary incontinence / Early / 0.1-1.0
    dysuria / Early / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    cystitis / Delayed / 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
    myopathy / Delayed / 0-0.1
    myasthenia / 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
    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 / 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
    alopecia / Delayed / 0.1-1.0
    maculopapular rash / Early / 0.1-1.0
    skin discoloration / Delayed / 0.1-1.0
    acne vulgaris / 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
    muscle cramps / Delayed / 0.1-1.0
    pelvic pain / 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.
    Abemaciclib: (Moderate) Monitor for an increase in abemaciclib-related adverse reactions if coadministration with fluoxetine is necessary; consider reducing the dose of abemaciclib in 50-mg decrements if toxicities occur. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. Abemaciclib is a CYP3A4 substrate. Fluoxetine is a weak CYP3A4 inhibitor, but its metabolite, norfluoxetine, is a moderate CYP3A4 inhibitor. Coadministration with other moderate CYP3A4 inhibitors is predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6- to 2.4-fold.
    Acarbose: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluoxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fluoxetine is a strong inhibitor of CYP2D6.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Acetaminophen; Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
    Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Acetaminophen; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluoxetine is necessary. If fluoxetine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluoxetine has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluoxetine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluoxetine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Pentazocine: (Major) Because of the potential risk and severity of serotonin syndrome reactions, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as pentazocine. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. If serotonin syndrome occurs, discontinue the offending agent(s) and institute appropriate therapy.
    Acetaminophen; 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: (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 tramadol. 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.
    Aclidinium; Formoterol: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albiglutide: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Albuterol: (Minor) Use fluoxetine with caution in combination with short-acting beta-agonists. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Use fluoxetine with caution in combination with short-acting beta-agonists. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting 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: (Moderate) Use caution when administering alfuzosin with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Alfuzosin may prolong the QT interval in a dose-dependent manner.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering almotriptan with fluoxetine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue fluoxetine and almotriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Alogliptin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Alogliptin; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Alogliptin; Pioglitazone: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Alpha-glucosidase Inhibitors: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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: (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) Avoid concomitant use of fluoxetine and amiodarone due to the potential for additive QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone.
    Amitriptyline: (Moderate) Coadministration of fluoxetine and amitriptyline may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
    Amitriptyline; Chlordiazepoxide: (Moderate) Coadministration of fluoxetine and amitriptyline may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP. (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; Celecoxib: (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) Fluoxetine, a potent CYP2D6 inhibitor, may increase the plasma concentrations of the tetracyclic antidepressant amoxapine, which is partially metabolized by CYP2D6. In several cases, symptoms of toxicity, including seizures, have been reported when tricyclic antidepressants were coadministered with an SSRI, including fluoxetine. At least one case report exists of a death thought to be due to impaired clearance of the tricyclic antidepressant amitriptyline by fluoxetine. Also, this combination may represent duplicative therapy. Patients receiving amoxapine should be monitored closely for toxicity if fluoxetine is added. Monitoring should be continued for several weeks following the discontinuation of fluoxetine due to the long half-life of norfluoxetine, the active metabolite of fluoxetine which has a half-life of 7 to 9 days and is a CYP2D6 inhibitor.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Avoid coadministration of clarithromycin with fluoxetine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP. QT prolongation and TdP have also been reported in patients treated with fluoxetine.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of clarithromycin with fluoxetine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP. QT prolongation and TdP have also been reported in patients treated with fluoxetine.
    Amphetamines: (Moderate) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and fluoxetine. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. In addition, amphetamines are partially metabolized by CYP2D6 and fluoxetine is a strong CYP2D6 inhibitor. Increased systemic exposure to amphetamines from CYP2D6 inhibition may result in high blood pressure, tachycardia, anxiety, irritability, insomnia, or other amphetamine-related adverse effects.
    Anagrelide: (Major) Do not use anagrelide with other drugs that prolong the QT interval, such as fluoxetine. Torsade de pointes (TdP) and ventricular tachycardia have been reported with anagrelide; dose-related increases in mean QTc and heart rate were observed in healthy subjects. QT prolongation and TdP have been reported in patients treated with fluoxetine. In addition, 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.
    Antithrombin III: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like antithrombin III. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Apixaban: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like apixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with fluoxetine since coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
    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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like low molecular weight heparins. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Arformoterol: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Major) Reduce the oral aripiprazole dosage by one-half of the usual dose in patients receiving strong CYP2D6 inhibitors such as fluoxetine. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP3A4 inhibitor, as aripiprazole is also metabolized by CYP3A4. Addtionally, aripiprazole and fluoxetine are both associated with prolongation of the QT interval; caution and close monitoring are recommended. Avoid concurrent use of Aristada Initio and fluoxetine because the dose of Aristada Initio cannot be modified. For other long-active aripiprazole injectables (e.g., Ability Maintena, Aristada), dose adjustments are recommended with strong CYP2D6 inhibitors and combined strong CYP2D6/CYP3A4 inhibitors; the recommendations are dependent on the aripiprazole IM depot dosage, the product given, and the duration of the concomitant inhibitors as specified in the product labels.
    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) Avoid coadministration of fluoxetine and artemether; lumefantrine due to the potential for additive QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Artemether; lumefantrine is also associated with QT interval prolongation. (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) Avoid coadministration of fluoxetine and asenapine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Asenapine has also been associated with QT prolongation.
    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) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (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) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluoxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fluoxetine is a strong inhibitor of CYP2D6. (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; Orphenadrine: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Carisoprodol: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation. (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) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (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; Citric Acid; Sodium Bicarbonate: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Dipyridamole: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding. (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Omeprazole: (Moderate) The combined use of selective serotonin reuptake inhibitors and aspirin, ASA may elevate the risk for an upper GI bleed. SSRIs may inhibit serotonin uptake by platelets, augmenting the antiplatelet effects of aspirin. Additionally, aspirin impairs the gastric mucosa defenses by inhibiting prostaglandin formation.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluoxetine is necessary. If fluoxetine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluoxetine has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluoxetine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluoxetine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to 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.
    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: (Moderate) Monitor for evidence of QT prolongation and increased atomoxetine-related adverse effects during coadministration with fluoxetine. In poor metabolizers of CYP2D6, the atomoxetine maximum dose should be restricted to 80 mg/day PO in adults and pediatric patients weighing more than 70 kg and 1.2 mg/kg/day PO in pediatric patients weighing 70 kg or less. Atomoxetine is a CYP2D6 substrate that has been associated with QT prolongation during therapeutic use and following overdose. Fluoxetine is a strong CYP2D6 inhibitor that has been reported to cause QT prolongation and torsade de pointes. In extensive metabolizers (EMs) taking atomoxetine who are treated concurrently with fluoxetine, the atomoxetine AUC is roughly 6 to 8-fold higher than if atomoxetine is given alone.
    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.
    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) Avoid coadministration of azithromycin with fluoxetine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    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) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    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.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with fluoxetine may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of fluoxetine in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6 and a weak inhibitor of CYP3A4. Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of benzhydrocodone and fluoxetine because of the potential risk of serotonin syndrome. Discontinue benzhydrocodone if serotonin syndrome is suspected. 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.
    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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like betrixaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal 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: (Moderate) Use fluoxetine with caution in combination with metronidazole. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Potential QT prolongation has been reported in limited case reports with metronidazole.
    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: (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. (Moderate) Use fluoxetine with caution in combination with metronidazole. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Potential QT prolongation has been reported in limited case reports with metronidazole.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    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) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting 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.
    Caffeine; Ergotamine: (Major) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Canagliflozin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Canagliflozin; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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.
    Cannabidiol: (Moderate) Consider a dose reduction of cannabidiol if coadministered with fluoxetine. Coadministration may increase cannabidiol plasma concentrations increasing the risk of adverse reactions. Cannabidiol is metabolized by CYP2C19 and CYP3A4; fluoxetine is a strong inhibitor of CYP2C19 and a moderate inhibitor of CYP3A4.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    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) Avoid coadministration of ceritinib with fluoxetine if possible due to the risk of QT prolongation. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; 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) Avoid coadministration of chloroquine with fluoxetine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); 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) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluoxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fluoxetine is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluoxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fluoxetine is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    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: (Moderate) Use fluoxetine with caution in combination with ciprofloxacin. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Rare cases of QT prolongation and TdP have been reported with ciprofloxacin during postmarketing surveillance.
    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) Avoid coadministration of clarithromycin with fluoxetine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Clarithromycin is associated with an established risk for QT prolongation and TdP. QT prolongation and TdP have also been reported in patients treated with fluoxetine.
    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.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with fluoxetine. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. QT prolongation and TdP have been reported in patients treated with fluoxetine.
    Clomipramine: (Moderate) Coadministration of fluoxetine and clomipramine may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
    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) Consider an alternative antidepressant to fluoxetine if possible in patients receiving clopidogrel. If coadministration is necessary, monitor patients for reduced clopidogrel effectiveness and signs and symptoms of bleeding. Fluoxetine may reduce the antiplatelet activity of clopidogrel through potent inhibition of the CYP2C19 metabolism of clopidogrel to its active metabolite. Additionally, selective serotonin reuptake inhibitors (SSRIs) affect platelet activation; therefore, concomitant use may increase the risk 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: (Moderate) Consider a clozapine dose reduction if coadministered with fluoxetine and monitor for adverse reactions including QT prolongation. If fluoxetine is discontinued, monitor for lack of clozapine effect and increase dose if necessary. Modest (less than 2-fold) elevations in concentrations of clozapine and its metabolites have been reported during concurrent use of fluoxetine. Clozapine is a CYP2D6 substrate that has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Fluoxetine is a strong CYP2D6 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    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.
    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.
    Cocaine: (Major) Concomitant use of cocaine with drugs that have CNS serotonergic properties, such as SSRIs, could potentiate serotonin neurotransmission, and result in the serotonin syndrome. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or neuroleptic malignant syndrome-like reactions. Additionally, citalopram causes dose-dependent QT interval prolongation. Local anesthetics (e.g., cocaine) are associated with a possible risk for QT prolongation and according to the manufacturer of citalopram, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended.
    Codeine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
    Codeine; Guaifenesin: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6.
    Codeine; Phenylephrine; Promethazine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Use fluoxetine with caution in combination with promethazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    Codeine; Promethazine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of codeine and fluoxetine because of the potential risk of serotonin syndrome, reduced codeine efficacy, and potential for opioid withdrawal symptoms. Discontinue codeine if serotonin syndrome is suspected. It is recommended to avoid this combination when codeine is being used for cough. Concomitant use may increase codeine plasma concentrations, but decrease the plasma concentration of the active metabolite, morphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of codeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease codeine plasma concentrations and increase morphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Fluoxetine is a strong inhibitor of CYP2D6. (Moderate) Use fluoxetine with caution in combination with promethazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    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) Avoid coadministration of crizotinib with fluoxetine due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine.
    Cyclobenzaprine: (Major) Because of the potential risk and severity of serotonin syndrome, concurrent use of cyclobenzaprine with other drugs that have serotonergic properties, such as the selective serotonin reuptake inhibitors (SSRIs), should generally be avoided. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If serotonin syndrome is suspected, milnacipran and concurrent serotonergic agents should be discontinued.
    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) such as fluoxetine. 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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like dabigatran. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Dalteparin: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like low molecular weight heparins. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Danaparoid: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like danaparoid. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Dapagliflozin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Dapagliflozin; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Dapagliflozin; Saxagliptin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (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. (Moderate) A dose reduction of fluoxetine may ne necessary if coadministered with ritonavir. Increased fluoxetine exposure may occur. Cardiac and neurologic events have been reported when ritonavir has been administered with fluoxetine.
    Dasatinib: (Moderate) Monitor for evidence of QT prolongation and torsade de pointes (TdP) if coadministration of dasatinib and fluoxetine is necessary. QT prolongation and TdP have been reported in patients treated with fluoxetine. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving fluoxetine as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    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: (Moderate) Coadministration of fluoxetine and desipramine may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
    Desmopressin: (Minor) 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, which may include monitoring serum sodium or electrolytes periodically. Ensure the patient is compliant with fluid restrictions and intake.
    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: (Moderate) 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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Dexmethylphenidate: (Moderate) 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. 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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    Dextromethorphan; Promethazine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome. (Moderate) Use fluoxetine with caution in combination with promethazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation.
    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). (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with fluoxetine. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly during treatment initiation and dose adjustment. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, fluoxetine may inhibit CYP2D6-mediated metabolism of dextromethorphan, increasing systemic dextromethorphan exposure. Increased dextromethorphan concentrations may result in adverse effects consistent with the serotonin syndrome.
    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: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of dihydrocodeine and fluoxetine because of the potential risk of serotonin syndrome, reduced dihydrocodeine efficacy, and potential for opioid withdrawal symptoms. Discontinue dihydrocodeine if serotonin syndrome is suspected. Concomitant use may increase dihydrocodeine plasma concentrations, but decrease the plasma concentration of the active metabolite, dihydromorphine, resulting in reduced efficacy or symptoms of opioid withdrawal. Monitor patients closely at frequent intervals and consider a dosage increase of dihydrocodeine until stable drug effects are achieved. Discontinuation of fluoxetine could decrease dihydrocodeine plasma concentrations and increase dihydromorphine plasma concentrations resulting in prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If fluoxetine is discontinued, monitor the patient carefully and consider reducing the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Fluoxetine is a strong inhibitor of CYP2D6.
    Dihydroergotamine: (Major) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Diltiazem: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers via inhibition of CYP3A4 metabolism.
    Dipeptidyl Peptidase-4 Inhibitors: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    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: (Major) Coadministration of dofetilide and fluoxetine is not recommended as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). QT prolongation and 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. The use of dofetilide with other drugs that prolong the QT interval has not been studied and is not recommended.
    Dolasetron: (Moderate) Administer dolasetron with caution in combination with fluoxetine as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Use fluoxetine and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Donepezil: (Moderate) 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: (Moderate) 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: (Moderate) Coadministration of fluoxetine and doxepin may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
    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.
    Dronabinol: (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 not be used in combination with any drug known to have potential to prolong the QT interval, such as fluoxetine. If coadministration cannot be avoided, use extreme caution; initiate droperidol at a low dose and increase the dose as needed to achieve the desired effect. Droperidol administration is associated with an established risk for QT prolongation and torsade de pointes (TdP). Some cases have occurred in patients with no known risk factors for QT prolongation and some cases have been fatal. QT prolongation and TdP have been reported in patients treated with 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) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like edoxaban. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Efavirenz: (Moderate) Consider an alternative to efavirenz if coadministration with fluoxetine is necessary as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. QTc prolongation has also been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider an alternative to efavirenz if coadministration with fluoxetine is necessary as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. QTc prolongation has also been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider an alternative to efavirenz if coadministration with fluoxetine is necessary as concurrent use may increase the risk of QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. QTc prolongation has also been observed with the use of efavirenz.
    Elagolix; Estradiol; Norethindrone acetate: (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.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering eletriptan with fluoxetine. Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and selective serotonin reuptake inhibitors (SSRIs). Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue fluoxetine and eletriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    Elexacaftor; tezacaftor; 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.
    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.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
    Elvitegravir; Cobicistat; 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.
    Empagliflozin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Empagliflozin; Linagliptin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Empagliflozin; Linagliptin; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Empagliflozin; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Use fluoxetine and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use fluoxetine and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    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.
    Encorafenib: (Major) Avoid coadministration of encorafenib and fluoxetine due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-half of the dose used prior to the addition of fluoxetine. Monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. If fluoxetine is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of fluoxetine. Encorafenib is a CYP3A4 substrate that has been associated with dose-dependent QT prolongation. Fluoxetine is a weak CYP3A4 inhibitor, but the norfluoxetine metabolite is a moderate CYP3A4 inhibitor; QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration of a moderate CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 2-fold and 45%, respectively.
    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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like low molecular weight heparins. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Entrectinib: (Major) Avoid coadministration of entrectinib with fluoxetine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    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) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Ergonovine: (Major) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Ergot alkaloids: (Major) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Ergotamine: (Major) Avoid use of ergot alkaloids with fluoxetine if possible due to decreased ergot alkaloid metabolism via CYP3A4. There is a potential risk for serious ergot-related toxicity including vasospasm when these drugs are used with ergotamine. Fluoxetine is a weak inhibitor of CYP3A4, and ergot alkaloids are metabolized via CYP3A4. This interaction has not been studied specifically. Weakness, hyperreflexia, and incoordination have been reported rarely when ergot alkaloids or other serotonin agonists have been co-administered with SSRI's (e.g., fluoxetine), which may be indicative of serotonin excess. If serotonin syndrome occurs, discontinue the offending agents and institute appropriate treatment.
    Eribulin: (Moderate) ECG monitoring is recommended if eribulin is administered with fluoxetine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Eribulin has also been associated with QT prolongation.
    Ertugliflozin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Ertugliflozin; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Ertugliflozin; Sitagliptin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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: (Major) 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. 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.
    Estradiol; Progesterone: (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.
    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) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Ezogabine: (Moderate) Use fluoxetine and ezogabine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Ezogabine has been associated with QT prolongation.
    Fedratinib: (Major) Avoid coadministration of fedratinib with fluoxetine as concurrent use may increase fedratinib exposure; fluoxetine exposure may also increase. Fedratinib is a substrate of both CYP3A4 and CYP2C19 and a moderate CYP2D6 inhibitor; fluoxetine is an inhibitor of both CYP3A4 and CYP2C19 and a CYP2D6 substrate. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Felodipine: (Moderate) Fluoxetine may decrease the clearance of calcium-channel blockers, including felodipine, via inhibition of CYP3A4 metabolism.
    Fenfluramine: (Moderate) Use fenfluramine and selective serotonin reuptake inhibitors with caution due to an increased risk of serotonin syndrome. Monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
    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: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluoxetine is necessary. If fluoxetine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. In addition, fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluoxetine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If fluoxetine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    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: (Moderate) Use fluoxetine with caution in combination with fingolimod due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    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: (Moderate) Use fluoxetine with caution in combination with fluconazole as concurrent use may increase the risk of QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with both drugs.
    Fluoxetine; Olanzapine: (Moderate) Caution is advised when administering olanzapine with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Fluphenazine: (Moderate) Use fluoxetine with caution in combination with fluphenazine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). Additionally, fluoxetine is a potent inhibitor of CYP2D6 and may result in increases in serum fluphenazine concentrations, leading to side effects. QT prolongation and TdP have been reported in patients treated with fluoxetine. Fluphenazine is associated with a possible risk for QT prolongation.
    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) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting 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: (Major) 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. 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.
    Fondaparinux: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like fondaparinux. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    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) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Foscarnet: (Major) Avoid coadministration of fluoxetine and foscarnet due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Foscarnet has been associated with postmarketing reports of both QT prolongation and TdP. QT prolongation and TdP have also been reported in patients treated with fluoxetine.
    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: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering frovatriptan with selective serotonin reuptake inhibitors (SSRIs). Serotonin syndrome has been reported during concurrent use of serotonin-receptor agonists and SSRIs. Some patients had used the combination previously without incident when serotonin syndrome occurred. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome particularly after a dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Discontinue the SSRI and frovatriptan and initiate symptomatic treatment if serotonin syndrome occurs.
    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.
    Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with fluoxetine is necessary; the risk is increased in CYP2D6 poor metabolizers. Based on in vitro data, gefitinib is metabolized to O-desmethyl gefitinib by CYP2D6 and fluoxetine is a CYP2D6 inhibitor. In healthy CYP2D6 poor metabolizers, the concentration of O-desmethyl gefitinib was not measurable and mean exposure to gefitinib was 2-fold higher compared to extensive metabolizers. The impact of CYP2D6 inhibitors on gefitinib pharmacokinetics has not been evaluated; however, the manufacturer recommends precautions based on exposure in patients with poor CYP2D6 metabolism.
    Gemifloxacin: (Moderate) Use fluoxetine and gemifloxacin together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) 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.
    Gilteritinib: (Major) Avoid coadministration of fluoxetine with gilteritinib if possible due to the potential for additive QT prolongation and decreased response to fluoxetine. Gilteritinib has been associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Coadministration has the potential for additive cardiotoxicity. Additionally, gilteritinib inhibits human 5HT2B receptor or sigma nonspecific receptors, which may reduce the effects of drugs like fluoxetine that target these receptors.
    Glasdegib: (Major) Avoid coadministration of glasdegib with fluoxetine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine
    Glipizide; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Glyburide; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Glycopyrrolate; Formoterol: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks in patients receiving other QT prolonging agents such as fluoxetine. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Androgen deprivation therapy (i.e., goserelin) may also prolong the QT/QTc interval.
    Granisetron: (Moderate) Use fluoxetine with caution in combination with granisteron as there is an increased risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue granisetron and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Granisetron has also been associated with QT prolongation.
    Guaifenesin; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    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: (Moderate) Use fluoxetine with caution in combination with haloperidol as concurrent use may increase the risk of QT prolongation and haloperidol-related adverse effects. Fluoxetine is a strong CYP2D6 inhibitor that has been associated with a risk of QT prolongation and torsade de pointes (TdP). Haloperidol is a CYP2D6 substrate; QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with CYP2D6 inhibitors.
    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) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Histrelin: (Moderate) Coadministration of fluoxetine and histrelin may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Androgen deprivation therapy (i.e., histrelin) may prolong the QT/QTc interval.
    Homatropine; Hydrocodone: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    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: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Hydrocodone; Ibuprofen: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Hydrocodone; Phenylephrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    Hydrocodone; Pseudoephedrine: (Moderate) Careful monitoring, particularly during treatment initiation and dose adjustment, is recommended during coadministration of hydrocodone and fluoxetine because of the potential risk of serotonin syndrome and prolonged opioid adverse reactions. Discontinue hydrocodone if serotonin syndrome is suspected. It is recommended to avoid this combination when hydrocodone is being used for cough. Concomitant use of hydrocodone with fluoxetine may increase hydrocodone plasma concentrations and prolong opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. Monitor patients closely at frequent intervals and consider a dosage reduction of hydrocodone until stable drug effects are achieved. Discontinuation of fluoxetine could decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to hydrocodone. If fluoxetine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Hydrocodone is a substrate for CYP2D6. Fluoxetine is a strong inhibitor of CYP2D6.
    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 fluoxetine and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with fluoxetine. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Postmarketing data indicate that hydroxyzine causes QT prolongation and torsade de pointes (TdP).
    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) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression, sedation, and serotonin syndrome if concurrent use of fluoxetine is necessary. If fluoxetine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like fluoxetine has resulted in serotonin syndrome. In addition, oxycodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like fluoxetine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If fluoxetine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    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.
    Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with fluoxetine is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Fluoxetine is a weak CYP3A4 inhibitor, but its metabolite norfluoxetine is a moderate inhibitor of CYP3A4. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
    Iloperidone: (Major) Avoid coadministration of fluoxetine and iloperidone due to the potential for additive QT prolongation and risk of torsade de pointes (TdP); iloperidone levels may also be increased. If concomitant use is necessary, reduce the iloperidone dose by one-half. If fluoxetine is discontinued, increase the iloperidone dose to the previous level. Iloperidone is a CYP2D6 substrate that has been associated with QT prolongation. Fluoxetine is a strong inhibitor of CYP2D6; QT prolongation and TdP have been reported in patients treated with fluoxetine. Coadministration of fluoxetine increased the AUC of iloperidone and its metabolite P88, by about 2- to 3-fold, and decreased the AUC of its metabolite P95 by one-half.
    Imatinib: (Moderate) Agents that inhibit cytochrome P450 3A4, such as fluoxetine, may decrease imatinib, STI-571 metabolism and increase concentrations leading to toxicity.
    Imipramine: (Moderate) Coadministration of fluoxetine and imipramine may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue fluoxetine and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Tricyclics, particularly at elevated concentrations, are associated with a possible risk of QT prolongation and TdP.
    Incretin Mimetics: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Indacaterol: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting 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) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Insulin Glargine; Lixisenatide: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Insulins: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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. Monitor the patient for serotonin-related effects during therapy transitions.
    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: (Moderate) Use fluoxetine with caution in combination with itraconazole. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Itraconazole has also been associated with prolongation of the QT interval.
    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.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with fluoxetine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    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.
    Ketoconazole: (Moderate) Use fluoxetine with caution in combination with ketoconazole. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Ketoconazole has also been associated with prolongation of the QT interval.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if coadministration of lapatinib with fluoxetine is necessary. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Prolongation of the QT interval and TdP have been reported in patients treated with fluoxetine.
    Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and selective serotonin reuptake inhibitors. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
    Lefamulin: (Major) Avoid coadministration of lefamulin with fluoxetine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine.
    Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with fluoxetine as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; fluoxetine is a weak CYP3A4 inhibitor and one metabolite, norfluoxetine, is a moderate CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with fluoxetine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation and torsade de pointes (TdP) have also been reported in patients treated with fluoxetine
    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: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks in patients receiving fluoxetine. Coadministration of fluoxetine and leuprolide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Androgen deprivation therapy may prolong the QT/QTc interval.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks in patients receiving fluoxetine. Coadministration of fluoxetine and leuprolide may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Androgen deprivation therapy may prolong the QT/QTc interval.
    Levalbuterol: (Minor) Use fluoxetine with caution in combination with short-acting beta-agonists. Coadministration may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levofloxacin: (Moderate) Use fluoxetine with caution in combination with levofloxacin. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of 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.
    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.
    Lidocaine; Prilocaine: (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) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Linagliptin; Metformin: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    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) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Lithium: (Moderate) Use fluoxetine with caution in combination with lithium. Coadministration may increase the risk for QT prolongation, torsade de pointes (TdP), and serotonin syndrome. If serotonin syndrome is suspected, discontinue lithium and concurrent serotonergic agents and initiate appropriate medical treatment. QT prolongation and TdP have been reported in patients treated with fluoxetine. Lithium has also been associated with QT prolongation.
    Lixisenatide: (Moderate) In patients with diabetes mellitus, fluoxetine may alter glycemic control. Hypoglycemia has occurred during fluoxetine therapy. Hyperglycemia has developed in patients with diabetes mellitus following discontinuation of the drug. The dosage of insulin and/or other antidiabetic agents may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
    Lofexidine: (Major) Monitor ECG for QT prolongation and monitor for orthostatic hypotension and bradycardia during concurrent use of lofexidine and fluoxetine. Coadministration may increase lofexidine exposure. Lofexidine is a CYP2D6 substrate that prolongs the QT interval. In addition, there are postmarketing reports of TdP. Fluoxetine is a CYP2D6 inhibitor associated with an established risk of QT prolongation and TdP. Coadministration with a strong CYP2D6 inhibitor increased the lofexidine AUC by 28%.
    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) Coadministration of fluoxetine and long-acting beta-agonists may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation and TdP have been reported in patients treated with fluoxetine. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Moderate) 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 TdP have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation and 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: (Moderate) 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 TdP have been reported in patients treated with fluoxetine. Coadministration may increase the risk for QT prolongation and 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) Avoid coadministration of lopinavir with fluoxetine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine. (Moderate) A dose reduction of fluoxetine may ne necessary if coadministered with ritonavir. Increased fluoxetine exposure may occur. Cardiac and neurologic events have been reported when ritonavir has been administered with fluoxetine.
    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: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like low molecular weight heparins. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    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